skeletal anomalies

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

Cataracts, Congenital, Deafness, Short Stature, Developmental Delay

Clinical Characteristics
Ocular Features: 

The facial features superficially resemble those often seen in Down syndrome patients with slanting (up or down) lid fissures and epicanthal folds. The amount of ptosis is variable.  Lens opacities are usually congenital in origin.  Hypopigmentation of the macula has been noted in two individuals.

Systemic Features: 

The characteristic facies may be evident at birth and requires karyotyping to rule out the trisomy of Down syndrome. Brachycephaly and a flat face may be present.  The mouth is often small and the nasal tip is shortened while the philtrum is long and smooth.  Some degree of intellectual disability and neurosensory hearing loss soon become evident.  There is postnatal growth delay and most individuals are short in stature.  The ears are low-set and rotated posteriorly.

The skeletal anomalies are not fully delineated but one patient had bilateral radioulnar synostosis while hip chondrolysis requiring hip replacement has been seen in two adult individuals.  Limited motion may be present in some joints, both large and small.  Seizures have been reported in a few individuals. Nails may appear dystrophic and there are variable tooth anomalies present. 

Genetics

The responsible heterozygous mutations are in the MAF gene (16q22-q23).  Type 4 (CCA4) (610202) autosomal dominant cerulean cataracts with multiple morphologies may also result from mutations in this transcription factor gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment for this condition is known.  Congenital cataracts can be removed.  Some patients may benefit from special education.   Seizure medications may be indicated and some patients can benefit from hearing aids.  Severe joint disease may require replacement.

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

Kabuki Syndrome 1

Clinical Characteristics
Ocular Features: 

The facial features and specifically the periocular anomalies are diagnostic and responsible for the eponymic designation (resembling the make-up of actors of a Japanese theatrical form known as Kabuki). The lid fissures are long and narrow and the lateral third of the lower lids are often everted.  The eyebrows are highly-arched and broad with some sparsity especially in the lateral portion.  The eyelashes are thick and ptosis is often noted. Strabismus may be present.  Blue sclerae have been reported.

Some patients may have extreme microphthalmia.

Systemic Features: 

Post-natal growth delay and short stature are present as a result of anomalies in the vertebrae often with secondary scoliosis.  Persistence of the fetal fingertip pads is common. Hypotonia and joint hypermobility have been noted and some degree of intellectual disability is common.  Seizures have been reported but these are not common. Cleft lip and palate are seen in about a third of patients and the palate is highly arched in about 75%.  The teeth are small, frequently malformed and widely spaced.  Feeding difficulties are common.  Anal anomalies such as imperforate anus, anovestibular fistulas, and an anteriorly placed opening may be present, especially in females.  A small penis, hypospadias, and cryptorchidism are common in males.

An ill-defined immune deficit seems to be a common feature as evident by susceptibility to infections, primarily otitis media in infants and later recurrent sinopulmonary infections.   The majority of patients have hypogammaglobulinemia with a variable pattern of antibody abnormalities resembling common variable immune deficiency and especially low levels of serum IgA.  

Hearing loss is seen in nearly half of patients, some of which is no doubt due to recurrent otitis media but CT radiography has demonstrated dysplastic morphology of inner ear structures and the petrous bone.  The ears are large and cupped and preauricular pits may be present as well.

Biliary atresia and a variety of morphological anomalies of the kidney have been reported.  Renal failure can occur.  Perhaps as many as 58% of patients have congenital heart defects, mostly septal in location. 

Genetics

Heterozygous mutations in KMT2D (12q13.12) (also called MLL2) are responsible for Kabuki syndrome 1 but parental transmission to offspring is rare and the majority of patients occur sporadically.  There is also an X-linked form (Kabuki 2) caused by mutations in KDM5A (Xp11.3).  Insufficient clinical data regarding the X-linked phenotype so far has precluded the ability to distinguish the two disorders without genotyping.

Residual genetic heterogeneity remains, however, as a substantial proportion of patients do not have mutations in the two mutant genes known.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this condition.  Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

MLL2 and KDM6A mutations in patients with Kabuki syndrome

Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A. 2013 Sep;161A(9):2234-43. 

