Genetic Syndromes

Total Page:16

File Type:pdf, Size:1020Kb

Genetic Syndromes 7 Genetic Syndromes ADENYLOSUCCINATE LYASE DEFICIENCY A disorder of purine synthesis, adenylosuccinate lyase deficiency is a rare condition, with only about 40 published cases. It presents in early life with mental retardation and seizures. Although no specific diagnostic criteria have been proposed for the clinical syndrome, Table 1 summarizes clinical findings in 20 patients and may be useful as a guide in suspecting the diagnosis. ALEXANDER’S DISEASE Alexander’s disease is a rare genetic disease, presenting primarily in childhood. The genetic basis of Alexander’s disease involves mutations in the glial fibrillar acidic protein (GFAP) gene. Individuals with Alexander’s disease may present as infants, children, or rarely, as adults. Infants and children typically present with seizures, megalencephaly, developmental delay, and spasticity. Particularly in older patients, there may be bulbar or pseudobulbar symptoms, and spasticity, especially of the legs. The disease is progressive, with most patients dying within 10 years of onset. Until recently, the diagnosis has been pathological, with demonstration of Rosenthal fibers on brain biopsy. Genetic testing combined with clinical course and neuroimaging may be sufficient for diagno- sis. Other similar clinical syndromes may be seen with mutations in other genes, and differential diag- nosis is that of other leukoencephalopathies. In the study presented in Table 2, patients were included if they fulfilled the following minimum criteria: (1) magnetic resonance imaging findings of white matter changes with preferential involvement of the frontal regions of the brain; (2) normal karyotype; (3) normal metabolic screening; and (4) no family history of any leukoencephalopathy. ANGELMAN SYNDROME These criteria are applicable for the three major types of Angelman syndrome: molecular deletions involving the critical region (deletion-positive), uniparental disomy, and nondeletion/nonuniparental disomy. Angelman syndrome is currently clinically diagnosed and can be confirmed by laboratory testing in about 80% of cases. Individuals whose developmental history conforms to that described in Table 3, and who have all of the clinical findings of groups A and B in Table 4 should have a chromosome study, as well as molecular analysis by fluorescence in situ hybridization, polymorphism analysis, or methy- lation testing to look for alterations in chromosome region 15q11–q13. A positive genetic test (Table 5) may confirm the diagnosis, but a normal result does not exclude the diagnosis. In individuals with fewer clinical findings, a positive genetic test is presumptive evidence for Angelman syndrome. The judgment of the clinician is crucial when genetic testing is negative and clinical findings suggest the syndromic diagnosis. For individuals with no deletion or uniparental disomy, the clinician should be reasonably certain that the clinical findings in Tables 3 and 4 are present if the diagnosis of Angelman syndrome is still considered. From: Current Clinical Neurology: Diagnostic Criteria in Neurology Edited by: A. J. Lerner © Humana Press Inc., Totowa, NJ 83 Table 1 Clinical Findings in 20 Patients With Adenylosuccinate Lyase Deficiency S-Ado/ Seizure Psychomotor Autistic SAICAR, Author Sex onset EEG retardation features Others CT/MRI md/mL Outcome Jaeken et al., 1984 F — Normal Yes No eye Axial Cerebellar — Severe mental contact hypotonia, hypoplasia retardation growth retardation M 7 years Generalized Yes No eye Axial Cerebellar — Seizure abnormalities contact, hypotonia, hypoplasia, controlled by no language growth cortical CBZ retardation, atrophy muscular wasting F 2 years Diffuse slowing Yes No eye Growth Cerebellar — Seizure 8 contact, retardation, hypoplasia controlled by 4 no language muscular CBZ wasting Jaeken et al., 1988 M NR Abnormal Yes — — — — Died (13 years) F NR Abnormal Yes No eye Unvoluntary Cerebellar — Mild mental contact movements of