Prevalence and Incidence of Rare Diseases: Bibilographic Data

Number 1 | March 2016

Prevalence and incidence of rare diseases:

Bibilographic data Prevalence, incidence or number of published cases listed by diseases (in alphabetical order)

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If a range of national data is available, the average is

Methodology calculated to estimate the worldwide or European prevalence or incidence. When a range of data sources is available, the most Orphanet carries out a systematic survey of literature in recent data source that meets a certain number of quality order to estimate the prevalence and incidence of rare criteria is favoured (registries, meta-analyses, diseases. This study aims to collect new data regarding population-based studies, large cohorts studies). point prevalence, birth prevalence and incidence, and to update already published data according to new For congenital diseases, the prevalence is estimated, so scientific studies or other available data. that: Prevalence = birth prevalence x (patient life This data is presented in the following reports published expectancy/general population life expectancy). biannually: When only incidence data is documented, the prevalence is estimated when possible, so that :  Prevalence, incidence or number of published cases listed by diseases (in alphabetical order); Prevalence = incidence x disease mean duration.

 Diseases listed by decreasing prevalence, incidence When neither prevalence nor incidence data is available, or number of published cases. which is the case for very rare diseases, the number of cases or families documented in the medical literature is Data collection provided.

A number of different sources are used : Limitations of the study  Registries (RARECARE, EUROCAT, etc) ; The prevalence and incidence data presented in this  National/international health institutes and agencies report are only estimations and cannot be considered to (Institut National de Veille Sanitaire (French Institute be absolutely correct. of Health Surveillance); American Center of Disease The average values presented in this report do not take Control and Prevention, American National Cancer Institute, European Medicines Agency, World Health into account the heterogeneous nature of the Organization etc) ; methodologies employed by the studies considered in the literature survey.  Medline is consulted using the following search algorithm : «Disease names» AND Epidemiology[MeSH:NoExp] OR The validity and exactitude of raw data sources is taken Incidence[Title/abstract] OR Prevalence[Title/ for granted and have not been verified. Thus, confusion abstract] OR Epidemiology[Title/abstract]; between terms such as incidence and prevalence and/or  Medical texts, grey literature and reports from experts birth prevalence is possible due to the interchangeable ; use of these terms in certain sources. It is possible that prevalence is overestimated in some  Orphanet collaborating experts. cases as epidemiological studies are generally based on hospital data in regions with higher prevalence. Data characteristics Data presentation The data published in this document are worldwide estimations, or European estimations if a worldwide Without specification, published figures are worldwide. estimation is not available. An asterisk * indicates European data. P indicates prevalence data The published data is raw collected data or I indicates incidence data. extrapolations of raw data at worldwide or European BP indicates birth prevalence level when no genetic founder effect is suspected as a cause of a disease.

Without specification, published figures are worldwide. An asterisk * indicates European data. P indicates prevalence data, I indicates incidence data and BP indicates birth prevalence Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016 - Number 1 http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf 2

Number of Prevalence, incidence or number of Estimated ORPHA Disease published prevalence/incidence Number or Group of diseases cases or published cases listed by diseases (in (/100,000) families alphabetical order) 238769 1q44 microdeletion syndrome 100 Cases

363680 2p13.2 microdeletion syndrome 2 Cases

2p15p16.1 microdeletion Number of 261349 9 Cases Estimated syndrome ORPHA Disease published prevalence/incidence 163693 2p21 microdeletion syndrome 7 Cases Number or Group of diseases cases or (/100,000) 2p21 microdeletion syndrome families 369881 2 Cases without cystinuria 2-aminoadipic 2-oxoadipic 79154 20 Cases 228402 2q23.1 microdeletion syndrome 18 Cases aciduria 2-methylbutyryl-CoA 2q23.1 microduplication 79157 30 Cases 313947 2 Cases dehydrogenase deficiency syndrome 3-hydroxy-3-methylglutaryl- 1617 2q24 microdeletion syndrome 23 Cases 35701 9 Cases CoA synthase deficiency 2q31.1 microduplication 294026 2 Cases 3-methylcrotonyl-CoA 6 2.65 BP * syndrome carboxylase deficiency 2q32q33 microdeletion 251019 25 Cases 3-methylglutaconic aciduria 67046 20 Cases syndrome type 1 251028 2q33.1 microdeletion syndrome 20 Cases 3-methylglutaconic aciduria 445038 22 Cases type 7 1001 2q37 microdeletion syndrome 10 Cases 7 3C syndrome 25 Cases 435638 3p25.3 microdeletion syndrome 8 Cases 3q26q27 microdeletion 2616 3M syndrome 200 Cases 356947 4 Cases syndrome 293843 3MC syndrome 32 Cases 397695 3q27.3 microdeletion syndrome 7 Cases 22 4-hydroxybutyric aciduria 450 Cases 238750 4q21 microdeletion syndrome 14 Cases 217064 5-fluorouracil poisoning 2.0 P * 5p13 microduplication 329802 7 Cases 33572 5-oxoprolinase deficiency 8 Cases syndrome 46,XX disorder of sex 228384 5q14.3 microdeletion syndrome 40 Cases 2975 development - skeletal 2 Cases 5q35 microduplication 228415 14 Cases anomalies syndrome 46,XX ovarian dysgenesis-short 444048 3 Cases 251046 6p22 microdeletion syndrome 19 Cases stature syndrome 46,XX ovotesticular disorder of 75857 6q terminal deletion syndrome 19 Cases 2138 2.5 BP sex development 171829 6q16 deletion syndrome 12 Cases 46,XX testicular disorder of sex 393 2.5 P development 251056 6q25 microdeletion syndrome 4 Cases 46,XY disorder of sex 7p22.1 microduplication 314034 2 Cases development - adrenal syndrome 168558 9 Cases insufficiency due to CYP11A1 251061 7q31 microdeletion syndrome 4 Cases deficiency 8p inverted 46,XY disorder of sex 96092 3.9 BP * duplication/deletion syndrome 753 development due to 5-alpha- 50 Families reductase 2 deficiency 251066 8p11.2 deletion syndrome 3 Cases 46,XY gonadal dysgenesis - 8p23.1 microduplication 168563 6 Cases 251076 1.72 P motor and sensory neuropathy syndrome 8q12 microduplication 8 47,XYY syndrome 50.0 BP * 228399 4 Cases syndrome 96263 48,XXXY syndrome 1.0 BP * 8q21.11 microdeletion 284160 13 Cases 10 48,XXYY syndrome 1.9 BP * syndrome 96264 49,XXXXY syndrome 0.55 BP * 178303 8q22.1 microdeletion syndrome 6 Cases 261534 49,XXXYY syndrome 2 Cases 324313 9p13 microdeletion syndrome 4 Cases 293948 1p21.3 microdeletion syndrome 9 Cases 352665 9q21 microdeletion syndrome 13 Cases 1p31p32 microdeletion 9q31.1q31.3 microdeletion 401986 5 Cases 401923 2 Cases syndrome syndrome 1q21.1 microduplication 11p15.4 microduplication 250994 46 Cases 300305 1 Family syndrome syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 11q22.2q22.3 microdeletion 20q11.2 microdeletion 444002 5 Cases 444051 11 Cases syndrome syndrome 12p12.1 microdeletion 21q22.11q22.12 microdeletion 313884 6 Cases 261323 12 Cases syndrome syndrome 21q22.13q22.2 microdeletion 94063 12q14 microdeletion syndrome 4 Cases 268261 12 Cases syndrome 13q12.3 microdeletion 412035 3 Cases syndrome 567 22q11.2 deletion syndrome 37.5 BP 14q11.2 microdeletion 261120 3 Cases 439232 AApoAIV amyloidosis 2 Cases syndrome 915 0.4 BP * 14q11.2 microduplication Aarskog-Scott syndrome 261229 7 Cases syndrome 916 Aase-Smith syndrome 10 Cases 261144 3 Cases 14q12 microdeletion syndrome 100006 ABeta amyloidosis, Dutch type 250 Cases 14q22q23 microdeletion Ablepharon macrostomia 264200 4 Cases 920 16 Cases syndrome syndrome 14q24.1q24.3 microdeletion 401935 3 Cases 921 Abruzzo-Erickson syndrome 4 Cases syndrome Absence of fingerprints - 314585 15q overgrowth syndrome 12 Cases 1658 14 Cases congenital milia 15q11.2 microdeletion Absence of the pulmonary 261183 11 Cases 980 0.5 I * syndrome artery 15q11q13 microduplication Absent thumb-short stature- 238446 30 Cases 2951 3 Cases syndrome immunodeficiency syndrome 15q13.3 microdeletion Absent tibia - polydactyly - 199318 246 Cases 3328 3 Cases syndrome arachnoid cyst 261190 4 Cases 15q14 microdeletion syndrome 67043 Acanthamoeba keratitis 1.0 P * 94065 15q24 microdeletion syndrome 4 Cases Acanthosis nigricans - Insulin 16p11.2p12.2 microdeletion 90301 resistance - muscle cramps - 5 Cases 261211 10 Cases syndrome acral enlargement 16p13.11 microdeletion 926 3.2 P * 261236 7.0 BP Acatalasemia syndrome 48818 Aceruloplasminemia 0.09 P 16p13.11 microduplication 261243 20 Cases syndrome 929 Achalasia - microcephaly 5 Cases 16q24.1 microdeletion 352629 10 Cases 931 Acheiropodia 10 Families syndrome 16q24.3 microdeletion 15 Achondroplasia 4.0 BP 261250 12 Cases syndrome 49382 Achromatopsia 2.7 P 17p13.3 microduplication 217385 50 Cases Acitretin/etretinate syndrome 40366 26 Cases embryopathy 97685 17q11 microdeletion syndrome 170 Cases 2561 Ackerman syndrome 8 Cases 17q11.2 microduplication 139474 7 Cases Acquired aneurysmal syndrome 90065 10.0 P * subarachnoid hemorrhage 17q12 microduplication 261272 12 Cases syndrome 91385 Acquired angioedema 200 Cases 17q21.31 microdeletion 363958 6.25 P * 46487 Acquired epidermolysis bullosa 0.03 I * syndrome Acquired generalized 17q23.1q23.2 microdeletion 79086 100 Cases 261279 9 Cases lipodystrophy syndrome 73274 Acquired hemophilia 0.1 P * 19p13.12 microdeletion 254346 6 Cases syndrome 73274 Acquired hemophilia 0.08 I 19p13.13 microdeletion Acquired hypertrichosis 357001 7 Cases 2221 60 Cases syndrome lanuginosa 19q13.11 microdeletion Acquired pseudoxanthoma 217346 12 Cases 228247 20 Cases syndrome elasticum 20p12.3 microdeletion Acquired von Willebrand 261295 3 Cases 99147 300 Cases syndrome syndrome 313781 20p13 microdeletion syndrome 4 Cases Acral dystrophic epidermolysis 158673 10 Families bullosa

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 263534 Acral peeling skin syndrome 40 Cases Acute encephalopathy with 363549 biphasic seizures and late 283 Cases Acral self-healing collodion 281127 2 Cases reduced diffusion baby Acute generalized 293173 0.3 I 2008 Acro-cardio-facial syndrome 9 Cases exanthematous pustulosis Acro-fronto-facio-nasal 1784 5 Cases Acute infantile liver failure due dysostosis 217371 to synthesis defect of mtDNA- 13 Cases 85203 Acro-pectoral syndrome 22 Cases encoded proteins Acute infantile liver failure- 956 12 Cases Acro-pectoro-renal dysplasia 370088 multisystemic involvement 6 Cases Acro-renal-mandibular syndrome 958 7 Cases syndrome Acute inflammatory 959 Acro-renal-ocular syndrome 20 Families 98916 demyelinating 3.1 P * polyradiculoneuropathy 36 Acrocallosal syndrome 34 Cases 79276 Acute intermittent porphyria 0.54 P * 221054 Acrocephalopolydactyly 8 Cases 79276 Acute intermittent porphyria 0.013 I * 949 Acrocraniofacial dysostosis 2 Cases 79126 Acute interstitial pneumonia 3.8 P * 950 Acrodysostosis 80 Cases 90062 Acute liver failure 20.0 P * Acrodysostosis with multiple 280651 40 Cases hormone resistance 178320 Acute lung injury 25.0 I * Acrofacial dysostosis, Catania 1786 6 Cases 513 Acute lymphoblastic leukemia 2.75 I * type 514 0.1 I * Acrofacial dysostosis, Kennedy- Acute monoblastic leukemia 64542 2 Cases Teebi type 519 Acute myeloid leukemia 2.5 I Acrofacial dysostosis, Rodríguez Acute peripheral arterial 1788 10 Cases 90064 16.0 P * type occlusion Acromegaloid facial 965 20 Cases 520 Acute promyelocytic leukemia 0.11 I * appearance syndrome Acute sensorineural hearing 963 Acromegaly 5.5 P loss by acute acoustic trauma or 90059 37.0 P * 963 Acromegaly 0.35 I sudden deafness or surgery induced acoustic trauma 39 Acromelanosis 10 Cases 139417 Acute transverse myelitis 1.6 I Acromesomelic dysplasia, 968 10 Cases Acute zonal occult outer Hunter-Thomson type 284454 150 Cases Acromesomelic dysplasia, retinopathy 40 50 Cases Acyl-CoA dehydrogenase 9 Maroteaux type 99901 16 Cases deficiency 969 Acromicric dysplasia 60 Cases 100008 ACys amyloidosis 9 Families 955 Acroosteolysis dominant type 80 Cases 55881 Adamantinoma 0.01 I * Acroosteolysis-keloid-like 363665 lesions-premature aging 3 Cases 85138 Addison disease 12.5 P * syndrome Adducted thumbs- 957 Acropectorovertebral dysplasia 30 Cases 2952 arthrogryposis syndrome, 3 Families Christian type 971 Acrorenal syndrome 20 Cases 99976 Adenocarcinoma of esophagus 0.7 I ACTH-dependent Cushing 99892 0.55 I Adenosine monophosphate syndrome 45 100 Cases Action myoclonus-renal failure deaminase deficiency 163696 17 Cases Adenylosuccinate lyase syndrome 46 56 Cases deficiency 397596 Activated PIK3-delta syndrome 18 Cases ADNP-related multiple Acute annular outer congenital anomalies- 284460 12 Cases 404448 10 Cases retinopathy intellectual disability-autism Acute bilateral depigmentation 69736 5 Cases spectrum disorder of the iris 1501 Adrenocortical carcinoma 0.75 P * Acute disseminated 83597 0.6 I * encephalomyelitis 1501 Adrenocortical carcinoma 0.03 I *

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Adult familial nephronophthisis 2666 2 Cases 79321 ALG3-CDG 10 Cases - spastic quadriparesia 79320 ALG6-CDG 58 Cases 874 Adult heart tumor 140.9 I * 79325 ALG8-CDG 8 Cases 178487 Adult intestinal botulism 19 Cases 79328 3 Cases Adult polyglucosan body ALG9-CDG 206583 50 Cases disease 280071 ALG11-CDG 2 Cases 978 14 Cases ADULT syndrome 79324 ALG12-CDG 11 Cases Adult-onset autosomal 99027 20 Families 324422 ALG13-CDG 1 Case dominant leukodystrophy Adult-onset distal myopathy Allan-Herndon-Dudley 329478 9 Cases 59 89 Cases due to VCP mutation syndrome Adult-onset dystonia- 700 Alopecia totalis 10.5 P * 199351 14 Cases parkinsonism 701 Alopecia universalis 25.0 P * Adult-onset proximal spinal 209335 muscular atrophy, autosomal 0.1 P * Alopecia-contractures- dominant 1005 dwarfism-intellectual disability 5 Cases syndrome 183669 Agammaglobulinemia 0.13 P * Alopecia-epilepsy-pyorrhea- 1008 12 Cases Agammaglobulinemia- intellectual disability syndrome 83617 microcephaly-craniosynostosis- 3 Cases Alopecia-intellectual disability- severe dermatitis syndrome 1014 hypergonadotropic 2 Cases 85448 AGel amyloidosis 475 Cases hypogonadism syndrome Agenesis of the corpus 726 Alpers-Huttenlocher syndrome 0.07 P * callosum-intellectual disability- 52055 2 Cases 726 Alpers-Huttenlocher syndrome 0.7 BP * coloboma-micrognathia syndrome 60 Alpha-1-antitrypsin deficiency 20.0 P * Aggressive systemic 98850 0.33 P * 100025 Alpha-heavy chain disease 400 Cases mastocytosis AHDC1-related intellectual 61 Alpha-mannosidosis 0.1 P * disability-obstructive sleep 412069 4 Cases Alpha-N- apnea-mild dysmorphism 3137 acetylgalactosaminidase 20 Cases syndrome deficiency 250977 AICA-ribosiduria 1 Case Alpha-N- 79279 acetylgalactosaminidase 10 Cases 51 Aicardi-Goutières syndrome 120 Cases deficiency type 1 90081 AIDS wasting syndrome 20.0 P * Alpha-N- AKT2-related familial partial 79280 acetylgalactosaminidase 10 Cases 79085 1 Family lipodystrophy deficiency type 2 Alpha-N- 85443 AL amyloidosis 11.0 P * 79281 acetylgalactosaminidase 10 Cases Alacrimia-choreoathetosis-liver 404454 8 Cases deficiency type 3 dysfunction syndrome Alpha-thalassemia-intellectual 52 Alagille syndrome 0.4 BP * 98791 disability syndrome linked to 20 Cases chromosome 16 178333 Åland Islands eye disease 5 Families Alpha-thalassemia- 231401 80 Cases Alar cartilages hypoplasia- myelodysplastic syndrome 2007 2 Cases coloboma-telecanthus Alpha-thalassemia-X-linked 847 200 Cases syndrome intellectual disability syndrome 53 1.0 P Albers-Schönberg osteopetrosis 63 Alport syndrome 2.0 P * 998 Albinism-deafness syndrome 1 Family Alport syndrome-intellectual ALDH18A1-related De Barsy 86818 disability-midface hypoplasia- 2 Families 35664 32 Cases syndrome elliptocytosis syndrome Aldosterone-producing 64 Alström syndrome 950 Cases 369929 2 Cases adenoma with seizures and Alternating hemiplegia of 2131 0.9 BP * neurological abnormalities childhood 79327 15 Cases ALG1-CDG 284 Alveolar echinococcosis 0.16 I * 79326 ALG2-CDG 1 Case

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 93561 ALys amyloidosis 7 Families 254411 Annular atrophic lichen planus 10 Cases Amaurosis-hypertrichosis Annular epidermolytic 1021 2 Cases 281139 7 Families syndrome ichthyosis 314422 Ameloblastic carcinoma 40 Cases 675 Annular pancreas 1.8 BP * Amelogenesis imperfecta- 171836 8 Cases 1094 Anonychia - microcephaly 5 Cases gingival hyperplasia syndrome 90390 14 Cases Amelogenesis imperfecta- Anonychia - onychodystrophy 1031 11 Cases nephrocalcinosis syndrome Anonychia with flexural 69125 3 Cases Aminopterin/methotrexate pigmentation 1908 17 Cases Anophthalmia - megalocornea - embryofetopathy 1101 3 Cases cardiopathy - skeletal anomalies 1034 Amniotic bands 2.5 BP * Anophthalmia - 98555 8.3 BP * 803 Amyotrophic lateral sclerosis 3.85 P microphthalmia 803 Amyotrophic lateral sclerosis 1.35 I 1104 Anophthalmia plus syndrome 4 Cases Amyotrophic lateral sclerosis Anophthalmia/microphthalmia 357043 70 Cases 77298 30 Cases type 4 - esophageal atresia 228113 Anal fistula 23.0 P * 93976 Anotia 0.028 BP * Antecubital pterygium 98841 Anaplastic large cell lymphoma 2.0 P * 2987 11 Cases syndrome 142 Anaplastic thyroid carcinoma 0.1 P * 90079 Anthracycline extravasations 0.3 P * 142 0.17 I * Anaplastic thyroid carcinoma Anti-glomerular basement 375 0.08 I * 157954 ANE syndrome 5 Cases membrane disease Aneurysm-osteoarthritis 81 Antisynthetase syndrome 3.5 P 284984 45 Cases syndrome 83 Antley-Bixler syndrome 34 Cases Angel-shaped phalango- 63442 20 Cases epiphyseal dysplasia 1457 Aorta coarctation 35.6 BP * Aortic arch anomaly - peculiar 72 Angelman syndrome 7.5 P 1110 4 Cases facies - intellectual disability 72 Angelman syndrome 1.1 BP * 2299 Aortic arch interruption 0.3 BP * 251671 Angiocentric glioma 52 Cases 3400 Aorto-ventricular tunnel 130 Cases Angioosteohypertrophic 2346 0.8 BP * Aphalangy - hemivertebrae - syndrome 1112 3 Cases urogenital-intestinal dysgenesis 370039 2 Cases Angora hair nevus Aphalangy - syndactyly - 1113 5 Cases Anhidrotic ectodermal microcephaly dysplasia-immunodeficiency- 69088 2 Cases Aphonia - deafness - retinal osteopetrosis-lymphedema 324540 dystrophy - bifid halluces - 2 Cases syndrome intellectual disability 77 Aniridia 1.75 P 1117 Aplasia cutis - myopia 4 Cases 77 Aniridia 1.3 I * 1114 Aplasia cutis congenita 10.0 BP Aniridia - ptosis - intellectual Aplasia cutis congenita - 1067 3 Cases 1116 3 Cases disability - familial obesity intestinal lymphangiectasia Aniridia - renal agenesis - 1064 2 Cases 99981 Apnea of prematurity 8.5 P * psychomotor retardation Aniridia-absent patella 425 Apolipoprotein A-I deficiency 30 Families 1069 3 Cases syndrome Arachnodactyly - abnormal Aniridia-cerebellar ataxia- 1129 ossification - intellectual 5 Cases 1065 30 Cases intellectual disability syndrome disability Aniridia-intellectual disability Arachnodactyly - intellectual 1068 2 Cases 1130 3 Cases syndrome disability - dysmorphism 1070 Anisakiasis 0.32 I 1133 AREDYLD syndrome 3 Cases Ankyloblepharon filiforme - 1074 3 Families 23 Argininosuccinic aciduria 0.5 P * imperforate anus 23 0.46 BP Ankylosing vertebral Argininosuccinic aciduria 2206 8 Cases hyperostosis with tylosis 91 Aromatase deficiency 20 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Aromatic L-amino acid 35708 100 Cases 1456 Atypical coarctation of aorta 0.17 BP * decarboxylase deficiency Atypical dentin dysplasia due to 314721 4 Cases 1134 Arrhinia 20 Cases SMOC2 deficiency Arrhinia - choanal atresia - Atypical glycine 1135 4 Cases 289863 20 Cases microphthalmia encephalopathy Arrhythmogenic right Atypical hemolytic-uremic 247 20.0 P 2134 1.0 P * ventricular cardiomyopathy syndrome Atypical hemolytic-uremic 1682 Arterial dissection - lentiginosis 4 Cases 357008 13 Cases syndrome with DGKE deficiency 3342 80 Cases Arterial tortuosity syndrome Atypical hypotonia - cystinuria 238523 2 Cases Arthrogryposis - 1485 2 Cases syndrome hyperkeratosis, lethal form 391411 Atypical juvenile parkinsonism 6 Families Arthrogryposis - renal 2697 100 Cases dysfunction - cholestasis 86797 Atypical lichen myxedematosus 20 Cases Arthrogryposis multiplex 1037 5.7 BP * 314466 Atypical Meigs syndrome 9 Cases congenita Auricular abnormalities - cleft Arthrogryposis multiplex 1150 10 Cases 77300 lip with or without cleft palate - 2 Cases congenita - whistling face ocular abnormalities Arthrogryposis-like hand 137888 Auriculocondylar syndrome 50 Cases 1144 anomaly - sensorineural 1 Family Auriculoocular anomalies - cleft deafness 71270 2 Cases lip 1253 Ascher syndrome 50 Cases 114 Auriculoosteodysplasia 2 Families 85175 Astley-Kendall dysplasia 5 Cases 137911 Autism - facial port-wine stain 4 Cases 251679 Astroblastoma 0.02 I * Autism spectrum disorder due 352490 7 Cases 94 Astrocytoma 2.5 P * to AUTS2 deficiency 94 Astrocytoma 8.0 I * Autism spectrum disorder- 370943 epilepsy-arthrogryposis 8 Cases 96 Ataxia with vitamin E deficiency 0.33 P * syndrome Ataxia-deafness-intellectual 1188 8 Cases Autism-epilepsy syndrome due disability syndrome to branched chain ketoacid 308410 5 Families Ataxia-intellectual disability- dehydrogenase kinase 370022 oculomotor apraxia-cerebellar 7 Cases deficiency cysts syndrome Autoerythrocyte sensitization 324636 170 Cases 100 Ataxia-telangiectasia 0.49 P * syndrome Autoimmune encephalopathy 1190 12 Cases Atelosteogenesis type I 420789 with parasomnia and 10 Cases 56304 Atelosteogenesis type II 25 Cases obstructive sleep apnea Autoimmune enteropathy and 56305 Atelosteogenesis type III 25 Cases 391487 endocrinopathy-susceptibility to 5 Cases Athabaskan brainstem 69739 10 Cases chronic infections syndrome dysgenesis syndrome 98375 Autoimmune hemolytic anemia 2.02 I * Atherosclerosis - deafness - 1192 diabetes - epilepsy - 2 Cases Autoimmune hemolytic anemia-autoimmune nephropathy 444463 6 Cases thrombocytopenia-primary 95713 Athyreosis 3.5 P * immunodeficiency syndrome Autoimmune interstitial lung 1193 Atkin-Flaitz syndrome 14 Cases 444092 5 Families disease-arthritis syndrome 163934 Atopic keratoconjunctivitis 15.0 P * Autoimmune 3261 500 Cases 1201 Atresia of small intestine 16.0 BP * lymphoproliferative syndrome Atrial septal defect - Autoimmune 1479 atrioventricular conduction 11 Cases 436159 lymphoproliferative syndrome 17 Cases defects due to CTLA4 haploinsuffiency Atrial tachyarrhythmia with Autoimmune 844 12 Cases short PR interval 275517 lymphoproliferative syndrome 1 Family Attenuated Chédiak-Higashi with recurrent viral infections 352723 100 Cases Autoimmune necrotizing syndrome 206569 300 Cases myopathy

