small mouth

Fraser Syndrome 2

Clinical Characteristics
Ocular Features: 

Cryptophthalmos, both unilateral and bilateral, is the ocular hallmark.  The lid margins may be fused.

Systemic Features: 

Multiple systemic malformations are usually present.  A small mouth, nasal dysplasia with hypoplastic alae nasi, and syndactyly may be seen.  Urogenital malformations such as renal dysgenesis or dysplasia, ambiguous genitalia, streak ovaries may be present.  Pulmonary hypoplasia and imperforate anus have been reported.

Genetics

Homozygous mutations in the FREM2 gene (13q13.3) have been identified in Fraser syndrome 2.  

See Fraser syndrome 1 (219000) for additional features that may be present in Fraser syndrome.

Fraser syndrome 3 (617667) results from homozygous mutations in GRIP1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Ayme-Gripp Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have congenital cataracts which may be mild and "oil drop" in appearance.  The eyes appear far apart, the eyebrows are broad, and the palpebral fissures may slant upward or downward.  Ptosis has been reported.  Aphakic glaucoma has been reported in one juvenile who had unilateral cataract surgery at 5 months of age.

Systemic Features: 

The phenotype is heterogeneous and not all patients have all features.  The facial features are said to resemble those of the Down syndrome with brachycephaly, a high forehead, and a flat midface with shallow orbits and malar hypoplasia.  The ears are small, low-set, and posteriorly rotated.  The nose is short and the nasal bridge is broad and flat.  The mouth is small and the upper lip is thin.  The scalp hair may be sparse and the nails sometimes appear dystrophic.

The fingers are sometimes brachydactylous and tapered.  Short stature is common and the joints may have limited motion.  Dislocation of the radial heads is seen rarely while radioulnar synostosis has been seen in a few individuals.  Postnatal short stature is common.

Seizures often occur.  The ventricles appear large and cerebral atrophy has been reported.  Intellectual disability and mental retardation are common. However, at least one individual attended university although he had been diagnosed in childhood with Asberger disease.   Neurosensory hearing loss is common.

Genetics

This autosomal dominant condition results from heterozygous mutations in the MAF (16q32.2) gene.  At least one mother/son transmission event has been reported.

Many of the same features are seen in what has been called the Fine-Lubinsky syndrome (601353) but without mutations in the MAF gene.  It may not be a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment has been reported but specific anomalies such as cataracts should be addressed.

References
Article Title: 

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies

Niceta M, Stellacci E, Gripp KW, Zampino G, Kousi M, Anselmi M, Traversa A, Ciolfi A, Stabley D, Bruselles A, Caputo V, Cecchetti S, Prudente S, Fiorenza MT, Boitani C, Philip N, Niyazov D, Leoni C, Nakane T, Keppler-Noreuil K, Braddock SR, Gillessen-Kaesbach G, Palleschi A, Campeau PM, Lee BH, Pouponnot C, Stella L, Bocchinfuso G, Katsanis N, Sol-Church K, Tartaglia M. Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies. Am J Hum Genet. 2015 May 7;96(5):816-25.

PubMed ID: 
25865493

Congenital Heart Defects, Dysmorphic Facies, and Intellectual Developmental Disorder

Clinical Characteristics
Ocular Features: 

The dysmorphic facial features primarily involve the periocular structures.  These include hypertelorism, ptosis, epicanthal folds, strabismus and upslanted palpebral fissures.

Systemic Features: 

Septal defects involving both the atrium and the ventricle are consistently present.  Pulmonary valve abnormalities are present in some patients.

Posteriorly rotated pinnae and a small mouth with a thin upper lip have been observed.  Camptodactyly and clinodactyly are common.  Some patients have mild microcephaly.

Global developmental delay is a consistent feature manifest as delays in walking and speech and eventual intellectual disability.  Feeding difficulties are common.  Hypotonia and hypermobile joints are often noted.  Imaging of the brain may reveal agenesis of the corpus callosum, incomplete formation of the inferior vermis, and leukomalacia of periventricular tissue.