hypoplasia retardation extremities, peripheral hypertonicity F 1 week Hypsarrhythmia Yes No eye Peripheral Cortical/ — Severe mental contact, hypertonicity cerebellar retardation, stereotypies atrophy intractable epilepsy M — Normal Yes No eye Strabismus, Normal — Severe mental contact, growth retardation stereotypies retardation F NR Diffuse slowing Yes No eye Growth Cerebral 4–5 Mild mental contact, retardation atrophy retardation, hypoacusia intractable epilepsy Jaeken et al., 1992 F 5 years Generalized Yes Aggressivity, — Slight cerebral 1.77 Mild mental abnormalities stereotypies atrophy retardation Salerno and Crifo F 7 months Focal/generalized Yes No language, Ataxia, — 1.2 Severe mental 1994 abnormalities stereotypies strabismus, retardation, muscular intractable wasting, epilepsy hyperactivity, Apraxia, growth retardation Sebesta et al., M NR Abnormal Yes — Hypotonia, Abnormal —Mild mental 1997 hyperactivity retardation FNRAbnormal Yes — Hypotonia, Abnormal —Mild mental hyperactivity retardation F 1 month Abnormal Yes — — Abnormal — Severe mental retardation F NR Abnormal Yes — — Abnormal — Died (15 years) M 1 month Abnormal Yes — — Abnormal — Severe mental retardation Maaswinkel-Mooij F 9 weeks HypsarrhythmiaYes— Axial Lack of 1.02 Severe mental 8 5 et al., 1997 hypotonia, myelinization retardation, peripheral intractable hypertoniaepilepsy Valik et al., 1997 F — Normal Yes — Muscular Increased T2 2.5–2.6 Severe mental hypotonia, signal in retardation fasciculations, semiovale strabismus center van den Bergh M2 days Burst Yes — Axial hypotonia— Died (7 months) et al., 1998 suppression Kohler et al., 1999 M 3 weeks Focal Yes No eye Muscular Slight 0.9 Severe mental abnormalities contact, hypotonia cerebral retardation, stereotypies atrophyseizure-free M3 days Status epilepticus, Yes — — Lack of 1.5 Died (6 months) burst suppression myelinization EEG, electroencephalography; CT, computerized tomography; MRI, magnetic resonance imaging; S-Ado, succinyladenosine; SAICA-R, succinylaminoimidazole carboxamide ribotide; NR, nonreferred; CBZ, carbamazepine. (Adapted with permission from Ciardo F, Costantino S, Curatolo P. Neurologic aspects of adenylosuccinate lyase deficiency. J Child Neurol 2001;16:301–308, and from BC Decker.) Table 2 Clinical and Molecular Findings in Patients With Alexander Disease Current status Mutation: Dementia exon/base Age at Bulbar and/or or Patient change/amino Initial onsetta/current pseudobulbar cognitive no./sex acid change presentation age ↑HCCb signs Seizures Spasticity deficits Other findings Infancy onset 1/F Exon 1 Seizures 3 months/ – Dysphagia, + + + Linear growth failure, 249C→G 3 years frequent vomiting, truncal hypotonia, no R79Gc or frequent language development choking episodes 2/M Exon 1 Seizures 6 months/ + Strabismus + – + Hypothyroidism 249C→T 5 years d 8 R79C 6 3/Me Exon 1 Seizures 18 months/ + Dysphagia, frequent + – + Born 3 weeks after 250G→A 9 yearsvomiting, or term; linear sebaceous R79Hd frequent choking nevi on scalp episodes; dysarthria or slurred speech 4/MMf Exon 1 Seizures 7 months/ + — ++ – 250G→A 2 years R79Hd 5/M Exon 4 Delayed motor 9 months/ + Dysarthria or – + – 729C→T development 4 years slurred speech R239Cd 6/M Exon 4 Failure to 12 months/ + Strabismus – – + 738T→G thrive; hypotonia 5 years Y242Dc 7/F Exon 6 Seizures 2 months/ + — + – N/A Born 10 days after 1131G→A 5 months term; noncongenital E373Kc truncal and appendicular hypotonia; poor weight gain, fussiness Juvenile onset 8/M Exon 1 Strabismus 9 years/ + Dysphagia, frequent + + + Stellate nevi 232T→G 15 years vomiting, or frequent M73R choking episodes; dysarthria or slurred speech; strabismus 9/M Exon 1 Excessive sleepiness, 7 years/ – Dysphagia, frequent – – + Linear growth failure 276C→T frequent vomiting 9 years vomiting, or frequent R88Cd choking episodes; dysarthria or slurred speech; strabismus 10e/M Exon 1 MRI changes N/Aa/4 years + — – – – Linear growth failure 276C→T observed during R88Cd evaluation for short stature 11/F Exon 8 