Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders
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Next Generation Sequencing Panels for Disorders of Sex Development
Next Generation Sequencing Panels for Disorders of Sex Development Disorders of Sex Development – Overview Disorders of sex development (DSDs) occur when sex development does not follow the course of typical male or female patterning. Types of DSDs include congenital development of ambiguous genitalia, disjunction between the internal and external sex anatomy, incomplete development of the sex anatomy, and abnormalities of the development of gonads (such as ovotestes or streak ovaries) (1). Sex chromosome anomalies including Turner syndrome and Klinefelter syndrome as well as sex chromosome mosaicism are also considered to be DSDs. DSDs can be caused by a wide range of genetic abnormalities (2). Determining the etiology of a patient’s DSD can assist in deciding gender assignment, provide recurrence risk information for future pregnancies, and can identify potential health problems such as adrenal crisis or gonadoblastoma (1, 3). Sex chromosome aneuploidy and copy number variation are common genetic causes of DSDs. For this reason, chromosome analysis and/or microarray analysis typically should be the first genetic analysis in the case of a patient with ambiguous genitalia or other suspected disorder of sex development. Identifying whether a patient has a 46,XY or 46,XX karyotype can also be helpful in determining appropriate additional genetic testing. Abnormal/Ambiguous Genitalia Panel Our Abnormal/Ambiguous Genitalia Panel includes mutation analysis of 72 genes associated with both syndromic and non-syndromic DSDs. This comprehensive panel evaluates a broad range of genetic causes of ambiguous or abnormal genitalia, including conditions in which abnormal genitalia are the primary physical finding as well as syndromic conditions that involve abnormal genitalia in addition to other congenital anomalies. -
Benign Fibro-Osseous Lesions Plus…
“Vision is the art of seeing things invisible.” Jonathan Swift 1667 - 1745 Benign Fibro-osseous Lesions Plus… Steven R. Singer, DDS [email protected] 212.305.5674 Benign Fibro-osseous Lesions Fibrous Dysplasia A group of lesions in which normal bone is Localized change in bone metabolism replaced initially by fibrous connective tissue Normal cancellous bone is replaced by Over time, the lesion is infiltrated by osteoid fibrous connective tissue and cementoid tissue The connective tissue contains varying amounts of abnormal bone with irregular This is a benign and idiopathic process trabeculae Trabeculae are randomly oriented. (Remember that normal trabeculae are aligned to respond to stress) Fibrous Dysplasia Fibrous Dysplasia Lesions may be solitary (monostotic) or Fibrous dysplasia is non-hereditary involve more than one bone (polyostotic) Caused by a mutation in a somatic cell. Monostotic form accounts for 70% of all Extent of lesions depends on the timing of cases the mutation. Polyostotic form is more common in the first If the mutation occurs earlier, the disease decade will be more widespread throughout the M=F except in McCune-Albright syndrome, body. An example is McCune-Albright which is almost exclusively found in females Syndrome 1 Fibrous Dysplasia Fibrous Dysplasia McCune-Albright Syndrome • Monostotic and polyostotic forms usually -Almost exclusively begins in the second decade of life females -Polyostotic fibrous • Slow, painless expansion of the jaws dysplasia • Patients may complain of swelling or have -
Prestin, a Cochlear Motor Protein, Is Defective in Non-Syndromic Hearing Loss
