blue sclerae

Kabuki Syndrome 1

Clinical Characteristics

Ocular Features

The facial features and specifically the periocular anomalies are diagnostic and responsible for the eponymic designation (resembling the make-up of actors of a Japanese theatrical form known as Kabuki). The lid fissures are long and narrow and the lateral third of the lower lids are often everted.  The eyebrows are highly-arched and broad with some sparsity especially in the lateral portion.  The eyelashes are thick and ptosis is often noted. Strabismus may be present.  Blue sclerae have been reported.

Systemic Features

Post-natal growth delay and short stature are present as a result of anomalies in the vertebrae often with secondary scoliosis.  Persistence of the fetal fingertip pads is common. Hypotonia and joint hypermobility have been noted and some degree of intellectual disability is common.  Seizures have been reported but these are not common.  cleft lip and palate are seen in about a third of patients and the palate is highly arched in about 75%.  The teeth are small, frequently malformed and widely spaced.  Feeding difficulties are common.  Anal anomalies such as imperforate anus, anovestibular fistulas, and an anteriorly placed opening may be present, especially in females.  A small penis, hypospadias, and cryptorchidism are common in males.

An ill-defined immune deficit seems to be a common feature as evident by susceptibility to infections, primarily otitis media in infants and later recurrent sinopulmonary infections.   The majority of patients have hypogammaglobulinemia with a variable pattern of antibody abnormalities resembling common variable immune deficiency and especially low levels of serum IgA.  

Hearing loss is seen in nearly half of patients, some of which is no doubt due to recurrent otitis media but CT radiography has demonstrated dysplastic morphology of inner ear structures and the petrous bone.  The ears are large and cupped and preauricular pits may be present as well.

Biliary atresia and a variety of morphological anomalies of the kidney have been reported.  Renal failure can occur.  Perhaps as many as 58% of patients have congenital heart defects, mostly septal in location. 

Genetics

Heterozygous mutations in KMT2D (12q13.12) (MLL2) are responsible for Kabuki syndrome 1 but parental transmission to offspring is rare and the majority of patients occur sporadically.  There is also an X-linked form (Kabuki 2) caused by mutations in KDM5A (Xp11.3).  Insufficient clinical data regarding the X-linked phenotype so far has precluded the ability to distinguish the two disorders without genotyping.

Residual genetic heterogeneity remains, however, as a substantial proportion of patients do not have mutations in the two mutant genes known.

Treatment Options

There is no general treatment for this condition.  Management guidelines are available (Management of Kabuki Syndrome).

References

Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A. 2013 Sep;161A(9):2234-43. 

PubMed ID: 
23913813

Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, Ishikawa N, Yamada Y, Fujita M, Umemoto H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet. 1988 Nov;31(3):565-89. Review.

PubMed ID: 
3067577

Osteogenesis Imperfecta, Type VII

Clinical Characteristics

Ocular Features

Shallow orbits sometimes lead to severe and even progressive proptosis.  Bluish sclerae are sometimes present.

Systemic Features

Infants may be born with multiple fractures and adults are often short in stature.  Hypoplasia of the midface, frontal bossing, sutural craniosynostosis, hydrocephalus, and shallow orbits are frequently present and contribute to what is sometimes considered a distinctive facial dysmorphism.  Dentinogenesis imperfecta and hearing loss are variable features.  Neurological development is normal.

Multiple fractures occur and may result in marked long bone deformities, scoliosis, and short stature.  When the ribs are involved, respiratory insufficiency may result and can be responsible for early death.  Type VII osteogenesis imperfecta is sometimes considered a lethal form of OI. 

Genetics

Homozygous mutations in the CRTAP gene (3p22.3) are responsible for this condition.  This gene codes for a cartilage-associated protein and in mice is highly expressed in chondrocytes at growth plates and around the chondroosseous junction.  

This condition has been confused with Cole-Carpenter 1 syndrome (112240) but the latter is due to heterozygous mutations in P4HB (17q25.3) (PDI gene family).

Treatment Options

Fractures require stabilization and hydrocephalus, if present, needs to be treated promptly.  Extreme proptosis can lead to inadequate hydration of the eye (especially the cornea) that may require lid surgery or orbital reconstruction.

References

Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F, Mort JS, B├Ąchinger HP, Moffatt P. Cole-Carpenter Syndrome Is Caused by a Heterozygous Missense Mutation in P4HB. Am J Hum Genet. 2015 Mar 5;96(3):425-31.

PubMed ID: 
25683117

Balasubramanian M, Pollitt RC, Chandler KE, Mughal MZ, Parker MJ, Dalton A, Arundel P, Offiah AC, Bishop NJ. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A. 2015 Jan 21. doi: 10.1002/ajmg.a.36916. [Epub ahead of print].

PubMed ID: 
25604815

Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundara UT, Lee B, Marini JC. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006 Dec 28;355(26):2757-64..

