mesodermal dysgenesis

Corneal Dystrophy, Congenital Endothelial 1

Clinical Characteristics
Ocular Features: 

(OMIM has combined this disorder with PPCD1 (122000) based on genetic and clinical evidence.)

Early onset limbus-to-limbus corneal clouding is the outstanding feature.  Some asymmetry is often present.  Vision is minimally impaired if at all in many children but slow progression occurs and adults often become visually impaired.  Nystagmus does not develop.  Photophobia and tearing are common.  The corneal appearance can lead to the erroneous diagnosis of congenital glaucoma.  However, some infants actually do have congenital glaucoma as well leading some to suggest this may be a disorder of anterior chamber dysgenesis.  The edematous cornea may be of 2-3 times normal thickness.  It may appear generally hazy and sometimes has a diffuse ground glass appearance.  

The posterior surface often appears mottled and has been described as having a peau d'orange appearance.  The endothelium is attenuated or even absent histologically and abnormal, disorganized collagen fibrils have been found in a thickened Descemet layer by electron microscopy.  The remaining endothelial cells are often vacuolated and heaped in double layers, with some containing melanin granules.  Some atrophy and edema of the epithelium with partial loss of Bowman's can be seen histologically.

Systemic Features: 

No systemic abnormalities are found in this disorder.

Genetics

This is an autosomal dominant disorder that maps to a locus on chromosome 20 (20p11.2-q11.2).   The molecular defect seems to involve the promotor of OVOL2 (20p11.23).  It is of interest that the posterior polymorphous corneal dystrophy 1 (PPCD1, 122000) mutation has been mapped to the same pericentric region, and it has been suggested that the two conditions may be allelic. These are now combined into a single entity in OMIM. 

This disorder should not be confused with congenital endothelial dystrophy type 2, CHED2 (217700) which is autosomal recessive, has an earlier presentation, and maps to a different region of chromosome 20.  Harboyan syndrome (217400) has similar corneal features but maps to a different location on chromosome 20 and is associated with sensorineural deafness.

The nosology of the corneal dystrophies is still evolving.  In the 2015 edition of the IC3D, this condition designated CHED1 is eliminated based on clinical and pathologic similarities to those in posterior polymorphous corneal dystrophy 1 (PPCD1, 122000).  However, while the loci for PPCD2 and CHED1 are located in the same pericentric region of chromosome 20, the purported mutations occur in different genes. 

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty carries a good visual prognosis, even when done late in life.

References
Article Title: 

IC3D classification of corneal dystrophies--edition 2

Weiss JS, Moller HU, Aldave AJ, Seitz B, Bredrup C, Kivela T, Munier FL, Rapuano CJ, Nischal KK, Kim EK, Sutphin J, Busin M, Labbe A, Kenyon KR, Kinoshita S, Lisch W. IC3D classification of corneal dystrophies--edition 2. Cornea. 2015 Feb;34(2):117-59. Erratum in: Cornea. 2015 Oct;34(10):e32.

PubMed ID: 
25564336

Corneal Dystrophy, Posterior Amorphous

Clinical Characteristics
Ocular Features: 

The iris abnormalities consisting of iridocorneal adhesions to Schwalbe's line and pupillary abnormalities suggest that PACD is a congenital disorder, perhaps a form of anterior chamber dysgenesis.  The corneal stroma and Descemet membrane contain sheet-like opacities with clear intervening areas.  These opacities are concentrated in the posterior stroma and are sometimes seen from limbus to limbus whereas in other cases they occur mostly peripherally.  The cornea may be thinner than normal and somewhat flattened.  There is little or no progression of the corneal opacification and vision varies widely.  Glaucoma has not been reported.

Histological and EM studies have revealed some fracturing and disorganization of the posterior stromal lamellae and focal attenuation of the endothelium.

Systemic Features: 

There is no associated systemic disease.

Genetics

A limited number of families with this disorder have been reported and the pattern in each is  generally consistent with autosomal dominant inheritance.  This may be a deletion syndrome based on the finding in a 1 year old African male with a heterozygous de novo deletion at 12q21.33-q22 containing 11 genes.  Anong the missing genes are those for the 4 small leucine-rich proteoglycans associated with this form of corneal dystrophy.  The parents did not have the deletion though.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is generally not required but penetrating keratoplasty can benefit those whose vision is significantly impaired.

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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