Intractable 5 years/ – Dysphagia, frequent – – – Prone to episodes of 1260C→T vomiting 7 years vomiting, or frequent syncope after R416Wd choking episodes hyperventilation 12g/M Exon 8 MRI changes N/Aa/11 years – –– – – – Clumsiness and poor 8 → 7 1260C Tobserved after coordination R416Wd accidental eye (nonprogressive) injury 13h/F—Seizures 2 months/ + — + – + Frontal and parietal 10 yearsb white matter changes aNo age at onset is reported for Patients 10 and 12; evaluation for leukodystrophy was initiated only after incidental findings of white matter changes were discovered by MRI performed as part of examination for other conditions. bIncreased head circumference (↑HC) (megalencephaly) is positive (+) when the occipitofrontal circumference is >95th percentile for age. Patient 1 had HC trending at 2nd percentile, although her height and weight were <10th percentile as well; no language development is noted at current age (3 years). cParents’ DNA tested negative for the mutation. dThese mutations have previously been described: R79C, R79H, R88C, R239C, R416W. ePatient 3 was also homozygous for a 879G→A nucleotide change that results in a D295N amino acid change. This nucleotide change has previously been observed in 3% of healthy control subjects. In addition, this patient was also heterozygous for a silent 872G→A nucleotide change previously found in 9% of control subjects. Patients 10 and 13 were likewise heterozygous for these two nucleotide changes. Both of these nucleotide changes are found in exon 5. fPatient 4 was also heterozygous for a silent 110T→C nucleotide change
Recommended publications
  • Diagnostic Investigations in Individuals with Mental Retardation: a Systematic Literature Review of Their Usefulness
    European Journal of Human Genetics (2005) 13, 6–25 & 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00 www.nature.com/ejhg REVIEW Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness Clara DM van Karnebeek1,2, Maaike CE Jansweijer2, Arnold GE Leenders1, Martin Offringa1 and Raoul CM Hennekam*,1,2 1Department of Paediatrics/Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands; 2Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands There are no guidelines available for diagnostic studies in patients with mental retardation (MR) established in an evidence-based manner. Here we report such study, based on information from original studies on the results with respect to detected significant anomalies (yield) of six major diagnostic investigations, and evaluate whether the yield differs depending on setting, MR severity, and gender. Results for cytogenetic studies showed the mean yield of chromosome aberrations in classical cytogenetics to be 9.5% (variation: 5.4% in school populations to 13.3% in institute populations; 4.1% in borderline- mild MR to 13.3% in moderate-profound MR; more frequent structural anomalies in females). The median yield of subtelomeric studies was 4.4% (also showing female predominance). For fragile X screening, yields were 5.4% (cytogenetic studies) and 2.0% (molecular studies) (higher yield in moderate-profound MR; checklist use useful). In metabolic investigations, the mean yield of all studies was 1.0% (results depending on neonatal screening programmes; in individual populations higher yield for specific metabolic disorders). Studies on neurological examination all showed a high yield (mean 42.9%; irrespective of setting, degree of MR, and gender).
    [Show full text]
  • MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature
    J M Wit and others Genetics of short stature 174:4 R145–R173 Review MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short stature 1 1 2 2 Jan M Wit , Wilma Oostdijk , Monique Losekoot , Hermine A van Duyvenvoorde , Correspondence Claudia A L Ruivenkamp2 and Sarina G Kant2 should be addressed to J M Wit Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Email The Netherlands [email protected] Abstract The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature.