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Autoimmune pulmonary Autosomal dominant hyper-IgE 747 0.5 P 2314 0.1 I * alveolar proteinosis syndrome Autoimmune pulmonary Autosomal dominant 747 0.04 I alveolar proteinosis 1810 hypohidrotic ectodermal 40 Cases Autoinflammation-PLCG2- dysplasia 324530 associated antibody deficiency- 2 Cases Autosomal dominant 89937 100 Cases immune dysregulation hypophosphatemic rickets Autoinflammatory syndrome Autosomal dominant 329173 with pyogenic bacterial 3 Cases 93114 intermediate Charcot-Marie- 21 Cases infection and amylopectinosis Tooth disease type E Autosomal Autosomal dominant 33110 100 Cases agammaglobulinemia 352670 intermediate Charcot-Marie- 8 Cases Autosomal dominant aplasia Tooth disease type F 314399 6 Cases and myelodysplasia Autosomal dominant Autosomal dominant cerebellar intermediate Charcot-Marie- 99 2.7 P 324585 9 Cases ataxia Tooth disease with neuropathic Autosomal dominant cerebellar pain 314404 24 Cases Autosomal dominant Larsen ataxia, deafness and narcolepsy 503 0.4 BP * Autosomal dominant Charcot- syndrome 435819 Marie-Tooth disease type 2 due 2 Cases Autosomal dominant limb- to TFG mutation 266 girdle muscular dystrophy type 2 Families Autosomal dominant Charcot- 1A 435387 Marie-Tooth disease type 2 due 7 Cases Autosomal dominant limb- to VCP mutation 34516 girdle muscular dystrophy type 5 Families Autosomal dominant Charcot- 1D 401964 Marie-Tooth disease type 2 with 3 Families Autosomal dominant limb- giant axons 34517 girdle muscular dystrophy type 5 Families Autosomal dominant Charcot- 1E 99940 5 Families Marie-Tooth disease type 2F Autosomal dominant limb- Autosomal dominant Charcot- 55595 girdle muscular dystrophy type 1 Family 99941 1 Family Marie-Tooth disease type 2G 1F Autosomal dominant Charcot- Autosomal dominant limb- 99944 3 Families Marie-Tooth disease type 2K 55596 girdle muscular dystrophy type 2 Families Autosomal dominant Charcot- 1G 99945 1 Family Marie-Tooth disease type 2L Autosomal dominant limb- Autosomal dominant Charcot- 238755 girdle muscular dystrophy type 11 Cases 228179 20 Cases Marie-Tooth disease type 2M 1H Autosomal dominant Charcot- Autosomal dominant 228174 28 Cases 140957 100 Cases Marie-Tooth disease type 2N macrothrombocytopenia Autosomal dominant Charcot- Autosomal dominant medullary 329258 8 Cases Marie-Tooth disease type 2Q 34149 cystic kidney disease with or 0.11 P * without hyperuricemia Autosomal dominant Charcot- 397735 2 Cases Marie-Tooth disease type 2U Autosomal dominant mendelian susceptibility to Autosomal dominant 319581 70 Cases mycobacterial diseases due to childhood-onset proximal spinal 363454 25 Cases partial IFNgammaR1 deficiency muscular atrophy with contractures Autosomal dominant mendelian susceptibility to 90348 50 Cases 319589 2 Cases Autosomal dominant cutis laxa mycobacterial diseases due to Autosomal dominant deafness- partial IFNgammaR2 deficiency 79499 22 Cases onychodystrophy syndrome Autosomal dominant multiple 65743 4 Cases Autosomal dominant familial pterygium syndrome 73229 hematuria - retinal arteriolar 8 Cases Autosomal dominant myopia- tortuosity - contractures midfacial retrusion- 440354 1 Family Autosomal dominant focal 329466 28 Cases sensorineural hearing loss- dystonia, DYT25 rhizomelic dysplasia syndrome Autosomal dominant focal non- Autosomal dominant epidermolytic palmoplantar 329211 99 Cases 402003 21 Cases neovascular inflammatory keratoderma with plantar vitreoretinopathy blistering

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Autosomal dominant nocturnal Autosomal erythropoietic 98784 100 Families 79278 0.012 I * frontal lobe epilepsy protoporphyria Autosomal dominant optic 98672 3.3 P 1027 Autosomal recessive amelia 3 Cases atrophy Autosomal recessive ataxia due Autosomal dominant optic 247815 2 Cases 67036 3 Families to PEX10 deficiency atrophy and cataract Autosomal recessive ataxia due Autosomal dominant optic 139485 31 Cases 1215 0.4 P * to ubiquinone deficiency atrophy plus syndrome Autosomal recessive ataxia, Autosomal dominant 88644 57 Cases 2783 33 Cases Beauce type osteopetrosis type 1 Autosomal recessive axonal Autosomal dominant 324442 neuropathy with 33 Families 1010 palmoplantar keratoderma and 10 Cases neuromyotonia congenital alopecia Autosomal recessive Autosomal dominant polycystic 139455 20 Cases bestrophinopathy 88924 kidney disease type 1 with 30 Cases Autosomal recessive cerebellar tuberous sclerosis 1172 3.3 P ataxia Autosomal dominant popliteal 1300 0.3 P Autosomal recessive cerebellar pterygium syndrome 95433 3 Families ataxia - blindness - deafness Autosomal dominant primary Autosomal recessive cerebellar 34528 hypomagnesemia with 18 Cases 95434 1 Family ataxia - saccadic intrusion hypocalciuria Autosomal recessive cerebellar Autosomal dominant proximal 412057 10 Families 314889 1 Family ataxia due to STUB1 deficiency renal tubular acidosis Autosomal recessive cerebellar Autosomal dominant 352641 10 Cases ataxia with late-onset spasticity 209867 rhegmatogenous retinal 38 Cases detachment Autosomal recessive cerebellar ataxia-epilepsy-intellectual Autosomal dominant Robinow 404499 2 Cases 3107 100 Cases disability syndrome due to syndrome KIAA0226 deficiency Autosomal dominant spastic 100988 10 Families Autosomal recessive cerebellar paraplegia type 6 ataxia-epilepsy-intellectual Autosomal dominant spastic 404493 3 Cases 100989 10 Families disability syndrome due to TUD paraplegia type 8 deficiency Autosomal dominant spastic 100990 7 Families Autosomal recessive cerebral paraplegia type 9 363969 4 Cases atrophy Autosomal dominant spastic 100991 10 Families Autosomal recessive congenital paraplegia type 10 363432 cerebellar ataxia due to GRID2 7 Cases Autosomal dominant spastic 100993 10 Families deficiency paraplegia type 12 Autosomal recessive congenital Autosomal dominant spastic 100994 10 Families 324262 cerebellar ataxia due to 10 Cases paraplegia type 13 MGLUR1 deficiency Autosomal dominant spastic Autosomal recessive congenital 100998 20 Families 281097 0.5 P * paraplegia type 17 ichthyosis Autosomal dominant spastic Autosomal recessive cutis laxa 100999 1 Family 90349 60 Cases paraplegia type 19 type 1 Autosomal dominant spastic Autosomal recessive cutis laxa 101009 1 Family 90350 40 Cases paraplegia type 29 type 2 Autosomal dominant spastic Autosomal recessive dopa- 171612 13 Cases 101150 50 Cases paraplegia type 37 responsive dystonia Autosomal dominant spastic 171617 1 Family Autosomal recessive early- paraplegia type 38 238569 onset inflammatory bowel 80 Cases Autosomal dominant spastic 444099 1 Family disease paraplegia type 73 Autosomal recessive facio- Autosomal dominant striatal 1974 16 Cases 228169 7 Cases digito-genital syndrome neurodegeneration Autosomal recessive Autosomal dominant 329329 7 Cases 3086 3 Cases frontotemporal pachygyria vitreoretinochoroidopathy Autosomal recessive infantile Autosomal erythropoietic 300547 12 Cases 79278 0.92 P * hypercalcemia protoporphyria

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Autosomal recessive Autosomal recessive mendelian 217055 intermediate Charcot-Marie- 8 Families susceptibility to mycobacterial 319574 5 Cases Tooth disease type A diseases due to partial Autosomal recessive IFNgammaR2 deficiency 254334 intermediate Charcot-Marie- 1 Case Autosomal recessive nail 280654 4 Cases Tooth disease type B dysplasia Autosomal recessive Autosomal recessive 93329 23 Cases 369867 intermediate Charcot-Marie- 3 Cases omodysplasia Tooth disease type C Autosomal recessive Autosomal recessive 1366 palmoplantar keratoderma and 8 Cases 435998 intermediate Charcot-Marie- 3 Cases congenital alopecia Tooth disease type D Autosomal recessive polycystic 731 1.17 P * Autosomal recessive isolated kidney disease 98676 5 Cases optic atrophy Autosomal recessive primary Autosomal recessive immunodeficiency with 437552 3 Cases leukoencephalopathy with defective spontaneous natural 314572 3 Cases ischemic stroke-retinitis killer cell cytotoxicity pigmentosa syndrome Autosomal recessive Robinow 1507 100 Cases Autosomal recessive limb-girdle syndrome 267 1.0 P * muscular dystrophy type 2A Autosomal recessive severe Autosomal recessive limb-girdle 420702 congenital neutropenia due to 4 Cases 353 0.2 P * muscular dystrophy type 2C CSF3R deficiency Autosomal recessive limb-girdle Autosomal recessive severe 119 0.1 P * muscular dystrophy type 2E 420699 congenital neutropenia due to 2 Cases Autosomal recessive limb-girdle CXCR2 deficiency 219 0.3 P * muscular dystrophy type 2F Autosomal recessive severe Autosomal recessive limb-girdle 331176 congenital neutropenia due to 57 Cases 34514 14 Cases muscular dystrophy type 2G G6PC3 deficiency Autosomal recessive limb-girdle Autosomal recessive severe 34515 1.0 P * muscular dystrophy type 2I 423384 congenital neutropenia due to 14 Cases Autosomal recessive limb-girdle JAGN1 deficiency 206549 14 Cases muscular dystrophy type 2L Autosomal recessive spastic Autosomal recessive limb-girdle 254343 ataxia - optic atrophy - 6 Cases 206554 3 Cases muscular dystrophy type 2M dysarthria Autosomal recessive limb-girdle Autosomal recessive spastic 280333 8 Cases muscular dystrophy type 2P 314603 ataxia with 54 Cases Autosomal recessive limb-girdle leukoencephalopathy 254361 6 Cases Autosomal recessive spastic muscular dystrophy type 2Q 100995 1 Family Autosomal recessive limb-girdle paraplegia type 14 363543 2 Cases Autosomal recessive spastic muscular dystrophy type 2R 100996 10 Families Autosomal recessive limb-girdle paraplegia type 15 369840 3 Cases Autosomal recessive spastic muscular dystrophy type 2S 209951 9 Cases Autosomal recessive limb-girdle paraplegia type 18 363623 2 Cases Autosomal recessive spastic muscular dystrophy type 2T 101003 1 Family Autosomal recessive limb-girdle paraplegia type 23 352479 8 Cases Autosomal recessive spastic muscular dystrophy type 2U 101004 1 Family Autosomal recessive lower paraplegia type 24 Autosomal recessive spastic 206580 motor neuron disease with 5 Cases 101005 1 Family childhood onset paraplegia type 25 Autosomal recessive Autosomal recessive spastic 238505 2 Cases 101006 10 Families lymphoproliferative disease paraplegia type 26 Autosomal recessive malignant Autosomal recessive spastic 667 0.75 BP * 101007 2 Families osteopetrosis paraplegia type 27 Autosomal recessive spastic Autosomal recessive mendelian 101008 6 Cases susceptibility to mycobacterial paraplegia type 28 319569 14 Cases Autosomal recessive spastic diseases due to partial 101010 3 Families IFNgammaR1 deficiency paraplegia type 30 Autosomal recessive spastic 171622 1 Family paraplegia type 32

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Autosomal recessive spastic 171629 1 Family 1226 Bamforth-Lazarus syndrome 8 Cases paraplegia type 35 1227 2 Cases Autosomal recessive spastic Bangstad syndrome 139480 2 Families paraplegia type 39 1228 Banki syndrome 1 Family Autosomal recessive spastic 306511 2 Cases 2995 Baraitser-Winter syndrome 30 Cases paraplegia type 48 Autosomal recessive spastic 1231 Barber-Say syndrome 11 Cases 431329 2 Cases paraplegia type 57 110 Bardet-Biedl syndrome 0.7 P * Autosomal recessive spastic 397946 2 Cases paraplegia type 58 110 Bardet-Biedl syndrome 0.2 BP * Autosomal recessive spastic 401795 3 Cases 111 Barth syndrome 0.22 P * paraplegia type 59 Autosomal recessive spastic 1234 Bartsocas-Papas syndrome 24 Cases 401800 1 Case paraplegia type 60 112 Bartter syndrome 0.1 I * Autosomal recessive spastic 401780 4 Cases paraplegia type 61 100976 Bathing suit ichthyosis 20 Cases Autosomal recessive spastic 401785 7 Cases 166113 Bazex syndrome 145 Cases paraplegia type 62 113 Bazex-Dupré-Christol syndrome 143 Cases Autosomal recessive spastic 401805 2 Cases paraplegia type 63 98895 Becker muscular dystrophy 1.53 P Autosomal recessive spastic 401810 4 Cases 98895 Becker muscular dystrophy 2.2 BP * paraplegia type 64 Autosomal recessive spastic Beckwith-Wiedemann 401815 2 Cases 116 2.3 BP * paraplegia type 66 syndrome Autosomal recessive spastic 1237 Beemer-Ertbruggen syndrome 2 Cases 401820 2 Cases paraplegia type 67 1241 Bencze syndrome 2 Families Autosomal recessive spastic 401825 1 Case Benign concentric annular paraplegia type 68 251287 27 Cases macular dystrophy Autosomal recessive spastic 401830 2 Cases Benign exophthalmos paraplegia type 69 71269 4 Cases syndrome Autosomal recessive spastic 401835 4 Cases Benign familial neonatal paraplegia type 70 1949 100 Families epilepsy Autosomal recessive spastic 401840 1 Case Benign familial neonatal- paraplegia type 71 140927 10 Families infantile seizures Autosomal recessive Benign familial nocturnal 401979 spondylometaphyseal dysplasia, 4 Cases 209973 alternating hemiplegia of 10 Cases Mégarbané type childhood Autosomal recessive Stickler 250984 4 Cases Benign infantile focal epilepsy syndrome 166308 with midline spikes and wave 36 Cases Autosomal recessive systemic 300345 7 Families during sleep lupus erythematosus Benign paroxysmal torticollis of Autosomal semi-dominant 71518 50 Cases infancy 280365 severe lipodystrophic 7 Cases Benign Samaritan congenital laminopathy 324581 4 Cases myopathy Autosomal spastic paraplegia 401849 14 Cases type 72 252164 Benign schwannoma 6.0 P * Berardinelli-Seip congenital 782 Axenfeld-Rieger syndrome 0.5 P * 528 0.25 P * lipodystrophy Axial spondylometaphyseal 168549 3 Cases dysplasia 274 Bernard-Soulier syndrome 100 Cases AXIN2-related attenuated 401911 4 Families 118 Beta-mannosidosis 0.14 BP * familial adenomatous polyposis Beta-propeller protein- 329284 5 Cases 79332 B4GALT1-CDG 2 Cases associated neurodegeneration B-cell chronic lymphocytic 67038 27.0 P * 848 Beta-thalassemia 1.0 I leukemia Beta-ureidopropionase 65287 5 Cases 36234 Bacterial toxic-shock syndrome 3.0 P deficiency Bilateral microtia - deafness - 93395 Ballard syndrome 12 Cases 140963 4 Cases cleft palate 1225 Baller-Gerold syndrome 30 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Bilateral striopallidodentate 1980 200 Cases 1262 Böök syndrome 26 Cases calcinosis 1263 Boomerang dysplasia 10 Cases 30391 Biliary atresia 18.5 BP Borjeson-Forssman-Lehmann 127 50 Cases 79241 Biotinidase deficiency 1.6 P * syndrome 79241 Biotinidase deficiency 1.6 BP 69737 Bosley-Salih-Alorainy syndrome 9 Cases 122 Birt-Hogg-Dubé syndrome 0.5 P * 1267 Botulism 0.05 I * 123 Björnstad syndrome 33 Cases 1270 Bowen-Conradi syndrome 60 Cases Brachydactyly - elbow wrist 124 Blackfan-Diamond anemia 0.67 BP * 1275 4 Families dysplasia 93930 Bladder exstrophy 3.05 BP 2946 Brachydactyly - long thumb 4 Cases Bleeding diathesis due to a 73271 20 Cases Brachydactyly - nystagmus - collagen receptor defect 1246 1 Family cerebellar ataxia Bleeding disorder due to 420566 3 Cases Brachydactyly - preaxial hallux CalDAG-GEFI deficiency 1278 8 Cases varus Blepharo-cheilo-odontic 1997 50 Cases syndrome 93389 Brachydactyly type A5 2 Families Blepharonasofacial 1252 3 Families 93382 Brachydactyly type A6 7 Cases malformation syndrome 93397 1 Family Blepharophimosis - epicanthus Brachydactyly type A7 126 2.0 P inversus - ptosis Brachydactyly-arterial 1276 10 Families Blepharophimosis - ptosis - hypertension syndrome 2057 6 Cases Brachydactyly-syndactyly, Zhao esotropia - syndactyly - short 93409 2 Families stature type Blepharophimosis-intellectual Brachymorphism - 293642 58 Cases disability syndrome 1292 onychodysplasia - 9 Cases Blepharophimosis-intellectual dysphalangism 329255 disability syndrome due to 4 Cases 1293 Brachyolmia 100 Cases UBE3B deficiency Brachytelephalangy - Blepharophimosis-intellectual 2728 30 Cases 1295 dysmorphism - Kallmann 2 Cases disability syndrome, Ohdo type syndrome Blepharophimosis-intellectual 3047 20 Cases 52047 Braddock syndrome 2 Cases disability syndrome, SBBYS type Blepharoptosis - myopia - 75374 Bradyopsia 5 Cases 1259 3 Cases ectopia lentis 178506 Brain calcification, Rajab type 8 Cases Blindness-scoliosis- 171844 4 Cases arachnodactyly syndrome Brain demyelination due to 168598 2 Cases Blomstrand lethal methionine adenosyltransferase 50945 13 Cases deficiency chondrodysplasia Brain dopamine-serotonin 125 400 Cases 352649 8 Cases Bloom syndrome vesicular transport disease 16 Blue cone monochromatism 1.0 P Brain malformation - congenital 75389 heart disease - postaxial 2 Cases 16 Blue cone monochromatism 1.0 BP polydactyly 1059 Blue rubber bleb nevus 200 Cases 209905 Brain-lung-thyroid syndrome 20 Cases 217266 BNAR syndrome 9 Families 1297 Branchio-oculo-facial syndrome 50 Cases Body skin hyperlaxity due to Branchio-skeleto-genital 1299 3 Cases 91135 vitamin K-dependent 10 Cases syndrome coagulation factor deficiency Branchiogenic deafness 50815 5 Cases 97297 Bohring-Opitz syndrome 30 Cases syndrome Bone dysplasia, lethal 85284 5 Cases 1842 7 Cases BRESEK syndrome Holmgren type 90354 Brittle cornea syndrome 65 Cases 223727 Bone sarcoma 9.29 P * 70589 Bronchopulmonary dysplasia 13.0 P * 223727 Bone sarcoma 0.8 I * 79493 Brooke-Spiegler syndrome 100 Cases Bonnemann-Meinecke-Reich 1261 4 Cases syndrome 2771 Bruck syndrome 40 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 130 Brugada syndrome 20.0 P * Cardiac anomalies- 369891 developmental delay-facial 4 Cases 131 Budd-Chiari syndrome 1.5 P * dysmorphism syndrome Cardiocranial syndrome, 36258 Buerger disease 16.0 P 2872 10 Cases Pfeiffer type Bullous diffuse cutaneous 280785 40 Cases Cardiodysrhythmic potassium- mastocytosis 37553 0.1 I * sensitive periodic paralysis Bullous dystrophy, macular 1867 2 Families Cardiofaciocutaneous type 1340 300 Cases syndrome Bullous systemic lupus 46489 70 Cases erythematosus 97292 Cardiogenic shock 40.0 P * Cardiomyopathy - cataract - hip 543 Burkitt lymphoma 0.17 I * 1345 9 Cases spine disease 1308 C syndrome 0.11 P * Cardiomyopathy - hypotonia - 91130 2 Cases 135 CACH syndrome 148 Cases lactic acidosis Cardiomyopathy - renal 136 CADASIL 3.0 P * 90022 2 Cases anomalies 369942 CADDS 4 Cases Cardiospondylocarpofacial 3238 3 Cases syndrome 1310 Caffey disease 100 Cases 1358 Carey-Fineman-Ziter syndrome 20 Cases 280062 Calciphylaxis 5.0 P * 1359 Carney complex 160 Cases Calvarial doughnut lesions - 85192 20 Cases bone fragility 139411 Carney triad 150 Cases 83472 5 Cases CAMOS syndrome 97286 Carney-Stratakis syndrome 20 Families 1318 Campomelia, Cumming type 8 Cases Carnitine palmitoyl transferase 156 50 Cases 1A deficiency 140 Campomelic dysplasia 0.33 BP * Carnitine palmitoyl transferase 228302 300 Cases 1319 Camptobrachydactyly 1 Family II deficiency, myopathic form Camptodactyly - fibrous tissue Carnitine palmitoyl transferase 1321 3 Cases 228308 18 Cases hyperplasia - skeletal dysplasia II deficiency, neonatal form Camptodactyly - tall stature - Carnitine palmitoyl transferase 85164 30 Cases scoliosis - hearing loss 228305 II deficiency, severe infantile 30 Cases form 1325 Camptodactyly - taurinuria 17 Cases Carnitine palmitoyltransferase Camptodactyly syndrome, 157 300 Cases 1327 8 Cases II deficiency Guadalajara type 1 Carnitine-acylcarnitine Camptodactyly syndrome, 159 60 Cases 1326 2 Cases translocase deficiency Guadalajara type 2 1361 0.2 BP Camptodactyly-arthropathy- Carnosinemia 2848 30 Families coxa-vara-pericarditis syndrome 53035 Caroli disease 0.1 I 1328 300 Cases Camurati-Engelmann disease 65759 Carpenter syndrome 70 Cases 141 1.0 BP Canavan disease 93973 Carpenter-Waziri syndrome 6 Cases 325004 10 Cases CANDLE syndrome 175 Cartilage-hair hypoplasia 4.34 BP * 171881 10 Cases Cap myopathy 195 Cat-eye syndrome 1.35 BP * 160148 67 Cases Cap polyposis 50839 Cat-scratch disease 6.6 P * Capillary malformation - 137667 261 Cases 1368 Cataract - ataxia - deafness 2 Cases arteriovenous malformation Carbamoyl-phosphate Cataract - deafness - 147 0.31 P 1383 3 Cases synthetase 1 deficiency hypogonadism Cataract - intellectual disability 70482 Carcinoma of esophagus 9.8 P 1387 20 Cases - hypogonadism 70482 Carcinoma of esophagus 7.0 I Cataract - nephropathy - 1380 2 Cases Carcinoma of gallbladder and encephalopathy 56044 12.0 I extrahepatic biliary tract 162 Cataract-glaucoma 3 Families 137628 Cardiac anomalies - heterotaxy 9 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Cataract-growth hormone Charcot-Marie-Tooth disease 101101 1 Family deficiency-sensory neuropathy- type 2B2 436174 3 Cases sensorineural hearing loss- Charcot-Marie-Tooth disease 101102 13 Cases skeletal dysplasia syndrome type 2H Cataract-microcornea Charcot-Marie-Tooth disease 1377 8 Families 300319 18 Cases syndrome type 2P Catecholaminergic polymorphic Charcot-Marie-Tooth disease 3286 10.0 P * 397968 1 Case ventricular tachycardia type 2R Charcot-Marie-Tooth disease 1388 Catel-Manzke syndrome 33 Cases 443950 2 Cases type 2T 66631 CEDNIK syndrome 7 Cases Charcot-Marie-Tooth disease Celiac disease, epilepsy and 99955 11 Families 1459 170 Cases type 4B1 cerebral calcification syndrome Charcot-Marie-Tooth disease 363981 3 Cases 3258 Cenani-Lenz syndrome 30 Cases type 4B3 Charcot-Marie-Tooth disease 2431 Central bilateral macrogyria 4 Cases 99954 10 Cases type 4H Central cloudy dystrophy of Charcot-Marie-Tooth disease 98972 24 Cases 139515 5 Cases Francois type 4J 178029 4.0 P * Central diabetes insipidus 138 CHARGE syndrome 6.5 BP Central nervous system 167 Chédiak-Higashi syndrome 500 Cases 3240 calcification - deafness - tubular 2 Cases acidosis - anemia 1221 Cheilitis glandularis 100 Cases 73256 Central neurocytoma 500 Cases 184 Cherubism 300 Cases 411527 Central retinal vein occlusion 28.0 P * 139 CHILD syndrome 60 Cases Centripetalis recessive 209908 Childhood apraxia of speech 22 Cases 89841 dystrophic epidermolysis 10 Cases Childhood disintegrative bullosa 168782 2.0 P * Cerebellar ataxia - areflexia - disorder 1171 pes cavus - optic atrophy - 10 Cases Childhood encephalopathy due sensorineural hearing loss 293955 to thiamine pyrophosphokinase 5 Cases Cerebellar-facial-dental deficiency 444072 3 Families syndrome Childhood-onset autosomal Cerebral arteriovenous 363677 recessive myopathy with 22 Cases 46724 6.0 P * malformation external ophthalmoplegia 2081 Cerebral gigantism - jaw cysts 10 Cases 3474 CHIME syndrome 8 Cases Cerebral sinovenous 137914 Choanal atresia 8.6 BP * 329217 0.35 I * thrombosis Choanal atresia-hearing loss- Cerebro-costo-mandibular 1200 5 Cases 1393 75 Cases cardiac defects-craniofacial syndrome dysmorphism syndrome Cerebro-facio-articular 314679 9 Cases 70567 Cholangiocarcinoma 2.1 P syndrome Cerebro-facio-thoracic 70567 Cholangiocarcinoma 4.2 I 1394 13 Cases dysplasia Cholestasis-lymphedema 1414 50 Cases 66625 Cerebro-oculo-nasal syndrome 10 Cases syndrome Cholestasis-pigmentary 3421 3 Families Cerebroretinal vasculopathy 1415 retinopathy-cleft palate 5 Cases 169079 Cernunnos-XLF deficiency 5 Cases syndrome Chondrodysplasia - disorder of Cervical hypertrichosis - 1422 2 Cases 2218 3 Cases peripheral neuropathy sex development Chondrodysplasia with joint Channelopathy-associated 88642 20 Cases 280586 4 Cases congenital insensitivity to pain dislocations, gPAPP type 404507 Chondromyxoid fibroma 50 Cases 46627 Char syndrome 10 Cases 55880 Chondrosarcoma 0.24 I * 166 Charcot-Marie-Tooth disease 25.0 P * Charcot-Marie-Tooth disease 251899 Choroid plexus carcinoma 0.01 I * 65753 17.5 P type 1 1433 Choroidal atrophy - alopecia 2 Cases 180 Choroideremia 1.5 P *

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Choroideremia - deafness - Classic congenital adrenal 1435 4 Cases obesity hyperplasia due to 21- 315306 7.5 P * 85278 Christianson syndrome 30 Cases hydroxylase deficiency, salt wasting form Chronic atrial and intestinal 435988 17 Cases Classic congenital adrenal dysrhythmia syndrome hyperplasia due to 21- 315306 7.5 BP * 2137 Chronic autoimmune hepatitis 23.5 P hydroxylase deficiency, salt 2137 Chronic autoimmune hepatitis 1.2 I wasting form Classic congenital adrenal Chronic diarrhea due to hyperplasia due to 21- 314373 guanylate cyclase 2C 32 Cases 315311 2.5 P * hydroxylase deficiency, simple overactivity virilizing form 379 Chronic granulomatous disease 0.46 BP Classic endocrine tumor of 329977 0.25 I 396 Chronic hiccup 1.0 P * appendix Chronic inflammatory 79239 Classic galactosemia 2.1 I * 2932 3.7 P * demyelinating polyneuropathy 391 Classic Hodgkin lymphoma 2.38 I * 521 Chronic myeloid leukemia 6.0 P * 394 Classic homocystinuria 1.65 P * 521 Chronic myeloid leukemia 1.25 I * 394 Classic homocystinuria 0.3 BP Chronic pain requiring 95426 12.0 P * 2584 0.5 I * intraspinal analgesia Classic mycosis fungoides Chronic primary adrenal 1995 Cleft lip - retinopathy 2 Cases 101959 14.0 P * insufficiency Cleft lip/palate - intestinal Chronic primary adrenal 2001 4 Cases 101959 0.4 I * malrotation - cardiopathy insufficiency 2014 Cleft palate 53.6 BP * Chronic recurrent multifocal 324964 0.3 P Cleft palate - short stature - osteomyelitis 2015 2 Cases Chronic recurrent multifocal vertebral anomalies 324964 2.5 I Cleft palate - stapes fixation - osteomyelitis 2010 2 Cases Chronic thromboembolic oligodontia 70591 3.0 P * Cleft palate-lateral synechia pulmonary hypertension 2016 11 Cases CHST3-related skeletal syndrome 263463 2 Cases dysplasia 1452 Cleidocranial dysplasia 0.1 P 93971 Chudley-Lowry-Hoar syndrome 3 Cases 1452 Cleidocranial dysplasia 0.4 BP * 314597 Chudley-McCullough syndrome 25 Cases 1453 Cleidorhizomelic syndrome 2 Cases 71 Chylomicron retention disease 55 Cases 284448 CLIPPERS 50 Cases CIDEC-related familial partial 435651 1 Case 314629 CLN11 disease 2 Cases lipodystrophy 352709 CLN13 disease 4 Cases 1451 CINCA syndrome 200 Cases Circumscribed palmoplantar 93929 Cloacal exstrophy 0.54 BP 69744 17 Cases hypokeratosis 140944 CLOVE syndrome 15 Cases Cirrhosis-dystonia- Cloverleaf skull - multiple 309854 polycythemia- 20 Cases 93267 3 Cases congenital anomalies hypermanganesemia syndrome COASY protein-associated 397725 2 Cases 247525 Citrullinemia type I 1.35 P * neurodegeneration 251383 CK syndrome 7 Cases 53721 Cobb syndrome 35 Cases 168984 CLAPO syndrome 6 Cases 51577 Cobblestone lissencephaly 1.0 BP * Classic congenital adrenal Cobblestone lissencephaly 90794 hyperplasia due to 21- 7.0 P * 352682 without muscular or ocular 4 Cases hydroxylase deficiency involvement Classic congenital adrenal 191 Cockayne syndrome 0.27 BP * 90794 hyperplasia due to 21- 7.0 BP hydroxylase deficiency 191 Cockayne syndrome 0.5 I * 1458 CODAS syndrome 12 Cases 192 Coffin-Lowry syndrome 1.5 P

