MAF

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

Cataracts, Congenital Cerulean

Clinical Characteristics
Ocular Features: 

Tiny lens opacities of blue or white color generally appear from birth through 18 and 24 months of age but may not be diagnosed until adulthood.  They first appear at the outer edge of the fetal lens nucleus or in more superficial cortical layers depending on the type.  Infants may be visually impaired from birth and develop nystagmus and amblyopia.  The opacities are usually bilateral and progressive.  Lens removal may be required in early infancy but often not until the 2nd to 4th decades.

Systemic Features: 

No systemic abnormalities are associated with cerulean cataracts.

Genetics

Lens opacities can, of course, be associated with chromosomal aberrations, developmental conditions, intrauterine infections, and metabolic errors as well as single gene mutations.   About 23% are familial but even among these there is considerable genetic and clinical heterogeneity that confounds the nosology despite notable recent progress in genotyping.  Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Cerulean cataracts of congenital or childhood onset can be due to mutations in genes that encode various lens crystallins.  Type 1 (CCA1; 115660) or 'blue dot' cerulean cataracts result from mutations in a gene located at 17q24 but its identity is as yet unknown. Intriguingly, it is located in the same chromosomal vicinity as the galactokinase deficiency gene (GALK1).  The lens opacities follow an autosomal dominant pattern of transmission. The mutation, however, does not appear to involve a gene that codes for any of the major structural proteins of the lens.

Type 2 (CCA2; 601547) results from mutations in the CRYBB2 gene (22q11.2-q12.2) encoding the beta-B2-crystallin protein.  Inheritance is autosomal dominant.

Type 3 (CCA3; 608983) is caused by mutations in CRYGD (2q33-q35) coding gamma-D-crystallin.  It has been reported in a single family in which it seemed to appear earlier and progress more rapidly than other types.  The pedigree pattern was consistent with autosomal dominant inheritance.  Mutations in the same gene also cause an allelic disorder designated nonnuclear polymorphic congenital cataracts or PCC (601286), which may simply be clinical heterogeneity of the same condition.

Type 4 (CCA4; 610202) is due to mutations in the MAF gene (16q22-q23) and is also inherited in an autosomal dominant pattern.  Lens opacities have a later, more juvenile onset and the lens opacities are located in a lamellar distribution in superficial cortical layers.  These are progressive and often result in posterior subcapsular opacification that requires lens extraction in adults.

Type 5 (CCA5; 614422) is the result of a mutation in a locus at 12q24 and is dominantly inherited.  The opacities are located throughout the lens but are most numerous in the cortex.   They are most commonly diagnosed in the second decade of life and lens extractions are required a decade or so later.

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include Volkmann type (115665), Coppock-like (604307), lamellar (116800), and congenital posterior polar (116600) cataracts. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known to prevent the opacities but serial evaluations and cataract surgery are required to prevent amblyopia as the opacities progress.

References
Article Title: 

Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state

Plotnikova OV, Kondrashov FA, Vlasov PK, Grigorenko AP, Ginter EK, Rogaev EI. Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am J Hum Genet. 2007 Jul;81(1):32-43.

PubMed ID: 
17564961
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