    [Show full text]
  • An Unusual Case of Cowden Syndrome Associated With
    Pistorius et al. Hereditary Cancer in Clinical Practice (2016) 14:11 DOI 10.1186/s13053-016-0051-8 CASE REPORT Open Access An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis Steffen Pistorius1,6*†, Barbara Klink2,7*†, Jessica Pablik3, Andreas Rump2, Daniela Aust3,7, Marlene Garzarolli4, Evelin Schröck2,7 and Hans K. Schackert5,6,7 Abstract Background: Ganglioneuromatous polyposis (GP) is a very rare disorder which may be associated with other clinical manifestations and syndromes, such as Cowden syndrome, multiple endocrine neoplasia (MEN) type II and neurofibromatosis (NF) 1. The risk for malignant transformation of ganglioneuromas is unknown, and the combination of GP with colon cancer has been only very seldom reported. Methods and results: We report the case of a 60-year old male patient with adenocarcinoma, adenomas and lipomas of the colon and multiple gastroduodenal lesions combined with generalised lipomatosis and macrocephaly. Based on the initial endoscopic and histological findings, a (restorative) proctocolectomy was recommended but declined by the patient. Instead, a colectomy was performed. The histological examination revealed an unforeseen GP in addition to the colon cancer. Extensive molecular diagnostics allowed for the differential diagnosis of the causes of the clinical manifestations, and the clinical suspicion of Cowden syndrome could not be confirmed using Sanger Sequencing and MLPA for the analysis of PTEN. Finally, a pathogenic germline mutation in PTEN (heterozygous stop mutation in exon 2: NM_000314 (PTEN):c.138C > A; p.Tyr46*) could be detected by next-generation sequencing (NGS), confirming an unusual presentation of Cowden syndrome with GP. Conclusions: Cowden syndrome should be considered in cases of GP with extracolonic manifestation and verified by combined clinical and molecular diagnostics.
    [Show full text]
  • Cutaneous Findings in Neurofibromatosis Type 1
    cancers Review Cutaneous Findings in Neurofibromatosis Type 1 Bengisu Ozarslan 1 , Teresa Russo 2, Giuseppe Argenziano 2 , Claudia Santoro 3 and Vincenzo Piccolo 2,* 1 Dermatology Unit, Doku Medical Center, 34381 Istanbul, Turkey; [email protected] 2 Dermatology Unit, University of Campania Luigi Vanvitelli, 80100 Naples, Italy; [email protected] (T.R.); [email protected] (G.A.) 3 Department of Woman, Neurofibromatosis Referral Centre, Child and of General and Specialised Surgery, University of Campania Luigi Vanvitelli, 80100 Naples, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-08-1566-6834; Fax: +39-08-1546-8759 Simple Summary: Neurofibromatosis type 1 (NF1) is characterized by major and minor cutaneous findings, whose recognition plays a key role in the early diagnosis of the disease. The disease affects multiple systems and clinical manifestation has a wide range of variability. Symptoms and clinical signs may occur over the lifetime, and the complications are very diverse. Although significant progress has been made in understanding the pathophysiology of the disease, no specific treatment has been defined. Multidisciplinary approach is required to provide optimum care for the patients. The aim of this paper is to provide the clinician with a complete guide of skin findings of NF1. Abstract: Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder associated with germline mutations in the NF1 tumor suppressor gene. NF1 belongs to a class of congenital anomaly syndromes called RASopathies, a group of rare genetic conditions caused by mutations in the Ras/mitogen-activated protein kinase pathway. Generally, NF1 patients present with dermatologic manifestations.
    [Show full text]
  • Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current Trends in Diagnosis and Management with a Focus on Novel Medical Therapies
    Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current trends in Diagnosis and Management with a focus on Novel Medical Therapies Simone Lisa Ardern-Holmes MBChB, MSc, FRACP A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Health Sciences, The University of Sydney February 2018 1 STATEMENT OF ORIGINALITY This is to certify that this submission is my own work and that, to the best of my knowledge, it contains no material previously published or written by another person, or material which to a substantial extent has been accepted for the award of any other degree or diploma of the university or other institute of higher learning, except where due acknowledgement has been made in the text. Simone L. Ardern-Holmes 2 SUMMARY Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are distinct single gene disorders, which share a predisposition to formation of benign nervous system tumours due to loss of tumour suppressor function. Since identification of the genes encoding NF1 and NF2 in the early 1990s, significant progress has been made in understanding the biological processes and molecular pathways underlying tumour formation. As a result, identifying safe and effective medical approaches to treating NF1 and NF2-associated tumours has become a focus of clinical research and patient care in recent years. This thesis presents a comprehensive discussion of the complications of NF1 and NF2 and approaches to treatment, with a focus on key tumours in each condition. The significant functional impact of these disorders in children and young adults is illustrated, demonstrating the need for coordinated care from experienced multidisciplinary teams.