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 1465 Coffin-Siris syndrome 190 Cases Combined oxidative 420728 phosphorylation deficiency type 2 Cases 1466 COFS syndrome 20 Cases 20 263508 COG1-CDG 3 Cases Combined oxidative 420733 phosphorylation deficiency type 2 Cases 435934 COG2-CDG 1 Case 21 263501 COG4-CDG 2 Cases Combined oxidative 444013 phosphorylation deficiency type 11 Cases 263487 9 Cases COG5-CDG 23 79333 COG7-CDG 9 Cases Combined oxidative 444458 phosphorylation deficiency type 3 Cases 95428 COG8-CDG 2 Cases 24 1467 Cogan syndrome 300 Cases Complement component 3 280133 15 Cases Cognitive impairment-coarse deficiency Complete androgen facies-heart defects-obesity- 99429 0.83 P 444077 pulmonary involvement-short 3 Cases insensitivity syndrome Complete androgen stature-skeletal dysplasia 99429 3.0 I * syndrome insensitivity syndrome 193 Cohen syndrome 200 Cases 1329 Complete atrioventricular canal 20.0 BP * 31824 Colchicine poisoning 0.1 P * 98949 Complete cryptophthalmia 15 Cases Cold-induced sweating 157820 6 Cases 268316 Complication in hemodialysis 13.0 I * syndrome Cone dystrophy with 209932 45 Cases 2050 Cole-Carpenter syndrome 4 Cases supernormal rod response 36205 Collagenous colitis 3.35 I 1872 Cone rod dystrophy 2.5 P * Coloboma of macula - Congenital absence/hypoplasia 1471 12 Cases brachydactyly type B 973 of fingers excluding thumb, 2 Families Colobomatous microphthalmia- unilateral 424099 5 Families rhizomelic dysplasia syndrome 418 Congenital adrenal hyperplasia 10.0 P * Colobomatous optic disc- 418 Congenital adrenal hyperplasia 6.7 BP * 435930 macular atrophy- 3 Cases chorioretinopathy syndrome 418 Congenital adrenal hyperplasia 13.35 I * Combined deficiency of factor V 35909 0.5 P * Congenital adrenal hyperplasia and factor VIII 90791 due to 3-beta-hydroxysteroid 68 Cases Combined hamartoma of the dehydrogenase deficiency 440727 retina and retinal pigment 120 Cases Congenital adrenal hyperplasia epithelium 90795 due to 11-beta-hydroxylase 0.47 P * Combined immunodeficiency deficiency 169090 due to CRAC channel 10 Cases Congenital adrenal hyperplasia dysfunction 90795 due to 11-beta-hydroxylase 0.75 BP * Combined immunodeficiency 217390 11 Cases deficiency due to DOCK8 deficiency Congenital adrenal hyperplasia Combined immunodeficiency 445018 23 Cases 90793 due to 17-alpha-hydroxylase 0.1 P * due to LRBA deficiency deficiency Combined immunodeficiency 397964 3 Cases Congenital adrenal hyperplasia due to MALT1 deficiency 95699 due to cytochrome P450 0.75 BP * Combined immunodeficiency oxidoreductase deficiency 317428 6 Cases due to ORAI1 deficiency Congenital alveolar capillary 210122 40 Cases Combined immunodeficiency dysplasia 431149 1 Case due to OX40 deficiency Congenital amegakaryocytic 3319 100 Cases Combined immunodeficiency 314689 7 Cases thrombocytopenia due to STK4 deficiency 86816 Congenital analbuminemia 50 Cases Combined immunodeficiency 231154 T+ B+ due to partial RAG1 9 Cases 1195 Congenital atransferrinemia 16 Cases deficiency Congenital bilateral absence of 48 50.0 P * Combined oxidative vas deferens 324535 5 Cases phosphorylation defect type 11 Congenital bile acid synthesis 79302 2 Cases Combined oxidative 369913 5 Cases defect type 3 phosphorylation defect type 17

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Congenital bile acid synthesis 79095 5 Cases 2185 Congenital hydrocephalus 46.5 BP * defect type 4 442 38.0 BP * Congenital brain dysgenesis Congenital hypothyroidism 71278 2 Cases Congenital hypothyroidism due due to glutamine synthetase 95711 21.3 P * deficiency to developmental anomaly Congenital bronchobiliary Congenital hypothyroidism due 2040 35 Cases fistula to transplacental passage of 95715 1.0 P * Congenital cataract - maternal TSH-binding inhibitory 1369 hypertrophic cardiomyopathy - 40 Cases antibodies mitochondrial myopathy Congenital ichthyosis - 2271 2 Cases Congenital cataract - microcephalus - tetraplegia progressive muscular hypotonia Congenital ichthyosis- 330054 3 Cases - hearing loss - developmental 352333 intellectual disability-spastic 2 Cases delay quadriplegia syndrome Congenital insensitivity to pain Congenital cataract-hearing 217399 2 Cases 300313 loss-severe developmental 5 Cases with hyperhidrosis delay syndrome Congenital intrauterine 1229 30 Cases Congenital cataracts - facial infection-like syndrome 48431 160 Cases dysmorphism - neuropathy Congenital intrinsic factor 332 100 Cases Congenital chronic diarrhea deficiency 329242 2 Cases with protein-losing enteropathy Congenital isolated 657 2.0 BP Congenital diaphragmatic hyperinsulinism 2140 30.0 BP hernia Congenital isolated thyroxine- 209893 46.0 P * Congenital disorder of binding globulin deficiency 137 1.5 BP * glycosylation 1954 Congenital lethal erythroderma 17 Cases Congenital dyserythropoietic 85 0.16 BP * Congenital lethal myopathy, anemia 210163 4 Cases Compton-North type Congenital dyserythropoietic 98870 3 Families anemia type III 1928 Congenital lobar emphysema 4.0 BP Congenital dyserythropoietic Congenital malabsorptive 293825 4 Cases anemia type IV 83620 diarrhea due to paucity of 7 Cases Congenital enterocyte heparan enteroendocrine cells 103910 3 Cases sulfate deficiency 93109 Congenital megacalycosis 25 Cases Congenital erosive and 231573 17 Cases Congenital membranous vesicular dermatosis nephropathy due to maternal Congenital erythropoietic 69063 15 Cases 79277 0.065 I * anti-neutral endopeptidase porphyria alloimmunization 325 Congenital factor II deficiency 0.05 P * Congenital microcephaly- severe encephalopathy- 326 Congenital factor V deficiency 0.1 P * 391376 9 Cases progressive cerebral atrophy 327 Congenital factor VII deficiency 0.33 P * syndrome Congenital muscular dystrophy 329 Congenital factor XI deficiency 0.1 P * 157973 15 Cases due to LMNA mutation 331 Congenital factor XIII deficiency 0.05 P * Congenital muscular dystrophy 280671 due to phosphatidylcholine 19 Cases 331 Congenital factor XIII deficiency 0.04 I * biosynthesis defect Congenital fibrinogen Congenital muscular dystrophy 335 0.15 P * 258 0.3 P * deficiency type 1A Congenital generalized Congenital muscular dystrophy 1023 40 Cases 34520 0.03 P * hypertrichosis, Ambras type with integrin alpha-7 deficiency 98976 Congenital glaucoma 3.6 BP * Congenital muscular dystrophy 329178 3 Cases 60041 Congenital heart block 4.54 BP with intellectual disability and severe epilepsy 88991 Congenital heart malformation 7.8 BP * Congenital myasthenic 590 0.3 P * Congenital hereditary syndrome 98975 68 Cases endothelial dystrophy type I Congenital myopathy with 424107 2 Cases Congenital hereditary facial myasthenic-like onset 306530 paralysis with variable hearing 13 Cases Congenital myopathy, Paradas 199329 2 Cases loss type

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Congenital nephrotic Contractures-webbed neck- syndrome-interstitial lung 314002 micrognathia-hypoplastic 2 Cases 306504 3 Cases disease-epidermolysis bullosa nipples syndrome syndrome 1487 Cooks syndrome 11 Cases Congenital neuronal ceroid 168486 10 Cases lipofuscinosis 1488 Cooper-Jabs syndrome 2 Cases Corneal dystrophy - perceptive Congenital neutropenia- 1490 10 Cases 369852 myelofibrosis-nephromegaly 7 Cases deafness syndrome Corneal intraepithelial Congenital non-bullous dyskeratosis-palmoplantar 79394 0.3 P * 352662 2 Cases ichthyosiform erythroderma hyperkeratosis-laryngeal Congenital osteogenesis dyskeratosis syndrome 2772 imperfecta - microcephaly - 3 Cases 3177 Corneal-cerebellar syndrome 2 Cases cataracts 199 Cornelia de Lange syndrome 1.9 P * 313906 Congenital pancreatic cyst 10 Cases 199 Cornelia de Lange syndrome 1.0 BP * 139414 Congenital panfollicular nevus 2 Cases Cortical blindness - intellectual Congenital pseudoarthrosis of 1389 3 Cases 66630 200 Cases disability - polydactyly clavicle Cortical dysgenesis with Congenital pulmonary airway 2444 8.2 BP * 300570 pontocerebellar hypoplasia due 12 Cases malformation to TUBB3 mutation Congenital pulmonary Corticosteroid-sensitive aseptic 2414 100 Cases 54251 49 Cases lymphangiectasia abscess syndrome Congenital pulmonary valve 3189 39.3 BP * 3071 Costello syndrome 300 Cases stenosis Congenital reticular 201 Cowden syndrome 0.5 P * 281190 40 Cases ichthyosiform erythroderma 1508 Coxoauricular syndrome 4 Cases 290 Congenital rubella syndrome 0.35 BP * 1509 Coxopodopatellar syndrome 47 Cases 290 Congenital rubella syndrome 0.03 I * 1525 Cranio-osteoarthropathy 30 Cases Congenital short bowel 2301 41 Cases syndrome 1513 Craniodiaphyseal dysplasia 20 Cases Congenital sideroblastic Craniodigital syndrome - 1514 5 Cases anemia-B-cell intellectual disability 369861 immunodeficiency-periodic 16 Cases 1515 Cranioectodermal dysplasia 39 Cases fever-developmental delay syndrome 85168 Craniofacial conodysplasia 1 Family 103908 Congenital sodium diarrhea 15 Cases Craniofacial dysplasia- 314555 5 Cases Congenital stromal corneal osteopenia syndrome 101068 5 Families dystrophy 1516 Craniofacial dyssynostosis 14 Cases Congenital sucrase-isomaltase Craniofacial-deafness-hand 35122 20.0 P * 1529 3 Cases deficiency syndrome Congenital total pulmonary Craniofrontonasal dysplasia - 99125 9.0 BP 1521 3 Cases venous return anomaly Poland anomaly 858 Congenital toxoplasmosis 33.0 BP * 50814 Craniolenticulosutural dysplasia 28 Cases Congenitally corrected 1522 Craniometaphyseal dysplasia 160 Cases 216694 transposition of the great 3.0 BP arteries 54595 Craniopharyngioma 2.0 P * Congenitally short 2391 1 Family 54595 Craniopharyngioma 1.0 I costocoracoid ligament Congenitally uncorrected 157832 Craniorhiny 3 Families 860 transposition of the great 24.25 BP * 1531 Craniosynostosis 24.3 BP * arteries Craniosynostosis - anal 85199 9 Cases 420794 Cono-spondylar dysplasia 3 Cases anomalies - porokeratosis Contractures - ectodermal 1484 2 Cases Craniosynostosis - Dandy- dysplasia - cleft lip/palate 1538 Walker malformation - 4 Cases Contractures-developmental hydrocephalus 436003 6 Cases delay-Pierre Robin syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Craniosynostosis - Cutis laxa with severe 1535 5 Cases dysmorphism - brachydactyly 221145 pulmonary, gastrointestinal and 4 Cases Craniosynostosis - fibular urinary anomalies 1533 2 Cases aplasia Cutis marmorata 1556 300 Cases Craniosynostosis - telangiectatica congenita hydrocephalus - Arnold-Chiari 171839 4 Cases 2686 Cyclic neutropenia 0.1 P * malformation type I - radioulnar Cyprus facial- synostosis 2674 neuromusculoskeletal 1 Family Craniosynostosis - intracranial 52054 3 Cases syndrome calcifications 400 Cystic echinococcosis 1.0 I * 1541 Craniosynostosis, Boston type 19 Cases 586 7.4 P * Craniosynostosis, Philadelphia Cystic fibrosis 1527 1 Family Cystic fibrosis - gastritis - type 2575 2 Cases megaloblastic anemia 90290 CREST syndrome 8.0 P * Cystic hamartoma of lung and 2111 5 Cases 204 Creutzfeldt-Jakob disease 0.1 P * kidney Cystic leukoencephalopathy 204 Creutzfeldt-Jakob disease 0.15 I 85136 50 Cases without megalencephaly 205 Crigler-Najjar syndrome 0.1 BP * 213 Cystinosis 0.75 BP 1545 Crisponi syndrome 30 Cases 214 Cystinuria 14.0 P 1461 Criss-cross heart 0.8 BP * 75381 Cystoid macular dystrophy 6 Families 2930 500 Cases Cronkhite-Canada syndrome Cytomegalovirus disease in patients with impaired cell 207 Crouzon disease 0.9 BP * 137698 25.5 P * mediated immunity deemed at Crouzon syndrome - acanthosis 93262 0.1 BP risk nigricans Cytophagic histiocytic 94087 100 Cases 1546 Cryptococcosis 11.0 I * panniculitis Cryptomicrotia - brachydactyly Czech dysplasia, metatarsal 1547 2 Cases 137678 20 Cases - excess fingertip arch type Cryptosporidiosis - chronic 357329 5 Cases 2437 Czeizel-Losonci syndrome 3 Cases cholangitis - liver disease 356978 D,L-2-hydroxyglutaric aciduria 13 Cases 1552 Currarino triad 1.0 P * 79315 D-2-hydroxyglutaric aciduria 80 Cases 1553 Curry-Jones syndrome 9 Cases 1562 Dacryocystitis - osteopoikilosis 5 Cases 96253 Cushing disease 4.0 P * Dahlberg-Borer-Newcomer 1563 2 Cases 96253 Cushing disease 0.2 I * syndrome 553 6.5 P * Dandy-Walker malformation - Cushing syndrome 1566 2 Cases postaxial polydactyly 553 Cushing syndrome 1.55 I * 218 Darier disease 3.4 P * Cushing syndrome due to 189427 macronodular adrenal 0.08 P * 300536 DDOST-CDG 1 Case hyperplasia 2962 De Barsy syndrome 40 Cases Cutaneous collagenous 280779 20 Cases Deaf blind hypopigmentation vasculopathy 3214 2 Cases syndrome, Yemenite type Cutaneous lupus 535 50.0 P * Deafness - enamel hypoplasia - erythematosus 3220 6 Cases nail defects Cutaneous neuroendocrine 79140 4.0 P * carcinoma Deafness - genital anomalies - 3224 metacarpal and metatarsal 2 Cases Cutaneous neuroendocrine 79140 0.27 I synostosis carcinoma Cutaneous photosensitivity - 90646 Deafness - hypogonadism 5 Cases 2881 3 Cases lethal colitis Deafness - intellectual 85321 3 Cases Cutis gyrata - acanthosis disability, Martin-Probst type 1555 6 Cases nigricans - craniosynostosis Deafness - lymphedema - 3226 20 Cases 209 Cutis laxa 0.1 BP * leukemia 3239 Deafness - vitiligo - achalasia 2 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Deafness with labyrinthine Developmental delay- 90024 aplasia, microtia, and 6 Families microcephaly-facial 363444 4 Cases microdontia dysmorphism syndrome, 94064 Deafness-infertility syndrome 3 Families Hutterite type Developmental malformations - Deafness-onychodystrophy 79107 2 Cases 3231 50 Cases deafness - dystonia syndrome Dianzani autoimmune 275523 30 Cases 99970 Dedifferentiated liposarcoma 0.27 I * lymphoproliferative disease Deficiency in anterior pituitary 66637 Diaphanospondylodysostosis 10 Cases 293978 function-variable 7 Cases Diaphragmatic defect - limb immunodeficiency syndrome 2141 4 Cases deficiency - skull defect 1578 Dehydratase deficiency 21 Cases 628 Diastrophic dwarfism 1.2 P * Dehydrated hereditary 3202 20 Families stomatocytosis 628 Diastrophic dwarfism 0.1 BP * 1627 Deletion 5q35 10 Cases 370046 Didymosis aplasticosebacea 18 Cases Differentiated thyroid 79134 DEND syndrome 40 Cases 146 5.25 I carcinoma 99828 Dengue fever 714.0 I 90060 Diffuse alveolar hemorrhage 1.0 P * 93571 2.5 P Dense deposit disease Diffuse cerebral and cerebellar atrophy-intractable seizures- 1652 Dent disease 250 Families 404437 4 Cases progressive microcephaly 99789 Dentin dysplasia type I 1.0 P * syndrome 99791 Dentin dysplasia type II 19 Families 79456 Diffuse cutaneous mastocytosis 30 Cases 49042 Dentinogenesis imperfecta 14.5 P * 544 Diffuse large B-cell lymphoma 16.0 P * Dentinogenesis imperfecta - Diffuse neonatal 2123 70 Cases 71267 short stature - hearing loss - 2 Cases hemangiomatosis intellectual disability Diffuse palmoplantar Dentinogenesis imperfecta type 86918 10 Cases 166260 14.6 P * keratoderma-acrocyanosis 2 syndrome 220 200 Cases Digital anomalies - intellectual Denys-Drash syndrome 352487 8 Cases disability - short stature 1656 Dermatitis herpetiformis 27.0 P * 1146 Digitotalar dysmorphism 10.0 P Dermato-cardio-skeletal 1266 3 Families Dihydropteridine reductase syndrome, Borrone type 226 150 Cases Dermatofibrosarcoma deficiency 31112 10.0 P * protuberans 38874 Dihydropyrimidinuria 7 Cases 1659 Dermatoleukodystrophy 2 Cases Dilated cardiomyopathy - 2229 hypergonadotropic 20 Families 221 6.0 P * Dermatomyositis hypogonadism 221 Dermatomyositis 0.55 I * Dimethylglycine 243343 1 Case Dermatoosteolysis, Kirghizian dehydrogenase deficiency 1657 5 Cases type 227 Diphallia 0.02 BP 1660 Dermo-odonto dysplasia 14 Cases 79168 Disorder of bile acid synthesis 0.6 P * 1425 50 Cases Disorder of sex development - Desbuquois syndrome 2983 3 Cases intellectual disability 873 Desmoid tumor 0.3 I * Disseminated peritoneal Desmoplastic small round cell 71274 150 Cases 83469 300 Cases leiomyomatosis tumor Distal 7q11.23 microdeletion 254351 41 Cases 35107 Desmosterolosis 9 Cases syndrome Developmental and speech Distal 7q11.23 microduplication 313892 9 Cases 261102 4 Cases delay due to SOX5 deficiency syndrome Developmental delay - Distal 17p13.1 microdeletion 163988 1 Family 319171 16 Cases deafness, Hildebrand type syndrome Distal 17p13.3 microdeletion Developmental delay with 261257 14 Cases 329195 autism spectrum disorder and 22 Cases syndrome gait instability 399096 Distal anoctaminopathy 8 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 329457 Distal arthrogryposis type 5D 7 Families 1203 Duodenal atresia 9.0 BP * Duplication of the pituitary 251515 Distal arthrogryposis type 10 53 Cases 314621 38 Cases gland Distal limb deficiencies - 1307 4 Cases micrognathia syndrome 237 Duplication of urethra 300 Cases Dyggve-Melchior-Clausen 96125 Distal monosomy 6p 35 Cases 239 60 Cases disease 96148 Distal monosomy 10q 40 Cases 1765 Dyschondrosteosis - nephritis 1 Family 280325 8 Cases Distal monosomy 12p Dyschromatosis symmetrica 41 300 Cases Distal myopathy with anterior 178400 4 Cases hereditaria tibial onset 1766 Dysequilibrium syndrome 37 Cases Distal myopathy with early 34521 24 Cases respiratory muscle involvement 1775 Dyskeratosis congenita 0.1 P * Distal myopathy with posterior Dysmorphism - short stature - 63273 leg and anterior hand 12 Cases 2282 deafness - disorder of sex 2 Cases involvement development Distal myopathy with vocal 600 12 Cases 85198 Dysspondyloenchondromatosis 16 Cases cord weakness 210571 Dystonia 16 12 Cases 3248 Distal symphalangism 5 Families 412217 Dystonia-aphonia syndrome 2 Cases 314588 Distal tetrasomy 15q 12 Cases Dystrophic epidermolysis 303 0.7 P 1745 Distal trisomy 6p 40 Cases bullosa Dystrophic epidermolysis 96102 Distal trisomy 10q 40 Cases 89843 100 Families bullosa pruriginosa Distal Xq28 microduplication 293939 9 Cases Dystrophic epidermolysis syndrome 158676 10 Families bullosa, nails only 404546 70 Cases DITRA Ear-patella-short stature 2554 67 Cases 91131 DK1-CDG 4 Cases syndrome Dominant hypophosphatemia Early infantile epileptic 369894 2 Cases 244305 with nephrolithiasis or 10 Cases encephalopathy without osteoporosis suppression burst Early myoclonic 2143 Donnai-Barrow syndrome 50 Cases 1935 80 Cases encephalopathy 79500 DOORS syndrome 50 Cases Early onset epileptic encephalopathy-cortical 255 Dopa-responsive dystonia 0.5 P 411986 3 Cases blindness-intellectual disability- Dopa-responsive dystonia due facial dysmorphism syndrome 70594 to sepiapterin reductase 43 Cases Early-onset generalized limb- 256 0.4 P * deficiency onset dystonia Dopamine beta-hydroxylase 230 21 Cases 324290 Early-onset Lafora body disease 3 Cases deficiency Early-onset progressive 3427 Double outlet left ventricle 0.5 BP 352654 neurodegeneration - blindness - 3 Cases Double uterus - hemivagina - 3411 60 Cases ataxia - spasticity renal agenesis Early-onset spastic ataxia- 313772 2 Cases 86309 DPAGT1-CDG 3 Cases neuropathy syndrome Early-onset X-linked isolated 79322 DPM1-CDG 14 Cases 98890 4 Families optic atrophy 263494 1 Case DPM3-CDG 199343 EAST syndrome 5 Cases 33069 2.5 BP Dravet syndrome 391320 East Texas bleeding disorder 1 Family Duane anomaly - myopathy - 50817 2 Cases 319218 Ebola hemorrhagic fever 28220 Cases scoliosis 233 Duane retraction syndrome 10.0 P * 1880 Ebstein malformation 1.25 P * 235 Dubowitz syndrome 0.2 BP * 1880 Ebstein malformation 3.5 BP * Ectodermal dysplasia - 98896 Duchenne muscular dystrophy 4.78 P 1806 2 Cases blindness 98896 Duchenne muscular dystrophy 15.1 BP * Ectodermal dysplasia - 247827 4 Cases 1203 Duodenal atresia 9.0 P * cutaneous syndactyly syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Ectodermal dysplasia - Endocrine-cerebro- 247820 6 Cases 199332 6 Cases syndactyly syndrome osteodysplasia syndrome Ectodermal dysplasia, Berlin Endosteal sclerosis - cerebellar 1816 4 Cases 85186 4 Cases type hypoplasia Ectopia lentis - chorioretinal 1884 4 Cases 60015 Enlarged parietal foramina 3.7 P dystrophy - myopia 85438 Enthesitis-related arthritis 5.7 P * 293936 EDICT syndrome 4 Families 402035 Eosinophilic colitis 196 Cases 1896 EEC syndrome 300 Cases 73247 Eosinophilic esophagitis 40.08 P 1897 EEM syndrome 7 Families 3165 Eosinophilic fasciitis 200 Cases 98249 Ehlers-Danlos syndrome 0.5 BP * 2070 280 Cases Ehlers-Danlos syndrome due to Eosinophilic gastroenteritis 230839 10 Cases tenascin-X deficiency Eosinophilic granulomatosis 183 1.5 P 90309 Ehlers-Danlos syndrome type 1 5.0 P * with polyangiitis Eosinophilic granulomatosis Ehlers-Danlos syndrome, 183 0.18 I * 230851 6 Cases with polyangiitis cardiac valvular type 301 0.2 I * Ehlers-Danlos syndrome, classic Ependymal tumor 287 5.0 P type 251636 Ependymoma 0.2 I * Ehlers-Danlos syndrome, 1901 7 Cases Epibulbar lipodermoid - dermatosparaxis type 231742 preauricular appendage - 1 Family Ehlers-Danlos syndrome, 75501 1 Family polythelia fibronectinemic type 35125 Epidermal nevus syndrome 400 Cases Ehlers-Danlos syndrome, 285 12.5 P * Epidermodysplasia hypermobility type 302 200 Cases Ehlers-Danlos syndrome, verruciformis 300179 kyphoscoliotic and deafness 6 Cases 304 Epidermolysis bullosa simplex 1.8 P type 304 Epidermolysis bullosa simplex 2.2 BP * Ehlers-Danlos syndrome, 1900 1.0 BP Epidermolysis bullosa simplex kyphoscoliotic type 412181 2 Cases due to BP230 deficiency Ehlers-Danlos syndrome, 2953 22 Cases Epidermolysis bullosa simplex musculocontractural type 412189 3 Cases due to exophilin 5 deficiency Ehlers-Danlos syndrome, 75392 62 Cases Epidermolysis bullosa simplex periodontitis type 257 40 Cases with muscular dystrophy Ehlers-Danlos syndrome, 157965 6 Cases Epidermolysis bullosa simplex, spondylocheirodysplastic type 79401 6 Families Ogna type Ehlers-Danlos syndrome, 286 1.0 P * Epilepsy - microcephaly - vascular type 1948 2 Cases Ehlers-Danlos syndrome, skeletal dysplasia 230845 3 Cases vascular-like type 1951 Epilepsy telangiectasia 6 Cases Epimetaphyseal skeletal 1902 Ehrlichiosis 50 Cases 1819 4 Cases dysplasia 79106 Eiken syndrome 6 Cases 79135 Episodic ataxia type 3 1 Family 228240 Elastoderma 4 Cases 79136 Episodic ataxia type 4 2 Families 289 Ellis Van Creveld syndrome 1.1 BP 211067 Episodic ataxia type 5 7 Cases Emery-Dreifuss muscular 261 0.3 P * dystrophy 209967 Episodic ataxia type 6 4 Cases Encephalocraniocutaneous 2396 77 Cases 209970 Episodic ataxia type 7 7 Cases lipomatosis Episodic ataxia with slurred Encephalopathy due to 401953 13 Cases 79155 30 Cases speech hydroxykynureninuria Encephalopathy due to 93928 Epispadias 2.4 BP * 139406 10 Cases prosaposin deficiency Epithelial recurrent erosion 293381 186 Cases Encephalopathy due to sulfite dystrophy 833 100 Cases oxidase deficiency Epithelio-exfoliative colitis - 103912 2 Cases 296 Enchondromatosis 1.0 P * deafness Epstein-Barr virus-associated 313920 1.2 I 877 Endocrine tumor 2.53 I * gastric carcinoma

