sclerocornea

Microphthalmia, Syndromic 7

Clinical Characteristics
Ocular Features: 

Microphthalmia and rarely clinical anophthalmia are the ocular hallmarks of this disorder.  Corneal leukomas and some degree of sclerocornea are usually present as well.  Orbital cysts have been observed.  Other less consistent findings include iridocorneal adhesions, glaucoma, microcornea, cataracts, aniridia, persistence of the anterior hyaloid artery and other vitreous opacities, and patchy hypopigmentation of the RPE.

Systemic Features: 

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions.  Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia.  There may be some healing of the skin defects.  The corpus callosum is sometimes absent.  Diaphragmatic hernias are often present.  Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects.   Preauricular pits and hearing loss have been found in some patients.  Patients may be short in stature and some have nail dysplasia.  GU and GI anomalies may be present.

Genetics

This is an X-linked dominant disorder with lethality in the hemizygous male.  Many patients (79%) have interstitial deletions of the Xp22.2 region of the X chromosome.  Sequence analysis of this region has revealed heterozygous point mutations in the HCCS gene (Xp22.2) in numerous other patients.  In several additional cases deleterious mutations have been found in the X-linked COX7B gene.  However, familial occurrence is uncommon.  X chromosome inactivation may be skewed with the abnormal X being inactive in virtually all cases. Several 46 XX males with this syndrome have been described.

Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here.  Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.

Other X-linked dominant disorders with lethality in hemizygous males and abnormalities in skin and the eye are Incontinentia pigmenti (308300) and Aicardi syndrome (304050).  The skin lesions and ocular anomalies are dissimilar to those in MLS and they often have far more severe CNS abnormalities.   Further, the mutation causing Aicardi is in the NEMO (IKBKG) gene at another location on the X chromosome.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Treatment is organ-specific with repair of septal defects and diaphragmatic hernias.  Progressive orbital prosthetics should be considered in patients with blind, microphthalmic and clinically anophthalmic eyes.

References
Article Title: 

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

Ogata T, Wakui K, Muroya K, Ohashi H, Matsuo N, Brown DM, Ishii T, Fukushima Y. Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. Hum Genet. 1998 Jul;103(1):51-6. Review.

PubMed ID: 
9737776

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: 

Cataracts, Congenital Zonular Pulverulent 1

Clinical Characteristics
Ocular Features: 

Bilateral lens opacities may be both nuclear and zonular.  The embryonic and fetal nuclei are usually involved and diffuse cortical opacities may also be seen in some patients.  The involved area is therefore larger than the somewhat similar Coppock-like cataract (604307) which is limited to the embryonic nucleus.  The lens opacities may be seen at birth or in early childhood and usually progress. There is considerable clinical variation in the degree and distribution of the usual dust-like opacities which may also be lamellar in distribution with a clear peripheral cortex and minimal nuclear involvement.  Microcornea has also been reported.  In mild cases the lens opacities are primarily clustered along the Y sutures resembling congenital zonular cataracts with sutural opacities (600881).

Three unrelated patients with mutations in GJA8 and total sclerocornea have been reported.  Two of these patients in addition had small abnormal lenses while the third had cataracts and micropthalmia.  Two of the three also develped glaucoma by one year of age.

The nature and morphology of the lens opacities in an adult have been studied by light and scanning electron microscopy.  They are located in the embryonic and fetal nuclei and appear "puffy" with lens fiber irregulaties and entanglement in adjacent areas. 

Systemic Features: 

None.

Genetics

Congenital zonular pulverulent cataracts are inherited in an autosomal dominant pattern resulting from missense mutations in the GJA8 gene (1q21.1) that codes for connexin 50.  These belong to a category of lens opacitites now designated "Cataract 1, Multiple Types" in OMIM (116200). They have been detected in multiple populations and ethnic groups around the world.

Mutations in CZP3 at 13q11-13 coding connexin 46 (601885) result in a similar phenotype (Cataracts, Congenital Zonular Pulverulent 3) suggesting that genetic heterogeneity is present.

This was the first disease locus to be linked on a human autosome, in this case to the Duffy blood group locus on chromosome 1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated for visually significant lens opacities which may be required late in the first or early in the second decade of life.

References
Article Title: 

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

Oculocerebral Syndrome with Hypopigmentation

Clinical Characteristics
Ocular Features: 

Patients have severe ocular malformations which so far lack full characterization.  Nearly complete scleralization of the cornea prevents internal evaluation in most cases.  There may be extensive neovascularization of corneal clouding.  Anterior synechiae and cataracts have been described.  Other patients presumed to have the same disorder have normal fundi or diffuse pigmentary changes.  No limbal landmarks can be seen.  The central cornea can be more transparent but no iris can be visualized.  The eyes are microphthalmic as well.  Slow, wandering eye movements are constant.  Spastic ectropion of the lower lids is present. Lashes and eyebrows have minimal pigmentation and like the scalp hair have a slight yellowish tinge.  There is no response to bright light in severe cases whereas in other more mildly affected individuals presumed to have this disorder there is only hypoplasia of the fovea with diffuse retinal pigmentary changes.

Systemic Features: 

Individuals have severe mental retardation from birth and never respond to environmental cues beyond having a marked startle response to auditory stimuli.  Grasp and sucking responses persist at least into the second decade.  The developmental delay persists from birth and patients never achieve normal milestones.  Athetoid, writhing movements are prominent.  The limbs are spastic, and deep tendon reflexes are hyperactive. Contractures are common.  Hypodontia, diastema, and gingival hyperplasia are usually present and the hard palate is highly arched.  The skin is hypopigmented but pigmented nevi may be present and the distribution of melanocytes is uneven microscopically. Cerebellar hypoplasia has been reported in some patients.

Genetics

This is a presumed autosomal recessive disorder based on its familial occurrence and parental consanguinity in some families.  An interstitial deletion [del(3)(q27.1-1q29)] has been identified in the paternal chromosome of a 4-year-old female but the molecular defect remains unknown. 

Clinically heterogeneous cases from Africa, Germany, Italy, Great Britain, and Belgium may not all have the same disorder and evidence for a distinctive phenotype remains elusive.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None available

References
Article Title: 

Oculocerebral syndrome with hypopigmentation (Cross

De Jong G, Fryns JP. Oculocerebral syndrome with hypopigmentation (Cross syndrome): the mixed pattern of hair pigmentation as an important diagnostic sign. Genet Couns. 1991;2(3):151-5.

PubMed ID: 
1801851
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