    [Show full text]
  • Case Report Neurofibromatosis Type I in Children: a Case Report and Literature Review
    Int J Clin Exp Pathol 2020;13(10):2656-2660 www.ijcep.com /ISSN:1936-2625/IJCEP0119042 Case Report Neurofibromatosis type I in children: a case report and literature review Jing Wang*, Yaqian Pang*, Feng Cao, Hao Zhu, Kai Zhang* Department of Stomatology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, Anhui, P. R. China. *Equal contributors. Received July 27, 2020; Accepted September 14, 2020; Epub October 1, 2020; Published October 15, 2020 Abstract: Neurofibromatosis is an autosomal dominant genetic disease that originates from neuroepithelial tissue and involves disorders of ectoderm and mesoderm. At present, there are relatively few reports of neurofibroma type I in children. Therefore, understanding the clinical manifestations, diagnosis, and treatment of neurofibromatosis is of great significance to the occurrence and development of neurofibroma type I. This study is a case of and literature review of neurofibromatosis type I in children. Keywords: Neurofibromatosis, autosomal dominant hereditary disease, literature review Introduction more than half a year”. Six months ago, the family members of the patient inadvertently Neurofibromatosis (NF) is a rare progressive found a “soybean” painless, hard mass on the disease, usually caused by mutations in a left face of the child. After seeing a doctor in specific gene. NF is mainly divided into three the local hospital, the patient was treated with types, and type I (NF1) and type II (NF2) are anti-inflammatory treatment (specific drugs are most common [1, 2]. The incidence of NF1 is unknown). The effect was poor, and the mass approximately 1/3,000 to 1/400, accounting gradually increased.
    [Show full text]
  • Clinical and Genetic Patterns Ofneurofibromatosis 1 and 2
    662 BritishJournalofOphthalmology 1993; 77: 662-672 PERSPECTIVE Br J Ophthalmol: first published as 10.1136/bjo.77.10.662 on 1 October 1993. Downloaded from Clinical and genetic patterns of neurofibromatosis 1 and 2 Nicola K Ragge General introduction to the neurofibromatoses Neurofibromatosis type 1 The diseases traditionally known as neurofibromatosis have now been formally separated into two types: neurofibromato- CLINICAL ASPECTS sis type 1 or NFl (the type described by von Recklinghausen) Neurofibromatosis type 1 (NFI) is the commonest form of and neurofibromatosis type 2 or NF2 (a much rarer form).' It neurofibromatosis and has a frequency of about 1 in 3000 to is now recognised that although they have overlapping 1 in 3500.192° Although the gene is almost 100% penetrant, features, including an inherited propensity to neurofibromas the disease itselfhas extremely variable expressivity.20 About and tumours of the central nervous system, they are indeed 50% ofindex cases and 30% ofall NFl cases are considered to separate diseases and map to different chromosomes - 17 for be new mutations. The high mutation rate may be due in part NFl and 22 for NF2. Furthermore, developmental abnor- to the large size of the gene and its transcript, or possibly to malities such as hamartomas occur in both types of neuro- the presence of sequences within the gene highly susceptible fibromatosis, illustrating a need to define the role of the to mutation. normal NF genes in development. There may also be further forms of neurofibromatosis, including NF3, NF4, multiple meningiomatosis, and spinal Clinicalfeatures schwannomatosis, that do not fit precisely into current Particular clinical features are critical for establishing the diagnostic classifications.