PubMed ID: 
17192541

Amor DJ, Savarirayan R, Schneider AS, Bankier A. New case of Cole-Carpenter syndrome. Am J Med Genet. 2000 Jun 5;92(4):273-7. Review.

PubMed ID: 
10842295

Roberts Syndrome

Clinical Characteristics

Ocular Features

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the reproductive cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Treatment Options

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References

Xu B, Lu S, Gerton JL. Roberts syndrome: A deficit in acetylated cohesin leads to nucleolar dysfunction. Rare Dis. 2014 Jan 21;2:e27743. eCollection 2014.

PubMed ID: 
25054091

Goh ES, Li C, Horsburgh S, Kasai Y, Kolomietz E, Morel CF. The Roberts syndrome/SC phocomelia spectrum--a case report of an adult with review of the literature. Am J Med Genet A. 2010 Feb;152A(2):472-8.

PubMed ID: 
20101700

Tomkins D, Hunter A, Roberts M. Cytogenetic findings in Roberts-SC phocomelia syndrome(s). Am J Med Genet. 1979;4(1):17-26. PubMed PMID: 495649.

PubMed ID: 
495649

Herrmann J, Opitz JM. The SC phocomelia and the Roberts syndrome: nosologic aspects. Eur J Pediatr. 1977 Jun 1;125(2):117-34.

PubMed ID: 
870834

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 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.

Treatment Options

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

References

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

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

Aldahmesh MA, Mohamed JY, Alkuraya FS. A novel mutation in PRDM5 in brittle cornea syndrome. Clin Genet. 2011 Nov 29. doi: 10.1111/j.1399-0004.2011.01808.x. [Epub ahead of print]

PubMed ID: 
22122778

Osteogenesis Imperfecta

Clinical Characteristics

Ocular Features

Blue sclerae, especially at infancy, is the most visible ocular sign in osteogenesis imperfecta but it is not always present.  It is also often present in normal infants.  In some patients, it is present early but disappears later in life. Some patients have significantly lower ocular rigidity, corneal diameters, and decreased globe length.  Interestingly, the intensity of the blue color in the sclerae does not seem to be correlated with scleral rigidity.

Systemic Features

A defect in type I collagen leading to brittle bones and frequent fractures is the systemic hallmark of this group of disorders.  Clinical and genetic heterogeneity is evident. The nosology is as yet not fully established and will likely require more molecular information.  Type I is considered the mildest of the several forms that have been reported.  Relatively minor trauma during childhood and adolescence can lead to fractures while adults have less risk.  Fractures generally heal rapidly without deformities  and with good callous formation in patients with milder disease.  However, those with more serious disease often end up with deformities and bowed bones.

Short stature, hearing loss, easy bruising, and dentinogenesis imperfecta are often seen as well.

Type II is more severe and fractures often occur in utero.  Fractures may involve long bones, skull bones and vertebrae.  At birth the rib case appears abnormally small and the underdeveloped pulmonary system may lead to severe respiratory problems and even death in some newborns.

Genetics

A number of conditions are associated with fragile bones and the classification of these in the early literature is confusing.  More confusion arises from classification schemes based solely on clinical degrees of severity.   

The designation ‘osteogenesis imperfecta’ is most accurately applied to disorders caused by construction defects in type I collagen fibers which are responsible in 90% of affected individuals.  The defect may occur in either the pro-alpha 1 or pro-alpha 2 chains which together form type I collagen.  The responsible genes are COL1A1 (17q21.31) and COL1A2 (7q22.1).  Clinical types I (166200), IIA (166210), III (259420), and IV (166220) map to these two loci.  The inheritance pattern is autosomal dominant.

Mutations in the CRTAP gene (610854; 3p22) cause an autosomal recessive OI-like phenotype classified as type VII while type VIII is an autosomal recessive OI-like disorder secondary to mutations in LEPRE1 (610915; 1p34).  However, these disorders, while clinically sharing some features of true OI, are better designated as separate conditions based on their unique molecular etiologies.

Treatment Options

Avoidance of trauma is paramount.   Periodic intravenous administration of pamidronate can increase bone density and reduce the risk of fractures. Oral bisphosphonates do not seem to be beneficial.  Prompt reduction of fractures is important to the prevention of deformities. A multidisciplinary team is important for the treatment and rehabilitation of patients.

References

Byers PH, Pyott SM. Recessively inherited forms of osteogenesis imperfecta. Annu Rev Genet. 2012 Dec 15;46:475-97.

PubMed ID: 
23145505

Lee YS, Low SL, Lim LA, Loke KY. Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta. Eur J Pediatr. 2001 Nov;160(11):641-4.

PubMed ID: 
11760017

Sillence D, Butler B, Latham M, Barlow K. Natural history of blue sclerae in osteogenesis imperfecta. Am J Med Genet. 1993 Jan 15;45(2):183-6.

