hearing loss

Encephalopathy, Progressive, Early-Onset, wtih Brain Atrophy and Spasticity

Clinical Characteristics
Ocular Features: 

Optic atrophy or cortical visual impairment with lack of visual tracking have been described in all patients.

Systemic Features: 

Microcephaly is evident at birth with global developmental delay and hearing loss.  One patient of 3 reported in 2 unrelated families had brief flexion seizures at 5 months.  Developmental regression and stagnation may become evident within the first months of life.  The EEG showed a hypsarrhythmia pattern.  Truncal hypotonia, spasticity, dystonia and/or myoclonus, scoliosis, and dysphagia are also features.  Two of the three reported patients had seizures. 

Brain MRI showed a pattern of pontine hypoplasia, partial agenesis of the corpus callosum, modified frontal gyri and diffuse cortical atrophy with enlarged ventricles have been described.  The cerebellum seems to be spared.

Genetics

Homozygous or compound heterozygous mutations in the TRAPPC12 gene (2p25.3) were found in 3 children in 2 unrelated families with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Joint Laxity, Short Stature, and Myopia

Clinical Characteristics
Ocular Features: 

Three of four brothers in one family had high myopia and two had retinal detachments as well as iris and chorioretinal colobomas.  In a second family with five sibs a teenage female was reported to have glaucoma and vision of legal blindness.  She and one brother had high myopia as well (parameters not reported).

Systemic Features: 

In one consanguineous family a brother and sister had multiple large joint dislocations including elbows, hips, knees and ankles.  The sister exhibited severe kyphoscoliosis while her brother had only mild kyphosis.  A single individual in each of the two sibships had hearing loss.

Three brothers in another consanguineous family had joint laxity and mild pectus carinatum.

Short stature was noted in all 5 affected individuals.  Cognitive development was reported as normal.

Genetics

Five individuals from 2 consanguineous Saudi sibships have been reported.  Homozygous mutations in the GZF1 gene (20p11.21) segregated as expected for an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.   Retinal detachment surgery and joint dislocation reduction should be considered in appropriate individuals.

References
Article Title: 

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

Patel N, Shamseldin HE, Sakati N, Khan AO, Softa A, Al-Fadhli FM, Hashem M, Abdulwahab FM, Alshidi T, Alomar R, Alobeid E, Wakil SM, Colak D, Alkuraya FS. GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome. Am J Hum Genet. 2017 May 4;100(5):831-836.

PubMed ID: 
28475863

3MC Syndromes

Clinical Characteristics
Ocular Features: 

The major ocular features involve the periocular structures.  These result in the typical facial dysmorphism and include hypertelorism, blepharoptosis, blepharophimosis, and highly arched eyebrows. Ptosis, unilateral or bilateral, can be present.

One patient was reported to have unilateral aniridia and a corneal leucoma.  Tear duct atresia was reported in another individual.

Systemic Features: 

Systemic features are highly variable in their presence and severity.   Facial clefting, growth deficiency, cognitive impairment, and hearing loss are present about half the time in some combination while craniosynostosis, urogenital anomalies, and radioulnar synostosis are seen in about a third of individuals.  More rare features include cardiac defects and abdominal midline defects (omphalocele and diastasis recti).

Genetics

This condition (3MC) is now postulated to include at least 3 disorders (Malpuech-Michels-Mingarelli-Carnevale syndromes) and considered here as a single autosomal recessive disease complex with overlapping clinical features that requires genotyping for diagnostic separation.  These are: 3MC1 syndrome (257920) resulting from homozygous mutations in the MASP1 gene (3q27.3), 3MC2 syndrome (265050) caused by mutations in the COLEC11 gene (2p25.3) and 3MC3 (248340) with mutations in the COLEC10 gene (8q24.12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective general treatment has been reported.

References
Article Title: 

COLEC10 is mutated in 3MC patients and regulates early craniofacial development

Munye MM, Diaz-Font A, Ocaka L, Henriksen ML, Lees M, Brady A, Jenkins D, Morton J, Hansen SW, Bacchelli C, Beales PL, Hernandez-Hernandez V. COLEC10 is mutated in 3MC patients and regulates early craniofacial development. PLoS Genet. 2017 Mar 16;13(3):e1006679. doi: 10.1371/journal.pgen.1006679. eCollection 2017 Mar.