Genetics

Heterozygous mutations have been identified in the CDK13 gene (7p14.1) in seven unrelated individuals.  Heterozygous parents may not have the full phenotype.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the generalized condition.

References
Article Title: 

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T; INTERVAL Study., Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J; UK10K Consortium., Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD; Deciphering Developmental Disorders Study., Hurles ME. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016 Sep;48(9):1060-5.

PubMed ID: 
27479907

Cataracts, Congenital, with Cleft Palate

Clinical Characteristics
Ocular Features: 

Bilateral congenital cataracts are usually present together with upward-slanting and narrowed lid fissures.  The upper eyelids appear abnormally thick and epicanthus is common.  Nothing is known about the location or morphology of the lens opacities.

Systemic Features: 

Anomalies of the palate consisting of clefting, bifid uvula, and sub-mucous clefts are consistently present.  Oral anomalies such as thickening of the lower lid and small mouth are commonly seen.  The nose may be both long and broad.  The face usually appears oval and the forehead is prominent.  A cartilaginous nodule often appears on the helix of low-set and anteriorly rotated ears.  The fingers may be long and thin.

No cardiac or neurologic defects have been reported.

Genetics

Based on the transmission pattern in the single 4 generation family reported, autosomal dominant inheritance is likely.  Array comparative genomic hybridization revealed an interstitial amplification at Xp21.1 but this did not segregate precisely with the clinical pattern and is possibly a copy number polymorphism.  Both sexes are about equally affected. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No data on vision or surgical treatment have been reported but surgery for cleft palate and cataracts may be indicated.

References
Article Title: 

Rubinstein-Taybi Syndrome 1

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this disorder.  Few patients have all of the clinical features and there is much variation in the severity of these.  Almost all segments of the eye can be involved.  The lashes are often lush and the eyebrows may be highly arched and bushy.  Lid fissures are often downward slanting (88%).  Congenital glaucoma, nystagmus, cataracts, lacrimal duct obstruction (37%), ptosis (29%), colobomas and numerous corneal abnormalities including keratoglobus, sclerocornea, and megalocornea have been reported.  Abnormal VEP waveforms and cone and cone-rod dysfunction have been found in the majority (78%) of patients tested.  Retinal pigmentary changes have been seen in some patients.  Refractive errors (usually myopia) occur in 56% of patients.  Visual acuities vary widely but about 20% of patients are visually handicapped.

Fluorescein angiography in a single patient revealed generalized vascular attenuation and extensive peripheral avascularity.  The AV transit time was prolonged with delayed venous filling and late small vessel leakage. 

Systemic Features: 

The facial features are reported to be characteristic but there are few distinctive signs.  The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip.  Smiles have been described as 'grimacing'.  It is common for the columella to protrude beyond the alae nasi.  The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties.  The ears may be rotated posteriorly.  The anterior hairline can appear low.

Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially.  However, the distal phalanges of all fingers may be broad as well.  Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life.  Hypotonia is a feature.  Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.

Developmental delays are common.  Infancy and childhood milestones are often delayed.  Many patients have cognitive delays and some are mildly retarded.  Postnatal growth is subnormal and obesity is common.  A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus.  Renal abnormalities occur frequently and almost all males have undescended testes.  Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system.  Other problems are constipation and hearing loss.

Genetics

Evidence points to an autosomal dominant mode of inheritance secondary to mutations in CREBBP (16p13.3) but there is some genetic heterogeneity as mutations in EP300 (22q13) have been associated with a similar disease (see Rubinstein-Taybi Syndrome 2; 613684).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific clinical features such as glaucoma and strabismus.  Special education and vocational training may be helpful.  Hearing loss may respond to standard treatment.  Fractures and dislocations should receive prompt attention.  Cardiac anomalies may require surgical correction.

References
Article Title: 
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