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Familial congenital mirror 35687 Erdheim-Chester disease 500 Cases 238722 11 Cases movements 999 3 Cases Ermine phenotype Familial cutaneous telangiectasia and 317 Erythrokeratodermia variabilis 200 Cases 313846 24 Cases oropharyngeal predisposition 1199 Esophageal atresia 24.3 BP * cancer syndrome 1957 0.02 I * Familial developmental Esthesioneuroblastoma 1799 6 Families dysphasia 51188 Ethylmalonic encephalopathy 40 Cases Familial dyskinesia and facial 324588 18 Cases 1959 Evans syndrome 0.1 P * myokymia Familial encephalopathy with 319 Ewing sarcoma 0.13 I * 85110 5 Families neuroserpin inclusion bodies Extraskeletal myxoid 209916 0.2 P * Familial episodic pain chondrosarcoma 391392 syndrome with predominantly 28 Cases Eyebrow duplication - 3172 3 Cases lower limb involvement syndactyly Familial episodic pain 324 Fabry disease 0.22 BP * 391389 syndrome with predominantly 21 Cases Facial dysmorphism - upper body involvement Familial glucocorticoid 352712 immunodeficiency - livedo - 11 Cases 361 50 Cases short stature deficiency Familial hyperaldosteronism Facial dysmorphism - 251274 7 Families 1970 macrocephaly - myopia - Dandy- 3 Cases type III Walker malformation 238475 Familial hypercholanemia 23 Cases Facial dysmorphism-lens Familial hyperthyroidism due to dislocation-anterior segment 424 28 Families 412022 4 Families mutations in TSH receptor abnormalities-spontaneous filtering blebs syndrome 300373 Familial infantile gigantism 3 Cases Facial onset sensory and motor Familial infantile myoclonic 85162 4 Cases 352582 7 Cases neuronopathy epilepsy Familial isolated dilated 1973 Faciocardiorenal syndrome 4 Cases 154 17.5 P * cardiomyopathy 269 Facioscapulohumeral dystrophy 4.5 P * Familial isolated dilated 154 2.91 I * FADD-related cardiomyopathy 306550 4 Cases immunodeficiency Familial isolated 2238 10 Families Fallot complex - intellectual hypoparathyroidism 3304 5 Cases disability - growth delay Familial isolated Familial acute necrotizing 2239 hypoparathyroidism due to 2 Families 88619 11 Cases encephalopathy agenesis of parathyroid gland Familial adenomatous Familial isolated pituitary 733 6.0 P * 314777 150 Cases polyposis adenoma Familial Alzheimer-like prion Familial isolated restrictive 280397 2 Cases 75249 2.5 P * disease cardiomyopathy 228277 Familial anetoderma 12 Families 79293 Familial LCAT deficiency 70 Cases Familial atrial tachyarrhythmia- 768 Familial long QT syndrome 40.0 BP * 436242 infra-Hisian cardiac conduction 7 Cases Familial median cleft of the disease 401942 8 Cases upper and lower lips Familial calcium pyrophosphate 1416 100 Families deposition 618 Familial melanoma 1.5 I * Familial multiple 1768 Familial caudal dysgenesis 4 Cases 338 7 Cases fibrofolliculoma Familial cerebral cavernous 221061 15.0 P Familial omphalocele syndrome malformation 280403 5 Cases with facial dysmorphism Familial chondromalacia 1428 5 Families Familial or sporadic hemiplegic patellae 569 10.0 P * migraine Familial chylomicronemia 444490 1.0 P * Familial papillary thyroid syndrome 97290 carcinoma with renal papillary 2 Cases Familial clubfoot due to 238578 10 Cases neoplasia 17q23.1q23.2 microduplication Familial partial lipodystrophy, 79084 20 Cases Köbberling type

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Familial platelet syndrome with Fatal mitochondrial disease due 71290 predisposition to acute 20 Families 168566 to combined oxidative 2 Cases myelogenous leukemia phosphorylation deficiency 3 Familial primary Fatal multiple mitochondrial 34526 500 Cases 401869 21 Cases hypomagnesemia dysfunction syndrome type 1 Familial primary Fatal multiple mitochondrial 401874 6 Cases hypomagnesemia with dysfunction syndrome type 2 306516 200 Cases hypercalciuria and Fatal post-viral 391343 2 Cases nephrocalcinosis neurodegenerative disorder Familial primary FBLN1-related developmental hypomagnesemia with 404451 delay-central nervous system 3 Cases 2196 hypercalciuria and 72 Cases anomaly-syndactyly syndrome nephrocalcinosis with severe Febrile infection-related 163703 1.0 P * ocular involvement epilepsy syndrome Familial primary 1305 Feingold syndrome 123 Cases hypomagnesemia with 31043 hypercalciuria and 110 Cases 391641 Feingold syndrome type 1 120 Cases nephrocalcinosis without severe 391646 Feingold syndrome type 2 3 Cases ocular involvement Female infertility due to zona Familial primary 404466 4 Cases hypomagnesemia with pellucida defect 34527 5 Families Female restricted epilepsy with normocalciuria and 101039 5 Families normocalcemia intellectual disability Familial progressive cardiac 2019 Femur-fibula-ulna complex 1.5 BP * 871 50 Cases conduction defect Ferro-cerebro-cutaneous Familial progressive hyper- and 397922 3 Cases 280628 3 Families syndrome hypopigmentation Fetal akinesia deformation Familial reactive perforating 994 0.6 BP * 79147 50 Cases sequence collagenosis Fetal akinesia-cerebral and 363409 3 Cases 231108 Familial rhabdoid tumor 5 Families retinal hemorrhage syndrome Familial scaphocephaly 1915 Fetal alcohol syndrome 1.6 BP * 168624 11 Cases syndrome, McGillivray type Fetal and neonatal alloimmune 853 112.5 BP * 166282 Familial sick sinus syndrome 11 Cases thrombocytopenia Fetal cytomegalovirus Familial steroid-resistant 294 40.0 P * 280406 nephrotic syndrome with 13 Cases syndrome sensorineural deafness 85212 Fetal Gaucher disease 50 Cases Familial thoracic aortic 91387 22 Cases 1917 Fetal methylmercury syndrome 800 Cases aneurysm and aortic dissection 93953 Familial thyroglossal duct cyst 22 Cases 291 Fetal varicella syndrome 100 Cases Familial thyroid FGFR2-related bent bone 95716 4.0 P * 313855 4 Cases dyshormonogenesis dysplasia Familial thyroid 2021 Fibrochondrogenesis 13 Cases 95716 2.67 I dyshormonogenesis Fibrodysplasia ossificans 337 0.05 P 84 Fanconi anemia 0.3 P progressiva 84 Fanconi anemia 0.62 BP * 84090 Fibronectin glomerulopathy 16 Families 333 Farber disease 80 Cases 2030 Fibrosarcoma 0.01 I * FASTKD2-related infantile 1118 Fibular aplasia - ectrodactyly 50 Cases 166105 mitochondrial 2 Cases 1757 Fibular dimelia - diplopodia 11 Cases encephalomyopathy Fatal congenital hypertrophic 93323 Fibular hemimelia 2.0 P * 439854 10 Cases cardiomyopathy due to 3255 Filippi syndrome 32 Cases glycogen storage disease 1272 Fine-Lubinsky syndrome 5 Cases 466 Fatal familial insomnia 27 Cases Fatal infantile hypertonic Finger hyperphalangy-toe 280553 11 Cases 369979 2 Cases myofibrillar myopathy anomalies-severe pectus excavatum syndrome 97232 Fingerprint body myopathy 20 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 79292 Fish-eye disease 30 Cases 282 Frontotemporal dementia 3.0 P * 293812 Fixed pigmented erythema 19 Cases 2059 Fryns syndrome 7.0 BP * 98970 Fleck corneal dystrophy 30 Cases 247790 FTH1-related iron overload 4 Cases 2044 Floating-Harbor syndrome 87 Cases 349 Fucosidosis 100 Cases 2047 Flynn-Aird syndrome 10 Cases 2854 Fuhrmann syndrome 11 Cases 2092 Focal dermal hypoplasia 300 Cases 24 Fumaric aciduria 100 Cases Focal epilepsy-intellectual 352 Galactosemia 2.0 BP * 352587 disability-cerebro-cerebellar 7 Cases malformation 352 Galactosemia 2.1 I * 398166 Focal facial dermal dysplasia 147 Cases 351 Galactosialidosis 100 Cases Focal facial dermal dysplasia 79133 81 Cases 2065 Galloway-Mowat syndrome 60 Cases type I Gamma-aminobutyric acid Focal facial dermal dysplasia 2066 3 Families 398173 22 Cases transaminase deficiency type II Gamma-glutamyl Focal facial dermal dysplasia 33573 7 Cases 1807 20 Cases transpeptidase deficiency type III Gamma-glutamylcysteine Focal facial dermal dysplasia 33574 9 Cases 398189 21 Cases synthetase deficiency type IV 100026 Gamma-heavy chain disease 120 Cases 48918 Focal myositis 115 Cases 2067 GAPO syndrome 38 Cases Focal, segmental or multifocal 1866 11.7 P * dystonia 79665 Gardner syndrome 9.1 BP Focal, segmental or multifocal 1866 2.0 I * Gastric adenocarcinoma and dystonia 314022 proximal polyposis of the 28 Cases 2048 Foix-Chavany-Marie syndrome 150 Cases stomach Follicular cholangitis and 100075 Gastric endocrine tumor 3.2 P * 300552 5 Cases pancreatitis 44890 Gastrointestinal stromal tumor 13.0 P * 545 Follicular lymphoma 36.0 P * 44890 Gastrointestinal stromal tumor 1.0 I 228371 Foodborne botulism 0.1 I * 2368 Gastroschisis 23.7 BP * 3219 Fountain syndrome 8 Cases 355 Gaucher disease 1.0 P * Foveal hypoplasia - presenile 2253 11 Cases cataract 355 Gaucher disease 1.3 BP Foveal hypoplasia-optic nerve 355 Gaucher disease 1.7 I * 397618 decussation defect-anterior 7 Families segment dysgenesis syndrome Gaucher disease - 2072 ophthalmoplegia - 10 Cases 908 Fragile X syndrome 32.5 P cardiovascular calcification 137834 Frank-Ter Haar syndrome 5 Cases 77259 Gaucher disease type 1 1.0 P * 2052 Fraser syndrome 0.2 BP * 77260 Gaucher disease type 2 0.01 P * 347 Frasier syndrome 88 Cases 77261 Gaucher disease type 3 0.05 P * GCGR-related 834 Free sialic acid storage disease 130 Cases 438274 8 Cases hyperglucagonemia 2053 Freeman-Sheldon syndrome 100 Cases 79330 GCS1-CDG 3 Cases 85335 Fried syndrome 1 Family 2623 Geleophysic dysplasia 27 Cases 95 Friedreich ataxia 2.0 P * Generalized congenital 228429 22 Cases 1826 Frontometaphyseal dysplasia 100 Cases lipodystrophy with myopathy Frontonasal dysplasia with Generalized eruptive 228390 5 Cases 411777 40 Cases alopecia and genital anomaly keratoacanthoma Frontonasal dysplasia-severe 98497 Genetic peripheral neuropathy 40.0 P 306542 microphthalmia-severe facial 3 Cases 85201 Genitopatellar syndrome 22 Cases clefting syndrome 2077 5 Cases 391474 Frontorhiny 0.0 P German syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 2078 Geroderma osteodysplastica 50 Cases Glycogen storage disease due 137625 to muscle and heart glycogen 3 Cases 643 Giant axonal neuropathy 20 Families synthase deficiency Gingival fibromatosis - facial 2025 2 Cases Glycogen storage disease due dysmorphism 99849 to muscle beta-enolase 1 Case Gingival fibromatosis - deficiency 2027 2 Families progressive deafness Glycogen storage disease due 358 Gitelman syndrome 2.5 P * 371 to muscle phosphofructokinase 30 Cases deficiency Glaucoma - ectopia - Glycogen storage disease due 2084 microspherophakia - stiff joints - 3 Cases 715 to muscle phosphorylase kinase 30 Cases short stature deficiency 2085 Glaucoma - sleep apnea 5 Cases Glycogen storage disease due Glaucoma secondary to 713 to phosphoglycerate kinase 1 30 Families 238763 spherophakia/ectopia lentis and 4 Cases deficiency megalocornea Glycogen storage disease due 182067 Glial tumor 10.0 P * 97234 to phosphoglycerate mutase 50 Cases deficiency 360 1.0 P Glioblastoma Glycogen storage disease due 360 Glioblastoma 3.0 I 370 to phosphorylase kinase 1.0 BP * deficiency Global developmental delay - 73223 3 Cases osteopenia - ectodermal defect 354 GM1 gangliosidosis 0.75 BP * Global developmental delay- 79255 GM1 gangliosidosis type 1 200 Cases 404476 lung cysts-overgrowth-Wilms 2 Cases tumor syndrome 79256 GM1 gangliosidosis type 2 50 Cases 141163 Glossopalatine ankylosis 30 Cases 79257 GM1 gangliosidosis type 3 70 Cases 97280 Glucagonoma 0.005 I * 309246 GM2 gangliosidosis, AB variant 10 Cases Glutaryl-CoA dehydrogenase 25 1.0 BP 329984 Goblet cell carcinoma 0.025 I deficiency Goldberg-Shprintzen Glutathione synthetase 66629 8 Families 32 65 Cases megacolon syndrome deficiency 166272 Goldblatt syndrome 11 Cases 407 Glycine encephalopathy 0.17 P * 374 2.8 BP * Glycogen storage disease due Goldenhar syndrome 365 0.8 BP * to acid maltase deficiency 53540 Goldmann-Favre syndrome 50 Cases Glycogen storage disease due 1986 Gollop-Wolfgang complex 200 Cases 364 to glucose-6-phosphatase 1.0 BP Gómez-López-Hernández deficiency 1532 34 Cases Glycogen storage disease due syndrome 79258 1.0 BP * Gonadal dysgenesis, XY type - to glucose-6-phosphatase 1770 2 Cases deficiency type a associated anomalies Glycogen storage disease due 169105 Good syndrome 241 Cases 79259 to glucose-6-phosphatase 150 Cases 65798 3 Cases deficiency type b Goodman syndrome Glycogen storage disease due 73 300 Cases 2088 200 Cases Gorham-Stout disease to GLUT2 deficiency 377 Gorlin syndrome 1.1 P Glycogen storage disease due Gorlin-Chaudhry-Moss 367 to glycogen branching enzyme 0.1 BP 2095 7 Cases deficiency syndrome Glycogen storage disease due 39812 Graft versus host disease 2.3 P * 263297 1 Case to glycogenin deficiency 79094 Grange syndrome 7 Cases Glycogen storage disease due Granulomatosis with 2089 to hepatic glycogen synthase 16 Cases 900 9.0 P * deficiency polyangiitis Glycogen storage disease due Granulomatosis with 34587 84 Cases 900 0.7 I * to LAMP-2 deficiency polyangiitis Glycogen storage disease due 33111 Granulomatous slack skin 50 Cases 264580 to liver phosphorylase kinase 1.0 BP * 721 Gray platelet syndrome 60 Cases deficiency

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Grayson-Wilbrandt corneal 293375 1 Family 2130 Hemimelia 4.15 P * dystrophy 79230 Hemochromatosis type 2 74 Cases 1426 Greenberg dysplasia 10 Cases 225123 Hemochromatosis type 3 33 Cases 381 Griscelli disease 60 Cases 139491 200 Cases Growth and developmental Hemochromatosis type 4 delay-hypotonia-vision 391348 2 Cases 280615 Hemoglobinopathy Toms River 10 Cases impairment-lactic acidosis Hemolytic anemia due to syndrome 86817 12 Cases adenylate kinase deficiency Growth delay due to insulin- Hemolytic anemia due to 73272 like growth factor type 1 5 Cases 712 glucophosphate isomerase 50 Cases deficiency deficiency Growth retardation-mild Hemolytic anemia due to 391366 developmental delay-chronic 2 Cases 90030 glutathione reductase 3 Cases hepatitis syndrome deficiency 2102 GTP cyclohydrolase I deficiency 16 Cases 448 Hemophilia 7.7 P * Guanidinoacetate 382 80 Cases methyltransferase deficiency 448 Hemophilia 6.25 I * 2103 Guillain-Barré syndrome 3.5 P * 98878 Hemophilia A 4.85 P 2103 Guillain-Barré syndrome 1.45 I 98878 Hemophilia A 11.25 BP Gyrate atrophy of choroid and 98879 Hemophilia B 1.7 P * 414 200 Cases retina Hemorrhagic disease due to 168569 H syndrome 100 Cases 178396 alpha-1-antitrypsin Pittsburgh 3 Cases mutation 99803 Haddad syndrome 60 Cases 324632 Hendra virus infection 7 Cases 2342 Haim-Munk syndrome 100 Cases 2136 Hennekam syndrome 50 Cases Hair defect - photosensitivity - 1408 3 Cases intellectual disability 2135 Hennekam-Beemer syndrome 2 Cases 58017 Hairy cell leukemia 0.29 I * Hepatic amyloidosis with 102069 50 Cases intrahepatic cholestasis 2107 Hall-Riggs syndrome 8 Cases 890 Hepatic veno-occlusive disease 11.0 P * 2108 Hallermann-Streiff syndrome 150 Cases Hepatic veno-occlusive disease Hamel cerebro-palato-cardiac 79124 25 Cases 93946 4 Cases - immunodeficiency syndrome 449 Hepatoblastoma 0.02 I * 2116 Hartnup disease 4.2 P 88673 Hepatocellular carcinoma 15.0 P * Hartsfield-Bixler-Demyer 2117 6 Cases Hepatoerythropoietic syndrome 95159 40 Cases porphyria 99872 Hashimoto-Pritzker syndrome 50 Cases 91378 Hereditary angioedema 1.0 P * 2118 Hawkinsinuria 5 Families Hereditary breast and ovarian 145 25.0 P * 1354 Heart defects - limb shortening 2 Cases cancer syndrome Hereditary cerebral 1350 Heart-hand syndrome type 2 2 Families 85458 350 Cases hemorrhage with amyloidosis 1342 Heart-hand syndrome type 3 3 Cases 676 Hereditary chronic pancreatitis 0.43 P * Heart-hand syndrome, 168796 10 Cases Hereditary combined deficiency Slovenian type 98434 of vitamin K-dependent clotting 30 Families 2119 HEC syndrome 2 Cases factors Hereditary cryohydrocytosis 178330 Heinz body anemia 10 Cases 398088 53 Cases with normal stomatin Helicoid peripapillary 86813 100 Cases Hereditary cryohydrocytosis chorioretinal degeneration 168577 2 Cases with reduced stomatin Hematopoietic stem cell 90053 0.65 P * Hereditary diffuse gastric transplantation 26106 1.5 I * cancer Hemidystonia-hemiatrophy 306741 100 Cases syndrome Hemihyperplasia-multiple 276280 10 Cases lipomatosis syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Hereditary diffuse Hereditary sensory and 391397 3 Cases leukoencephalopathy with autonomic neuropathy type 7 313808 27 Cases axonal spheroids and Hereditary sensory and pigmented glia 139573 autonomic neuropathy with 4 Cases Hereditary folate deafness and global delay 90045 30 Cases malabsorption Hereditary sensory and 469 Hereditary fructose intolerance 5.0 P * 139578 autonomic neuropathy with 12 Cases spastic paraplegia Hereditary hemorrhagic 774 16.0 P * telangiectasia 685 Hereditary spastic paraplegia 5.0 P * Hereditary thrombocytosis with 3197 Hereditary hyperekplexia 150 Cases 329319 3 Families transverse limb defect Hereditary hyperferritinemia 163 64 Cases with congenital cataracts 71291 Hereditary vascular retinopathy 9 Families Hereditary hypotrichosis with 217407 4 Cases 3467 Hereditary xanthinuria 9.05 I * recurrent skin vesicles Heritable pulmonary arterial Hereditary inclusion body 275777 0.08 P * hypertension 79091 myopathy - joint contractures - 19 Cases ophthalmoplegia 79430 Hermansky-Pudlak syndrome 0.15 P Hereditary inclusion body Hermansky-Pudlak syndrome 324381 17 Cases 231531 2 Cases myopathy type 4 type 7 Hereditary leiomyomatosis and Hermansky-Pudlak syndrome 523 200 Cases 231537 6 Cases renal cell cancer type 8 Hereditary motor and sensory Hermansky-Pudlak syndrome 90117 120 Cases 280663 2 Cases neuropathy, Okinawa type type 9 Hermansky-Pudlak syndrome Hereditary myoclonus - 183678 8 Cases 2590 progressive distal muscular 10 Cases with neutropenia atrophy 63261 HERNS syndrome 2 Families Hereditary myopathy with 1930 0.3 I 43115 lactic acidosis due to ISCU 19 Cases Herpes simplex encephalitis deficiency 189 Hidrotic ectodermal dysplasia 1.0 P * Hereditary neurocutaneous Hidrotic ectodermal dysplasia, 1062 10 Families 1808 6 Cases angioma Christianson-Fourie type Hereditary neuropathy with Hidrotic ectodermal dysplasia, 640 3.5 P * 1809 4 Cases liability to pressure palsies Halal type 279943 Hereditary neutrophilia 16 Cases High bone mass osteogenesis 314029 2 Cases Hereditary North American imperfecta 168583 36 Cases Indian childhood cirrhosis High myopia-sensorineural 363396 7 Cases 30 Hereditary orotic aciduria 20 Cases deafness syndrome 388 Hirschsprung disease 10.9 BP * 79141 Hereditary painful callosities 2 Families Hirschsprung disease - deafness Hereditary 2155 2 Cases - polydactyly 29072 pheochromocytoma- 0.3 I Hirschsprung disease - type D paraganglioma 2150 4 Cases brachydactyly Hereditary progressive 158025 13 Cases Hirschsprung disease-nail mucinous histiocytosis 2153 3 Cases hypoplasia-dysmorphism Hereditary proximal myopathy 178464 10 Families with early respiratory failure 98293 Hodgkin lymphoma 2.4 I * Hereditary sclerosing 93970 Holmes-Gang syndrome 3 Cases 221043 poikiloderma with tendon and 15 Cases Holocarboxylase synthetase pulmonary involvement 79242 0.5 BP * deficiency Hereditary sensorimotor 280598 neuropathy with hyperelastic 4 Cases 2162 Holoprosencephaly 13.4 BP * skin 392 Holt-Oram syndrome 0.7 BP * Hereditary sensory and 139564 2 Families 2168 4 Cases autonomic neuropathy type 1B Homocarnosinosis Hereditary sensory and Homocystinuria without 970 35 Cases 622 73 Cases autonomic neuropathy type 2 methylmalonic aciduria Hereditary sensory and Homozygous familial 314381 4 Cases 391665 0.1 P autonomic neuropathy type 6 hypercholesterolemia

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Hoyeraal-Hreidarsson Hypergonadotropic 3322 33 Cases syndrome 2410 hypogonadism - cataract 3 Cases 85295 HSD10 disease, atypical type 5 Cases syndrome Hyperimmunoglobulinemia D 343 200 Cases 391457 HSD10 disease, neonatal type 3 Cases with periodic fever Hyperinsulinism due to HNF1A 228116 Hughes-Stovin syndrome 30 Cases 324575 2 Cases deficiency 3265 Humero-radial synostosis 150 Cases Hyperinsulinism due to INSR 263458 10 Cases 3266 Humero-radio-ulnar synostosis 30 Cases deficiency Hyperinsulinism due to short 94056 Humero-ulnar synostosis 5 Cases 71212 chain 3-hydroxylacyl-CoA 10 Cases Hunter-McAlpine 97340 10 Cases dehydrogenase deficiency craniosynostosis Hyperinsulinism due to UCP2 276556 2 Cases 399 Huntington disease 2.7 P deficiency 399 Huntington disease 0.38 I 682 Hyperkalemic periodic paralysis 0.5 P * Hyperkeratosis- 98934 Huntington disease-like 2 50 Families 1336 10 Cases hyperpigmentation syndrome Huntington disease-like 412 Hyperlipoproteinemia type 3 10.0 P 401901 syndrome due to C9ORF72 10 Cases expansions Hyperornithinemia- 415 hyperammonemia- 111 Cases 93473 Hurler syndrome 0.5 P * homocitrullinuria syndrome 93473 0.7 BP * Hurler syndrome 443098 Hyperostosis cranialis interna 13 Cases Hutchinson-Gilford progeria 740 0.005 P 238583 Hyperphenylalaninemia 0.2 P syndrome Hutchinson-Gilford progeria Hyperphosphatasia-intellectual 740 0.025 BP 247262 24 Cases syndrome disability syndrome Hydrocephalus - blue sclerae - Hyperplastic polyposis 2186 1 Family 157798 1.0 I nephropathy syndrome Hydrocephalus - costovertebral Hypertelorism - hypospadias - 2180 8 Cases 2211 3 Families dysplasia - Sprengel anomaly polysyndactyly syndrome Hydrocephalus - obesity - 1519 Hypertelorism, Teebi type 20 Cases 2183 2 Cases hypogonadism Hypertelorism-microtia-facial Hydrocephalus with stenosis of 2213 9 Cases 2182 1.7 P clefting syndrome the aqueduct of Sylvius Hypertelorism-preauricular Hydrocephalus with stenosis of 2182 1.7 BP 293958 sinus-punctual pits-deafness 13 Cases the aqueduct of Sylvius syndrome Hydrocephaly - tall stature - Hypertrichosis cubiti - short 2181 2 Cases 2220 28 Cases joint laxity stature Hyperammonemic Hypertrichosis lanuginosa 2222 100 Cases 401948 encephalopathy due to carbonic 4 Cases congenita anhydrase VA deficiency Hypertrichosis-acromegaloid Hyperandrogenism due to 966 20 Cases 168588 11 Cases facial appearance syndrome cortisone reductase deficiency Hypertrichotic 276405 Hyperbiliverdinemia 2 Cases 1517 osteochondrodysplasia, Cantu 40 Cases Hypercholesterolemia due to type 209902 cholesterol 7alpha-hydroxylase 24 Cases Hypertrophic cardiomyopathy deficiency 324525 and renal tubular disease due to 3 Cases Hypercoagulability syndrome mitochondrial DNA mutation due to 2224 Hypertryptophanemia 12 Cases 83639 2 Cases glycosylphosphatidylinositol Hyperuricemia - anemia - renal 217330 21 Cases deficiency failure 163985 Hyperekplexia - epilepsy 2 Cases Hyperuricemia-pulmonary 363694 hypertension-renal failure- 4 Families 168956 Hypereosinophilic syndrome 1.5 P * alkalosis syndrome Hypereosinophilic syndrome of 3260 10.0 P * 429 Hypochondroplasia 3.3 P * undetermined significance Hypocomplementemic 36412 200 Cases urticarial vasculitis

