anterior chamber dysgenesis

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Iridogoniodysgenesis, Type 1

Clinical Characteristics
Ocular Features: 

Glaucoma often develops in the latter part of the first decade of life but has been diagnosed in the neonatal period.  It affects at least half of patients with IRID1.  The disorder may be suspected in at-risk families by the hypoplasia of the iris stroma resulting in a dark chocolate color with prominent vessels. The irides may also have a dark slate gray color.  Further, the anterior iris surface appears smooth without the usual crypts.  There are no defects in the pigment layer of the iris, and the sphincter is intact while the pupil is in the normal position.  In many patients the iris is inserted anteriorly with numerous iris processes spanning the angle and inserting into the Schwalbe line.  In yet other patients tissue seems to fill the angle obscuring other anatomical structures.

Systemic Features: 

Systemic signs and symptoms are usually absent although CNS imaging has revealed cerebellar vermis hypoplasia in one family.

Genetics

This type of iridogoniodysgenesis results from alterations in the forkhead transcription factor gene (FOXC1) (6p25.3).  It is inherited in an autosomal dominant pattern.  Rare individuals may have deletions in the 6p area while duplications in FOXC1 are more common than point mutations.

Mutations in the same gene may also be responsible for Axenfeld-Rieger syndrome type 3 (602482), Peters anomaly (604229), and anterior segment mesenchymal dysgenesis (107250).

Another iridogoniodysgenesis disorder (IRID2) (137600) is caused by mutations in the PITX2 gene (4q25-q26), while iridogoniodysgenesis and skeletal anomalies (609515) is an autosomal recessive disorder due to as yet unknown mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All members of families in which this disorder segregates should have close surveillance for the presence of glaucoma which obviously requires treatment when present.

References
Article Title: 

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

Microcoria, Congenital

Clinical Characteristics
Ocular Features: 

This disorder is a type of anterior chamber dysgenesis since the pupil and iris anomalies are associated with goniodysgenesis (prominent iris processes and high iris root insertion) and glaucoma.  The dilator muscle of the iris is hypoplastic and even topical mydriatics have little impact on pupil size. The pupil has a mean diameter of 0.8 mm and only dilates to a mean size of 1.4 mm.  The iris stroma is also hypoplastic and often lacks crypts and collarettes.  Transillumination defects of the iris are consistently present.  Axial myopia is a feature in some families (83% of affected individuals have refractive errors in the range of -10D) and seems to be progressive .  Juvenile glaucoma is frequently present (at least 30% require treatment) and is usually detected in the second (20%) through fourth decades of life.  All patients with glaucoma have evidence of 'trabeculodysgenesis' but the same features may also be seen in some patients without glaucoma.  The intraocular pressure is difficult to control pharmacologically.  Visual acuity varies widely but no retinal changes have been described.

Ultrastructural studies show lack of myofilaments and desmin in the stromal cytoplasmic processes of the anterior pigmented cells of the iris suggesting failure of full development of the pupil dilator muscle cells.

Systemic Features: 

There are no systemic abnormalities in this condition.

Genetics

This is an autosomal dominant disorder secondary to a mutation located at 13q13-q32.  The specific mutation responsible has not been identified but a large deletion at 13q32.1 in one patient has been reported. 

Congenital microcoria is also a feature of autosomal recessive Pierson syndrome (609049) caused by homozygous mutations in the LAMB2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma often requires surgery for control of intraocular pressure.

References
Article Title: 

Submicroscopic deletions at 13q32.1 cause congenital microcoria

Fares-Taie L, Gerber S, Tawara A, Ramirez-Miranda A, Douet JY, Verdin H, Guilloux A, Zenteno JC, Kondo H, Moisset H, Passet B, Yamamoto K, Iwai M, Tanaka T, Nakamura Y, Kimura W, Bole-Feysot C, Vilotte M, Odent S, Vilotte JL, Munnich A, Regnier A, Chassaing N, De Baere E, Raymond-Letron I, Kaplan J, Calvas P, Roche O, Rozet JM. Submicroscopic deletions at 13q32.1 cause congenital microcoria. Am J Hum Genet. 2015 Apr 2;96(4):631-9.

