posterior embryotoxon

Foveal Hypoplasia and Anterior Chamber Dysgenesis

Clinical Characteristics
Ocular Features: 

This is a congenital disorder with poor vision (20/120-20/400) and nystagmus from birth according to family history.  Three of five patients in one family had a posterior embryotoxon and two had Axenfeld anomaly.  No glaucoma was present although no individuals were older than 15 years of age at the time of examination.  The foveal reflex was absent and there was a poorly defined foveal avascular zone with no distinction of the foveomacular area.   Reduced ERG amplitudes and similar VEP responses were found in 4 affected individuals but these recordings were normal in the parents.  Chiasmal misrouting has been reported in two affected members of one family.  The combination of foveal hypoplasia and decussation defects is characteristic of disorders of pigmentation (albinism) but no iris defects or other evidence of pigmentary anomalies have been found in this condition of foveal hypoplasia.

Systemic Features: 

No systemic abnormalities were described.

Genetics

Consanguinity has been reported.  A region containing 33 genes at 16q23.2-24.2 co-segregates with the disorder but no mutation has been identified.  Mutations in FOXC2 and PAX6 (that code for transcription factors) have been specifically ruled out in selected families.  However, the phenotype is consistent with dysfunction of some other as yet unidentified transcription control factor or promotor region.    

An autosomal dominant disorder with somewhat similar features known as anterior segment mesenchymal dysgenesis (107250) has been described but its unique status remains to be established.  Foveal hypoplasia has not been reported but an associated mutation in FOXE3 could be responsible. 

Isolated foveal hypoplasia without anterior chamber malformations (136520) has been reported among families of Jewish Indian ancestry in which homozygous mutations SLC38A8 cosegregated.

With the widespread utilization of OCT measurements, it has become apparent that underdevelopment of the fovea can be a feature of numerous ocular disorders (more than 20 in this database).  In most conditions, the foveal dysplasia is part of a disease complex as in this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known.

References
Article Title: 

A new recessively inherited disorder composed of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis maps to chromosome 16q23.3-24.1

Al-Araimi M, Pal B, Poulter JA, van Genderen MM, Carr I, Cudrnak T, Brown L, Sheridan E, Mohamed MD, Bradbury J, Ali M, Inglehearn CF, Toomes C. A new recessively inherited disorder composed of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis maps to chromosome 16q23.3-24.1. Mol Vis. 2013 Nov 1;19:2165-72. PubMed PMID: 24194637;

PubMed ID: 
24194637

Axenfeld-Rieger Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

As in RIEG1 and RIEG3, glaucoma is the most serious ocular problem.  In a large family with 11 affected members, 9 had glaucoma.  All had the classic ocular signs of anterior segment dysgenesis, primarily posterior embryotoxon and iris adhesions (for a full description of the ocular features see Axenfeld-Rieger syndrome, RIEG1 [180500]).

Systemic Features: 

Oligodontia, microdontia, and premature loss of teeth are common in type 2.  Maxillary hypoplasia is less common as is hearing loss.  Umbilical anomalies were not present in any affected individuals.  Cardiac defects are rare.

Genetics

This is an autosomal dominant disorder as in the other types.  The locus is at 13q14 but no molecular defect has been defined.  At least two individuals purported to have type 2 were found to have deletions of this segment of chromosome 13.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The high risk of glaucoma demands lifelong monitoring of intraocular pressure.

References
Article Title: 

Sclerocornea

Clinical Characteristics
Ocular Features: 

This is a disorder of the cornea and anterior chamber that is sometimes considered to be a form of anterior segment or mesenchymal dysgenesis.  The primary feature is corneal clouding, most prominent peripherally and extending to the central cornea to a variable extent.  Vascular arcades are usually present over the area of clouding and there is no clear limbal demarcation.  Corneal fibers are often disorganized and larger than normal.  The anterior chamber may appear shallow and the iris usually has a flat appearance, often with a posterior embryotoxon.  Iris processes to the cornea and anterior synechiae are frequently present.  Some degree of microcornea has also been noted in many cases.  Rotary and horizontal nystagmus are uncommon. Sclerocornea may be a feature of cornea plana as well and the distinction between these disorders is unclear, especially in reported dominant pedigrees in which hyperopia is a feature.