Human Molecular Genetics, 2003, Vol. 12, No. 10 1155–1162 DOI: 10.1093/hmg/ddg127 Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss Xue Zhong Liu1,*, Xiao Mei Ouyang1, Xia Juan Xia2, Jing Zheng3, Arti Pandya2, Fang Li1, Li Lin Du1, Katherine O. Welch4, Christine Petit5, Richard J.H. Smith6, Bradley T. Webb2, Denise Yan1, Kathleen S. Arnos4, David Corey7, Peter Dallos3, Walter E. Nance2 and Zheng Yi Chen8 1Department of Otolaryngology, University of Miami, Miami, FL 33101, USA, 2Department of Human Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0033, USA, 3Department of Communication Sciences and Disorders, Auditory Physiology Laboratory (The Hugh Knowles Center), Northwestern University, Evanston, IL, USA, 4Department of Biology, Gallaudet University, Washington, DC 20002, USA, 5Unite´ de Ge´ne´tique des De´ficits Sensoriels, CNRS URA 1968, Institut Pasteur, Paris, France, 6Department of Otolaryngology University of Iowa, Iowa City, IA 52242, USA, 7Neurobiology Department, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA and 8Department of Neurology, Massachusetts General Hospital and Neurology Department, Harvard Medical School Boston, MA 02114, USA Received January 14, 2003; Revised and Accepted March 14, 2003 Prestin, a membrane protein that is highly and almost exclusively expressed in the outer hair cells (OHCs) of the cochlea, is a motor protein which senses membrane potential and drives rapid length changes in OHCs. Surprisingly, prestin is a member of a gene family, solute carrier (SLC) family 26, that encodes anion transporters and related proteins. Of nine known human genes in this family, three (SLC26A2, SLC26A3 and SLC26A4 ) are associated with different human hereditary diseases. -
PTEN Mutations the PTEN Hamartoma Tumor Synd
Updated December 2019 (NCCN v1.2020) Cowden Syndrome/PTEN Hamartoma Tumor Syndrome: PTEN Mutations The PTEN Hamartoma Tumor Syndrome (PHTS) is a spectrum of highly variable conditions with overlapping features. This spectrum includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and PTEN-related autism spectrum disorder.1-3 The term PHTS describes any individual with a germline pathogenic PTEN mutation, regardless of their clinical presentation.4 PHTS is a multisystem syndrome primarily characterized by noncancerous (benign), tumor-like growths called hamartomas that can develop throughout the body. There is also an increased risk of adult-onset cancers.5 Cancer Risks and General Management Recommendations PTEN Mutation General Surveillance/Management Recommendations9 Carrier Cancer Population Risks2,4-8 Lifetime Cancer Risks Female Breast: 12.4% Surveillance Primary: 33-60% Breast awareness, including periodic, consistent breast self exams, Second Primary: starting at age 18 years 29% within 10 Clinical breast exam every 6-12 months starting at age 25 years, or 5- years10 10 years before the earliest breast cancer diagnosis in the family (whichever comes first) Annual mammogram with consideration of tomosynthesis and breast MRI with contrast at age 30-35 years, or 5-10 years before the earliest breast cancer diagnosis in the family (whichever comes first) Age >75 years: Management should be considered on an individual basis Surgery Discuss option of risk-reducing mastectomy, including degree of protection, reconstruction -
The Genetic Basis for Skeletal Diseases
insight review articles The genetic basis for skeletal diseases Elazar Zelzer & Bjorn R. Olsen Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, Massachusetts 02115, USA (e-mail: [email protected]) We walk, run, work and play, paying little attention to our bones, their joints and their muscle connections, because the system works. Evolution has refined robust genetic mechanisms for skeletal development and growth that are able to direct the formation of a complex, yet wonderfully adaptable organ system. How is it done? Recent studies of rare genetic diseases have identified many of the critical transcription factors and signalling pathways specifying the normal development of bones, confirming the wisdom of William Harvey when he said: “nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path”. enetic studies of diseases that affect skeletal differentiation to cartilage cells (chondrocytes) or bone cells development and growth are providing (osteoblasts) within the condensations. Subsequent growth invaluable insights into the roles not only of during the organogenesis phase generates cartilage models individual genes, but also of entire (anlagen) of future bones (as in limb bones) or membranous developmental pathways. Different mutations bones (as in the cranial vault) (Fig. 1). The cartilage anlagen Gin the same gene may result in a range of abnormalities, are replaced by bone and marrow in a process called endo- and disease ‘families’ are frequently caused by mutations in chondral ossification. Finally, a process of growth and components of the same pathway. -