PubMed ID: 
25772937

Walker-Warburg Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are usually small and contain either retinal dysplasia or a congenital retinal detachment.  Colobomas, PHPV, cataracts, glaucoma, buphthalmos, anterior chamber dysgenesis, optic atrophy, and optic nerve hypoplasia have also been reported. 

Systemic Features: 

Hydrocephalus and congenital muscular dystrophy are the most important systemic features of these syndromes.  A Dandy-Walker malformation is often present.  Type II lissencephaly, cerebellar malformations and severe mental retardation are other features.  More variable signs include macro- or microcephaly, ventricular dilatation, cleft lip and/or palate, and congenital contractures.  WWS has a severe phenotype and death often occurs in the first year of life.  Brain histology shows severely disorganized cytoarchitecture and suggests a neuronal migration disorder. Microtia has been reported in several patients.

Most developmental milestones are delayed or never achieved and death may occur in early childhood. 

Genetics

The MDDGs (muscular dystrophy dystroglycanopathies) comprise a genetically and clinically heterogeneous group of disorders (sometimes called muscle-eye-brain disease) of which the A types are more severe than the B types.  The mutant genes responsible are involved in glycosylation of DAG1 (alpha-dystroglycan). 

Types A1 (MDDGA1; 236670), B1 (MDDGB1; 613155) and C1 (MDDGC1; 609308) result from mutations in a gene known as POMT1 (9p34.1).  The muscular dystrophy in type C1 is of the limb-girdle type LGMD2K.

A2 (MDDGA2; 613150) is caused by mutations in POMT2 (14q24.3).  Mutations in POMT2 may also cause the less severe muscle-eye-brain disease (MEB) type B2 (MDDGB2; 613156), and a similar disease (C2) in which the muscle dystrophy is of the limb-girdle type LGMD2N and eye findings may be absent (MDDGC2; 613158).

Mutations in POMGNT1 (1p34-p33) cause type A3 (MDDGA3; 253280) and type B3 (MDDGB3; 613151).  The muscular dystrophy in B3 is of the limb-girdle type.  POMGNT1 mutations may be associated with congenital glaucoma, retinal dysplasia, and high myopia. Type C3 (MDDGC3; 613157), also with a limb-girdle type of muscular dystrophy (LGMD2O), is caused by mutations in POMGNT1 as well.

FKTN mutations cause type A4 MDDG (MDDGA4; 253800) associated with the Fukuyama type of congenital muscular dystrophy but they can also cause type B4 (MDDGB4; 613152) which does not have mental retardation, and type C4 (MDDGC4; 611588) with seizures and a limb-girdle type (LGMD2M) of muscular dystrophy.

Types A5 (MDDG5A; 613153) and B5 (MDDGB5; 606612) are the result of mutations in the FKRP gene (19q13.3).  Of the two the latter is the less severe and the muscular dystrophy is of the limb-girdle type.  The eyes may be microphthalmic and have retinal pigmentary changes and congenital glaucoma.

Type A6 (MDDGA6; 613154) and B6 (MGGDB6; 608840) are caused by mutations in the LARGE gene (22q12.3).  MDDGA7, or type A7 (614643) results from homozygous or compound heterozygous mutations in the ISPD gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available but early indications are that FKRP gene therapy restores functional glycosylation and improves muscle functions.

References
Article Title: 

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study

Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E, Comi GP, D'Amico A, Aiello C, Biancheri R, Berardinelli A, Boffi P, Cassandrini D, Laverda A, Moggio M, Morandi L, Moroni I, Pane M, Pezzani R, Pichiecchio A, Pini A, Minetti C, Mongini T, Mottarelli E, Ricci E, Ruggieri A, Saredi S, Scuderi C, Tessa A, Toscano A, Tortorella G, Trevisan CP, Uggetti C, Vasco G, Santorelli FM, Bertini E. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9.