Most cases are bilateral but there is often considerable asymmetry between the two eyes.  Visual acuity is dependent on the extent of corneal opacification but may be normal.  It is not a progressive disease.

Systemic Features: 

No systemic abnormalities have been reported.  However, sclerocornea can be a feature of numerous somatic and chromosomal disorders (e.g., oculocerbral syndrome with hypopigmentation (257800 ).

Genetics

No DNA mutations have as yet been found.  Most cases occur sporadically, and others are part of anterior chamber dysgenesis disorders.  However, rare autosomal dominant pedigrees have been reported in which the degree of opacification and anterior chamber anomalies are not as severe as those in which the pattern is most consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Severe cases in which the central media is compromised may require corneal transplantation.  Glaucoma requires treatment as well.

References
Article Title: 

A review of anterior

Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior
segment dysgeneses. Surv Ophthalmol. 2006 May-Jun;51(3):213-31. Review.

PubMed ID: 
16644364

Hereditary sclerocornea

Elliott JH, Feman SS, O'Day DM, Garber M. Hereditary sclerocornea. Arch
Ophthalmol. 1985 May;103(5):676-9.

PubMed ID: 
3994576

Alagille Syndrome

Clinical Characteristics
Ocular Features: 

The ocular findings in Alagille syndrome are often of little functional significance but can be sufficient to suggest the diagnosis without further study of the systemic features.  Posterior embryotoxon is found in 95% of individuals while iris abnormalities such as ectopic pupils are seen in 45%, abnormal fundus pigmentation is common (hypopigmentation in 57%, diffuse pigment speckling in 33%), and optic disc anomalies have been reported in 76%.  One study found that 90% of individuals have optic disk drusen by ultrasonography.  The anterior chamber anomalies are considered by some to be characteristic of Axenfeld anomaly.  The presence of these ocular findings in children with cholestasis should suggest Alagille syndrome.  Ocular examination of the parents can also be helpful in this autosomal dominant disorder as some of the same changes are present in one parent in more than a third of cases.

Systemic Features: 

A variety of  systemic features, some of them serious malformations, occur in Alagille syndrome.  Among the most common is a partial intrahepatic biliary atresia leading to cholestasis and jaundice.  Skeletal malformations include 'butterfly' vertebrae, shortened digits, short stature, a broad forehead, and a pointed chin.  The tip of the nose may appear bulbous.  These features have suggested to some that there is a characteristic facial dysmorphology.  Vascular malformations are common including aneurysms affecting major vessels, valvular insufficiency, coarctation of the aorta, and stenosis and these are often responsible for the most serious health problems.  In fact, vascular events have been reported to be responsible for mortality in 34% of one cohort.  Chronic renal insufficiency develops in a minority of patients.  This disorder should always be considered in children with cholestasis, especially when accompanied by cystic kidney disease.  Brain MRIs may show diffuse or focal hyperintensity of white matter even in the absence of hepatic encephalopathy.

Genetics

This is an autosomal dominant condition secondary to various mutations in the JAG1 gene located on chromosome 20 (20p12).  Penetrance is nearly 100% but there is considerable variation in expression.  A far less common variant of this disorder, ALGS2 (610205), is caused by a mutation in the NOTCH2 gene (1p13-p11).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No cure is available but individual organ disease may be treatable.  The ocular abnormalities generally do not cause vision difficulties.

Reversible of white matter changes has been noted in a single child following liver transplantation.

 

References
Article Title: 

CT-defined phenotype of pulmonary artery

Rodriguez RM, Feinstein JA, Chan FP. CT-defined phenotype of pulmonary artery
stenoses in Alagille syndrome. Pediatr Radiol. 2016 Apr 4. [Epub ahead of print].

PubMed ID: 
27041277

Alagille syndrome: clinical and ocular pathognomonic features

El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM. Alagille syndrome: clinical and ocular pathognomonic features. Eur J Ophthalmol. 2010 Jul 28. pii: 192165A5-8631-4C06-9C47-9AD63688B02A. [Epub ahead of print]

PubMed ID: 
20677167

Ocular abnormalities in Alagille syndrome

Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli-Vergani G, Bird AC, Aclimandos WA. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999 Feb;106(2):330-7.

PubMed ID: 
9951486
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