broad nasal root

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

Axenfeld-Rieger Syndrome, Type 4

Clinical Characteristics
Ocular Features: 

The ocular features of this syndrome are similar to types 1-3 and primarily involve the anterior segment.  The iris stroma is hypoplastic and the pupil location may be eccentric.  Full thickness defects in the iris can lead to pseudopolycoria.   There may be anterior displacement of the angle structures with posterior embryotoxon and localized corneal opacification.    Glaucoma is a common feature and it may be present in early childhood, associated with tearing, a hazy cornea, and buphthalmos.  Vitreous condensation was noted in all 4 reported individuals.

Systemic Features: 

The midface is flat due to maxillary underdevelopment and the teeth may be abnormally small.  Micrognathia has been reported while the nasal root is abnormally broad.  The umbilical defect consists of redundant skin that failed to involute normally.  Congenital hip anomalies of undetermined nature and a hearing defect were reported in 2 of 4 individuals.

Genetics

Heterozygous mutations in the PRDM5 gene (4q25-q26) are responsible for this condition.  Mutations in CYP1b1, PITX2, and FOXC1 were not present.  One extended pedigree with 4 affected individuals from Pakistan has been reported. 

Type 1 Axenfeld-Rieger syndrome (180500) results from heterozygous mutations in PITX2RIEG2 (601499) from heterozygous mutations in 13q14, and RIEG3 (602482) from heterozygous mutations in the FOXC1 gene.  Thus in three types of Axenfeld-Rieger syndrome (1,3, and 4) the responsible mutation occurs in a transcription factor gene which may explain why the phenotype is highly variable with considerable overlap in clinical signs.

Autosomal recessive brittle cornea syndrome type 2 (614170) is also caused by mutations in the PRDM5 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at correction of individual problems such as glaucoma and dental anomalies.  One patient required surgery for a retinal detachment. Lifelong ocular monitoring is recommended. 

References
Article Title: 

Axenfeld-Rieger Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features.  Common to all types are the presence of ocular, dental, facial, skeletal abnormalities and autosomal dominant inheritance.  Anterior chamber dysgenesis of some form is universally present and severe glaucoma occurs in 50% of patients.  This may have its onset in childhood with typical symptoms of congenital glaucoma such as photophobia, excessive tearing and corneal clouding.  Hypoplasia of the iris is common and when progressive may result in an ectopic pupil and/or pseudopolycoria.  Iris insertion and Schwalbe's line are often anteriorly displaced with iridocorneal adhesions, a pattern that leads to the inclusion of this disorder among those with iridogoniodysgenesis or anterior chamber dysgenesis.  Pupillary ectropion of the posterior pigmented layer of the iris may be seen.

There is considerable clinical overlap among conditions with iris dysgenesis.  Some patients with typical systemic features of Axenfeld-Rieger syndrome may even have typical anterior chamber features of Axenfeld-Rieger anomaly in one eye and severe iris hypoplasia resembling aniridia in the other.

Systemic Features: 

Dental anomalies and mid-facial hypoplasia secondary to underdeveloped maxillary sinuses are among the most common systemic features in type 1.  The nasal root often appears abnormally broad and the lower lip appears to protrude. The teeth are frequently small and conical in shape with wide spaces between them (diastema).  Some teeth may be missing.  The umbilicus may fail to involute normally and retains excessive, redundant skin that sometimes leads to the erroneous diagnosis of an umbilical hernia for which unnecessary surgery may be performed.  Hypospadius is frequently present while cardiac defects, sensorineural deafness, and anal stenosis are less common.

Genetics

There is clinical and genetic heterogeneity in this syndrome and precise classification of many families remains elusive without knowing the genotype.  Mutations in at least four genes are responsible and all are are responsible for phenotypes transmitted in autosomal dominant patterns.  Type 1 discussed here is caused by a mutation in the homeobox transcription factor gene, PITX2, located at 4q25-q26.  A type of iris hypoplasia (IH)/iridogoniodysgenesis (IGDS) (IRID2; 137600) disorder has been classified separately but is caused by a mutation in PITX2 as well and many cases have the same systemic features.  Mutations in the same gene have also been found in ring dermoid of the cornea (180550) and in some cases of Peters anomaly (604229).

RIEG2 (601499) is rare but a deletion of 13q14 has been reported in several cases.  Mapping in a large family with 11 affected individuals yielded a locus in the same region.  Clinical signs overlap types 1 and 3 with dental, craniofacial, and ocular features, but with hearing impairment and rare umbilical anomalies.

Mutations in the FOXC1 gene (6p25) may be responsible for RIEG3 (602482).  However, a family has been reported with a severe 'Axenfeld-Rieger phenotype' in which a digenic etiology may have been responsible: patients had mutations in both FOXC1 and PITX2

Heterozygous mutations in the PRDM5 gene (4q25-q26) have been identified in 4 members of a Pakistani family with typical features of the Axenfeld-Rieger syndrome. It is labeled type 4 Axenfeld-Rieger syndrome in this database. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The presence of glaucoma requires prompt and vigorous treatment but control is difficult with blindness too often the result.  Oral surgery may be beneficial for dental problems.  Low vision aids can be useful.

References
Article Title: 

The Rieger syndrome

Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet. 1978;2(3):307-18.

PubMed ID: 
263445
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