vertebral clefting

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.

Some patients may have extreme microphthalmia.

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) (also called 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.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

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

References
Article Title: 

MLL2 and KDM6A mutations in patients with Kabuki syndrome

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

Rhizomelic Chondrodysplasia Punctata

Clinical Characteristics
Ocular Features: 

Congenital cataracts are the outstanding ocular feature of this syndrome and are present in over 70% of patients.  They are usually bilateral and symmetrical and may not be present for several months after birth.

Systemic Features: 

The name of this disorder comes from the punctate calcification seen in cartilage.   The vertebrae have coronal clefting.  The cartilage abnormalities result in defective bone growth with severe growth retardation, short stature, and joint contractures.  Many infants die during the neonatal period and few survive beyond the first decade of life. However, milder forms have been reported. The skin can be ichthyotic and severe mental retardation is often accompanied by seizures.  Red cells are deficient in plasmalogens while phytanic acid and very long chain fatty acids accumulate in the plasma, a biochemical profile characteristic of RCDP1.

Other types of chondrodysplasia punctata also exist (RCDP2 and RCDP3). The X-linked recessive (CDPX1; 302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

A phenocopy sometimes results from maternal ingestion of dicoumarol in early pregnancy.

Genetics

This rare autosomal recessive condition results from mutations in the PEX7 gene (6q22-q24) causing a peroxisomal biogenesis disorder.  Some clinical features overlap with those of Zellweger syndrome (214100) and infantile Refsum disease (266510), also peroxisomal biogenesis disorders. 

Mutations in the same gene are responsible for adult Refsum disease-2 (266500).  The latter, however, has other neurological symptoms as well as clinical features of retinitis pigmentosa with night blindness and restricted visual fields.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available beyond supportive measures. Cataract removal may improve vision but the poor prognosis for longevity requires caution be used.

References
Article Title: 
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