    [Show full text]
  • Neurocutaneous Syndromes Maria A
    6 Neurocutaneous Syndromes Maria A. Musarella he neurocutaneous disorders are a group of clinically and Tgenetically heterogeneous diseases that are characterized mainly by harmatomas and tumor growth, involving tissues derived by the embryonic germ layer. Older literature has called these disorders “phakomatoses” (mother-spot). The modern nomenclature and traditional eponyms of these entities are given in Table 6-1. Each of the neurocutaneous diseases is rec- ognized as a distinct clinical disorder. This chapter covers the ophthalmic aspects of these syn- dromes, as well as the numerous and varied multisystemic man- ifestations. Although Proteus syndrome and multiple endocrine neoplasia (MEN) 2B are considered separate from the neurocu- taneous diseases, they are covered here because of the clinical resemblance to classic phakomatoses. NEUROFIBROMATOSIS 1 Historical Perspective Dr. Robert William Smith first described neurofibromatosis 1 (NF1) in 1849 in his treatise on Pathology Diagnosis and Treat- ment of Neuroma.100 However, this work received little atten- tion. Neurofibromatosis is most closely linked with the German pathologist, von Recklinghausen, who described the main fea- tures of this entity in his classic paper of 1882.111 Etiology About 50% of cases of NF1 result from new mutations. The NF1 gene has been mapped to 17q11.2 and positionally cloned. The 291 292 handbook of pediatric eye and systemic disease TABLE 6-1. Neurocutaneous Syndromes. Modern nomenclature Eponyms Neurofibromatosis 1 von Recklinghausen disease Peripheral neurofibromatosis Neurofibromatosis 2 Central neurofibromatosis Tuberous sclerosis Bourneville disease von Hippel–Lindau Disease Ataxia telangiectasia Louis–Bar syndrome Sturge–Weber Encephalotrigeminal angiomatosis Klippel–Trenaunay Angiosteohypertrophy Wyburn-Mason syndrome Racemose angiomatosis Multiple endocrine neoplasia 2B Mucosal neuroma syndrome (Wagenmann–Froboese) Proteus syndrome NF1 gene is one of the largest genes in which mutations lead to a disease in humans.
    [Show full text]
  • Neurofibromatosis Type 1
    Handbook of Clinical Neurology, Vol. 132 (3rd series) Neurocutaneous Syndromes M.P. Islam and E.S. Roach, Editors © 2015 Elsevier B.V. All rights reserved Chapter 4 Neurofibromatosis type 1 JACQUELINE L. ANDERSON AND DAVID H. GUTMANN* Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA INTRODUCTION background (Huson et al., 1989; Rasmussen and Friedman, 2000; Johnson et al., 2013). While NF1 is an History autosomal dominant condition, only 50% of people have Neurofibromatosis type 1 (NF1), previously known as an affected family member with NF1 (familial cases). As von Recklinghausen disease, is a common neurogenetic such, 50% of patients will be the first person in their fam- condition affecting 1:2500 people worldwide. NF1 prob- ily with NF1, arising from a sporadic NF1 gene mutation ably existed in ancient times, with art and literature from (De Luca et al., 2004; Evans et al., 2010). Life expectancy the 3rd century BCE documenting descriptions consistent is reduced by 8–15 years relative to the general popula- with the disease (Zanca, 1980). In 1849, an Irish surgeon tion, with malignancy constituting the major reason named Robert W. Smith differentiated patients with for death prior to the age of 30 (Rasmussen et al., traumatic neuromas from those with cases of multiple, 2001; Evans et al., 2011). With the establishment of an idiopathic neuromas (Smith, 1849). However, it was not online worldwide registry for patients with NF1, new until 1882 that the disease entity was fully recognized: the insights into the epidemiology of this common condition German pathologist Frederick von Recklinghausen first will likely emerge (Johnson et al., 2013).
    [Show full text]
  • Neurofibromatosis Type 1
    Neurofibromatosis type 1 Description Neurofibromatosis type 1 is a condition characterized by changes in skin coloring ( pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people. Beginning in early childhood, almost all people with neurofibromatosis type 1 have multiple café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. These spots increase in size and number as the individual grows older. Freckles in the underarms and groin typically develop later in childhood. Most adults with neurofibromatosis type 1 develop neurofibromas, which are noncancerous (benign) tumors that are usually located on or just under the skin. These tumors may also occur in nerves near the spinal cord or along nerves elsewhere in the body. Some people with neurofibromatosis type 1 develop cancerous tumors that grow along nerves. These tumors, which usually develop in adolescence or adulthood, are called malignant peripheral nerve sheath tumors. People with neurofibromatosis type 1 also have an increased risk of developing other cancers, including brain tumors and cancer of blood-forming tissue (leukemia). During childhood, benign growths called Lisch nodules often appear in the colored part of the eye (the iris). Lisch nodules do not interfere with vision. Some affected individuals also develop tumors that grow along the nerve leading from the eye to the brain (the optic nerve). These tumors, which are called optic gliomas, may lead to reduced vision or total vision loss. In some cases, optic gliomas have no effect on vision.