PubMed ID: 
28301481

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat Genet. 2011 Mar;43(3):197-203.

PubMed ID: 
21258343

SHORT Syndrome

Clinical Characteristics
Ocular Features: 

Deeply set eyes are frequently noted and perhaps are a result of the lipodystrophy.  Anterior segment abnormalities resembling Rieger anomalies are often associated with congenital glaucoma. 

Systemic Features: 

There is considerable clinical heterogeneity.  The facial gestalt, however, is said to be characteristic.  These are: triangular progeroid facies with a prominent forehead, absence of facial fat, midface hypoplasia, and hypoplastic nasal alae.  Insulin resistance seems to be a consistent feature as well and nephrocalcinosis is common.  Serum and urinary calcium may be elevated even in infancy.

Teeth are late to erupt and bone age is delayed with shortness of stature the final result in many cases.  Joints are often hyperextensible.  A neurosensory hear loss has been found in some individuals.  Notably, developmental milestones are usually timely although mild cognitive delays are rarely seen and speech may be delayed.  Inguinal hernias are part of the syndrome. 

Genetics

Heterozygous mutations in the PIK3R1 gene (5q31.1) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serum and urinary calcium should be monitored.  The risk of glaucoma is high and patients should be monitored and treated appropriately.  Blood sugar and insulin levels may require treatment.  Inguinal hernias may require surgical repair.

References
Article Title: 

Mutations in PIK3R1 cause SHORT syndrome

Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL; FORGE Canada Consortium., Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. 

PubMed ID: 
23810382

Mental Retardation, X-Linked 99, Syndromic, Female-Restricted

Clinical Characteristics
Ocular Features: 

Palpebral fissures are generally shortened and may slant up or down.  Cataracts of unknown morphology have been reported and strabismus is common.

Systemic Features: 

The systemic phenotype is highly variable.  Skull and facial anomalies are common with brachycephaly, bitemporal narrowing, and a broad low nasal bridge. There is general developmental delay in both motor and cognitive abilities.  Patients are short in stature while scoliosis, hip dysplasia, and post-axial polydactyly may be present.  The teeth may be malformed and numerous (29%) of individuals have hypertrichosis.  Nearly a third of individuals have a cleft palate/bifid uvula.   Heart malformations, primarily atrial septal defects, are found in about half of affected individuals and urogenital anomalies such as renal dysplasia are relatively common.  Feeding difficulties have been reported while anal atresia is present in about half of patients.   

Brain imaging reveals hypoplasia of the corpus callosum, enlarged ventricles, Dandy-Walker malformations, cerebellar hypoplasia, and abnormal gyration patterns in the frontal lobe.  Generalized hypotonia has been diagnosed in half of reported patients and seizures occur in 24%.

Genetics

This female-restricted syndrome is caused by heterozygous mutations in the USP9X gene (Xp11.4).  X-chromosome inactivation is skewed greater than 90% in the majority of females but the degree of skewing in one study was independent of clinical severity.  The majority of cases occur de novo.

In males, hemizygous mutations in the USP9X gene (300919) cause a somewhat similar disorder (MRX99) without the majority of the congenital malformations having mainly the intellectual disabilities, hypotonia, and behavioral problems.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

There is no known treatment for the general disorder but individual anomalies or defects such as atrial septal defects, cleft palate, and anal atresia might be surgically corrected.

References
Article Title: 

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Reijnders MR, Zachariadis V, Latour B, Jolly L, Mancini GM, Pfundt R, Wu KM, van Ravenswaaij-Arts CM, Veenstra-Knol HE, Anderlid BM, Wood SA, Cheung SW, Barnicoat A, Probst F, Magoulas P, Brooks AS, Malmgren H, Harila-Saari A, Marcelis CM, Vreeburg M, Hobson E, Sutton VR, Stark Z, Vogt J, Cooper N, Lim JY, Price S, Lai AH, Domingo D, Reversade B; DDD Study, Gecz J, Gilissen C, Brunner HG, Kini U, Roepman R, Nordgren A, Kleefstra T. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb 4;98(2):373-81.

PubMed ID: 
26833328

Behr Syndrome

Clinical Characteristics
Ocular Features: 

Optic atrophy is the hallmark of this condition.  It is usually considered infantile in onset which may be helpful in the clinical diagnosis as many other forms of optic atrophy have their onset somewhat later.   Central scotomas and dyschromatopsia may be present.  Visual impairment is often severe but the progression can plateau in early midlife and remains static as first reported by Behr.

