retinal dysplasia

Takenouchi-Kosaki Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype consists of mild ptosis, synophrys, exotropia, and eversion of the lower eyelids.  One of two reported patients was described as having bilateral retinal dysplasia and a falciform retinal detachment in one eye.  Visual acuity is significantly impaired.

Systemic Features: 

Affected individuals may be of normal birth weight but skeletal growth is subnormal and there is general developmental delay.  Congenial cardiac anomalies such as persistent ductus arteriosus may be present.  Lymphedema has been noted at one year of age and probably persists throughout life.  Protein-losing enteropathy secondary to intestinal lymphangiectasia was present in one individual.  The same patient had pericardial effusion, hydrothorax, and ascites.  Intellectual disability may be severe although there is no evidence of progression.  Neurosensory hearing loss has been described in one patient.

Thrombocytopenia is a consistent finding and has been described as early as one year of age.  Platelet numbers as low as 52,000/microL have been recorded and appear larger than normal. 

Genetics

Both unrelated female patients reported have heterozygous missense mutations in the CDC42 gene (1p36). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

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

Microphthalmia, AR

Clinical Characteristics
Ocular Features: 

The most consistent feature associated with mutations in the VSX2 gene is, of course, microphthalmia/anophthalmia.  Other anomalies include dysplasia of the retina, cataracts and/or dislocated lenses, and iris anomalies ranging from hypoplasia to colobomas and absence of the pupils. Colobomas may also involve the posterior uveal tract as well as the optic nerve. The majority of patients are blind.   

Systemic Features: 

No systemic features are associated.

Genetics

This is an autosomal recessive disorder resulting from mutations in the VSX2 (formerly CHX10) gene located at 14q24.3.  The gene is expressed in progenitor cells of the developing neuroretina and in inner nuclear cells of the adult retina.   Most parents are consanguineous.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None other than rehabilitation.

References
Article Title: 

Aphakia, Congenital Primary

Clinical Characteristics
Ocular Features: 

There is complete absence of the lens and with it aplasia of the anterior segment including complete absence of the iris, ciliary body, and trabecular meshwork.  In an autopsied case, the cornea was thinned and lacked endothelium, Bowman layer, and Descemet membrane while the retina was dysplastic.  In the single family reported, 2 sibs had sclerocornea and one had megalocornea.  Normal pressure was reported in several eyes but a single eye in one patient at the age of 3 years developed buphthalmos with elevated pressure.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Homozygosity of a nonsense mutation in the FOXE3 transcription factor gene (1p32) seems to be responsible for this autosomal recessive disorder.  The same gene has been implicated in rare cases of Peters anomaly (604229) and in anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known to restore vision.

References
Article Title: 

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

Osteoporosis-Pseudoglioma Syndrome

Clinical Characteristics
Ocular Features: 

Retrolental masses often present at birth have been mistaken for retinoblastomas.  Hyperplasias of the vitreous, corneal opacities, and secondary glaucoma have been described.  Band keratopathy may account for some of the corneal clouding and opacities.  Most patients are blind soon after birth although some retain some vision into the second decade.

Systemic Features: 

Some patients have been described as mentally retarded but others have normal intelligence.  Hypotonia and hyperflexible joints have been noted.  Bone fractures are common sometimes resulting in scoliosis, short stature and limb deformities.  Radiography of the skeletal reveals porotic and thin bones.

Genetics

This disorder, sometimes called the ocular form of osteogenesis imperfecta, results from mutations in LRP5 (11q13.4).  The same gene is mutant in the EVR4 type of familial exudative vitreoretinopathy (601813) which has some of the same ocular and bone features.  Most descriptions of OPPG were published before the gene mutation was found and many reports do not include detailed ocular examinations.  Certainly the two disorders are allelic and likely the same condition. 

Mutations in LRP5 lead to EVR4 disease in both the heterozygous and homozygous configuration but most cases of OPPG have homozygous or compound heterozygous mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone fractures need to be repaired and glaucoma treated when present.  Bisphosphonate treatment may lead to increased bone density if initiated early.  The retrolental masses need to be carefully evaluated to rule out retinoblastoma.

References
Article Title: 

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13

Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996 Jul;59(1):146-51.

PubMed ID: 
8659519

Norrie Disease

Clinical Characteristics
Ocular Features: 

Norrie disease often presents at birth or soon thereafter with leukocoria.  There may be no response to light even at this early stage.  Microphthalmos, iris atrophy, and synechiae are often noted as well.  The posterior chamber contains a whitish-yellow mass associated with retinal folds and sometimes retinal detachment (pseudoglioma).  The vitreous may appear membranous and fibrovascular, often with traction on the retina.  Cataracts frequently develop early.  These signs may be unilateral or bilateral.  Corneal abnormalities such as opacities or sclerocornea may be present.  The mass in the posterior pole has to be distinguished from a retinoblastoma but the appearance may also resemble familial exudative vitreoretinopathy, Coats disease, persistent hyperplastic vitreous retinopathy, or retinopathy of prematurity.

Histology shows hemorrhagic necrosis of an undifferentiated glial mass.  The primary defect seems to lie in the neuroretina with absence of the ganglion cells and dysplasia of the remaining layers.  Many eyes become phthisical.

Systemic Features: 

Many individuals have growth and developmental delays with cognitive impairment and/or behavioral disorders (50%).  Frank psychoses have been reported in some patients.  Approximately 10% of patients have a chronic seizure disorder. Sensorineural deafness of some degree develops by the second decade in up to 100% of individuals.

Peripheral vascular disease (varicose veins, venous stasis ulcers, and erectile dysfunction) is present in nearly all men over the age of 50 years, perhaps the result of small vessel angiopathy.  Its age of onset is similar to that of the hearing deficit and the time course of progression is similar.

Genetics

This is an X-linked disorder as a result of mutations in the NDP gene (Xp11.4) encoding norrin.  Many mutations causing Norrie disease are novel or at least rare as might be expected for a disorder that leads to a marked reduction in reproductive fitness in males.  Carrier females usually do not have any evidence of disease.

Mutations in NDP also are responsible for a sex-linked form of familial exudative vitreoretinopathy, EVR2 (305390).  They have also been found in some cases of persistent hyperplastic primary vitreous and even in Coates' disease.  The latter conditions are usually present unilaterally, however, and some consider bilaterality to be a characteristic of NDP-related retinopathies.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Mutations in the Norrie disease gene

Schuback DE, Chen ZY, Craig IW, Breakefield XO, Sims KB. Mutations in the Norrie disease gene. Hum Mutat. 1995;5(4):285-92.

PubMed ID: 
7627181
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