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Hypoglossia-hypodactyly Hypospadias - hypertelorism - 989 47 Cases 157788 2 Cases syndrome coloboma and deafness Hypogonadism - mitral valve Hypotonia with lactic acidemia 2233 2 Cases 137908 3 Cases prolapse - intellectual disability and hyperammonemia Hypogonadotropic Hypotonia-cerebral atrophy- 363424 2 Cases 2230 hypogonadism - frontoparietal 6 Cases hyperglycinemia syndrome alopecia 163690 Hypotonia-cystinuria syndrome 22 Cases Hypogonadotropic 2235 hypogonadism - retinitis 2 Cases 55654 Hypotrichosis simplex 38 Cases pigmentosa Hypotrichosis with juvenile 1573 50 Cases Hypogonadotropic macular degeneration hypogonadism-severe Hypotrichosis-deafness 330029 1 Case 293967 microcephaly-sensorineural 4 Cases syndrome hearing loss-dysmorphism Hypotrichosis-intellectual 2266 2 Cases syndrome disability, Lopes type Hypohidrosis-enamel Hypotrichosis-lymphedema- hypoplasia-palmoplantar 363523 12 Cases 69735 telangiectasia-renal defect 4 Cases keratoderma-intellectual syndrome disability syndrome 254509 Iatrogenic botulism 180 Cases Hypohidrotic ectodermal 238468 6.7 P * dysplasia 2268 ICF syndrome 66 Cases Hypohidrotic ectodermal Ichthyosis - alopecia - eclabion - 2269 4 Cases 1882 dysplasia - hypothyroidism - 3 Cases ectropion - intellectual disability ciliary dyskinesia Ichthyosis - Hypohidrotic ectodermal 2274 hepatosplenomegaly - 2 Cases 98813 dysplasia with 0.2 BP * cerebellar degeneration immunodeficiency Ichthyosis - hypotrichosis - 59303 12 Cases Hypoinsulinemic hypoglycemia 293964 5 Cases sclerosing cholangitis and body hemihypertrophy Ichthyosis - oral and digital 2272 2 Cases 681 Hypokalemic periodic paralysis 1.0 P * anomalies Hypomandibular faciocranial Ichthyosis follicularis - alopecia 1790 4 Cases 2273 40 Cases dysostosis - photophobia Hypomyelination - congenital Ichthyosis hystrix of Curth- 85163 10 Cases 79503 6 Families cataract Macklin Hypomyelination with atrophy Ichthyosis prematurity 139441 19 Cases 88621 16 Families of basal ganglia and cerebellum syndrome Ichthyosis-hypotrichosis Hypomyelination with brain 91132 4 Cases 363412 stem and spinal cord 10 Cases syndrome involvement and leg spasticity Ichthyosis-short stature- Hypomyelination- 363992 brachydactyly- 4 Cases hypogonadotropic- microspherophakia syndrome 88637 105 Cases hypogonadism-hypodontia 930 Idiopathic achalasia 8.0 P syndrome 930 Idiopathic achalasia 0.77 I Hypoparathyroidism - deafness 2237 12 Cases Idiopathic acute eosinophilic - renal disease 724 100 Cases pneumonia 436 Hypophosphatasia 0.21 BP * Idiopathic acute transverse 139423 0.25 I * Hypopigmentation-punctate myelitis 324561 palmoplantar keratoderma 6 Families Idiopathic and/or familial syndrome 422 pulmonary arterial 1.0 P * Hypoplastic left heart 2248 24.0 BP hypertension syndrome 88 Idiopathic aplastic anemia 0.4 P * Hypoplastic pancreas-intestinal 293864 atresia-hypoplastic gallbalder 16 Cases 2810 Idiopathic facial palsy 25.0 I syndrome Idiopathic neonatal atrial 45452 1.5 BP * Hypoplastic right heart 98723 3.3 BP * flutter syndrome Idiopathic pulmonary arterial 275766 1.1 P * Hyposmia - nasal and ocular hypertension 2250 hypoplasia - hypogonadotropic 2 Cases 2032 Idiopathic pulmonary fibrosis 16.7 P hypogonadism

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 2032 Idiopathic pulmonary fibrosis 3.81 I * Infantile hypertrophic 352563 cardiomyopathy due to MRPL44 2 Cases Idiopathic pulmonary 99931 0.0425 I * deficiency hemosiderosis 2591 Infantile myofibromatosis 0.67 BP * 90003 IgG4-related hepatopathy 140 Cases Infantile neuroaxonal IgG4-related retroperitoneal 35069 150 Cases 49041 0.35 I * dystrophy fibrosis Infantile onset panniculitis with Ileal pouch anal anastomosis 238621 3.0 P * 251304 uveitis and systemic 4 Cases related faecal incontinence granulomatosis 85173 IMAGe syndrome 25 Cases Infantile onset spinocerebellar 1186 24 Cases 42062 Iminoglycinuria 6.68 P * ataxia Infantile spams - psychomotor 42062 6.67 BP * Iminoglycinuria 263410 retardation - progressive brain 4 Cases Immune dysregulation- atrophy - basal ganglia disease 37042 polyendocrinopathy- 136 Cases Infantile-onset ascending 293168 17 Families enteropathy-X-linked syndrome hereditary spastic paralysis Immune thrombocytopenic 3002 25.0 P * Infantile-onset mesial temporal purpura 391316 lobe epilepsy with severe 3 Cases Immune thrombocytopenic cognitive regression 3002 6.75 I * purpura 247257 Inhalational anthrax 0.1 P * Immunodeficiency by defective 572 100 Cases expression of HLA class 2 254504 Inhalational botulism 10 Cases Immunodeficiency due to CD25 Inherited congenital spastic 169100 2 Cases 210141 5 Cases deficiency tetraplegia Immunodeficiency due to 79361 Inherited epidermolysis bullosa 0.8 P * 70592 interleukin-1 receptor- 15 Cases associated kinase-4 deficiency 79361 Inherited epidermolysis bullosa 1.9 BP * Immunodeficiency due to 63259 Iniencephaly 50.0 P * 70593 selective anti-polysaccharide 100 Cases 411593 404 Cases antibody deficiency Insulin autoimmune syndrome Immunodeficiency with factor I 97279 Insulinoma 0.25 I 200418 35 Families anomaly Intellectual disability - balding - Incessant infant ventricular 3041 5 Cases 45453 1.5 BP * patella luxation - acromicria tachycardia Intellectual disability - cataracts 171860 3 Cases 611 Inclusion body myositis 0.5 P * - kyphosis 464 Incontinentia pigmenti 0.7 BP * Intellectual disability - 329224 craniofacial dysmorphism - 2 Cases 98848 Indolent systemic mastocytosis 3.8 P * cryptorchidism Infant acute respiratory distress Intellectual disability - 70587 20.0 P * syndrome 3044 dysmorphism - hypogonadism - 4 Cases Infant acute respiratory distress diabetes mellitus 70587 3.5 I * syndrome Intellectual disability - 1495 hypoplastic corpus callosum - 3 Cases 178478 Infant botulism 0.2 BP * preauricular tag 178478 Infant botulism 0.3 I * Intellectual disability - Infant epilepsy with migrant 356996 hypotonia - spasticity - sleep 3 Cases 1943 29 Cases focal crisis disorder Infantile cerebellar-retinal Intellectual disability - obesity - 313850 11 Cases degeneration 352530 brain malformations - facial 2 Cases Infantile cerebral and dysmorphism cerebellar atrophy with Intellectual disability - sparse 402364 5 Cases 3051 61 Cases postnatal progressive hair - brachydactyly microcephaly Intellectual disability, Birk-Barel 166108 1 Family Infantile choroidocerebral type 1313 10 Cases calcification syndrome Intellectual disability-coarse 397709 7 Cases 199267 Infantile digital fibromatosis 200 Cases face-macrocephaly-cerebellar hypotrophy syndrome 238455 Infantile dystonia-parkinsonism 16 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Intellectual disability- Isolated 1048 35.0 BP * 3454 developmental delay- 5 Families anencephaly/exencephaly contractures syndrome 250923 Isolated aniridia 1.31 I * Intellectual disability- Isolated anophthalmia - 436151 expressive aphasia-facial 13 Cases 2542 5.3 BP * microphthalmia dysmorphism syndrome Isolated anorectal Intellectual disability-facial 557 20.0 BP malformation 404440 dysmorphism syndrome due to 7 Cases Isolated anterior cervical SETD5 haploinsufficiency 3387 20 Cases hypertrichosis Intellectual disability-facial 370010 dysmorphism-hand anomalies 3 Cases Isolated autosomal dominant 199326 21 Cases syndrome hypomagnesemia, Glaudemans type Intellectual disability-feeding Isolated cloverleaf skull 363611 difficulties-developmental 3 Cases 2343 120 Cases delay-microcephaly syndrome syndrome Intellectual disability- 79143 Isolated congenital anonychia 50 Cases 369847 5 Cases hyperkinetic movement-truncal 88620 Isolated congenital anosmia 15 Cases ataxia syndrome Intellectual disability- 91396 Isolated cryptophthalmia 30 Cases hypotonia-brachycephaly- Isolated Dandy-Walker 314575 2 Cases 217 2.1 P * pyloric stenosis-cryptorchidism malformation syndrome Isolated Dandy-Walker 217 1.0 BP * Intellectual disability-obesity- malformation 397973 prognathism-eye and skin 2 Cases 1885 Isolated ectopia lentis 90 Cases anomalies syndrome Isolated hereditary congenital Intellectual disability-seizures- 306527 8 Families facial paralysis 369837 hypotonia-ophthalmologic- 4 Cases skeletal anomalies syndrome 2345 Isolated Klippel-Feil syndrome 2.0 P * Intellectual disability-seizures- 2345 Isolated Klippel-Feil syndrome 0.6 BP * 369950 macrocephaly-obesity 7 Cases syndrome 718 Isolated Pierre Robin syndrome 5.0 BP * Intellectual disability-severe 2924 Isolated polycystic liver disease 1.0 P * 391372 speech delay-mild dysmorphism 10 Cases Isolated sedoheptulokinase syndrome 440713 2 Cases deficiency Intellectual disability- 363528 34 Cases strabismus syndrome 823 Isolated spina bifida 18.6 BP * Isolated succinate-CoQ 981 Internal carotid agenesis 100 Cases 3208 37 Cases reductase deficiency Interstitial granulomatous 79099 53 Cases dermatitis with arthritis 3366 Isolated trigonocephaly 6.7 BP * 182095 Interstitial lung disease 5.4 I * 2306 Isotretinoin-like syndrome 6 Cases 92050 Intestinal epithelial dysplasia 1.5 BP * 33 Isovaleric acidemia 1.0 P * Intestinal obstruction in the 439254 ITM2B amyloidosis 2 Families 314376 newborn due to guanylate 16 Cases cyclase 2C deficiency 435 Ito hypomelanosis 10.85 I * Intractable diarrhea - choanal 137622 3 Cases 2307 IVIC syndrome 4 Families atresia - eye anomalies 1540 Jackson-Weiss syndrome 200 Cases Intrahepatic cholestasis of 69665 1000.0 I * pregnancy 2308 Jacobsen syndrome 1.0 BP * Intrauterine growth restriction- 1873 Jalili syndrome 49 Cases 436144 short stature-early adult-onset 15 Cases diabetes syndrome 79139 Japanese encephalitis 0.65 I * Inverse Klippel-Trénaunay 329324 15 Cases 313795 Jawad syndrome 4 Cases syndrome Jervell and Lange-Nielsen 209981 IRIDA syndrome 74 Cases 90647 0.3 P syndrome 209943 IRVAN syndrome 30 Cases 474 Jeune syndrome 0.6 BP * 84142 Isaac syndrome 150 Cases 324999 JMP syndrome 3 Cases 229717 Isolated agammaglobulinemia 0.3 P

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 2315 Johanson-Blizzard syndrome 0.4 BP * 2329 Karsch-Neugebauer syndrome 10 Cases Joubert syndrome and related Karyomegalic interstitial 140874 1.1 BP 401996 12 Families disorders nephritis Joubert syndrome with hepatic 1454 8 Cases 2330 Kasabach-Merritt syndrome 300 Cases defect 2332 59 Cases Joubert syndrome with Jeune KBG syndrome 397715 8 Cases asphyxiating thoracic dystrophy KCNQ2-related epileptic 439218 11 Families Joubert syndrome with encephalopathy 2318 17 Cases oculorenal defect 480 Kearns-Sayre syndrome 2.0 P * Joubert syndrome with 2754 2 Families 2333 Kenny-Caffey syndrome 65 Cases orofaciodigital defect Keratoderma hereditarium 2319 Juberg-Hayward syndrome 10 Cases 79395 50 Cases mutilans with ichthyosis 93972 Juberg-Marsidi syndrome 16 Cases Keratosis follicularis - dwarfism 2339 6 Cases Junctional epidermolysis - cerebral atrophy 79403 100 Cases bullosa - pyloric atresia Keratosis palmaris et plantaris - 86919 20 Cases Junctional epidermolysis clinodactyly 79405 9 Cases bullosa inversa Ketamine-induced biliary 293807 2 Cases Junctional epidermolysis dilatation 79404 0.17 BP bullosa, Herlitz type Ketoacidosis due to 438075 9 Cases 1941 Juvenile absence epilepsy 7.5 I * monocarboxylate transporter-1 deficiency Juvenile cataract - microcornea 247794 12 Cases 85202 30 Cases - renal glucosuria Keutel syndrome 93672 Juvenile dermatomyositis 0.295 I 477 KID syndrome 100 Cases 248111 Juvenile Huntington disease 0.6 P * 50918 Kikuchi-Fujimoto disease 1052 Cases 248111 Juvenile Huntington disease 0.04 I * 482 Kimura disease 300 Cases 2028 Juvenile hyaline fibromatosis 50 Cases 2908 Kindler syndrome 250 Cases 92 Juvenile idiopathic arthritis 1.5 I * 261494 Kleefstra syndrome 114 Cases Juvenile myelomonocytic Kleefstra syndrome due to 86834 0.1 P * 96147 86 Cases leukemia 9q34 microdeletion Kleefstra syndrome due to a 2801 Juvenile Paget disease 50 Cases 261652 23 Cases point mutation 79076 Juvenile polyposis of infancy 11 Cases 90308 Klippel-Trénaunay syndrome 0.007 P * 2929 Juvenile polyposis syndrome 3.85 I * 96169 Koolen-De Vries syndrome 4.0 P * Juvenile primary lateral 247604 4 Cases Koolen-De Vries syndrome due sclerosis 363965 4 Cases to a point mutation 85436 Juvenile psoriatic arthritis 4.2 P * 99749 Kostmann syndrome 45 Cases Juvenile rheumatoid factor- 85408 8.0 P * 2351 5 Cases negative polyarthritis Kousseff syndrome Juvenile rheumatoid factor- Kozlowski-Brown-Hardwick 85435 4.2 P * 2352 2 Cases positive polyarthritis syndrome 26137 Juvenile temporal arteritis 20 Cases 487 Krabbe disease 1.0 P * Juvenile-onset diabetes 487 Krabbe disease 0.7 BP 445062 5 Cases mellitus-central and peripheral KRT14-related epidermolysis 89838 19 Cases neurodegeneration syndrome bullosa simplex 2322 3.1 P * Kabuki syndrome 79314 L-2-hydroxyglutaric aciduria 140 Cases 2324 Kaler-Garrity-Stern syndrome 2 Cases L-Arginine:glycine 35704 9 Cases amidinotransferase deficiency 478 Kallmann syndrome 3.75 P * 440731 2 Cases Kallmann syndrome - heart L-ferritin deficiency 2326 8 Cases Lacrimoauriculodentodigital disease 2363 20 Cases syndrome 33276 Kaposi sarcoma 0.34 I * 501 Lafora disease 300 Cases 2328 Kapur-Toriello syndrome 4 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families LAMB2-related infantile-onset 306507 14 Cases 548 Leprosy 3.7 I nephrotic syndrome 509 0.1 I * Lambert-Eaton myasthenic Leptospirosis 43393 0.35 P syndrome 510 Lesch-Nyhan syndrome 0.34 BP * 313 Lamellar ichthyosis 0.55 P * Lethal acantholytic 158687 4 Cases Laminopathy type Decaudain- epidermolysis bullosa 137871 9 Cases Lethal arteriopathy syndrome Vigouroux 314718 22 Cases due to fibulin-4 deficiency 2632 Langer mesomelic dysplasia 50 Cases Lethal ataxia with deafness and 1187 2 Families 502 Langer-Giedion syndrome 100 Cases optic atrophy 389 Langerhans cell histiocytosis 1.5 P * Lethal encephalopathy due to 330050 mitochondrial and peroxisomal 1 Case Large congenital melanocytic 626 2.75 P * fission defect nevus Lethal faciocardiomelic 1972 3 Cases 633 Laron syndrome 0.3 P * dysplasia Laron syndrome with 220465 10 Cases Lethal fetal brain immunodeficiency malformation-duodenal atresia- 444069 4 Cases Laryngeal abductor paralysis - bilateral renal hypoplasia 2375 20 Cases intellectual disability syndrome Laryngo-tracheo-esophageal Lethal fetal 2004 7.5 BP * cleft 439897 cerebrorenogenitourinary 2 Cases Laryngo-tracheo-esophageal agenesis/hypoplasia syndrome 93940 30 Cases cleft type 3 Lethal hemolytic anemia - 1046 2 Cases Laryngo-tracheo-esophageal genital anomalies 93941 20 Cases cleft type 4 2347 Lethal Kniest-like dysplasia 2 Cases Late-onset focal dermal 228227 5 Cases 2371 Lethal Larsen-like syndrome 10 Cases elastosis Late-onset junctional Lethal multiple pterygium 79406 37 Cases 33108 28 Families epidermolysis bullosa syndrome Late-onset localized junctional Lethal neonatal spasticity- 231556 epidermolysis bullosa - 2 Cases 435845 epileptic encephalopathy 8 Cases intellectual disability syndrome Lethal occipital encephalocele- 2789 Lateral meningocele syndrome 14 Cases 293925 4 Cases skeletal dysplasia syndrome 46059 Lathosterolosis 4 Cases Lethal omphalocele-cleft palate 2736 3 Cases 650 LCAT deficiency 125 Cases syndrome Lethal osteosclerotic bone 1832 8 Families 330015 Lead poisoning 2.3 P * dysplasia Lethal polymalformative 65 Leber congenital amaurosis 2.5 P 210144 8 Cases syndrome, Boissel type 65 2.5 BP Leber congenital amaurosis Lethal recessive 1423 4 Cases Leber hereditary optic 104 4.3 P chondrodysplasia neuropathy 99870 Letterer-Siwe disease 0.2 P * 99718 Leber plus disease 0.04 P * 2968 Leukocyte adhesion deficiency 350 Cases 549 1.1 I * Legionellosis Leukocyte adhesion deficiency 99842 0.1 P * 137605 Legius syndrome 2.2 BP type I Leukocyte adhesion deficiency 506 Leigh syndrome 2.8 BP * 99843 10 Cases type II 507 Leishmaniasis 0.1 P * Leukocyte adhesion deficiency 99844 17 Cases type III 507 Leishmaniasis 25.0 I Leukoencephalopathy - 163684 2 Cases 140936 Lelis syndrome 8 Cases dystonia - motor neuropathy Leukoencephalopathy - 137839 Lemierre syndrome 10.0 I * 83629 4 Cases metaphyseal chondrodysplasia 2382 Lennox-Gastaut syndrome 15.0 P * Leukoencephalopathy with 2382 Lennox-Gastaut syndrome 0.1 I * 139444 bilateral anterior temporal lobe 29 Cases cysts Lenz-Majewski hyperostotic 2658 10 Cases dwarfism

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Leukoencephalopathy with Lissencephaly due to TUBA1A 171680 15 Cases 137898 brain stem and spinal cord 127 Cases mutation involvement - high lactate Lissencephaly type 3 - familial 86821 5 Cases Leukoencephalopathy with fetal akinesia sequence 363540 mild cerebellar ataxia and white 6 Cases Lissencephaly type 3 - 86822 2 Cases matter edema metacarpal bone dysplasia Leukoencephalopathy-ataxia- Lissencephaly with cerebellar 100012 50 Cases 137639 hypodontia-hypomyelination 8 Cases hypoplasia type B syndrome Lissencephaly with cerebellar 100013 10 Cases Leukoencephalopathy- hypoplasia type C 2386 palmoplantar keratoderma 4 Cases 533 Listeriosis 0.337 I syndrome LMNA-related cardiocutaneous Leukoencephalopathy- 363618 5 Cases 314051 thalamus and brainstem 12 Cases progeria syndrome anomalies-high lactate 2407 LOC syndrome 50 Cases Leukonychia totalis - 93685 Localized Castleman disease 1.0 P 210133 acanthosis-nigricans-like lesions 11 Cases - abnormal hair Localized junctional 251393 epidermolysis bullosa, non- 20 Cases 48162 0.9 P * Lewis-Sumner syndrome Herlitz type 65285 Lhermitte-Duclos disease 220 Cases Localized lichen 90398 myxedematosus with mixed 10 Cases 524 Li-Fraumeni syndrome 6.0 P features of different subtypes 525 Lichen planopilaris 300 Cases Localized lichen myxedematosus with 254478 Lichen planus pemphigoides 100 Cases 90399 5 Cases monoclonal gammopathy or 2390 Lichstenstein syndrome 2 Cases systemic symptoms 526 Liddle syndrome 80 Cases 2406 Locked-in syndrome 33 Cases 99812 LIG4 syndrome 27 Cases 60030 Loeys-Dietz syndrome 52 Families Long chain 3-hydroxyacyl-CoA 97231 Ligneous conjunctivitis 200 Cases 5 1.0 BP * dehydrogenase deficiency Limb-girdle muscular dystrophy Lower motor neuron syndrome 445110 2 Cases 276435 31 Cases due to POMK deficiency with late-adult onset 69085 27 Cases Limb-mammary syndrome 2409 Lowry-MacLean syndrome 3 Cases 171673 3.0 P * Limbal stem cell deficiency 1824 Lowry-Wood syndrome 10 Cases Limbic encephalitis with DPP6 Lung agenesis - heart defect - 329341 4 Cases 1120 9 Cases antibodies thumb anomalies 220407 Limited systemic sclerosis 200 Cases Lung fibrosis - 137631 2 Cases 140933 Linear atrophoderma of Moulin 30 Cases immunodeficiency - 46,XX gonadal dysgenesis 228236 Linear focal dermal elastosis 30 Cases 90283 Lupus erythematosus tumidus 250 Cases Linear nevus sebaceus 2612 10.0 BP * 91546 21.9 I syndrome Lyme disease LIPE-related familial partial 538 0.15 P 435660 2 Cases Lymphangioleiomyomatosis lipodystrophy 538 Lymphangioleiomyomatosis 0.0135 I Lipodystrophy - intellectual 50811 3 Cases disability - deafness 2415 Lymphatic malformation 12.5 P * Lipodystrophy due to peptidic Lymphedema - atrial septal 1979 1 Family 86915 3 Cases growth factors deficiency defects - facial changes Lipoic acid synthetase Lymphedema - cerebral 401859 3 Cases 86914 5 Cases deficiency arteriovenous anomaly 530 300 Cases Macrocephaly - short stature - Lipoid proteinosis 2427 2 Cases paraplegia 69078 Liposarcoma 1.0 I * Macrocephaly-autism 210548 40 Cases 401862 Lipoyl transferase 1 deficiency 2 Cases syndrome Lisch epithelial corneal Macrostomia - preauricular 98955 36 Cases 83619 9 Cases dystrophy tags - external ophthalmoplegia

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Macular coloboma-cleft palate- 91494 2 Cases 99826 Marburg hemorrhagic fever 500 Cases hallux valgus 2461 50 Cases Maculopapular cutaneous Marden-Walker syndrome 79457 450.0 BP * mastocytosis 558 Marfan syndrome 15.0 P 137867 200 Cases Madras motor neuron disease 558 Marfan syndrome 25.0 I * 163634 Maffucci syndrome 250 Cases Marfanoid habitus - inguinal 314041 2 Cases hernia - advanced bone age 77297 Majeed syndrome 4 Families 559 Marinesco-Sjögren syndrome 200 Cases 87503 Mal de Meleda 1.0 P 560 Marshall syndrome 17 Cases 420179 Malan overgrowth syndrome 20 Cases 561 Marshall-Smith syndrome 33 Cases 673 Malaria 3.0 P * 98292 Mastocytosis 9.0 P * 673 Malaria 73.0 I Maternal 14q32.2 Male hypergonadotropic 254534 3 Cases hypermethylation syndrome 2234 hypogonadism - intellectual 2 Cases Maternal 14q32.2 disability - skeletal anomalies 254528 6 Cases microdeletion syndrome 679 Malignant atrophic papulosis 200 Cases 2209 Maternal phenylketonuria 10.0 I * Malignant germ cell tumor of 35807 0.08 I * ovary 411712 Maternal riboflavin deficiency 1 Case Malignant hyperthermia - Maternally-inherited 2215 4 Cases arthrogryposis - torticollis 1349 cardiomyopathy and hearing 2 Families Malignant melanoma of the loss 168999 0.26 I * mucosa Maternally-inherited diabetes 225 0.1 P * Malignant migrating partial and deafness 293181 94 Cases seizures of infancy 2470 Matthew-Wood syndrome 40 Cases Malignant peripheral nerve Mayer-Rokitansky-Küster- 3148 1.0 I 3109 11.0 BP sheath tumor Hauser syndrome Malignant peritoneal Mayer-Rokitansky-Küster- 168811 1.5 P * 2578 1.0 BP * mesothelioma Hauser syndrome type 2 Malignant sex cord stromal 35808 1.85 P * 57782 Mazabraud syndrome 54 Cases tumor of ovary Malignant sex cord stromal 562 McCune-Albright syndrome 0.55 P * 35808 0.13 I * tumor of ovary 2473 McKusick-Kaufman syndrome 90 Cases 252212 Malignant triton tumor 170 Cases McLeod neuroacanthocytosis Malignant tumor of fallopian 59306 100 Cases 180242 1.0 P * syndrome tubes 3097 Meacham syndrome 15 Cases 398043 Malignant tumor of penis 1.075 I * 564 Meckel syndrome 4.0 BP 943 Malonic aciduria 34 Cases 70588 Meconium aspiration syndrome 2.44 P * 52417 MALT lymphoma 4.0 P * 2006 Median cleft lip/mandibule 70 Cases 52417 MALT lymphoma 0.3 I * 2699 Median nodule of the upper lip 3 Families Mammary-digital-nail 238744 11 Cases syndrome 370127 Medich giant platelet syndrome 3 Cases 397941 7 Cases Medium chain acyl-CoA MAN1B1-CDG 42 6.85 P Mandibular hypoplasia- dehydrogenase deficiency 363649 4 Cases Medium chain acyl-CoA deafness-progeroid syndrome 42 12.0 BP * dehydrogenase deficiency 2457 Mandibuloacral dysplasia 40 Cases 171851 MEDNIK syndrome 4 Families Mandibulofacial dysostosis - 357158 2 Cases macroblepharon - macrostomia 1332 Medullary thyroid carcinoma 7.0 P * Mandibulofacial dysostosis 443995 4 Cases 1332 Medullary thyroid carcinoma 0.22 I * with alopecia Mandibulofacial dysostosis- 616 Medulloblastoma 1.0 P * 79113 60 Cases microcephaly syndrome 616 Medulloblastoma 0.11 I * 52416 Mantle cell lymphoma 3.5 P * 98954 Meesmann corneal dystrophy 250 Cases 511 Maple syrup urine disease 0.67 BP