To View the ESE Recommended Curriculum of Specialisation in Clinical Endocrinology, Diabetes and Metabolism
European Society of Endocrinology Recommended Curriculum of Specialisation in Clinical Endocrinology, Diabetes and Metabolism Version 2, November 2019 Contents Endorsement ........................................................................................................................................ 2 Introduction .......................................................................................................................................... 3 1. Diabetes mellitus .............................................................................................................................. 4 2. Lipid disorders ................................................................................................................................... 5 3. Obesity and bariatric endocrinology ................................................................................................. 5 4. Pituitary ............................................................................................................................................ 5 5. Thyroid .............................................................................................................................................. 6 6. Parathyroid, calcium and bone ......................................................................................................... 7 7. Adrenal ............................................................................................................................................. 8 8. Reproductive endocrinology and sexual function -
Crouzon Syndrome Genetic and Intervention Review
Journal of Oral Biology and Craniofacial Research 9 (2019) 37–39 Contents lists available at ScienceDirect Journal of Oral Biology and Craniofacial Research journal homepage: www.elsevier.com/locate/jobcr Crouzon syndrome: Genetic and intervention review ∗ T N.M. Al-Namnama, , F. Haririb, M.K. Thongc, Z.A. Rahmanb a Department of Oral Biology, Faculty of Dentistry, University of MAHSA, 42610, Jenjarum, Selangor, Malaysia b Department of Oro-Maxillofacial Clinical Science, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia c Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia ARTICLE INFO ABSTRACT Keywords: Crouzon syndrome exhibits considerable phenotypic heterogeneity, in the aetiology of which genetics play an Crouzon syndrome important role. FGFR2 mediates extracellular signals into cells and the mutations in the FGFR2 gene cause this Molecular pathology syndrome occurrence. Activated FGFs/FGFR2 signaling disrupts the balance of differentiation, cell proliferation, Genetic phenotype and apoptosis via its downstream signal pathways. However, very little is known about the cellular and mole- cular factors leading to severity of this phenotype. Revealing the molecular pathology of craniosynostosis will be a great value for genetic counselling, diagnosis, prognosis and early intervention programs. This mini-review summarizes the fundamental and recent scientific literature on genetic disorder of Crouzon syndrome and presents a graduated strategy for the genetic approach, diagnosis and the management of this complex cra- niofacial defect. 1. Introduction known. CS commonly starts at the first three years of life.4 Craniosy- nostosis can be suspected during antenatal stage via ultrasound scan Craniosynostosis is a birth defect characterized by premature fusion otherwise is often detected at birth from its classic crouzonoid features of one or more of the calvarial sutures before the completion of brain of the newborn. -