PubMed ID: 
23913813

Microphthalmia, Syndromic 1

Clinical Characteristics
Ocular Features: 

Microphthalmia is often a part of other ocular and systemic anomalies.  The full range of essential features of Lenz microphthalmia remains unknown but is often diagnosed in males when colobomas and microcornea are associated with mental deficits together with urogenital and skeletal anomalies.  Microphthalmos may be unilateral and ocular cysts are common.  The globes may be sufficiently small that anophthalmia is sometimes diagnosed but this is a misnomer as some ocular tissue is always present.   Sixty per cent of eyes have colobomas which are often bilateral and may involve the optic disc, choroid, ciliary body, and iris.  Blindness is common.  

Systemic Features: 

A large number of associated systemic anomalies have been reported with this type of microphthalmia.  Skeletal features include microcephaly, spinal deformities, high arched palate, pectus excavatum, absent or dysplastic clavicles (accounting for the narrow or sagging shoulders), and digital anomalies including syndactyly, duplicated thumbs and clinodactyly.  Physical growth retardation is evident by shortness of stature.   Urogenital malformations are present in 77% of individuals and include hypospadius, cryptorchidism, hydroureter, and renal dysgenesis.  Dental anomalies include oligodontia and irregular lower incisors that may be widely spaced.  Some degree of intellectual disability is present in 63%.  The ears may be abnormally shaped, low-set, rotated posteriorly, and anteverted. 

Genetics

This is a rare X-linked disorder that is apparently due to an unknown mutation at Xq27-Xq28.  No male-to-male transmission has been observed but affected males rarely reproduce as a result of various urogenital anomalies.

A somewhat similar X-linked syndrome of microphthalmia, sometimes called OFCD syndrome (syndromic 2 microphthalmia; 300166) has been reported to be caused by mutations in BCOR (Xp11.4).  This MCOPS2 disorder is often considered to be X-linked dominant with lethality in males.

Another X-linked non-syndromic form of microphthalmia with colobomas has been reported (Microphthalmia with Coloboma, X-Linked; 300345).  In addition there is a similar disorder of simple Microphthalmia with Coloboma that is inherited either in an autosomal dominant or autosomal recessive pattern (605738, 610092, 611638, 613703, 251505 ).

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no treatment beyond supportive care for specific health issues. 

References
Article Title: 

Cataracts, Congenital, Facial Dysmorphism, and Neuropathy

Clinical Characteristics
Ocular Features: 

Cataracts, microphthalmia, and microcornea (mean diameter ~7.5 mm) are present at birth and precede the onset of neurological symptoms.  The lens opacities often consist of anterior and posterior subcapsular opacities but the entire lens may be opaque as well.  Some adults have bilateral ptosis.  The pupils are often small and have sluggish responses to light and mydriatics.  Strabismus and horizontal pendular nystagmus are common.  Visual impairment may be severe.

Systemic Features: 

The neuropathy is primarily motor and usually begins in the lower extremities but is progressive and eventually involves the arms as well.  Motor development is slow and walking is often unsteady from the start.  Speaking may not have its onset until 3 years of age.   Mild, nonprogresssive cognitive defects and mental retardation are often present.  Sensory neuropathy with numbness and tingling develops in the second decade.  Mild chorea, upper limb tremor, mild ataxia, and extensor plantar responses may be seen.  Deafness has been described.  Nerve conduction studies and biopsies have documented a demyelinating polyneuropathy while MRIs demonstrate cerebral and spinal cord atrophy which may be seen in the first decade of life.  The MRI in many patients reveals diffuse cerebral atrophy, enlargement of the lateral ventricles and focal lesions in subcortical white matter.  Most individuals have mild cognitive deficits while psychometric testing reveals borderline intelligence in a minority.

Patients are susceptible to acute rhabdomyolysis following viral infections.  Most are severely disabled by the third decade.

The facial dysmorphism appears in childhood and consists of a prominent midface, hypognathism, protruding teeth, and thickening of the lips.  Spinal deformities occur in the majority of individuals along with foot and hand claw deformities.  All patients are short in stature.  Hypogonadotropic hypogonadism is a common feature and females may be infertile.  Amenorrhea is often present by the age of 25-35 years.

Genetics

This is an autosomal recessive disorder found primarily among European Gypsies.  It is caused by mutations in the CTDP1 gene (18q23-qter).  It is sometimes confused with Marinesco-Sjogren syndrome (248800) with which it shares some clinical features but the two are genetically distinct.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts often require removal in the first decade of life. Scoliosis and foot deformities may benefit from surgical correction.  Supportive care and physical therapy can be helpful.

References
Article Title: 

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations

Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol. 1999 Jun;45(6):742-50.

PubMed ID: 
10360766
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