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Megacystis-microcolon- Metaphyseal chondrodysplasia 166035 2 Cases 2241 intestinal hypoperistalsis 230 Cases - retinitis pigmentosa syndrome Metaphyseal chondrodysplasia, 33067 16 Cases Megalencephalic Jansen type 2478 leukoencephalopathy with 100 Cases Metaphyseal chondrodysplasia, 166038 2 Cases subcortical cysts Kaitila type Megalencephaly - Metaphyseal dysplasia - 83473 polymicrogyria - postaxial 6 Cases 2504 maxillary hypoplasia - 2 Families polydactyly - hydrocephalus brachydacty Megalencephaly-capillary 2635 Metatropic dysplasia 81 Cases 60040 malformation-polymicrogyria 170 Cases syndrome 1923 Methimazole embryofetopathy 40 Cases Methylcobalamin deficiency 352328 MEGDEL syndrome 20 Cases 2169 27 Cases type cblE 85282 MEHMO syndrome 8 Cases Methylcobalamin deficiency 2170 33 Cases 2484 Melnick-Needles syndrome 70 Cases type cblG Methylmalonic acidemia with 2485 Melorheostosis 0.09 P * 26 500 Cases homocystinuria Melorheostosis with Methylmalonic acidemia with 1879 5 Families 79284 15 Cases osteopoikilosis homocystinuria type cblF 401973 MEND syndrome 19 Cases Methylmalonic acidemia with 79282 500 Cases Mendelian susceptibility to homocystinuria, type cblC mycobacterial diseases due to Methylmalonic acidemia with 319547 12 Cases 79283 17 Cases complete IFNgammaR2 homocystinuria, type cblD deficiency Methylmalonic acidemia with 369955 2 Cases Mendelian susceptibility to homocystinuria, type cblJ 319558 mycobacterial diseases due to 49 Cases Methylmalonic acidemia with 369962 18 Cases complete IL12B deficiency homocystinuria, type cblX Mendelian susceptibility to Methylmalonic aciduria due to 280183 5 Cases 319552 mycobacterial diseases due to 140 Cases transcobalamin receptor defect complete IL12RB1 deficiency 29 Mevalonic aciduria 30 Cases Mendelian susceptibility to 319563 mycobacterial diseases due to 3 Cases 79329 MGAT2-CDG 4 Cases complete ISG15 deficiency 2510 Micro syndrome 203 Cases Mendelian susceptibility to Microbrachycephaly - ptosis - 319600 mycobacterial diseases due to 2 Cases 2511 2 Cases cleft lip partial IRF8 deficiency Microcephalic osteodysplastic Mendelian susceptibility to 85172 4 Cases dysplasia, Saul-Wilson type 319595 mycobacterial diseases due to 8 Cases Microcephalic osteodysplastic partial STAT1 deficiency 2637 150 Cases primordial dwarfism type II 2495 0.15 I * Meningioma Microcephalic osteodysplastic 565 Menkes disease 0.33 BP * 2636 primordial dwarfism types I and 30 Cases III Mesoaxial synostotic 157801 syndactyly with phalangeal 6 Families Microcephalic primordial 329228 7 Cases reduction dwarfism due to ZNF335 deficiency Mesomelia-synostoses 2496 5 Cases syndrome Microcephalic primordial 436182 dwarfism-insulin resistance 2 Cases Mesomelic dysplasia, 1836 5 Families syndrome Kantaputra type Microcephaly - albinism - digital 2513 2 Cases 2499 Metachondromatosis 25 Cases anomalies Microcephaly - brachydactyly - 512 Metachromatic leukodystrophy 0.1 P * 3433 3 Cases kyphoscoliosis 512 Metachromatic leukodystrophy 1.47 BP * Microcephaly - cardiac defect - 2516 3 Cases 512 Metachromatic leukodystrophy 1.5 I * lung malsegmentation Metaphyseal 2515 Microcephaly - cardiomyopathy 3 Cases 1240 4 Cases acroscyphodysplasia 2521 Microcephaly - cleft palate 3 Cases 1040 Metaphyseal anadysplasia 27 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Microcephaly - digital 83463 Microtia 15.5 BP 137653 anomalies - intellectual 2 Cases Microtia-eye coloboma- disability 139450 imperforation of the 1 Family Microcephaly - facio-cardio- nasolacrimal duct 217026 skeletal syndrome, 5 Cases Hadziselimovic type 2290 Microvillus inclusion disease 137 Cases Microcephaly - 2557 Mietens syndrome 9 Cases 2172 glomerulonephritis - marfanoid 2 Cases habitus 2558 Mikati-Najjar-Sahli syndrome 5 Cases Microcephaly - intellectual 169799 Mild hemophilia B 0.6 P * 137658 disability - phalangeal and 3 Cases 531 1.0 BP * neurological anomalies Miller-Dieker syndrome Microcephaly - lymphedema - 98919 Miller-Fisher syndrome 0.1 I * 2526 50 Families chorioretinopathy Minimal pigment Microcephaly - polymicrogyria - 352734 10 Cases 171703 4 Cases oculocutaneous albinism type 1 corpus callosum agenesis Mirror polydactyly - vertebral 3004 0.3 P * Microcephaly - seizures - segmentation - limbs defects 2519 2 Cases intellectual disability - heart MITF-related melanoma and disease 293822 renal cell carcinoma 30 Families Microcephaly-capillary 294016 10 Cases predisposition syndrome malformation syndrome Mitochondrial DNA deletion Microcephaly-cerebellar 352470 syndrome with progressive 4 Cases 329332 hypoplasia-cardiac conduction 4 Cases myopathy defect syndrome Mitochondrial DNA depletion Microcephaly-complex motor syndrome, encephalomyopathic 423894 3 Cases 1933 2 Cases and sensory axonal neuropathy form with methylmalonic Microcephaly-short stature- aciduria 423306 intellectual disability-facial 2 Cases Mitochondrial DNA depletion dysmorphism syndrome syndrome, encephalomyopathic 369897 20 Cases Microcephaly-thin corpus form with variable craniofacial 397951 callosum-intellectual disability 4 Cases anomalies syndrome Mitochondrial DNA depletion Microcornea - posterior 363534 syndrome, hepatocerebrorenal 3 Cases 231736 megalolenticonus - persistent 8 Cases form fetal vasculature - coloboma Mitochondrial DNA depletion 254875 45 Cases Microcornea-myopic syndrome, myopathic form 369970 chorioretinal atrophy- 14 Cases Mitochondrial hypertrophic telecanthus syndrome 314637 cardiomyopathy with lactic 8 Cases Microcytic anemia with liver 83642 3 Cases acidosis due to MTO1 deficiency iron overload Mitochondrial membrane Microduplication Xp11.22- 289560 0.1 P 217377 12 Cases protein-associated p11.23 syndrome neurodegeneration Microgastria - limb reduction Mitochondrial myopathy and 2538 16 Cases 2598 7 Cases defect sideroblastic anemia Microlissencephaly - 50810 2 Cases Mitochondrial micromelia 298 neurogastrointestinal 0.1 P * 77299 Microphthalmia - brain atrophy 3 Cases encephalomyopathy Microphthalmia - retinitis Mitochondrial oxidative 2443 9.0 P * 251279 pigmentosa - foveoschisis - optic 4 Cases phosphorylation disorder due to nuclear DNA anomalies disc drusen Mitochondrial trifunctional Microphthalmia with brain and 746 100 Cases 139471 2 Families protein deficiency digit anomalies Microphthalmia with limb Möbius syndrome - axonal 1106 35 Families 2560 neuropathy - hypogonadotropic 7 Cases anomalies hypogonadism Microphthalmia with linear skin 2556 55 Cases Moderate and severe traumatic defects syndrome 90056 37.8 P * brain injury 58220 6.0 I * Microscopic colitis Moderately severe hemophilia 169796 0.6 P * 727 Microscopic polyangiitis 1.0 I * B

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 570 Moebius syndrome 300 Cases 53271 Muenke syndrome 1.8 BP * 52368 Mohr-Tranebjaerg syndrome 91 Cases 587 Muir-Torre syndrome 205 Cases 2563 MOMO syndrome 8 Cases 2576 MULIBREY nanism 140 Cases Monoclonal Ig light chain- Müllerian derivatives - 91136 100 Cases 1655 3 Cases associated Fanconi syndrome lymphangiectasia - polydactyly Monocytopenia with 228423 22 Cases 93686 Multicentric Castleman disease 100 Cases susceptibility to infections Multicentric osteolysis- Mononen-Karnes-Senac 371428 50 Cases 2565 5 Cases nodulosis-arthropathy spectrum syndrome Multicentric 139436 200 Cases 77301 Monosomy 9q22.3 30 Cases reticulohistiocytosis 1598 Monosomy 18p 200 Cases 1851 Multicystic dysplastic kidney 23.26 BP 574 Monosomy 21 50 Cases 3282 Multifocal atrial tachycardia 0.67 BP 48652 Monosomy 22q13 200 Cases 641 Multifocal motor neuropathy 1.5 P Multinodular goiter - cystic 261476 Monosomy Xp21 100 Cases 2091 3 Cases kidney - polydactyly 96061 3.0 I * Mosaic trisomy 8 Multiple congenital anomalies - 280633 10 Cases Mosaic variegated aneuploidy hypotonia - seizures syndrome 1052 41 Cases syndrome Multiple congenital anomalies Motor developmental delay 254519 due to 14q32.2 maternally 26 Cases 254516 due to 14q32.2 paternally 26 Cases expressed gene defect expressed gene defect Multiple congenital anomalies- 3347 Mounier-Kühn syndrome 300 Cases 300496 hypotonia-seizures syndrome 5 Cases type 2 2152 Mowat-Wilson syndrome 1.7 BP * Multiple endocrine neoplasia 652 3.3 P * Moyamoya angiopathy-short type 1 stature-facial dysmorphism- Multiple endocrine neoplasia 280679 9 Cases 653 2.9 P * hypergonadotropic type 2 hypogonadism 251 Multiple epiphyseal dysplasia 5.0 P * 2573 Moyamoya disease 0.035 I * Multiple epiphyseal dysplasia, Moyamoya disease with early- 166024 4 Cases 401945 9 Cases Al-Gazali type onset achalasia Multiple epiphyseal dysplasia, 166011 1 Family 79323 MPDU1-CDG 7 Cases Beighton type Multiple epiphyseal dysplasia, 79319 MPI-CDG 20 Cases 166032 2 Cases with miniepiphyses 263347 MRCS syndrome 7 Cases Multiple epiphyseal dysplasia, 166029 3 Cases 100024 Mu-heavy chain disease 35 Cases with severe proximal femoral dysplasia 575 Muckle-Wells syndrome 200 Cases 29073 Multiple myeloma 11.9 P * 576 Mucolipidosis type II 0.84 BP * 29073 Multiple myeloma 6.0 I 577 Mucolipidosis type III 1.0 BP * Multiple paragangliomas 324299 2 Cases Mucolipidosis type III associated with polycythemia 423461 13.0 P alpha/beta Multiple sclerosis - ichthyosis - 3151 2 Cases 579 Mucopolysaccharidosis type 1 8.0 P * factor VIII deficiency Multiple self-healing squamous 65748 100 Cases 579 Mucopolysaccharidosis type 1 0.82 BP epithelioma 580 Mucopolysaccharidosis type 2 6.7 P * 585 Multiple sulfatase deficiency 50 Cases 580 Mucopolysaccharidosis type 2 0.68 BP 3237 Multiple synostoses syndrome 30 Families Mucopolysaccharidosis type 2, 217085 0.4 BP * 102 Multiple system atrophy 3.5 P severe form 102 Multiple system atrophy 1.8 I 581 Mucopolysaccharidosis type 3 0.87 BP * Multiple system atrophy, 98933 2.4 P * 583 Mucopolysaccharidosis type 6 0.16 BP * parkinsonian type 584 0.01 P * Multisystemic smooth muscle Mucopolysaccharidosis type 7 404463 7 Cases dysfunction syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Muscle-eye-brain disease with 255229 Navajo neurohepatopathy 49 Cases 370997 bilateral multicystic 2 Cases Nebulin-related early-onset leucodystrophy 399103 4 Families distal myopathy Muscular atrophy - ataxia - 2579 retinitis pigmentosa - diabetes 10 Cases 607 Nemaline myopathy 2.0 BP * mellitus Neonatal acute respiratory 217563 0.067 BP Muscular dystrophy with distress due to SP-B deficiency 424261 progressive weakness, distal 3 Cases Neonatal antiphospholipid 398097 34 Cases contractures and rigid spine syndrome Muscular dystrophy, Selcen Neonatal autoimmune 199340 12 Cases 398109 2 Cases type hemolytic anemia Muscular hypertrophy - 324416 2 Cases 398117 Neonatal dermatomyositis 3 Cases hepatomegaly - polyhydramnios Neonatal diabetes - congenital Mutilating palmoplantar hypothyroidism - congenital 659 keratoderma with periorificial 73 Cases 79118 2 Cases glaucoma - hepatic fibrosis - keratotic plaques polycystic kidneys 589 Myasthenia gravis 7.77 P 224 Neonatal diabetes mellitus 1.1 BP * 589 Myasthenia gravis 0.53 I 446 Neonatal hemochromatosis 35 Cases Mycophenolate mofetil 268249 25 Cases Neonatal inflammatory skin embryopathy 294023 2 Cases and bowel disease 178566 Mycosis fungoides and variants 0.59 I * 398127 Neonatal scleroderma 6 Cases 52688 Myelodysplastic syndrome 1.5 I * 94058 Neovascular glaucoma 24.4 P * Myelofibrosis with myeloid 824 3.0 P * metaplasia 654 Nephroblastoma 10.0 BP * Myelofibrosis with myeloid 654 0.14 I * 824 1.0 I * Nephroblastoma metaplasia 223 Nephrogenic diabetes insipidus 0.15 P * MYH7-related late-onset Nephrogenic syndrome of 437572 scapuloperoneal muscular 12 Cases 93606 21 Cases dystrophy inappropriate antidiuresis Nephropathy-deafness- 182050 MYH9-related disease 0.3 P * 2668 5 Cases hyperparathyroidism syndrome 2588 Myhre syndrome 21 Cases Nephrosis - deafness - urinary 2669 5 Cases 86909 Myoclonic epilepsy of infancy 106 Cases tract - digital malformations Nephrotic syndrome-deafness- Myoclonus-cerebellar ataxia- 2589 4 Cases 300333 pretibial epidermolysis bullosa 3 Cases deafness syndrome syndrome Myopathy due to calsequestrin 88635 4 Cases Nestor-Guillermo progeria and SERCA1 protein overload 280576 2 Cases syndrome 206647 Myotonic dystrophy 6.7 P 634 Netherton syndrome 0.5 P * 99967 Myxoid/round cell liposarcoma 0.1 I * 634 Netherton syndrome 0.5 BP * 2608 N syndrome 3 Cases 2671 Neu-Laxova syndrome 72 Cases Naegeli-Franceschetti- 69087 0.035 P * Jadassohn syndrome 3388 Neural tube defect 91.05 BP * 245 Nager syndrome 110 Cases 635 Neuroblastoma 11.0 P * Nail and teeth abnormalities- 635 Neuroblastoma 5.8 BP * marginal palmoplantar 423454 6 Cases 635 1.26 I keratoderma-oral Neuroblastoma hyperpigmentation syndrome 2481 Neurocutaneous melanocytosis 1.25 P * 2613 Nail-patella-like renal disease 3 Cases Neurodegeneration due to 3- 88639 4 Cases 2615 Nakajo-Nishimura syndrome 30 Cases hydroxyisobutyryl-CoA hydrolase deficiency 627 Nance-Horan syndrome 50 Families Neurodegeneration with brain 385 0.2 P * 2073 Narcolepsy-cataplexy 25.0 P * iron accumulation Neurodegenerative syndrome Nasopalpebral lipoma - 2399 30 Cases 217382 due to cerebral folate transport 3 Cases coloboma - telecanthus deficiency

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Neuroectodermal 33445 20 Cases 357034 Non-hereditary retinoblastoma 0.038 I * melanolysosomal disease 547 11.6 I * Neuroectodermal-endocrine Non-Hodgkin lymphoma 2676 4 Cases Non-hypoproteinemic syndrome 329883 1 Family hypertrophic gastropathy 157846 Neuroferritinopathy 50 Cases 363999 Non-immune hydrops fetalis 42.0 BP 636 Neurofibromatosis type 1 21.3 P * 90061 Non-infectious posterior uveitis 18.0 P * 636 Neurofibromatosis type 1 33.3 BP Non-papillary transitional cell 209989 37.0 P * 637 Neurofibromatosis type 2 1.7 P * carcinoma of the bladder Neurogenic arthrogryposis Non-progressive cerebellar 1143 4.3 BP * multiplex congenita 314647 ataxia with intellectual 15 Cases Neuroleptic malignant disability 94093 15.0 P * syndrome Non-seminomatous germ cell 363494 1.21 I * Neuroleptic malignant tumor of testis 94093 170.0 I syndrome Non-spherocytic hemolytic Neurologic Waardenburg-Shah 90031 anemia due to hexokinase 17 Families 163746 30 Cases syndrome deficiency Neurometabolic disorder due 35705 30 Cases 648 Noonan syndrome 70.0 BP * to serine deficiency Noonan syndrome with 500 296 Cases 71211 Neuromyelitis optica 1.5 P * multiple lentigines Neuropathy with hearing Noonan syndrome-like disorder 139512 1 Family 2701 27 Cases impairment with loose anagen hair 165 Neutral lipid storage disease 50 Cases 649 Norrie disease 400 Cases North Carolina macular 98908 Neutral lipid storage myopathy 3 Cases 75327 2 Families dystrophy Neutrophil immunodeficiency 183707 2 Cases Not NOTCH3-related small syndrome 77304 2 Cases vessel disease of the brain 263432 Nevus of Ito 1.17 P * NPHP3-related Meckel-like 3032 10 Cases New-onset refractory status syndrome 363558 19 Cases epilepticus Obesity - colitis - hypothyroidism - cardiac 77292 Niemann-Pick disease type A 0.25 BP * 88643 2 Cases hypertrophy - developmental 77293 Niemann-Pick disease type B 0.4 P * delay Obesity due to CEP19 646 Niemann-Pick disease type C 1.0 P * 397615 15 Cases deficiency 647 1.0 BP Nijmegen breakage syndrome Obesity due to congenital 66628 30 Cases 99825 Nipah virus disease 556 Cases leptin deficiency 217031 34 Cases 263665 NK-cell enteropathy 8 Cases Obesity due to MC3R deficiency Obesity due to pro- Nodular lymphocyte 71526 7 Cases 86893 predominant Hodgkin 0.12 I opiomelanocortin deficiency Obesity due to prohormone lymphoma 71528 16 Cases Non-acquired combined convertase I deficiency 467 29.0 BP * pituitary hormone deficiency 198 Occipital horn syndrome 20 Cases Non-acquired combined Occipital pachygyria and 280640 3 Cases 231720 pituitary hormone deficiency 13 Cases polymicrogyria with spine abnormalities 2704 Ochoa syndrome 100 Cases Non-acquired isolated growth 631 0.39 P Ocular albinism with congenital hormone deficiency 352740 5 Families Non-epidermolytic sensorineural deafness 2337 2.5 P * Ocular albinism with late-onset palmoplantar keratoderma 1000 7 Cases Non-eruption of teeth - sensorineural deafness 2972 maxillary hypoplasia - genu 4 Cases 194 Ocular coloboma 8.0 BP * valgum Ocular motor apraxia, Cogan 1125 50 Cases Non-functioning pituitary 91349 80.025 P * type adenoma Oculo-palato-cerebral 2714 5 Cases Non-functioning pituitary 91349 1.05 I syndrome adenoma

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Oculoauriculofrontonasal 398156 41 Cases 300512 Onychomatricoma 50 Cases syndrome 2745 3.0 P * Oculocerebrocutaneous Opitz G/BBB syndrome 1647 38 Cases syndrome 2746 Opsismodysplasia 30 Cases Oculocerebrofacial syndrome, Opsoclonus-myoclonus 2707 9 Cases 1183 0.02 I * Kaufman type syndrome Oculocerebrorenal syndrome of Optic atrophy-intellectual 534 0.2 P 401777 6 Cases Lowe disability syndrome 55 Oculocutaneous albinism 5.9 P Optic nerve edema- 313800 3 Cases splenomegaly syndrome 352731 Oculocutaneous albinism type 1 2.5 P 2086 0.12 I Oculocutaneous albinism type Optic pathway glioma 79431 1.3 P 1A 52994 Orbital leiomyoma 16 Cases Oculocutaneous albinism type Ornithine transcarbamylase 79434 1.3 P 664 1.77 BP 1B deficiency 79432 Oculocutaneous albinism type 2 2.55 P Orofaciodigital syndrome type 2750 1.2 BP * 1 79435 Oculocutaneous albinism type 4 1.0 P Orofaciodigital syndrome type 2751 3 Cases 370091 Oculocutaneous albinism type 5 1 Family 2 Orofaciodigital syndrome type 370097 Oculocutaneous albinism type 6 1 Case 2752 16 Cases 3 352745 9 Cases Oculocutaneous albinism type 7 Orofaciodigital syndrome type 2753 29 Cases Oculodental syndrome, 4 2709 1 Family Rutherfurd type Orofaciodigital syndrome type 2919 4 Cases 2710 Oculodentodigital dysplasia 243 Cases 5 Oculogastrointestinal muscular Orofaciodigital syndrome type 1876 1 Family 2755 20 Cases dystrophy 8 Oculoosteocutaneous Orofaciodigital syndrome type 2713 3 Cases 141007 10 Cases syndrome 9 Orofaciodigital syndrome type 99806 Oculootodental syndrome 1 Family 434179 2 Families 14 2718 Oculotrichodysplasia 2 Cases Ossification anomalies - Odonto-onycho-dermal 73230 psychomotor development 2 Cases 2721 15 Cases dysplasia delay Odonto-tricho-ungual-digito- 2764 Osteochondritis dissecans 35.0 P * 69082 21 Cases palmar syndrome Osteochondrodysplatic nanism 2653 2 Cases 77295 Odontoleukodystrophy 4 Cases - deafness - retinitis pigmentosa 1811 Odontomicronychial dysplasia 5 Cases 2763 Osteocraniostenosis 30 Cases 2723 Odontotrichomelic syndrome 4 Cases 666 Osteogenesis imperfecta 7.5 P * Osteogenesis imperfecta - 75382 Oguchi disease 50 Cases 2773 retinopathy - seizures - 2 Cases 2729 Okamoto syndrome 2 Cases intellectual disability 85410 Oligoarticular juvenile arthritis 20.5 P * 216804 Osteogenesis imperfecta type 2 0.7 BP * 75378 Oligocone trichromacy 14 Cases 216828 Osteogenesis imperfecta type 5 47 Cases Osteopathia striata - cranial 46484 Oligodendroglial tumor 0.7 I * 2780 100 Cases sclerosis Oligodontia - cancer 300576 2 Families Osteopenia - myopia - hearing predisposition syndrome 91133 loss - intellectual disability - 2 Cases 2920 Oliver syndrome 7 Cases facial dysmorphism 39041 Omenn syndrome 25 Cases 2781 Osteopetrosis 1.0 I * Osteopetrosis - 2733 Omodysplasia 30 Cases 178389 8 Cases hypogammaglobulinemia 660 Omphalocele 11.7 BP * Osteopetrosis with renal 2785 100 Cases 352540 Oncogenic osteomalacia 400 Cases tubular acidosis Osteoporosis - oculocutaneous 2786 3 Cases 300504 Onychocytic matricoma 5 Cases hypopigmentation syndrome

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Paraplegia - brachydactyly - 2788 Osteoporosis - pseudoglioma 0.05 P * 2823 5 Cases cone-shaped epiphysis 668 0.23 I * Osteosarcoma Paraplegia - intellectual 2824 6 Cases Osteosclerosis - ichthyosis - 75325 3 Cases disability - hyperkeratosis premature ovarian failure 143 Parathyroid carcinoma 0.02 I * Osteosclerosis-developmental 178377 delay-craniosynostosis 13 Cases 2825 PARC syndrome 2 Cases syndrome Parietal foramina with 251290 8 Cases 2791 Otodental syndrome 10 Families cleidocranial dysplasia Paris-Trousseau 669 30 Cases 851 50 Cases Otopalatodigital syndrome thrombocytopenia Otospondylomegaepiphyseal Parkinsonism due to ATP13A2 1427 30 Cases 314632 4 Cases dysplasia deficiency 213500 30.0 P * Paroxysmal exertion-induced Ovarian cancer 98811 50 Cases dyskinesia 99853 Ovarioleukodystrophy 17 Cases Paroxysmal extreme pain Overgrowth - macrocephaly - 46348 4 Families 137634 6 Families disorder facial dysmorphism 157835 Paroxysmal hemicrania 2.0 P * Overhydrated hereditary 3203 20 Families Paroxysmal kinesigenic stomatocytosis 98809 0.6 P dyskinesia 36355 P2Y12 defect 14 Cases Paroxysmal nocturnal 447 0.2 P * 2796 Pachydermoperiostosis 204 Cases hemoglobinuria Paroxysmal non-kinesigenic 2309 Pachyonychia congenita 1000 Cases 98810 0.1 P dyskinesia 1952 Pacman dysplasia 10 Cases 79087 Partial acquired lipodystrophy 250 Cases 991 PAGOD syndrome 6 Cases 1330 Partial atrioventricular canal 30.0 P * 1993 Pai syndrome 37 Cases 1330 Partial atrioventricular canal 20.0 BP * Painful orbital and systemic 1646 Partial chromosome Y deletion 41.65 P 300501 neurofibromas-marfanoid 4 Cases habitus syndrome Partial corpus callosum agenesis-cerebellar vermis 672 Pallister-Hall syndrome 100 Cases 401959 2 Cases hypoplasia with posterior fossa Palmoplantar keratoderma - XX cysts syndrome 85112 5 Cases sex reversal - predisposition to Partial deep dermal and full squamous cell carcinoma 90076 10.0 P * thickness burns Palmoplantar keratoderma, 140966 20 Cases 2805 50 Cases Nagashima type Partial pancreatic agenesis Palmoplantar keratoderma- 94083 2 Families 2202 10 Families Partington syndrome deafness syndrome 86789 Patella aplasia/hypoplasia 5 Families Palmoplantar keratoderma- 2198 esophageal carcinoma 10 Families 706 Patent arterial duct 50.0 BP * syndrome Patent ductus arteriosus - Palmoplantar keratoderma- 2201 25 Cases 228190 bicuspid aortic valve - hand 7 Cases spastic paralysis syndrome anomalies 97253 Pancreatic endocrine tumor 0.21 I * Paternal 14q32.2 254531 7 Cases Pancreatic hypoplasia - hypomethylation syndrome Paternal 14q32.2 microdeletion 2255 diabetes - congenital heart 10 Cases 254525 6 Cases disease syndrome Pancreatic insufficiency - Paternal 20q13.2q13.3 199337 4 Cases 261304 2 Cases anemia - hyperostosis microdeletion syndrome Patterson-Stevenson-Fontaine 677 Pancreatoblastoma 60 Cases 2439 10 Cases syndrome Pancytopenia-developmental 401764 2 Cases PCNA-related progressive delay syndrome 438134 neurodegenerative 4 Cases Pantothenate kinase-associated 157850 0.15 P * photosensitivy syndrome neurodegeneration PDE4D haploinsufficiency 439822 7 Cases 678 Papillon-Lefèvre syndrome 0.25 P syndrome 63455 Paraneoplastic pemphigus 60 Cases 699 Pearson syndrome 60 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Peroxisomal acyl-CoA oxidase 93682 Pediatric Castleman disease 150 Cases 2971 40 Cases deficiency Pediatric hepatocellular 33402 0.15 I * carcinoma 2855 Perrault syndrome 61 Cases 263548 Peeling skin syndrome type A 40 Families 178509 Perry syndrome 53 Cases 263553 Peeling skin syndrome type B 30 Families 97341 Persistent placoid maculopathy 5 Cases Peeling skin-leukonuchia-acral Persistent polyclonal B-cell 300324 154 Cases 444138 punctate keratoses-cheilitis- 4 Cases lymphocytosis knuckle pads syndrome 708 Peters anomaly 60 Cases 702 Pelizaeus-Merzbacher disease 0.25 P * 709 Peters plus syndrome 80 Cases Pelizaeus-Merzbacher disease, 280219 0.17 P * classic form 2869 Peutz-Jeghers syndrome 0.4 P * Pelizaeus-Merzbacher disease, 280210 0.03 P * 2869 Peutz-Jeghers syndrome 2.2 BP connatal form 42642 PFAPA syndrome 500 Cases Pelizaeus-Merzbacher disease, 280224 0.03 P * transitional form 710 Pfeiffer syndrome 1.0 I * 83628 PELVIS syndrome 54 Cases 42775 PHACE syndrome 100 Cases 2839 Pelvis-shoulder dysplasia 10 Cases Phakomatosis 2874 34 Cases pigmentokeratotica 93333 Pelviscapular dysplasia 4 Cases Phalangeal microgeodic 352636 50 Cases 704 Pemphigus vulgaris 18.0 P * syndrome 705 Pendred syndrome 7.0 P * 2876 PHAVER syndrome 2 Cases 49 Penile agenesis 80 Cases 716 Phenylketonuria 10.0 BP * Phosphoenolpyruvate 313936 PENS syndrome 13 Cases 2880 10 Cases carboxykinase deficiency 1335 Pentalogy of Cantrell 0.67 BP Phosphoribosylpyrophosphate 3222 30 Families Pericardial and diaphragmatic synthetase superactivity 2847 20 Cases defect Pierre Robin syndrome - 2888 2 Cases 65250 Perineural cyst 50.0 I * faciodigital anomaly Periodic fever-infantile 2670 Pierson syndrome 22 Cases 436166 enterocolitis-autoinflammatory 4 Cases Pigmented paravenous 251295 8 Cases syndrome retinochoroidal atrophy Periodic paralysis with later- 397750 9 Cases 2890 Pili torti - onychodysplasia 1 Family onset distal motor neuropathy Pilodental dysplasia - refractive Periodic paralysis with 2892 2 Cases errors 397755 transient compartment-like 4 Cases syndrome 251909 Pineoblastoma 0.02 I * Perioral myoclonia with 139426 10 Cases 2896 Pitt-Hopkins syndrome 50 Cases absences 221150 Pitt-Hopkins-like syndrome 105 Cases 563 Peripartum cardiomyopathy 30.0 BP Peripheral neuropathy- 300385 Pituitary carcinoma 0.04 I * 397744 myopathy-hoarseness-hearing 15 Cases 2897 Pityriasis rubra pilaris 48 Cases loss syndrome 439167 33.0 P Peripheral resistance to thyroid Placental insufficiency 97927 2.5 P * Placental site trophoblastic hormones 99928 0.02 I * tumor 168816 Peritoneal cystic mesothelioma 150 Cases PLCG2-associated antibody 2849 Perlman syndrome 30 Cases 300359 deficiency and immune 3 Families Permanent congenital dysregulation 226292 33.3 BP * hypothyroidism 99969 Pleomorphic liposarcoma 0.05 I * Permanent neonatal diabetes 99885 0.38 BP * 50251 3.1 P * mellitus Pleural mesothelioma Permanent neonatal diabetes 50251 Pleural mesothelioma 1.9 I * 65288 mellitus - pancreatic and 4 Cases 64742 Pleuropulmonary blastoma 0.5 BP * cerebellar agenesis