PubMed ID: 
8456800

Kaiser-Kupfer MI, McCain L, Shapiro JR, Podgor MJ, Kupfer C, Rowe D. Low ocular rigidity in patients with osteogenesis imperfecta. Invest Ophthalmol Vis Sci. 1981 Jun;20(6):807-9.

PubMed ID: 
7239850

Ehlers-Danlos Syndrome, Type VIA

Clinical Characteristics

Ocular Features

The globe is thin and fragile and ruptures easily.  This results from scleral fragility which is in contrast to type VIB EDS  (229200) in which the cornea seems to be more fragile.  Retinal detachment is always a risk but no quantitative assessment can be made since early case reports did not always provide good classification of EDS types.  Other ocular abnormalities such as keratoconus and structural changes in the cornea are less common but frequent changes in classification and lack of genotyping in early cases make definitive clinical correlations difficult.

Systemic Features

The primary clinical manifestations of this form (VIA) of Ehlers-Danlos syndrome are extraocular.   The skin is soft, thin, easily extensible, and bruises easily.  The joints are highly flexible with a tendency to dislocate.  Arterial ruptures are not uncommon, often with severe consequences.  Scoliosis begins almost at birth and often progresses to severe kyphoscoliosis.  Patients are floppy (hypotonic).  Intellect is normal and there are generally no developmental delays.  Thirty per cent of infants have a club foot at birth.

Genetics

This an autosomal recessive disorder caused by molecular defects in the PLOD1 gene (1p36.3-p36.2).  The gene product is an enzyme, lysyl hydroxylase 1, important for the normal crosslinking of collagen. Mutations in PLOD1 may result in hydroxylase dysfunction with abnormal hydroxylation of lysine, weakened crosslinks, and fragile tissue.  

Treatment Options

Joint dislocations, ocular trauma and vascular ruptures require prompt attention.  Longevity is not impacted by this syndrome.

References

Giunta C, Randolph A, Steinmann B. Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Mol Genet Metab. 2005 Sep-Oct;86(1-2):269-76.

PubMed ID: 
15979919

Wenstrup RJ, Murad S, Pinnell SR. Ehlers-Danlos syndrome type VI: clinical manifestations of collagen lysyl hydroxylase deficiency. J Pediatr. 1989 Sep;115(3):405-9.

PubMed ID: 
2504907

Brittle Cornea Syndrome 1

Clinical Characteristics

Ocular Features

This seems to be a subtype of the Ehlers-Danlos syndrome in which the ocular features are prominent.  The cornea is thin and can perforate following relatively minor trauma.  It is often misshapen as well resulting in keratoglobus and keratoconus.  The external appearance can suggest buphthalmos but intraocular pressure is normal.  The sclerae are bluish suggesting that the connective tissue defect is more widespread among eye tissues. The lens is not hypermobile, however.  This disorder differs from Ehlers-Danlos type VIA (225400) (sometimes called the ocular-scoliotic form) in which there is a defect in lysyl hydroxylase although the ocular phenotype has some similarities.

Systemic Features

The skin is hyperelastic as in other forms of Ehlers-Danlos and the joints are hypermobile and are susceptible to dislocation.  Some but not all cases reported from the Middle East have red hair and it has been suggested this may be part of the syndrome, at least in that part of the world.

Genetics

A mutation in the ZNF469 gene (16q24), encoding a zinc finger protein, is responsible for at least some cases of autosomal recessive brittle cornea syndrome.  This confirms its identity as a unique type of connective tissue disease apart from other forms of Ehlers-Danlos in which ocular disease is present (such as type VIA in which the mutation is in the PLOD1 gene).

Homozygous mutations in PRDM5 (4q27) have been found in several families with brittle cornea syndrome 2 (614170).

Treatment Options

Treatment beyond corneal repair is limited.

References

Walker LC, Overstreet MA, Willing MC, Marini JC, Cabral WA, Pals G, Bristow J, Atsawasuwan P, Yamauchi M, Yeowell HN. Heterogeneous basis of the type VIB form of Ehlers-Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation. Am J Med Genet A. 2004 Dec 1;131(2):155-62.

PubMed ID: 
15523625

Ticho U, Ivry M, Merin S. Brittle cornea, blue sclera, and red hair syndrome (the brittle cornea syndrome). Br J Ophthalmol. 1980 Mar;64(3):175-7.

PubMed ID: 
7387950

Judisch GF, Waziri M, Krachmer JH. Ocular Ehlers-Danlos syndrome with normal lysyl hydroxylase activity. Arch Ophthalmol. 1976 Sep;94(9):1489-91.

PubMed ID: 
962660

Aldahmesh MA, Mohamed JY, Alkuraya FS. A novel mutation in PRDM5 in brittle cornea syndrome. Clin Genet. 2011 Nov 29. doi: 10.1111/j.1399-0004.2011.01808.x. [Epub ahead of print]

PubMed ID: 
22122778