high arched palate

Brittle Cornea Syndrome 2

Clinical Characteristics
Ocular Features: 

Corneal thinning and extreme fragility are characteristic of BCS2.  Ruptures of the cornea may occur with minimal trauma and repair is often unsatisfactory due to the lack of healthy tissue.  Keratoconus, acute hydrops, keratoglobus, and high myopia are frequently present as well.  Some patients have sclerocornea that obscures the normal limbal landmarks.  The sclera is also thin and the underlying pigmented uveal tissue imparts a bluish discoloration to the globe which is especially evident in the area overlying the ciliary body creating what some call a blue halo.

Systemic Features: 

Skin laxity with easy bruisability, pectus excavatum, scoliosis, congenital hip dislocation, a high arched palate, mitral valve prolapse and recurrent shoulder dislocations are often present.  Hearing impairment with mixed sensorineural/conductive defects is common.

Genetics

This autosomal recessive disorder results from homozygous mutations in PRDM5 (4q27).  Heterozygous carriers may have blue sclerae, small joint hypermobility, and mild thinning of the central cornea. 

BCS2 has many clinical similarities to brittle cornea syndrome 1 (229200) which results from homozygous mutations in ZNF469.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment for specific defects such as joint dislocations and mitral valve malfunction may be helpful.

References
Article Title: 

Brittle cornea syndrome: recognition, molecular diagnosis and management

Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, Black GC. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis. 2013 May 4;8(1):68. [Epub ahead of print]

PubMed ID: 
23642083

Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance

Burkitt Wright EM, Spencer HL, Daly SB, Manson FD, Zeef LA, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GC. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011 Jun 10;88(6):767-77. Erratum in: Am J Hum Genet. 2011 Aug 12;89(2):346.

PubMed ID: 
21664999

Glaucoma, Congenital Primary D

Clinical Characteristics
Ocular Features: 

Evidence of glaucoma can appear in early childhood but may appear much later.  However, typical signs such as enlarged corneas or frank buphthalmos, cloudiness of the corneas, tearing and photophobia are present only when the pressure is elevated due to pupillary block or when the lens migrates into the anterior chamber.  Most patients have additional signs such as ectopia lentis and spherophakia.

Systemic Features: 

Some patients have osteopenia, a high arched palate, and a marfanoid habitus.

Genetics

This form of congenital glaucoma has been described primarily in Middle Eastern and Asian as well as Roma/Gypsy families and is inherited in an autosomal recessive pattern.  The mutations occur in the LTBP2 gene (14q24) which is in close proximity to GLC3C, another putative gene with mutations causing congenital glaucoma. 

Mutations in other genes are also associated with primary congenital glaucoma such as in CYP1B1 causing type A (231300) and in GLC3B causing type B (600975).

THIS IS NOT A PRIMARY GLAUCOMA DISORDER.  Microspherophakia and ectopia lentis are not features of primary congenital glaucoma.  Elevated pressures in these patients are found only when there is a pupillary block or when the lens dislocates into the anterior chamber.  The enlarged cornea is clear and has no breaks in the Descemet membrane.  THIS CONDITION IS THEREFORE RECLASSIFIED AS "MEGALOCORNEA, ECTOPIA LENTIS, AND SPHEROPHAKIA".     

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The usual surgical and pharmacological treatments for glaucoma apply but vision preservation is a challenge.  The spherophakic or dislocated lenses may need to be removed.

References
Article Title: 

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Azmanov DN, Dimitrova S, Florez L, Cherninkova S, Draganov D, Morar B, Saat R, Juan M, Arostegui JI, Ganguly S, Soodyall H, Chakrabarti S, Padh H, L??pez-Nevot MA, Chernodrinska V, Anguelov B, Majumder P, Angelova L, Kaneva R, Mackey DA, Tournev I, Kalaydjieva L. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet. 2011 Mar;19(3):326-33.

PubMed ID: 
21081970

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

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 been associated with a similar 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: 

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