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Pleuropulmonary blastoma Pontocerebellar hypoplasia 369920 5 Cases 284343 family tumor susceptibility 0.007 I type 9 syndrome Pontocerebellar hypoplasia 411493 23 Cases PLIN1-related familial partial type 10 280356 3 Cases lipodystrophy 294963 Popliteal pterygium syndrome 0.3 P * 54028 Plummer-Vinson syndrome 25 Cases Porencephaly-microcephaly- Pneumonia caused by 306547 bilateral congenital cataract 8 Cases 90066 Pseudomonas aeruginosa 50.0 P * syndrome infection Porokeratotic eccrine ostial and 166286 25 Cases 221046 Poikiloderma with neutropenia 50 Cases dermal duct nevus 738 Porphyria 5.25 P 2911 Poland syndrome 1.1 BP * Poliomyelitis in patients with 101330 Porphyria cutanea tarda 4.0 P * 330009 8.0E-4 P * immunodeficiencies deemed at 101330 Porphyria cutanea tarda 0.6 I * risk 79473 Porphyria variegata 0.32 P * 767 Polyarteritis nodosa 3.0 P * Polycystic ovaries - urethral 79473 Porphyria variegata 0.008 I * 2795 33 Cases sphincter dysfunction 246 Postaxial acrofacial dysostosis 30 Cases 729 Polycythemia vera 30.0 P * Postaxial polydactyly-anterior 729 Polycythemia vera 1.9 I * 420584 pituitary anomalies-facial 112 Cases dysmorphism syndrome 2917 Polydactyly-myopia syndrome 1 Family Posterior amorphous corneal 98971 11 Families 397937 Polyglucosan body myopathy 11 Cases dystrophy Posterior column ataxia - Polymalformative genetic 88628 20 Cases retinitis pigmentosa 183422 syndrome with increased risk of 10.0 P * Posterior fusion of lumbosacral developing cancer 2064 3 Cases vertebrae - blepharoptosis Polymicrogyria due to TUBB2B 300573 36 Cases mutation 268810 Posterior meningocele 100.0 BP * Polymicrogyria with optic nerve 250972 4 Cases 93110 Posterior urethral valve 2.0 P * hypoplasia 93110 Posterior urethral valve 4.125 BP * 732 Polymyositis 7.1 P * 279947 Postorgasmic illness syndrome 45 Cases 732 Polymyositis 0.585 I * Posttransplant Polyneuropathy - hearing loss - 70568 26.2 P * lymphoproliferative disease 171848 ataxia - retinitis pigmentosa - 19 Cases cataract 52022 Potocki-Shaffer syndrome 23 Cases Polysyndactyly - cardiac 2934 6 Cases 217067 Pouchitis 22.0 P * malformation PPARG-related familial partial Polyvalvular heart disease 79083 10 Cases 228410 19 Cases lipodystrophy syndrome Pontine tegmental cap 739 Prader-Willi syndrome 2.8 BP * 269229 22 Cases dysplasia Prader-Willi syndrome due to 398069 6 Cases Pontocerebellar hypoplasia point mutation 2254 40 Families type 1 398073 Prader-Willi-like syndrome 117 Cases Pontocerebellar hypoplasia Prader-Willi-like syndrome due 2524 81 Families 398079 4 Cases type 2 to point mutation Pontocerebellar hypoplasia Pre-Descemet corneal 97249 3 Families 293462 5 Cases type 3 dystrophy Pontocerebellar hypoplasia 166063 10 Families 275555 45.0 P * type 4 Preeclampsia Pontocerebellar hypoplasia Premature aging appearance- 166068 3 Cases type 5 276432 developmental delay-cardiac 8 Cases Pontocerebellar hypoplasia arrhythmia syndrome 166073 10 Cases Pretibial dystrophic type 6 79410 40 Families Pontocerebellar hypoplasia epidermolysis bullosa 284339 4 Cases type 7 186 Primary biliary cirrhosis 21.05 P Pontocerebellar hypoplasia 324569 6 Cases 186 Primary biliary cirrhosis 3.0 I type 8

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Progeria - short stature - 169464 Primary CD59 deficiency 6 Cases 2959 10 Cases pigmented nevi 244 5.0 BP * Primary ciliary dyskinesia Progeroid and marfanoid 300382 7 Cases Primary ciliary dyskinesia - aspect-lipodystrophy syndrome 247522 20 Cases retinitis pigmentosa Progeroid features- Primary congenital 435953 3 Cases 226295 37.5 P * hepatocellular carcinoma hypothyroidism predisposition syndrome Primary cutaneous CD30+ T-cell Progressive bifocal 541 0.18 I * 75373 2 Families lymphoproliferative disease chorioretinal atrophy Progressive cavitating 542 Primary cutaneous lymphoma 0.75 I * 139447 19 Cases leukoencephalopathy Primary cutaneous T-cell 171901 24.0 P * Progressive cerebello-cerebral lymphoma 247198 7 Cases atrophy Primary cutaneous T-cell 171901 5.2 I * lymphoma Progressive demyelinating 217396 neuropathy with bilateral 4 Cases 48686 Primary effusion lymphoma 200 Cases striatal necrosis 90026 Primary erythermalgia 30 Families Progressive encephalopathy 431361 2 Cases Primary hepatic with leukodystrophy due to 100085 0.2 I neuroendocrine carcinoma DECR deficiency Primary hypergonadotropic Progressive external 2232 7 Cases 352447 6 Cases hypogonadism - partial alopecia ophthalmoplegia - myopathy - emaciation 93598 0.2 P * Primary hyperoxaluria type 1 Progressive myoclonic epilepsy 263516 3 Cases 93599 Primary hyperoxaluria type 2 10 Cases type 3 Progressive myoclonic epilepsy 93600 Primary hyperoxaluria type 3 50 Cases 402082 3 Cases type 5 Primary hypomagnesemia with Progressive myoclonic epilepsy 30924 100 Cases 280620 12 Cases secondary hypocalcemia type 6 Primary immunodeficiency due Progressive myoclonic epilepsy 431166 7 Cases 435438 13 Cases to STAT2 deficiency type 7 Primary immunodeficiency Progressive myoclonic epilepsy 90023 4 Cases 424027 4 Cases syndrome due to p14 deficiency type 8 Primary immunodeficiency with Progressive myoclonic epilepsy 352596 5 Cases 75391 natural-killer cell deficiency and 4 Cases with dystonia adrenal insufficiency 100070 Progressive non-fluent aphasia 2.5 P * 35689 Primary lateral sclerosis 1.5 P * 100070 Progressive non-fluent aphasia 0.7 I * 77240 Primary lymphedema 16.7 P * Progressive non-infectious Primary membranoproliferative 2062 90 Cases 54370 16.0 P * anterior vertebral fusion glomerulonephritis Progressive retinal dystrophy 352718 4 Cases Primary microcephaly-epilepsy- due to retinol transport defect 306558 3 Cases permanent neonatal diabetes Progressive sensorineural syndrome 228012 hearing loss - hypertrophic 4 Families Primary microcephaly-mild cardiomyopathy 391408 intellectual disability-young- 3 Cases 683 Progressive supranuclear palsy 6.0 P onset diabetes syndrome 238606 Primary orthostatic tremor 390 Cases 683 Progressive supranuclear palsy 0.65 I Primary pigmented nodular Progressive supranuclear palsy 189439 0.04 P * 240103 0.6 P * adrenocortical disease - corticobasal syndrome Progressive supranuclear palsy 95432 Primary progressive aphasia 7.0 P 240112 10 Cases - progressive non fluent aphasia Primary progressive apraxia of 314566 16 Cases 742 Prolidase deficiency 90 Cases speech 171 Primary sclerosing cholangitis 8.1 P 35 Propionic acidemia 0.2 P * 171 Primary sclerosing cholangitis 0.65 I 35 Propionic acidemia 1.5 I Proximal 16p11.2 PRKAR1B-related 261197 20.0 P * 412066 neurodegenerative dementia 12 Cases microdeletion syndrome Proximal myopathy with with intermediate filaments 401768 15 Cases extrapyramidal signs

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Pulmonary capillary 606 Proximal myotonic myopathy 1.0 P * 199241 100 Cases hemangiomatosis Proximal spinal muscular 70 20.0 BP * Pulmonary fibrosis - hepatic atrophy 210136 hyperplasia - bone marrow 4 Cases Proximal spinal muscular 70 2.6 I * hypoplasia atrophy Pulmonary fungal infections in Proximal spinal muscular 217080 22.0 P * 83330 0.26 I * patients deemed at risk atrophy type 1 Pulmonary venoocclusive Proximal spinal muscular 31837 0.015 I * 83418 1.23 I * disease atrophy type 2 Punctate palmoplantar Proximal spinal muscular 79501 35 Families 83419 1.1 I * keratoderma type 1 atrophy type 3 PURA-related severe neonatal Proximal spinal muscular 83420 0.32 I * hypotonia-seizures- atrophy type 4 438216 24 Cases encephalopathy syndrome due 52530 Pseudo-von Willebrand disease 60 Cases to a point mutation Pure hair and nail ectodermal 85174 Pseudodiastrophic dysplasia 10 Cases 69084 20 Cases dysplasia Pseudohypoaldosteronism type 756 70 Cases Purine nucleoside 1 760 70 Cases phosphorylase deficiency Pseudohypoaldosteronism type 757 80 Families 2 763 Pycnodysostosis 0.13 P Pseudohypoaldosteronism type 300525 24 Cases 3003 Pyknoachondrogenesis 5 Cases 2D 3005 Pyle disease 30 Cases Pseudohypoaldosteronism type 300530 17 Cases Pyogenic arthritis - pyoderma 2E 69126 34 Cases gangrenosum - acne 26790 Pseudomyxoma peritonei 0.1 I Pyogenic bacterial infections 183713 24 Cases 2985 Pseudoprogeria syndrome 2 Cases due to MyD88 deficiency 758 Pseudoxanthoma elasticum 2.5 P * 3006 Pyridoxine-dependent epilepsy 0.2 BP * Pseudoxanthoma elasticum-like 3008 Pyruvate carboxylase deficiency 0.4 BP * 436274 skin manifestations with retinis 13 Cases Pyruvate carboxylase pigmentosa 353320 10 Cases deficiency, benign type Pseudoxanthomatous diffuse 280794 10 Cases Pyruvate dehydrogenase E3 cutaneous mastocytosis 2394 20 Cases deficiency Psychomotor retardation due 3010 3 Cases 88618 to S-adenosylhomocysteine 3 Cases Qazi-Markouizos syndrome hydrolase deficiency 70475 Radiation proctitis 35.0 P * Pterygium colli - intellectual 2988 2 Cases Radio-ulnar synostosis - disability - digital anomalies 71289 amegakaryocytic 20 Cases Ptosis - strabismus - ectopic 2999 1 Family thrombocytopenia pupils 1051 Ramos-Arroyo syndrome 6 Cases Ptosis - syndactyly - learning 238766 5 Cases difficulties 3021 RAPADILINO syndrome 20 Cases Ptosis - upper ocular movement Rapid-onset childhood obesity - 228396 limitation - absence of lacrimal 3 Cases hypothalamic dysfunction - 293987 48 Cases punctum hypoventilation - autonomic Pulmonary arterial 182090 3.3 P * dysregulation syndrome hypertension Rapid-onset dystonia- 71517 100 Cases Pulmonary arterial parkinsonism 275803 hypertension associated with 0.57 P * 217074 Rare carcinoma of pancreas 3.5 P congenital heart disease Pulmonary arterial 217074 Rare carcinoma of pancreas 3.9 I 275798 hypertension associated with 0.25 P * Rare epithelial tumor of 63443 18.6 I * connective tissue disease stomach Pulmonary arteriovenous 2038 2.5 I 182114 Rare urogenital tumor 0.13 I * fistula RARS-related autosomal Pulmonary artery coming from 99050 200 Cases 438114 4 Cases the aorta recessive hypomyelinating leukodystrophy 64741 Pulmonary blastoma 350 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families RAS-associated autoimmune 268114 20 Cases 791 Retinitis pigmentosa 26.7 P leukoproliferative disease Retinitis pigmentosa - Rasmussen subacute 1929 100 Cases 3085 intellectual disability - deafness 2 Families encephalitis - hypogenitalism Recessive aplasia cutis 1115 6 Cases Retinitis pigmentosa-juvenile congenita of limbs 436245 cataract-short stature- 3 Cases Recessive dystrophic 79409 100 Cases intellectual disability syndrome epidermolysis bullosa inversa 790 Retinoblastoma 6.0 BP Recessive hereditary 139380 100 Cases methemoglobinemia type 2 790 Retinoblastoma 0.05 I * Recessive intellectual disability Retinohepatoendocrinologic 3087 7 Cases 280384 - motor dysfunction - multiple 12 Cases syndrome joint contractures 778 Rett syndrome 4.0 P * 461 Recessive X-linked ichthyosis 16.6 P * 778 Rett syndrome 5.0 BP * 461 Recessive X-linked ichthyosis 15.0 I * Reunion Island's Larsen 294049 30 Cases 64740 Recurrent acute pancreatitis 10.0 P * syndrome Recurrent hepatitis C virus 3088 Revesz syndrome 3 Cases 90052 induced liver disease in liver 7.0 P * 244310 RFT1-CDG 6 Cases transplant recipients Recurrent infections - 69077 Rhabdoid tumor 500 Cases 251523 inflammatory syndrome due to 5 Cases 780 Rhabdomyosarcoma 0.59 I * zinc metabolism disorder 97239 Reducing body myopathy 4 Families 3099 Rheumatic fever 5.0 I * Rhizomelic chondrodysplasia 773 Refsum disease 0.1 P * 177 1.0 P * punctata 83450 Regional odontodysplasia 140 Cases 59315 Rhombencephalosynapsis 50 Cases 98961 Reis-Bücklers corneal dystrophy 81 Cases 140976 RHYNS syndrome 4 Cases 728 Relapsing polychondritis 0.35 I Riboflavin transporter 97229 80 Cases deficiency 1848 Renal agenesis, bilateral 1.7 BP * Ribose-5-P isomerase 440706 1 Case 93100 Renal agenesis, unilateral 50.0 BP deficiency Richieri Costa-Pereira 217071 Renal cell carcinoma 42.0 P * 3102 33 Cases syndrome 1475 Renal coloboma syndrome 180 Cases 83312 Rickettsialpox 800 Cases 93108 Renal dysplasia 43.5 BP * 420741 RIDDLE syndrome 2 Cases Renier-Gabreels-Jasper 93975 5 Cases syndrome 293848 Right temporal lobar atrophy 200 Cases 3242 Renpenning syndrome 64 Cases 217335 RIN2 syndrome 3 Cases Resistance to thyrotropin- 99832 2 Cases 363203 Ring chromosome 2.0 BP releasing hormone syndrome 1437 Ring chromosome 1 34 Cases 1662 Restrictive dermopathy 30 Cases 96173 Ring chromosome 9 31 Cases 33355 Reticular dysgenesis 0.03 I * 1438 Ring chromosome 10 16 Cases Reticulate acropigmentation of 178307 130 Cases Kitamura 1440 Ring chromosome 14 50 Cases 75326 Retinal arterial tortuosity 100 Cases 1441 Ring chromosome 17 14 Cases Retinal degeneration - 1574 7 Cases 1442 Ring chromosome 18 70 Cases nanophthalmos - glaucoma Retinal dystrophy with inner 1444 Ring chromosome 20 50 Cases 397758 retinal dysfunction and ganglion 14 Cases 91481 Ring dermoid of cornea 30 Cases cell anomalies Retinal ischemic syndrome - 3103 Roberts syndrome 150 Cases digestive tract small vessel 3018 3 Cases 97360 Robinow syndrome 200 Cases hyalinosis - diffuse cerebral calcifications 3105 Robinow-like syndrome 2 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 353298 Roifman syndrome 7 Cases 801 Scleroderma 42.0 P 101016 Romano-Ward syndrome 40.0 P * 801 Scleroderma 1.41 I 158014 Rosaï-Dorfman disease 1000 Cases 167635 Scleromyxedema 300 Cases Scleromyxedema without 2909 Rothmund-Thomson syndrome 300 Cases 90400 15 Cases monoclonal gammopathy Rothmund-Thomson syndrome 221008 100 Cases type 1 806 Scott syndrome 4 Cases Rothmund-Thomson syndrome 221016 200 Cases 158029 Sea-blue histiocytosis 60 Cases type 2 Seborrhea-like dermatitis with 168606 44 Cases 3111 Rotor syndrome 50 Cases psoriasiform elements 83616 Rubella panencephalitis 20 Cases 808 Seckel syndrome 50 Cases Segmental odontomaxillary 783 Rubinstein-Taybi syndrome 0.6 BP * 67039 32 Cases dysplasia Sacral agenesis-abnormal Segmental progressive ossification of the vertebral 397927 4 Cases 314662 overgrowth syndrome with 10 Cases bodies-persistent notochordal canal syndrome fibroadipose hyperplasia Seizures - intellectual disability 794 3.0 BP * 79156 3 Cases Saethre-Chotzen syndrome due to hydroxylysinuria 300493 Sagliker syndrome 60 Cases 281122 Self-healing collodion baby 25 Cases 3128 5 Cases Sensorineural deafness with Sakati-Nyhan syndrome 217622 2 Families dilated cardiomyopathy 140969 Saldino-Mainzer syndrome 10 Cases Sensorineural hearing loss - 66633 3 Cases 370938 Salt-and-pepper syndrome 3 Cases early graying - essential tremor 796 Sandhoff disease 0.67 BP * 90051 Sepsis in premature infants 32.0 P * 79269 Sanfilippo syndrome type A 0.5 P * 3157 Septo-optic dysplasia spectrum 10.0 BP * 79269 Sanfilippo syndrome type A 1.4 BP 139466 SERKAL syndrome 3 Cases 79270 Sanfilippo syndrome type B 0.09 P * Severe achondroplasia - 85165 developmental delay - 4 Cases 797 Sarcoidosis 12.5 P acanthosis nigricans Severe autosomal recessive 3129 Sarcosinemia 2.0 BP 438207 2 Cases macrothrombocytopenia 3132 Say-Barber-Miller syndrome 2 Cases Severe combined 183660 1.65 BP * Scalp defects - postaxial immunodeficiency 1003 2 Cases polydactyly Severe combined 370052 SCALP syndrome 3 Cases 277 immunodeficiency due to 0.2 P * adenosine deaminase deficiency 2036 Scalp-ear-nipple syndrome 30 Cases Severe combined Scapuloperoneal spinal 277 immunodeficiency due to 0.3 BP * 431255 22 Cases muscular atrophy adenosine deaminase deficiency 3134 SCARF syndrome 2 Cases Severe combined 357237 immunodeficiency due to 2 Cases Scarring in glaucoma filtration 90080 22.0 P * CARD11 deficiency surgical procedures Severe combined 2353 Schilbach-Rott syndrome 18 Cases 228003 immunodeficiency due to 6 Cases Schimke immuno-osseous CORO1A deficiency 1830 71 Cases dysplasia Severe combined 798 Schinzel-Giedion syndrome 46 Cases 420573 immunodeficiency due to CTPS1 8 Cases deficiency 37748 150 Cases Schnitzler syndrome Severe combined 98967 Schnyder corneal dystrophy 115 Cases 397787 immunodeficiency due to IKK2 4 Cases deficiency Schöpf-Schulz-Passarge 50944 25 Cases syndrome Severe combined 280142 immunodeficiency due to LCK 4 Cases 800 Schwartz-Jampel syndrome 100 Cases deficiency Severe congenital hypochromic 185 Scimitar syndrome 2.0 BP * 300298 3 Cases anemia with ringed sideroblasts