Systemic Features: 

A wide range of neurologic non-specific signs and symptoms may be present.  Behr's patients had ataxia, spasticity, sensory loss, and cognitive deficits.  Deafness has been reported in some patients.  All these may progress for a period of time and then remain static.  Heterozygous carriers have been reported to have mild neurologic manifestations.

It is important to emphasize that case descriptions reported in the literature often cannot be accurately assigned to a specific condition without genotyping.   For this reason histological reports of retinal ganglion cell loss and histological alterations in the brain such as gliosis and neuronal loss may or may not be a part of Behr syndrome.  Further studies should clarify what is now a confusing category of clinical disease.

Genetics

Homozygous or compound heterozygous mutations in the OPA1 gene (3q29) have been found in families with early-onset atrophy called Behr optic atrophy.  However, heterozygous mutations in the same gene have also been associated with optic atrophy (165500).  

Optic atrophy is a common sign among neurologic disorders such as spinocerebellar ataxias and in developmental (e.g., microphthalmia), and degenerative (e.g., retinal dystrophies) disorders of the eye.  More than 130 conditions with optic atrophy are described in this database.  Because of the overlapping clinical features, genotyping may be necessary to accurately determine which disorder is present.

See 165500 for a summary of the genetic heterogeneity of optic atrophy with links to other heritable forms OPA2 through OPA8.

See Behr Early Onset Optic Atrophy Syndromes in this database for more information on phenotypes and genotypes.

Homozygous mutations in OPA1 are also responsible for the mitochondrial DNA depletion syndrome 14 (616896) reported in a single family.  The clinical features include encephalomypathy, hypertrophic cardiomyopathy, and abnormal pursuit movements with optic atrophy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation

Spiegel R, Saada A, Flannery PJ, Burte F, Soiferman D, Khayat M, Eisner V, Vladovski E, Taylor RW, Bindoff LA, Shaag A, Mandel H, Schuler-Furman O, Shalev SA, Elpeleg O, Yu-Wai-Man P. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet. 2016 Feb;53(2):127-31.

PubMed ID: 
26561570

Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Bonneau D, Colin E, Oca F, Ferre M, Chevrollier A, Gueguen N, Desquiret-Dumas V, N'Guyen S, Barth M, Zanlonghi X, Rio M, Desguerre I, Barnerias C, Momtchilova M, Rodriguez D, Slama A, Lenaers G, Procaccio V, Amati-Bonneau P, Reynier P. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain. 2014 Oct;137(Pt 10):e301.

PubMed ID: 
25012220

Multi-system neurological disease is common in patients with OPA1 mutations

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133(Pt 3):771-86.

PubMed ID: 
20157015

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

Clinical Characteristics
Ocular Features: 

Patients have been described as having variable oculofacial features including epicanthal folds, hypertelorism, strabismus, and 'tapetoretinal degeneration'.    

Systemic Features: 

The full phenotype is variable and unknown based on the 5 reported patients from 4 families of whom 3 were consanguineous.  Recurrent infections (especially respiratory and otitis media) seem to be among the most consistent features.  Others include intrauterine growth retardation, developmental delay including psychomotor delays, a flat midface with various anomalies, low-set ears, renal dysgenesis, polydactyly, severe agammaglobulinemia, hypospadias, and cryptorchidism.  Normal T-cell function and normal B cells are present.  Conductive hearing loss, polydactyly, and scoliosis may be features as well.  Two of the 5 reported patients with ICF3 were reported to have mental retardation.  One patient died at the age of 26 years.

Genetics

Homozygosity of CDCA7 (2q31.1) mutations with centromeric instability and hypomethylation of selected juxtacentromeric heterochromatin regions is responsible for this (ICF3) autosomal recessive condition.  There is genetic heterogeneity in ICF (ICF1, ICF2, ICF3, and ICF4 [see 242860).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome

Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Gungor T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870.

PubMed ID: 
26216346

Vici Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts, both unilateral and bilateral are common.  The fundus appears hypopigmented. Nystagmus, optic neuropathy, and mild ptosis have been reported.  Nothing is known regarding acuity. 