    [Show full text]
  • Klippel-Trenaunay Syndrome with Extensive Lymphangiomas
    Hindawi Publishing Corporation Case Reports in Pediatrics Volume 2015, Article ID 581394, 6 pages http://dx.doi.org/10.1155/2015/581394 Case Report Klippel-Trenaunay Syndrome with Extensive Lymphangiomas Sirin Mneimneh, Ali Tabaja, and Mariam Rajab Pediatric Department, Makassed General Hospital, Lebanon Correspondence should be addressed to Sirin Mneimneh; [email protected] Received 18 July 2015; Revised 2 October 2015; Accepted 8 October 2015 Academic Editor: Piero Pavone Copyright © 2015 Sirin Mneimneh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Klippel-Trenaunay syndrome (KTS) is a rare disorder characterized by the triad of vascular malformations, venous varicosities, and bone and soft-tissue hypertrophy. We present a case of Klippel-Trenaunay syndrome with limb hypertrophy, port-wine stains, lymphangiomas, and venous varicosities in the limbs. 1. Introduction syndactyly of the second and third toes of the right foot (Figure 5). The patient had dilated tortuous veins over the Klippel-Trenaunay syndrome (KTS) was first described in chest and the left leg (venous varicosities). 1900 by two French physicians, Klippel and Trenaunay [1]. The patient had no dysmorphic features or facial The term describes a rare congenital syndrome of venous, malformations; on examination she had no murmur, no lymphatic, and capillary malformations and soft tissue and organomegaly, good muscle power, and no deficits with bone hypertrophy [2]. positive deep tendon reflexes along with normal developmen- 63% of patients with KLS have the manifestation of the tal milestones and normal growth parameters.
    [Show full text]
  • Pathogenesis of Horrifying Rare Genetic
    The Pharma Innovation Journal 2017; 6(5): 85-89 ISSN (E): 2277- 7695 ISSN (P): 2349-8242 NAAS Rating 2017: 5.03 Pathogenesis of horrifying rare genetic disorders in TPI 2017; 6(5): 85-89 © 2017 TPI humans – A review www.thepharmajournal.com Received: 16-03-2017 Accepted: 17-04-2017 Gummalla Pitchaiah and E Pushpalatha Gummalla Pitchaiah Associate Professor Abstract Department of Pharmacology The identification of novel mutations causing genetic disease has seen more progress in the last few years Bharat Institute of Technology, than in the previous twenty. This increased body of research has resulted in a wealth of information Mangalpally (V), regarding the pathogenesis of rare genetic diseases. In this review, we illustrate the underlying Ibrahimpatnam (M), Ranga pathogenesis of few horrifying rare genetic diseases like Ectrodactyly, Proteus syndrome, Polymelia, Reddy (Dt), Telangana, India Neurofibromatoses, Diprosopus, Anencephaly, Cutaneous horn, Harlequin ichthyosis and Cyclopia in humans. E Pushpalatha Bharat Institute of Technology, Mangalpally (V), Keywords: Pathogenesis, rare disease, genetic Ibrahimpatnam (M), Ranga Reddy (Dt), Telangana, India 1. Introduction Diseases that affect less than 1/2000 individuals are referred to as rare; those with a prevalence lower than 1/50000 are referred to as ultra-rare. Rare genetic diseases are one of the most scientifically complex health challenges of our time. There are currently 7,000 known rare [1-2] diseases, of which 80% are genetic origin and half of which affect children . Rare diseases are characterized by diversity of symptoms that vary not only disease to disease but also from patient to patient affected by same disease. Rare diseases caused by altered functions of single genes can be chronically debilitating and life-limiting.
    [Show full text]