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 42738 Severe congenital neutropenia 0.07 P Severe neonatal-onset 209370 encephalopathy with 30 Cases 42738 Severe congenital neutropenia 0.4 BP * microcephaly Severe dermatitis-multiple Severe neurodegenerative 363400 6 Cases 369992 allergies-metabolic wasting 3 Cases syndrome with lipodystrophy syndrome Severe X-linked intellectual 3078 7 Cases Severe early-onset axonal disability, Gustavson type 228374 neuropathy due to NEFL 4 Cases Severe X-linked mitochondrial 238329 2 Cases deficiency encephalomyopathy Severe early-onset obesity- Sex cord-stromal tumor of 363489 0.02 I * 329249 insulin resistance syndrome due 13 Cases testis to SH2B1 deficiency 104008 Short bowel syndrome 3.4 P * Severe feeding difficulties - Short fifth metacarpals - insulin 352577 failure to thrive - microcephaly 4 Cases 66518 6 Cases due to ASXL3 deficiency resistance Short rib-polydactyly 169802 Severe hemophilia A 2.8 P * 93269 34 Cases syndrome, Majewski type 169793 Severe hemophilia B 0.8 P * Short stature - intellectual Severe intellectual disability 2649 disability - eye anomalies - cleft 3 Cases 280763 and progressive spastic 15 Cases lip/palate paraplegia Short stature - pituitary and Severe intellectual disability- 85442 cerebellar defects - small sella 5 Families 94066 epilepsy-anal anomalies-distal 2 Cases turcica Short stature - webbed neck - phalangeal hypoplasia 2865 4 Cases Severe intellectual disability- heart disease epilepsy-cataract syndrome due Short stature due to GHSR 438178 3 Cases 314811 8 Cases to fatty acyl-CoA reductase 1 deficiency deficiency Short stature due to growth 629 3 Cases Severe intellectual disability- hormone qualitative anomaly 436141 hypotonia-strabismus-coarse 6 Cases 2867 Short stature, Brussels type 2 Cases face-planovalgus syndrome Short stature-advanced bone Severe intellectual disability- 435804 age-early onset osteoarthritis 3 Families poor language-strabismus- 363686 4 Cases syndrome grimacing face-long fingers Short stature-auditory canal syndrome 397623 atresia-mandibular hypoplasia- 4 Cases Severe intellectual disability- skeletal anomalies syndrome progressive postnatal Short stature-onychodysplasia- 397933 microcephaly- midline 3 Cases 314394 facial dysmorphism- 14 Cases stereotypic hand movements hypotrichosis syndrome syndrome Short stature-optic atrophy- Severe intellectual disability- 391677 34 Cases Pelger-Huët anomaly syndrome 404473 progressive spastic diplegia 4 Cases syndrome 3163 SHORT syndrome 32 Cases Severe intellectual disability- Short tarsus - absence of lower 2832 11 Cases short stature-behavioral eyelashes 391307 3 Cases troubles-facial dysmorphism Short ulna - dysmorphism - syndrome 357175 hypotonia - intellectual 4 Cases Severe lateral tibial bowing disability 324307 2 Cases with short stature 2462 Shprintzen-Goldberg syndrome 60 Cases Severe motor and intellectual Shwachman-Diamond 369939 disabilities-sensorineural 7 Cases 811 0.28 P syndrome deafness-dystonia syndrome Shwachman-Diamond Severe neonatal hypotonia- 811 0.5 BP syndrome seizures-encephalopathy 314655 7 Cases syndrome due to 5q31.3 309294 Sialidosis 0.05 BP * microdeletion 232 Sickle cell anemia 15.0 P * Severe neonatal lactic acidosis 397593 due to NFS1-ISD11 complex 5 Cases 3167 Siegler-Brewer-Carey syndrome 2 Cases deficiency 71276 Silent sinus syndrome 98 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 3168 Sillence syndrome 5 Cases Spastic tetraplegia - retinitis 3011 pigmentosa - intellectual 2 Cases 813 Silver-Russell syndrome 0.8 BP * disability Spasticity - intellectual 813 Silver-Russell syndrome 15.5 I * 3175 6 Cases disability - X-linked epilepsy Silver-Russell syndrome due to 397590 8 Cases Spasticity-ataxia-gait anomalies a point mutation 401866 3 Cases syndrome Simpson-Golabi-Behmel 373 250 Cases Spectrin-associated autosomal syndrome 352403 2 Families recessive cerebellar ataxia Simpson-Golabi-Behmel 79022 4 Cases syndrome type 2 99865 Spermatocytic seminoma 0.03 I * Spigelian hernia-cryptorchidism 85191 Singleton-Merten dysplasia 10 Cases 314432 15 Cases syndrome Sinoatrial node dysfunction and 324321 8 Cases deafness 90058 Spinal cord injury 32.0 P * 3169 Sirenomelia 0.01 P Spinal muscular atrophy - 73245 Dandy-Walker malformation - 2 Cases 3169 Sirenomelia 0.98 BP cataracts 2882 Sitosterolemia 100 Cases Spinal muscular atrophy with 404521 1 Case Skeletal dysplasia - intellectual respiratory distress type 2 1436 2 Families disability 98755 Spinocerebellar ataxia type 1 1.5 P Skin fragility-woolly hair- 98756 Spinocerebellar ataxia type 2 1.5 P 293165 palmoplantar keratoderma 7 Cases syndrome 98757 Spinocerebellar ataxia type 3 1.5 P 238459 SLC35A1-CDG 1 Case 98766 Spinocerebellar ataxia type 5 3 Families 356961 SLC35A2-CDG 4 Cases 98767 Spinocerebellar ataxia type 11 51 Cases 70573 Small cell lung cancer 11.2 P * 98762 Spinocerebellar ataxia type 12 40 Families Smith-Fineman-Myers 93974 11 Families 98768 Spinocerebellar ataxia type 13 20 Cases syndrome 98763 Spinocerebellar ataxia type 14 20 Families 818 Smith-Lemli-Opitz syndrome 3.7 BP * 98759 Spinocerebellar ataxia type 17 100 Families 819 Smith-Magenis syndrome 4.0 P 98771 Spinocerebellar ataxia type 18 26 Cases 820 Sneddon syndrome 0.4 I * Spinocerebellar ataxia type Snowflake vitreoretinal 98772 12 Cases 91496 50 Cases 19/22 degeneration Sodium channelopathy-related 101110 Spinocerebellar ataxia type 20 20 Cases 306577 8 Cases small fiber neuropathy 98773 Spinocerebellar ataxia type 21 20 Cases 3394 Soft tissue sarcoma 23.7 P * 101108 Spinocerebellar ataxia type 23 4 Families 97230 Solar urticaria 36.0 P * 101111 Spinocerebellar ataxia type 25 10 Cases 209964 Solitary rectal ulcer syndrome 1.0 I * 101112 Spinocerebellar ataxia type 26 1 Family 97283 Somatostatinoma 0.0025 I * 98764 Spinocerebellar ataxia type 27 30 Cases 821 Sotos syndrome 7.1 BP 208513 Spinocerebellar ataxia type 29 50 Cases Sparse hair - short stature - skin 79132 4 Cases 211017 6 Cases anomalies Spinocerebellar ataxia type 30 Spastic paraplegia - glaucoma - 217012 30 Families 2818 2 Families Spinocerebellar ataxia type 31 intellectual disability 276183 Spinocerebellar ataxia type 32 1 Family Spastic paraplegia - nephritis - 2820 4 Cases deafness 1955 Spinocerebellar ataxia type 34 25 Cases Spastic paraplegia - Paget 329475 1 Family 276193 Spinocerebellar ataxia type 35 3 Families disease of bone Spastic paraplegia - precocious 276198 Spinocerebellar ataxia type 36 90 Cases 2826 2 Cases puberty 363710 Spinocerebellar ataxia type 37 9 Cases 99015 Spastic paraplegia type 2 100 Cases 423296 Spinocerebellar ataxia type 38 4 Families 99013 Spastic paraplegia type 7 4.0 P * 423275 Spinocerebellar ataxia type 40 5 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Spondylometaphyseal dysplasia 71271 Split hand - split foot - deafness 22 Cases 85167 18 Cases - cone-rod dystrophy Split hand-split foot 2440 5.4 BP * Spondylometaphyseal malformation 168555 2 Cases dysplasia, A4 type Spondylo-megaepiphyseal- 228387 12 Cases Spondylometaphyseal metaphyseal dysplasia 93315 30 Cases dysplasia, 'corner fracture' type 3275 24 Cases Spondylocarpotarsal synostosis Spondylometaphyseal 370019 2 Cases Spondylocostal dysostosis - dysplasia, Czarny-Ratajczak type 94095 anal and genitourinary 4 Cases Spondylometaphyseal 168544 3 Cases malformations dysplasia, Golden type Spondylocostal dysostosis - Spondylometaphyseal 93316 7 Cases 329252 hypospadias - intellectual 2 Cases dysplasia, Schmidt type disability Spondylometaphyseal 93317 9 Cases 1855 Spondyloenchondrodysplasia 36 Cases dysplasia, Sedaghatian type Spondyloepimetaphyseal Spontaneous periodic 168451 2 Cases 29822 50 Cases dysplasia - abnormal dentition hypothermia Spondyloepimetaphyseal Sporadic adult-onset ataxia of 168443 5 Cases 247234 7.6 P * dysplasia - hypotrichosis unknown etiology Spondyloepimetaphyseal 826 Sporotrichosis 55 Cases 93346 dysplasia congenita, Strudwick 30 Cases Squamous cell carcinoma of 99977 5.2 I type esophagus Spondyloepimetaphyseal Squamous cell carcinoma of 171866 3 Cases 67037 49.0 P * dysplasia, aggrecan type head and neck Spondyloepimetaphyseal Squamous cell carcinoma of 168448 3 Cases 67037 8.7 I dysplasia, Bieganski type head and neck Spondyloepimetaphyseal Squamous cell carcinoma of 168454 2 Cases 398058 0.57 I * dysplasia, Geneviève type penis Spondyloepimetaphyseal Squamous cell carcinoma of 370015 2 Cases 418959 55.0 I dysplasia, Isidor type stomach Spondyloepimetaphyseal 156728 1 Family 370927 SSR4-CDG 1 Case dysplasia, matrilin-3 type Spondyloepimetaphyseal 83484 St. Louis encephalitis 0.38 I * 93356 14 Cases dysplasia, Missouri type Stapes ankylosis with broad 140917 6 Families Spondyloepimetaphyseal 93282 17 Cases thumbs and toes dysplasia, PAPSS2 type 827 Stargardt disease 10.0 P * Spondyloepimetaphyseal 93352 4 Cases dysplasia, Shohat type 273 Steinert myotonic dystrophy 12.5 P Spondyloepiphyseal dysplasia Sterile multifocal osteomyelitis 94068 1.0 BP * 210115 10 Cases congenita with periostitis and pustulosis Spondyloepiphyseal dysplasia Stern-Lubinsky-Durrie 163665 3 Cases 3194 7 Cases tarda, Kohn type syndrome Spondyloepiphyseal dysplasia, 163654 4 Cases 2017 Sternal cleft 2.0 BP * Cantu type Steroid dehydrogenase Spondyloepiphyseal dysplasia, 3196 1 Family 93283 1 Family deficiency - dental anomalies Kimberley type Spondyloepiphyseal dysplasia, 36426 Stevens-Johnson syndrome 0.36 I * 163668 4 Cases MacDermot type 828 Stickler syndrome 0.5 BP * Spondyloepiphyseal dysplasia, Stiff person syndrome and 263482 10 Cases 3198 0.1 P * Maroteaux type related disorders Spondyloepiphyseal dysplasia, 163649 4 Cases 3199 2 Cases Nishimura type Stimmler syndrome Spondyloepiphyseal dysplasia, STING-associated vasculopathy 163662 1 Family 425120 9 Cases Reardon type with onset in infancy 254 Spondylometaphyseal dysplasia 1.0 BP * 3200 Stoll-Alembik-Finck syndrome 2 Cases Stormorken-Sjaastad-Langslet Spondylometaphyseal dysplasia 3204 6 Cases 168552 - bowed forearms - facial 2 Cases syndrome dysmorphism 137599 Stromal keratitis 16.0 P * 370921 STT3A-CDG 2 Cases

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Syringocystadenoma 370924 STT3B-CDG 1 Case 840 300 Cases papilliferum 3205 Sturge-Weber syndrome 3.5 BP * 3280 Syringomyelia 8.4 P * 166277 3 Cases Suarez-Stickler syndrome Systemic capillary leak 188 150 Cases 48377 Subcorneal pustular dermatosis 200 Cases syndrome Subepithelial mucinous corneal 2467 Systemic mastocytosis 3.75 P 98959 1 Family dystrophy 2467 Systemic mastocytosis 0.9 I * Succinyl-CoA:3-ketoacid CoA 832 33 Cases Systemic primary carnitine transferase deficiency 158 3.2 BP * deficiency Sudden infant death - 168593 21 Cases dysgenesis of the testes 90291 Systemic sclerosis 15.4 P * Systemic-onset juvenile 3210 Summitt syndrome 3 Cases 85414 5.0 P * idiopathic arthritis 57145 6.7 P * SUNCT syndrome T-cell immunodeficiency with Superficial epidermolytic 324294 2 Cases 455 20 Cases epidermodysplasia ichthyosis verruciformis T-cell large granular 46485 Superficial pemphigus 1.2 P * 86872 0.4 I * lymphocyte leukemia 247245 Superficial siderosis 300 Cases 3287 Takayasu arteritis 0.6 P * 141096 Supernumerary nostril 32 Cases 3287 Takayasu arteritis 0.19 I * 3193 Supravalvular aortic stenosis 13.3 P * Tall stature - scoliosis - 329191 2 Families 3193 Supravalvular aortic stenosis 4.0 BP * macrodactyly of the great toes SURF1-related Charcot-Marie- Tall stature-intellectual 391351 3 Cases Tooth disease type 4 404443 disability-facial dysmorphism 13 Cases syndrome 838 Susac syndrome 304 Cases Talo-patello-scaphoid 50809 2 Cases 3243 Sweet syndrome 100 Cases osteolysis Symmetrical thalamic 31150 Tangier disease 100 Cases 1314 29 Cases calcifications Tarsal-carpal coalition 1412 10 Families 79098 Sympathetic ophthalmia 0.6 P * syndrome Symphalangism with multiple Taurodontia - absent teeth - 3246 6 Cases 2731 15 Cases anomalies of hands and feet sparse hair Syndactyly - camptodactyly and 845 Tay-Sachs disease 0.28 BP 357332 clinodactyly of fifth fingers - 26 Cases TCR-alpha-beta-positive T-cell 397959 2 Cases bifid toes deficiency Syndactyly - telecanthus - 3291 Teebi-Shaltout syndrome 2 Cases 140952 anogenital and renal 6 Cases Temperature-sensitive malformations 352737 10 Cases oculocutaneous albinism type 1 93402 Syndactyly type 1 25.0 BP * 284227 TEMPI syndrome 10 Cases 93405 Syndactyly type 4 4 Cases 420561 Temple-Baraitser syndrome 7 Cases 93406 Syndactyly type 5 10 Cases Temtamy preaxial 363417 18 Cases 84064 Syndromic diarrhea 44 Cases brachydactyly syndrome Syndromic microphthalmia 1777 7 Families 178364 20 Cases Temtamy syndrome type 5 Terminal osseous dysplasia - 88630 18 Cases Syndromic multisystem pigmentary defects 228426 10 Cases autoimmune disease due to Itch Testicular seminomatous germ 842 1.71 I * deficiency cell tumor 281090 Syndromic X-linked ichthyosis 1.3 P * 3303 Tetralogy of Fallot 34.0 BP Syndromic X-linked intellectual 85274 10 Cases 884 4.0 BP * disability 7 Tetrasomy 12p Syndromic X-linked intellectual 9 Tetrasomy X 40 Cases 85279 disability due to JARID1C 10 Families 3312 Thalidomide embryopathy 0.77 P mutation 3262 Syngnathia multiple anomalies 2 Cases 2655 Thanatophoric dysplasia 3.5 BP *

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families Thiamine-responsive 199348 2 Cases 101028 Transaldolase deficiency 23 Cases encephalopathy 859 40 Cases Thiamine-responsive Transcobalamin deficiency 49827 80 Cases megaloblastic anemia syndrome Transient bullous dermolysis of 79411 30 Cases Thickened earlobes - the newborn 2405 2 Families Transient congenital conductive deafness 178045 1000.0 I * hypothyroidism 98960 Thiel-Behnke corneal dystrophy 173 Cases Transient infantile 614 Thomsen and Becker disease 1.0 P 300293 hypertriglyceridemia and 10 Cases 3317 Thoracolaryngopelvic dysplasia 10 Cases hepatosteatosis Transient neonatal diabetes Thrombocytopenia - absent 99886 0.3 BP * 3320 0.2 BP * mellitus radius Transient neonatal multiple Thrombocytopenia - Robin 3323 2 Cases 329942 acyl-CoA dehydrogenase 1 Case sequence deficiency Thrombocytopenia with Transmissible spongiform 67044 congenital dyserythropoietic 3 Families 56970 0.3 P * encephalopathy anemia Transmissible spongiform Thrombomodulin-related 56970 0.15 I * 436169 15 Cases encephalopathy bleeding disorder Transposition of the great Thrombotic thrombocytopenic 216675 31.7 BP * 54057 25.5 P * arteries purpura Thumb stiffness - brachydactyly 861 Treacher-Collins syndrome 2.0 BP * 1078 6 Cases - intellectual disability Tricho-dento-osseous 3352 30 Cases 3398 Thymic epithelial neoplasm 0.17 I * syndrome Tricho-retino-dento-digital Thymic-renal-anal-lung 1264 9 Cases 3326 3 Cases syndrome dysplasia 3351 Trichodental syndrome 5 Families 99867 Thymoma 0.14 I * Trichodysplasia - amelogenesis 79129 1 Family 3327 Thyrocerebrorenal syndrome 2 Cases imperfecta 100088 Thyroid carcinoma 12.7 P Trichomegaly - retina 3363 pigmentary degeneration - 11 Cases 100088 Thyroid carcinoma 3.1 I dwarfism 95712 Thyroid ectopia 14.3 P * 3355 Trichoodontoonychial dysplasia 4 Cases 95719 25.0 P Trichorhinophalangeal Thyroid hemiagenesis 77258 100 Cases syndrome type 1 and 3 95720 Thyroid hypoplasia 3.5 P 33364 Trichothiodystrophy 201 Cases 100087 Thyroid tumor 3.2 I 1209 Tricuspid atresia 4.2 BP * 3329 Tibial aplasia - ectrodactyly 0.1 P * Trigonocephaly - bifid nose - 3368 2 Cases 93322 Tibial hemimelia 0.1 BP * acral anomalies 609 Tibial muscular dystrophy 6.0 P * 3365 Trigonocephaly - broad thumbs 2 Cases Trigonocephaly - short stature - 42665 Tietz syndrome 2 Families 3369 3 Cases developmental delay 65283 Timothy syndrome 20 Cases Triose phosphate-isomerase 868 50 Cases 314667 TMEM165-CDG 5 Cases deficiency Triphalangeal thumb - 2950 15 Families 3460 Torg-Winchester syndrome 12 Cases polysyndactyly syndrome Triphalangeal thumbs - 3338 Toriello-Carey syndrome 60 Cases 2947 4 Families brachyectrodactyly Toriello-Lacassie-Droste 3339 19 Cases syndrome 869 Triple A syndrome 100 Cases Torticollis - keloids - 3341 7 Cases 3376 Triploidy 12.6 BP * cryptorchidism - renal dysplasia 1742 Trisomy 5p 40 Cases 95455 Toxic epidermal necrolysis 0.19 I 1752 Trisomy 8q 30 Cases 3346 Tracheal agenesis 2.0 BP * 171929 50 Cases Tracheobronchopathia Trisomy 10p 3348 400 Cases osteochondroplastica 1699 Trisomy 12p 2.0 BP

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families 3378 Trisomy 13 3.7 BP * 3412 VACTERL with hydrocephalus 10 Families 3380 Trisomy 18 16.7 BP 887 VACTERL/VATER association 6.25 BP * 1715 Trisomy 18p 25 Cases 3417 Van den Bosch syndrome 1 Family 3375 Trisomy X 42.5 P * 2460 Van den Ende-Gupta syndrome 18 Cases 88629 Tritanopia 4.8 P * 314652 Variant ABeta2M amyloidosis 5 Cases 3384 Truncus arteriosus 4.3 BP 52759 Vasculitis 6.3 P * 3389 Tuberculosis 20.0 P * 1480 Ventricular septal defect 272.0 BP * Ventriculomegaly-cystic kidney 3389 Tuberculosis 139.0 I 443988 11 Cases disease 805 Tuberous sclerosis complex 10.0 BP * 70476 Vernal keratoconjunctivitis 32.0 P * Tubular renal disease - 73224 2 Cases cardiomyopathy 1493 Vici syndrome 20 Cases Virus-associated 1063 Tufted angioma 200 Cases 228379 7 Cases trichodysplasia spinulosa 182130 64.0 P * Tumor of endocrine glands Visceral neuropathy - brain 182130 Tumor of endocrine glands 3.75 I * 73246 anomalies - facial dysmorphism 2 Cases - developmental delay 363472 Tumor of testis and paratestis 3.15 I * Vitamin B12-responsive 28 192 Cases 881 Turner syndrome 5.5 BP * methylmalonic acidemia Vitamin B12-responsive 99745 Typhoid 3.0 I * 79310 methylmalonic acidemia type 60 Cases 882 Tyrosinemia type 1 0.9 BP cblA Vitamin B12-unresponsive 28378 Tyrosinemia type 2 150 Cases 79312 methylmalonic acidemia type 450 Cases 69723 Tyrosinemia type 3 20 Cases mut- 3403 Uhl anomaly 1.0 BP 3439 Von Voss-Cherstvoy syndrome 15 Cases 3404 Ulbright-Hodes syndrome 3 Cases 903 Von Willebrand disease 12.5 P Ulna hypoplasia - intellectual 83453 380 Cases 2249 2 Cases Vulvovaginal gingival syndrome disability 2804 W syndrome 6 Cases 3138 Ulnar-mammary syndrome 117 Cases 3440 Waardenburg syndrome 0.37 BP * Ulnar/fibula ray defect - 52056 1 Family brachydactyly 897 Waardenburg-Shah syndrome 50 Cases Umbilical cord ulceration - 3405 15 Cases 898 Wagner disease 100 Cases intestinal atresia Undifferentiated pleomorphic 893 WAGR syndrome 0.2 BP 2023 0.9 I * sarcoma Waldenström 33226 1.0 P * Unilateral multicystic dysplastic macroglobulinemia 97363 23.2 BP kidney Waldenström 33226 0.81 I * 1464 Univentricular heart 7.5 BP macroglobulinemia Univentricular heart with single 899 Walker-Warburg syndrome 1.65 BP * 99069 2 Cases atrio-ventricular valve 280558 Warsaw breakage syndrome 4 Cases 3408 Upington disease 1 Family 3447 Weaver syndrome 48 Cases 94059 Uremic pruritus 35.0 P * 3448 Weaver-Williams syndrome 30 Cases 210128 Urocanic aciduria 4 Cases 3449 Weill-Marchesani syndrome 1.0 P 886 Usher syndrome 4.8 P * Well-differentiated 99971 0.51 I * 178338 UV-sensitive syndrome 7 Cases liposarcoma Uveal coloboma-cleft lip and 901 Wells syndrome 80 Cases 1473 12 Cases palate-intellectual disability 902 Werner syndrome 0.5 P * 39044 Uveal melanoma 0.5 I * 3451 West syndrome 8.0 P * 98715 Uveitis 38.0 P * 3451 West syndrome 3.7 BP 98715 Uveitis 17.0 I *

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families X-linked distal arthrogryposis 51636 WHIM syndrome 65 Cases 1145 14 Families multiplex congenita 370131 1 Family White platelet syndrome X-linked dominant 35173 0.25 BP * Wiedemann-Rautenstrauch chondrodysplasia punctata 3455 25 Cases syndrome X-linked dominant Wild type ABeta2M 163966 10 Cases 85446 4.5 P * chondrodysplasia, Chassaing- amyloidosis Lacombe type 330001 Wild type ATTR amyloidosis 30.0 P * X-linked dyserythropoetic 363727 anemia with abnormal platelets 1 Family 904 Williams syndrome 10.8 BP and neutropenia X-linked Ehlers-Danlos 905 Wilson disease 3.3 P 75497 2 Families syndrome 905 Wilson disease 2.2 BP X-linked Emery-Dreifuss 98863 1.0 P 3459 Wilson-Turner syndrome 28 Cases muscular dystrophy X-linked Emery-Dreifuss 906 Wiskott-Aldrich syndrome 0.1 P * 98863 1.0 BP muscular dystrophy 1667 Wolcott-Rallison syndrome 60 Cases X-linked endothelial corneal 293621 35 Cases 280 Wolf-Hirschhorn syndrome 2.0 BP * dystrophy X-linked hereditary sensory and 3463 Wolfram syndrome 0.13 P 139583 autonomic neuropathy with 5 Families 3464 Woodhouse-Sakati syndrome 30 Cases deafness X-linked hypohidrotic Woolly hair - hypotrichosis - 181 0.75 BP * ectodermal dysplasia 1409 everted lower lip - outstanding 1 Family ears X-linked immunodeficiency with magnesium defect, Woolly hair-palmoplantar 317476 7 Cases 420686 8 Cases Epstein-Barr virus infection and keratoderma syndrome neoplasia Woolly hair-palmoplantar X-linked immunoneurologic 65282 keratoderma-dilated 7 Cases 2571 5 Cases disorder cardiomyopathy syndrome X-linked intellectual disability - 85327 2 Cases 3465 Worster-Drought syndrome 3.7 P * acromegaly - hyperactivity X-linked intellectual disability - 178475 Wound botulism 0.1 I * 85338 9 Cases ataxia - apraxia 2834 Wrinkly skin syndrome 30 Cases X-linked intellectual disability - 3466 WT limb-blood syndrome 3 Families 324410 cardiomegaly - congestive heart 2 Cases failure 43 X-linked adrenoleukodystrophy 5.0 BP X-linked intellectual disability - 137831 12 Families 47 X-linked agammaglobulinemia 0.22 P cerebellar hypoplasia X-linked intellectual disability - 391327 X-linked calvarial hyperostosis 1 Family 85330 corpus callosum agenesis - 4 Cases X-linked central congenital spastic quadriparesis 329235 27 Cases hypothyroidism with late-onset X-linked intellectual disability - 163979 7 Cases testicular enlargement craniofacioskeletal syndrome X-linked Charcot-Marie-Tooth X-linked intellectual disability - 64747 1.6 P * 85280 5 Cases disease cubitus valgus - dysmorphism X-linked Charcot-Marie-Tooth 101078 7 Cases X-linked intellectual disability - disease type 4 1568 Dandy-Walker malformation - 10 Cases X-linked Charcot-Marie-Tooth 352675 8 Cases basal ganglia disease - Seizures disease type 6 X-linked intellectual disability - 2958 8 Cases X-linked colobomatous dysmorphism - cerebral atrophy microphthalmia-microcephaly- 431140 1 Family X-linked intellectual disability - intellectual disability-short 85319 epilepsy - progressive joint 2 Cases stature syndrome contractures - dysmorphism X-linked complicated corpus 1497 11 Cases X-linked intellectual disability - callosum dysgenesis hypogammaglobulinemia - X-linked cone dysfunction 85317 3 Cases 90001 10 Families progressive neurological syndrome with myopia deterioration X-linked creatine transporter 52503 150 Cases X-linked intellectual disability - deficiency 85331 hypogonadism - ichthyosis - 4 Cases obesity - short stature

Number of Number of Estimated Estimated ORPHA Disease published ORPHA Disease published prevalence/incidence prevalence/incidence Number or Group of diseases cases or Number or Group of diseases cases or (/100,000) (/100,000) families families X-linked intellectual disability - X-linked intellectual disability, 85289 8 Cases 85329 hypotonia - facial dysmorphism 10 Cases Vitale type - aggressive behavior X-linked intellectual disability, 85290 3 Cases X-linked intellectual disability - Wilson type 85320 12 Cases macrocephaly - macroorchidism X-linked intellectual disability, 85291 3 Cases X-linked intellectual disability - Wittwer type 2898 2 Cases plagiocephaly X-linked intellectual disability, 85337 6 Cases X-linked intellectual disability - Zorick type 85318 3 Cases precocious puberty - obesity X-linked intellectual disability- X-linked intellectual disability - limb spasticity-retinal 3077 6 Cases 423479 2 Cases psychosis - macroorchidism dystrophy-diabetes insipidus X-linked intellectual disability - syndrome 3052 4 Cases seizures - psoriasis X-linked lissencephaly with 452 200 Cases X-linked intellectual disability - abnormal genitalia 163982 9 Cases spastic quadriparesis X-linked lymphoproliferative 2442 0.05 P * X-linked intellectual disability disease 67045 with isolated growth hormone 3 Families X-linked mandibulofacial 1131 7 Cases deficiency dysostosis X-linked intellectual disability, X-linked mendelian 85273 8 Cases Abidi type 319605 susceptibility to mycobacterial 13 Cases X-linked intellectual disability, diseases 85276 6 Cases Armfield type X-linked mendelian X-linked intellectual disability, susceptibility to mycobacterial 85293 24 Families 319612 4 Cases Cabezas type diseases due to IKBKG X-linked intellectual disability, deficiency 85277 9 Cases Cantagrel type X-linked microcephaly-growth X-linked intellectual disability, 435938 retardation-prognathism- 3 Cases 163971 4 Cases Cilliers type cryptorchidism syndrome X-linked intellectual disability, X-linked myopathy with 93947 3 Cases 25980 15 Families Golabi-Ito-Hall type excessive autophagy X-linked intellectual disability, X-linked myopathy with 163961 3 Cases 178461 1 Family Kroes type postural muscle atrophy X-linked intellectual disability, X-linked neurodegenerative 85283 4 Cases 85334 7 Cases Miles-Carpenter type syndrome, Bertini type X-linked intellectual disability, X-linked neurodegenerative 163937 35 Families 85336 10 Cases Najm type syndrome, Hamel type X-linked intellectual disability, X-linked non progressive 85322 1 Family 314978 3 Families Pai type cerebellar ataxia X-linked intellectual disability, X-linked osteoporosis with 85285 4 Cases 391330 5 Families Schimke type fractures X-linked intellectual disability, X-linked parkinsonism- 85323 4 Cases 363654 5 Cases Seemanova type spasticity syndrome X-linked intellectual disability, X-linked recessive intellectual 85286 9 Cases Shashi type 83648 disability - macrocephaly - 1 Family X-linked intellectual disability, ciliary dysfunction 85324 3 Cases X-linked recessive ocular Shrimpton type 54 0.58 BP * X-linked intellectual disability, albinism 85287 2 Families Siderius type X-linked reticulate pigmentary X-linked intellectual disability, 85453 disorder with systemic 6 Families 3063 11 Cases Snyder type manifestations X-linked intellectual disability, 792 X-linked retinoschisis 5.0 P 85325 4 Cases Stevenson type X-linked scapuloperoneal 431272 14 Cases X-linked intellectual disability, muscular dystrophy 85288 1 Family Stocco Dos Santos type X-linked severe congenital 86788 45 Cases X-linked intellectual disability, 85326 4 Cases neutropenia Stoll type 75563 X-linked sideroblastic anemia 200 Cases X-linked intellectual disability, 163976 7 Cases X-linked sideroblastic anemia Van Esch type 2802 5 Families and ataxia

Number of Estimated ORPHA Disease published prevalence/incidence Number or Group of diseases cases or (/100,000) families X-linked spastic paraplegia type 100997 1 Family 16 X-linked spastic paraplegia type 171607 24 Cases 34 X-linked spinocerebellar ataxia 85297 5 Cases type 3 X-linked spinocerebellar ataxia 85292 1 Family type 4 910 Xeroderma pigmentosum 0.23 BP * Xeroderma pigmentosum 276252 10 Families complementation group B Xeroderma pigmentosum 276255 50 Cases complementation group C Xeroderma pigmentosum 276258 30 Cases complementation group D Xeroderma pigmentosum 276261 10 Cases complementation group E Xeroderma pigmentosum 276264 22 Cases complementation group F Xeroderma pigmentosum 276267 10 Cases complementation group G Xeroderma pigmentosum 90342 50 Cases variant Xeroderma pigmentosum- 220295 30 Cases Cockayne syndrome complex 3469 XK aprosencephaly 10 Cases Xq12-q13.3 duplication 314389 3 Cases syndrome Xq27.3q28 duplication 261483 8 Cases syndrome 370930 XYLT1-CDG 2 Cases 662 Yellow nail syndrome 150 Cases Young adult-onset distal 314485 3 Cases hereditary motor neuropathy 2828 Young-onset Parkinson disease 15.0 P * 3472 Yunis-Varon syndrome 25 Cases 97240 Zebra body myopathy 10 Cases 217017 Zechi-Ceide syndrome 3 Cases Zellweger-like syndrome 50812 2 Cases without peroxisomal anomalies Zimmermann-Laband 3473 52 Cases syndrome 3253 Zlotogora-Ogur syndrome 50 Cases 913 Zollinger-Ellison syndrome 0.125 I

For any questions or comments, please contact us: [email protected] Editor-in-chief :Ana Rath – Editor of the report:Stéphanie Stéphanie Nguengang Wakap – Technical support : Samuel Demarest and Valérie Lanneau The correct form when quoting this document is : «Prevalence of rare diseases: Bibliographic data », Orphanet Report Series, Rare Diseases collection, March 2016, Number 1 : Diseases listed in alphabetical order http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_diseases.pdf

This Orphanet Report Series is part of the joint action 677024 RD-ACTION which has received funding from the European Union’s Health Programme (2014-2020).

The content of this Orphanet Report Series represents the views of the author only and is his/her sole responsibility; it can not be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.