corectopia

Corneal Dystrophy, Posterior Polymorphous 4

Clinical Characteristics
Ocular Features: 

The posterior corneal surface becomes highly irregular as the endothelial cells become variable in size and in number.  There may be focal areas of multilayering of endothelial cells.  Most patients have a significant reduction in endothelial cell density which eventually leads to corneal edema and blurred vision.  Some patients have anterior synechiae and corectopia with secondary glaucoma.

Corneal edema has been noted in infants at several months of age.  Painful bullous keratopathy or uncontrollable glaucoma may lead to enucleation in adult life.

Systemic Features: 

The posterior corneal surface becomes highly irregular as the endothelial cells become highly irregular in size and in number.  There may be focal areas of multilayering of endothelial cells.  Most patients have a significant reduction in endothelial cell density which eventually leads to corneal edema and blurred vision.  Some patients have anterior synechiae and corectopia with secondary glaucoma.

Corneal edema has been noted in infants at several months of age.  Painful bullous keratopathy or uncontrollable glaucoma may lead to enucleation in adult life.

Genetics

Heterozygous mutations in the GRHL2 gene (8q22.3-q24.12) are responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation may benefit selected patients.E

References
Article Title: 

Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4

Liskova P, Dudakova L, Evans CJ, Rojas Lopez KE, Pontikos N, Athanasiou D, Jama H, Sach J, Skalicka P, Stranecky V, Kmoch S, Thaung C, Filipec M, Cheetham ME, Davidson AE, Tuft SJ, Hardcastle AJ. Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. Am J Hum Genet. 2018 Mar 1;102(3):447-459.

PubMed ID: 
29499165

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 PITX2, RIEG2 (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: 

Iridogoniodysgenesis and Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Megalocornea, congenital glaucoma, a concave iris with stromal atrophy and corectopia, and deep anterior chambers are typical ocular features.  High myopia has been reported and retinal detachments have been observed.  Glaucoma control can be difficult to achieve and there is a significant risk of cataracts and phthisis bulbi following surgery.  Posterior embryotoxon has not been observed.

Systemic Features: 

Facial features seem to be consistent.  The forehead is wide, the nose appears broad with a large nasal tip and broad nares although the bridge appears narrow.  The philtrum is long and wide.  The ears may appear large and the neck is short.  The thorax is abnormally wide and the nipples are widely spaced and umbilicated.  The long bones are slender with thin cortices and wide metaphyses.  There is generalized osteopenia.  Vertebral bodies are cuboid-shaped with narrow vertebral canals and enlarged apophyses

Genetics

Two non-consanguineous families each with 3 sibs have been reported suggesting autosomal recessive inheritance.  Nothing is known about the mutation or its locus.

The ocular features may resemble Rieger or Axenfeld anomaly but these are inherited in autosomal dominant patterns and the skeletal features are dissimilar.       

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Vigorous treatment of glaucoma is indicated but successful control, even with surgery, is difficult to achieve.

References
Article Title: 

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: 

Axenfeld-Rieger Syndrome, Type 3

Clinical Characteristics
Ocular Features: 

The most important ocular feature is glaucoma, found in greater than 50% of patients.  It is frequently difficult to control and blindness is far too common.  The ocular phenotype has many similar features found in type 1 (RIEG1) but is discussed separately in this database since it is caused by a different mutation (see Axenfeld-Rieger syndrome, type 1 for a full description of the phenotype).  It has the typical findings of anterior segment dysgenesis including anterior displacement of Schwalbe's line, iris stromal hypoplasia, correctopia, and, of course, glaucoma.

Systemic Features: 

Patients with this type of Axenfeld-Rieger disorder are less likely to have the systemic anomalies such as craniofacial and dental defects often seen in RIEG1.  However, they often have a sensorineural hearing impairment and many have cardiac valvular and septal defects not usually seen in RIEG1.

Genetics

This is an autosomal dominant disorder resulting from a mutation in the FOXC1, a transcription factor gene located at 6p25.  Mutations in the same gene also cause iris hypoplasia/iridogoniodysgenesis (IGDA) (IRID1) 601631) which is sometimes reported as a unique disorder but is either allelic or the same disorder as the type of Axenfeld-Rieger syndrome discussed here.

Type 1 Axenfeld-Rieger syndrome (180500) results from mutations in the PITX1 transcription factor gene and type 4 from mutations in PRDM5, also a transcription factor gene.  However, digenic cases have also been reported with mutations in both PITX1 and FOXC1 genes.

The mutation responsible for type 2 Axenfeld-Rieger syndrome (601499) has as yet not been identified.  Diagnosis is best made by ruling out mutations in PITX1 and FOXC1 although it is claimed that maxillary hypoplasia and umbilical defects are less common in type 2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All patients with Axenfeld-Rieger syndromes must be monitored and treated for glaucoma throughout their lives.

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

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
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