Systemic Features: 

Infants at birth have striking hypotonia with a weak cry and feeding difficulties.  Dysmorphic features such as micrognathia, microcephaly, low-set ears, some degree of generalized hypopigmentation (hair and skin), and a broad nose with a long philtrum may be present. The face may appear triangular.  Cleft lip and palate may be present.  Evidence of cardiac dysfunction may also be present early with both dilated and hypertrophic cardiomyopathy reported.  Hearing loss has been reported in some individuals.  Recurrent infections are common and immunologic studies have revealed, in some patients, granulocytopenia, low T cell counts (primarily T4+ cells), thymic dysplasia, and low levels of IgG.  Seizures may occur.  Liver dysfunction has been variably reported.

Neurological and brain evaluations have reported agenesis of the corpus callosum, defects in the septum pellucidum, and hypoplasia of the cerebellar vermis along with pontocerebellar hypoplasia.  Psychomotor retardation is severe in most individuals along with general growth retardation.

Histologic studies of skeletal muscle fibers have shown considerable variation in fiber size, centralized nuclei, fucsinophilic inclusions, and enlarged abnormal mitochondria.  Other central nervous system abnormalities include in some individuals a paucity of white matter, schizencephaly, neuronal heterotopias, and enlargement of the ventricles.

The cumulative effects of these multiorgan abnormalities lead to death within the first year or two of life, generally of heart failure or sepsis. 

Genetics

Homozygous or compound heterozygous mutations in the EPG5 gene (18q12.3) have been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Vici syndrome: a

Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: a
review
. Orphanet J Rare Dis. 2016 Feb 29;11(1):

PubMed ID: 
4772338

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, Simpson MA, Yau S, Bertini E, McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wijburg FA, ten Hoedt AE, Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM, Windpassinger C, Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel HH, Sewry CA, Abbs S, Mohammed S, Josifova D, Gautel M, Jungbluth H. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013 Jan;45(1):83-7.

PubMed ID: 
23222957

Spondyloocular Syndrome

Clinical Characteristics
Ocular Features: 

Cataracts have been noted in several patients in the first and second decades of life.  Nystagmus and ‘amblyopia’ have also been reported.  Several individuals have had retinal detachments.

Systemic Features: 

Only a small number of families have been reported.  Poor bone mineralization with frequent fractures in long bones and vertebral compression seem to be consistent features often noted in the first and second decades of life.  Moderate osteoporosis and advanced bone age with platyspondyly may be present.  The vertebral fractures lead to abnormal spinal curvature and may result in shortened stature. 

Some sensorineural hearing loss is sometimes detected in the first decade.  The ears have been described as low-set and posteriorly rotated.  A variety of cardiac defects have been reported including mitral valve prolapse, septal defects, and anomalies of the aortic valve. 

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in the XYLT2 gene located at 17q21.33. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pamidronate given intravenously seems to have little therapeutic value.  Hearing aids can be beneficial.  Lensectomy may be of benefit although no reports of cataract surgery have been reported.  Fractures need immediate attention.  Patient may become wheelchair-bound by the second decade.  Special education may be helpful for those with learning difficulties.

References
Article Title: 

CHOPS Syndrome

Clinical Characteristics
Ocular Features: 

There is usually some degree of proptosis and apparent hypertelorism.  The eyebrows are bushy and the eyelashes are luxurious.  One of three patients had cataracts and another had mild optic atrophy.

Systemic Features: 

The overall facial appearance may resemble Cornelia de Lange syndrome with hypertrichosis and a coarse, round facies.  Head circumference is low normal.  Septal defects and a patent ductus arteriosus are often present.  Laryngeal and tracheal malacia predispose to recurrent pulmonary infections and chronic lung disease.  Skeletal dysplasia includes brachydactyly and anomalous vertebral bodies resulting in short stature (3rd percentile).  Genitourinary abnormalities include cryptorchidism, horseshoe kidney, and vesiculoureteral reflux.  Delayed gastric emptying and reflux have been reported.

Genetics

Heterozygous mutations in the AFF4 gene (5q31.1) have been identified in 3 unrelated individuals with this condition.  No familial cases have been identified.  The gene is a core component of the super elongation complex that is critical to transcriptional elongation during embryogenesis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the general disorder.  Tracheostomy was required in 2 of three reported patients. 

References
Article Title: 

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44.

PubMed ID: 
25730767

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