Advances in Understanding the Genetics of Syndromes Involving Congenital Upper Limb Anomalies
Review Article Page 1 of 10 Advances in understanding the genetics of syndromes involving congenital upper limb anomalies Liying Sun1#, Yingzhao Huang2,3,4#, Sen Zhao2,3,4, Wenyao Zhong1, Mao Lin2,3,4, Yang Guo1, Yuehan Yin1, Nan Wu2,3,4, Zhihong Wu2,3,5, Wen Tian1 1Hand Surgery Department, Beijing Jishuitan Hospital, Beijing 100035, China; 2Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; 3Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing 100730, China; 4Department of Orthopedic Surgery, 5Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China Contributions: (I) Conception and design: W Tian, N Wu, Z Wu, S Zhong; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Y Huang; (V) Data analysis and interpretation: L Sun; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Wen Tian. Hand Surgery Department, Beijing Jishuitan Hospital, Beijing 100035, China. Email: [email protected]. Abstract: Congenital upper limb anomalies (CULA) are a common birth defect and a significant portion of complicated syndromic anomalies have upper limb involvement. Mostly the mortality of babies with CULA can be attributed to associated anomalies. The cause of the majority of syndromic CULA was unknown until recently. Advances in genetic and genomic technologies have unraveled the genetic basis of many syndromes- associated CULA, while at the same time highlighting the extreme heterogeneity in CULA genetics. Discoveries regarding biological pathways and syndromic CULA provide insights into the limb development and bring a better understanding of the pathogenesis of CULA. -
2018 Etiologies by Frequencies
2018 Etiologies in Order of Frequency by Category Hereditary Syndromes and Disorders Count CHARGE Syndrome 958 Down syndrome (Trisomy 21 syndrome) 308 Usher I syndrome 252 Stickler syndrome 130 Dandy Walker syndrome 119 Cornelia de Lange 102 Goldenhar syndrome 98 Usher II syndrome 83 Wolf-Hirschhorn syndrome (Trisomy 4p) 68 Trisomy 13 (Trisomy 13-15, Patau syndrome) 60 Pierre-Robin syndrome 57 Moebius syndrome 55 Trisomy 18 (Edwards syndrome) 52 Norrie disease 38 Leber congenital amaurosis 35 Chromosome 18, Ring 18 31 Aicardi syndrome 29 Alstrom syndrome 27 Pfieffer syndrome 27 Treacher Collins syndrome 27 Waardenburg syndrome 27 Marshall syndrome 25 Refsum syndrome 21 Cri du chat syndrome (Chromosome 5p- synd) 16 Bardet-Biedl syndrome (Laurence Moon-Biedl) 15 Hurler syndrome (MPS I-H) 15 Crouzon syndrome (Craniofacial Dysotosis) 13 NF1 - Neurofibromatosis (von Recklinghausen dis) 13 Kniest Dysplasia 12 Turner syndrome 11 Usher III syndrome 10 Cockayne syndrome 9 Apert syndrome/Acrocephalosyndactyly, Type 1 8 Leigh Disease 8 Alport syndrome 6 Monosomy 10p 6 NF2 - Bilateral Acoustic Neurofibromatosis 6 Batten disease 5 Kearns-Sayre syndrome 5 Klippel-Feil sequence 5 Hereditary Syndromes and Disorders Count Prader-Willi 5 Sturge-Weber syndrome 5 Marfan syndrome 3 Hand-Schuller-Christian (Histiocytosis X) 2 Hunter Syndrome (MPS II) 2 Maroteaux-Lamy syndrome (MPS VI) 2 Morquio syndrome (MPS IV-B) 2 Optico-Cochleo-Dentate Degeneration 2 Smith-Lemli-Opitz (SLO) syndrome 2 Wildervanck syndrome 2 Herpes-Zoster (or Hunt) 1 Vogt-Koyanagi-Harada -
Phenotypic and Genotypic Characterisation of Noonan-Like
1of5 ELECTRONIC LETTER J Med Genet: first published as 10.1136/jmg.2004.024091 on 2 February 2005. Downloaded from Phenotypic and genotypic characterisation of Noonan-like/ multiple giant cell lesion syndrome J S Lee, M Tartaglia, B D Gelb, K Fridrich, S Sachs, C A Stratakis, M Muenke, P G Robey, M T Collins, A Slavotinek ............................................................................................................................... J Med Genet 2005;42:e11 (http://www.jmedgenet.com/cgi/content/full/42/2/e11). doi: 10.1136/jmg.2004.024091 oonan-like/multiple giant cell lesion syndrome (NL/ MGCLS; OMIM 163955) is a rare condition1–3 with Key points Nphenotypic overlap with Noonan’s syndrome (OMIM 163950) and cherubism (OMIM 118400) (table 1). N Noonan-like/multiple giant cell lesion syndrome (NL/ Recently, missense mutations in the PTPN11 gene on MGCLS) has clinical similarities with Noonan’s syn- chromosome 12q24.1 have been identified as the cause of drome and cherubism. It is unclear whether it is a Noonan’s syndrome in 45% of familial and sporadic cases,45 distinct entity or a variant of Noonan’s syndrome or indicating genetic heterogeneity within the syndrome. In the cherubism. 