PubMed ID: 
19299310

Rubinstein-Taybi Syndrome 1

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this disorder.  Few patients have all of the clinical features and there is much variation in the severity of these.  Almost all segments of the eye can be involved.  The lashes are often lush and the eyebrows may be highly arched and bushy.  Lid fissures are often downward slanting (88%).  Congenital glaucoma, nystagmus, cataracts, lacrimal duct obstruction (37%), ptosis (29%), colobomas and numerous corneal abnormalities including keratoglobus, sclerocornea, and megalocornea have been reported.  Abnormal VEP waveforms and cone and cone-rod dysfunction have been found in the majority (78%) of patients tested.  Retinal pigmentary changes have been seen in some patients.  Refractive errors (usually myopia) occur in 56% of patients.  Visual acuities vary widely but about 20% of patients are visually handicapped.

Fluorescein angiography in a single patient revealed generalized vascular attenuation and extensive peripheral avascularity.  The AV transit time was prolonged with delayed venous filling and late small vessel leakage. 

Systemic Features: 

The facial features are reported to be characteristic but there are few distinctive signs.  The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip.  Smiles have been described as 'grimacing'.  It is common for the columella to protrude beyond the alae nasi.  The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties.  The ears may be rotated posteriorly.  The anterior hairline can appear low.

Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially.  However, the distal phalanges of all fingers may be broad as well.  Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life.  Hypotonia is a feature.  Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.

Developmental delays are common.  Infancy and childhood milestones are often delayed.  Many patients have cognitive delays and some are mildly retarded.  Postnatal growth is subnormal and obesity is common.  A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus.  Renal abnormalities occur frequently and almost all males have undescended testes.  Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system.  Other problems are constipation and hearing loss.

Genetics

Evidence points to an autosomal dominant mode of inheritance secondary to mutations in CREBBP (16p13.3) but there is some genetic heterogeneity as mutations in EP300 (22q13) have also been associated with this disease (see Rubinstein-Taybi Syndrome 2; 613684).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific clinical features such as glaucoma and strabismus.  Special education and vocational training may be helpful.  Hearing loss may respond to standard treatment.  Fractures and dislocations should receive prompt attention.  Cardiac anomalies may require surgical correction.

References
Article Title: 

Pfeiffer Syndrome

Clinical Characteristics
Ocular Features: 

Patients may have extreme proptosis (95%) secondary to shallow orbits and exposure keratitis (41%) is a risk.  Hypertelorism, strabismus, and antimongoloid lid slants are common.  More rare signs include anterior chamber anomalies and optic nerve hypoplasia.

Systemic Features: 

Pfeiffer syndrome has been divided into 3 types, of which cases with types 2 and 3 often die young.  Type 1 has the more typical features with midface hypoplasia, broad thumbs and toes, craniosynostosis, and often some degree of syndactyly.  Adult patients with type 1 may be only mildly affected with some degree of midface hypoplasia and minor broadening of the first digits.  Hearing loss secondary to bony defects is relatively common.  Cleft palate is uncommon.  Airway malformations especially in the trachea can cause respiratory problems.

Genetics

This is a genetically heterogeneous disorder resulting from mutations in at least 2 genes, FGFR1 (8p11.2-p11.1) and FGFR2 (10q26).  The less common cases with the latter mutation are allelic to Apert (101200), Crouzon (123500), and Jackson-Weiss (123150) syndromes.  Inheritance is autosomal dominant but some cases are only mildly affected.  New mutations exhibit a paternal age effect.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Beare-Stevenson Syndrome (123790), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Exposure keratitis requires the usual treatment.  Fronto-orbital advancement surgery for the midface underdevelopment is generally helpful for the complications of proptosis.  Airway obstruction may require tracheostomy or surgical correction of the air passages.

References
Article Title: 

FGFR2 mutations in Pfeiffer syndrome

Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet. 1995 Feb;9(2):108.

PubMed ID: 
7719333

Corneal Dystrophy, Posterior Polymorphous 3

Clinical Characteristics
Ocular Features: 

This is a genetically and clinically heterogeneous type of corneal dystrophy.  Endothelial metaplasia seems to play a role as these cells acquire some characteristics of epithelial cells.  The posterior cornea has guttae and lesions of various sizes surrounded by a grayish halo.  These may become confluent and lead to stromal edema extending into the epithelium.  The thickness of the Descemet membrane is highly variable and a retrocorneal membrane may be present.  Onset is variable as some infants will have corneal edema whereas many, if not most, adults are asymptomatic.  The condition in severely affected children may resemble congenital hereditary corneal dystrophy.

