short palpebral fissures

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

Feingold Syndrome 1

Clinical Characteristics
Ocular Features: 

Short, narrow palpebral fissures have been reported (73%).  The fissures may be up slanting and epicanthal folds have been noted.   

Systemic Features: 

The face can appear asymmetrical and triangular and the head is small in 89% of individuals.  Micrognathia is usually present and the lips appear full.  The nasal bridge is broad and the nostrils are anteverted.  The ears are often low-set and rotated posteriorly.  Syndactyly of the toes is common (97%) and the fingers are often anomalous (particularly 5th finger clinodactyly and brachydactyly) with hypoplastic thumbs.  Shortening of the 2nd and 5th middle phalanx of the fingers is especially common.  True short stature is uncommon but 60% are below the 10th centile.  Rare individuals have a sensorineural hearing loss.

Tracheoesophageal fistulas are often present, together with atresia of the duodenum and sometimes the esophagus as well.  Cardiac, renal, and vertebral malformations are seen in a minority of patients.

Intelligence may be normal but more often is below average and learning difficulties are often present.

Genetics

This is an autosomal dominant disorder secondary to mutations in the MYCN gene (2p24.3).

MYCN is up regulated in some patients with retinoblastoma (180200).

Feingold syndrome 2 (614326) is caused by hemizygous deletions of the MIR17HG gene but no ocular signs have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for the syndrome but surgery can be important for some of the external and internal malformations. Special education and treatment of hearing loss are important.

References
Article Title: 

Genotype-phenotype correlations in MYCN-related Feingold syndrome

Marcelis CL, Hol FA, Graham GE, Rieu PN, Kellermayer R, Meijer RP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer AP. Genotype-phenotype correlations in MYCN-related Feingold syndrome. Hum Mutat. 2008 Sep;29(9):1125-32.

PubMed ID: 
18470948
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