5 study by Tartaglia et al, there was a family in which three N Three unrelated patients with NL/MGCLS were char- members had features of Noonan’s syndrome; two of these acterised, two of whom were found to have mutations had incidental mandibular giant cell lesions.3 All three in the PTPN11 gene, the mutation found in 45% of members were found to have a PTPN11 mutation known to patients with Noonan’s syndrome. -
Skeletal Dysplasias
Skeletal Dysplasias North Carolina Ultrasound Society Keisha L.B. Reddick, MD Wilmington Maternal Fetal Medicine Development of the Skeleton • 6 weeks – vertebrae • 7 weeks – skull • 8 wk – clavicle and mandible – Hyaline cartilage • Ossification – 7-12 wk – diaphysis appears – 12-16 wk metacarpals and metatarsals – 20+ wk pubis, calus, calcaneus • Visualization of epiphyseal ossification centers Epidemiology • Overall 9.1 per 1000 • Lethal 1.1 per 10,000 – Thanatophoric 1/40,000 – Osteogenesis Imperfecta 0.18 /10,000 – Campomelic 0.1 /0,000 – Achondrogenesis 0.1 /10,000 • Non-lethal – Achondroplasia 15 in 10,000 Most Common Skeletal Dysplasia • Thantophoric dysplasia 29% • Achondroplasia 15% • Osteogenesis imperfecta 14% • Achondrogenesis 9% • Campomelic dysplasia 2% Definition/Terms • Rhizomelia – proximal segment • Mezomelia –intermediate segment • Acromelia – distal segment • Micromelia – all segments • Campomelia – bowing of long bones • Preaxial – radial/thumb or tibial side • Postaxial – ulnar/little finger or fibular Long Bone Segments Counseling • Serial ultrasound • Genetic counseling • Genetic testing – Amniocentesis • Postnatal – Delivery center – Radiographs Assessment • Which segment is affected • Assessment of distal extremities • Any curvatures, fracture or clubbing noted • Are metaphyseal changes present • Hypoplastic or absent bones • Assessment of the spinal canal • Assessment of thorax. Skeletal Dysplasia Lethal Non-lethal • Thanatophoric • Achondroplasia • OI type II • OI type I, III, IV • Achondrogenesis • Hypochondroplasia -
RD-Action Matchmaker – Summary of Disease Expertise Recorded Under
Summary of disease expertise recorded via RD-ACTION Matchmaker under each Thematic Grouping and EURORDIS Members’ Thematic Grouping Thematic Reported expertise of those completing the EURORDIS Member perspectives on Grouping matchmaker under each heading Grouping RD Thematically Rare Bone Achondroplasia/Hypochondroplasia Achondroplasia Amelia skeletal dysplasia’s including Achondroplasia/Growth hormone cleidocranial dysostosis, arthrogryposis deficiency/MPS/Turner Brachydactyly chondrodysplasia punctate Fibrous dysplasia of bone Collagenopathy and oncologic disease such as Fibrodysplasia ossificans progressive Li-Fraumeni syndrome Osteogenesis imperfecta Congenital hand and fore-foot conditions Sterno Costo Clavicular Hyperostosis Disorders of Sex Development Duchenne Muscular Dystrophy Ehlers –Danlos syndrome Fibrodysplasia Ossificans Progressiva Growth disorders Hypoparathyroidism Hypophosphatemic rickets & Nutritional Rickets Hypophosphatasia Jeune’s syndrome Limb reduction defects Madelung disease Metabolic Osteoporosis Multiple Hereditary Exostoses Osteogenesis imperfecta Osteoporosis Paediatric Osteoporosis Paget’s disease Phocomelia Pseudohypoparathyroidism Radial dysplasia Skeletal dysplasia Thanatophoric dwarfism Ulna dysplasia Rare Cancer and Adrenocortical tumours Acute monoblastic leukaemia Tumours Carcinoid tumours Brain tumour Craniopharyngioma Colon cancer, familial nonpolyposis Embryonal tumours of CNS Craniopharyngioma Ependymoma Desmoid disease Epithelial thymic tumours in