Systemic Features: 

No consistent systemic abnormalities have been reported.  However, some patients have been reported with inguinal hernias, hydroceles, and possible bone abnormalities suggesting that the ZEB1 mutation may have extraocular effects as well.

Genetics

This is an autosomal dominant disorder caused by a mutation in the ZEB1 gene (10p11.2).  Mutations in the same gene have recently been found in some cases with late-onset Fuchs endothelial dystrophy.

For other forms of posterior polymorphous dystrophy see PPCD1 (122000) and PPCD2 (609140).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Most patients do well and require no treatment.  Corneal transplantation may be required for the more severe cases but, as in many dystrophies, the lesions tend to recur in the graft.

References
Article Title: 

Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells

Krafchak CM, Pawar H, Moroi SE, Sugar A, Lichter PR, Mackey DA, Mian S, Nairus T, Elner V, Schteingart MT, Downs CA, Kijek TG, Johnson JM, Trager EH, Rozsa FW, Mandal MN, Epstein MP, Vollrath D, Ayyagari R, Boehnke M, Richards JE. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am J Hum Genet. 2005 Nov;77(5):694-708.

PubMed ID: 
165384081

Corneal Dystrophy, Posterior Polymorphous 1

Clinical Characteristics
Ocular Features: 

This form of corneal dystrophy is often asymptomatic but some patients experience endothelial decompensation and corneal edema, which may even be seen soon after birth. The edema may extend into the epithelium.  The basic mechanism entails metaplasia of endothelial cells which seem to acquire some characteristics of epithelial cells.  Posterior corneal lesions of variable morphology appear in various patterns and are often surrounded by grayish halos.  When these become confluent the corneal edema is more severe and may resemble a congenital endothelial dystrophy.  The endothelial cell count is often low.  The Descemet layer also becomes abnormal.  The posterior border of the cornea appears nodular and grayish in color, often in a geographic pattern.  Surprisingly, endothelial function often is maintained and patients may remain asymptomatic for many years.

Some patients have features of anterior chamber dysgenesis with iris anomalies, anterior synechiae, and glaucoma.  It is also sometimes confused with EDICT syndrome (614303).

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

This is a genetically heterogeneous autosomal dominant disorder caused by several mutations including the promotor of OVOL2 at 20p11.23 responsible for PPCD1 described here.  Another locus for this disease has been mapped to 20q11, the same locus responsible for congenital hereditary corneal edema 1 (CHED1) and it is possible that these are allelic or clinical variants of the same mutation.  The latter is made more likely by the fact that both disorders have been found in relatives.  OMIM has combined the entities CHED1 and PPCD1 as a single disorder (122000).

For other forms of posterior polymorphous corneal dystrophy see, PPCD2 (609140) and PPCD3 (609141).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Few patients require treatment since the endothelial changes are frequently stable. Among those that do undergo corneal transplantation, the changes often recur in the donor button.

References
Article Title: 

EDICT Syndrome

Clinical Characteristics
Ocular Features: 

This is a rare disorder with multiple anterior segment anomalies.  The corneal stroma is thinned in the range of 330 to 460 um with uniform steepening (no cone).  The epithelium may be irregular and edematous, the stroma is diffusely hazy, and the endothelium is irregular with many guttae.  Anterior polar cataracts are likely congenital and often require removal before the age of 20 years.  The pupils are often eccentric and difficult to dilate.  The iris stroma may appear atrophic.  Visual acuity, even in the aphakic condition, is in the range of 20/30 to 20/160.

Histological studies show attenuation of the endothelium with cellular overlapping and aggregates of fibrillar material that stains for cytokeratin.  Descemet membrane is thickened as is the epithelial basement membrane and both intracellular and extracellular lipid deposition is seen throughout the stroma and the Bowman membrane.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant disorder resulting from a heterozygous single base substitution (57C-T) in the MIR184 gene (15q25.1).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract removal and penetrating keratoplasty can be helpful.  It is unknown whether the donor corneal tissue develops similar opacities.

References
Article Title: 

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