anterior chamber dysgenesis

Strømme Syndrome

Clinical Characteristics
Ocular Features: 

The core complex of Stromme syndrome consists of intestinal atresia and ocular abnormalities of the anterior segment.  The ocular anomalies consist of variable amounts of angle dysgenesis, anterior synechiae, corneal leukoma, iris colobomas and hypoplasia, sclerocornea, cataracts, and sometimes microcornea.  However, microphthalmia, tortuous retinal vessels, and optic nerve hypoplasia may also be present.  Hypertelorism and deep-set eyes have been described.  Glaucoma has not been reported.  Only about 10 cases have been reported since Stromme 's first report in 1993.  Most patients have been too young for reliable acuity testing. 

Systemic Features: 

The phenotype is highly variable.  The ears are often large and low-set.  Microcephaly is often present along with a cleft palate and micrognathia.  The intestinal atresia seems to involve the jejunum primarily and is usually surgically correctable.  The duodenum may also be involved and intestinal malrotation has been described.  Myopathic changes in the myocardium have been seen along with small cardiomyoctes.  Microcephaly seems to be progressive.  Short stature has been noted and the amount of developmental delay is highly variable.  Renal hypodysplasia and hydronephrosis have been described.

Some patients seem to develop and function almost normally while more severely affected individuals may not live beyond early infancy or childhood.

Genetics

Compound heterozygous mutations in the CENPF gene (1q41) segregate with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Infants do well following intestinal surgery.  Ocular surgery has not been reported.

References
Article Title: 

Stromme Syndrome: New Clinical Features

Stromme Syndrome: New Clinical Features Bayram Ali Dorum, Irmak Tanal Sambel, Hilal Ozkan, Irfan Kiristioglu, Nilgun Koksal APSP J Case Rep. 2017 Mar-Apr; 8(2): 14. Published online 2017 Mar 18.

PubMed ID: 
5371687

Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF

Filges I, Bruder E, Brandal K, Meier S, Undlien DE, Waage TR, Hoesli I, Schubach M, de Beer T, Sheng Y, Hoeller S, Schulzke S, Rosby O, Miny P, Tercanli S, Oppedal T, Meyer P, Selmer KK, Stromme P. Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF. Hum Mutat. 2016 Jan 28. doi: 10.1002/humu.22960. [Epub ahead of print].

PubMed ID: 
26820108

Ectopia Lentis et Pupillae

Clinical Characteristics
Ocular Features: 

This disorder is generally considered to consist of simple displacement of the pupil and dislocation of the lens (usually in opposite directions).  However, other abnormalities are often present such as persistent pupillary membrane (87%), iridohyaloid adhesions, increased corneal thickness, enlarged corneal diameters, and axial myopia.  The iris may transilluminate (67%) and the pupils dilate poorly.  Iridodenesis is common (85%).  The lens is often malformed and in some cases frankly microspherophakic.  The lens displacement can progress and cataracts seem to form at a relatively young age.  Visual acuity is highly variable, ranging from 20/20 to light perception depending upon the density of cataracts which often develop at a relatively young age. Prominent iris processes into the anterior chamber angle have been reported and glaucoma, both acute and chronic, is sometimes seen.  Retinal detachment is a risk.

Studies in families with ectopia lentis et papillae have revealed that as many as 50% of individuals with dislocated lenses do not have ectopic pupils.

Systemic Features: 

None reported

Genetics

This disorder is usually inherited in an autosomal recessive pattern.  Multiple affected sibs have been born to consanquineous matings.  However, other families in which detailed ophthalmological examinations were done have suggested dominant inheritance based upon the presence of more subtle ocular signs in relatives.  This is likely a more clinically heterogeneous disorder than has been appreciated.

In five Norwegian families a homozygous 20 bp deletion has been found in the gene ADAMTSL4 on chromosome 1 (c.767_786del20) (1q21.3) producing a frameshift and the introduction of a stop codon leading to truncation of the protein product.  Mutations in the same gene have also been found in the autosomal recessive form of isolated ectopia lentis (225100).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma, retinal detachments, and cataracts may require surgery.

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

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: 

Axenfeld-Rieger syndrome

Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017 Oct 3. doi: 10.1111/cge.13148. [Epub ahead of print] Review.

PubMed ID: 
28972279

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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