vertebral anomalies

Kabuki Syndrome 2

Clinical Characteristics
Ocular Features: 

The facial features are characteristic primarily because of the appearance of the periocular features.  The eyebrows are highly arched and sparse.  The lid fissures are long with eversion of the lateral portion of the lower eyelid.  The eyelashes are bushy.  Nystagmus and strabismus have been reported.

Systemic Features: 

Only a small number of individuals with Kabuki syndrome 2 have been reported and the phenotype is incompletely described.  Most of the features in type 2 are similar to those in type 1 with defects in multiple organs.  There are often cardiac malformations including septal defects.  Otitis media and hearing loss are common.  The pinnae are large and cupped.  A highly arched or cleft palate may be present and the teeth are usually small.  The joints are highly mobile and general hypotonia is often present. The fifth finger is often short and clinodactylous.  Persistent fetal fingerpads are common.  The amount of intellectual disability varies considerably with some patients functioning normally.  Urogenital anomalies are less common than found in Kabuki syndrome 1 and anal malformations do not seem to be a feature.

Genetics

Kabuki syndrome 2 is an X-linked disorder, usually as the result of a mutation in the KDM6A gene (Xp11.3).   Patients with the X-linked form of Kabuki represent about 5-10% of cases.   

Kabuki syndrome 1 (147920) is an autosomal dominant condition caused by heterozygous mutations in the KMT2D gene but remaining heterogeneity is suggested by the fact that a substantial proportion (30%) of individuals with Kabuki syndrome features has neither of these mutations.

In a 3 generation family two males had the typical Kabuki phenotype whereas their mother and grandmother (all had the KMT2D mutation) had various attenuated features.

Treatment
Treatment Options: 

Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients

Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, De Nittis P, Pellico MT, Mandriani B, Fischetto R, Boccone L, Silengo M, Biamino E, Perria C, Sotgiu S, Serra G, Lapi E, Neri M, Ferlini A, Cavaliere ML, Chiurazzi P, Monica MD, Scarano G, Faravelli F, Ferrari P, Mazzanti L, Pilotta A, Patricelli MG, Bedeschi MF, Benedicenti F, Prontera P, Toschi B, Salviati L, Melis D, Di Battista E, Vancini A, Garavelli L, Zelante L, Merla G. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014 Jul;35(7):841-50.

PubMed ID: 
24633898

CODAS Syndrome

Clinical Characteristics
Ocular Features: 

Dense nuclear cataracts can be seen by six months of age.  Some patients have ptosis. The fundi have been described as normal at one month of age in a single infant but vision was described at the 20/200 level at 2 years of age.  Cataracts noted at 4 months had been removed.

Systemic Features: 

Patients have multiple severe systemic abnormalities.  There is generalized developmental delay along with mild microcephaly and hypotonia.   The forehead is often broad while the face appears flattened with anteverted nares, a flat nasal bridge, a short philtrum, low-set and crumpled ears.  Infants may have an inadequate upper respiratory apparatus with atrophic vocal cords and some die of laryngeal obstruction in the first days of life.  Sialorrhea and difficulty swallowing have been noted.  Mild to moderate neurosensory hearing loss is often present but there may also be a conduction component to this. 

Brain imaging has revealed large ventricles, with subcortical hypomyelination, a thin corpus callosum, and prominent cortical sulci.  The vertebrae may have coronal clefts and scoliosis often develops. Generalized metaphyseal dysplasia and delayed bone age are usually present.  The anus may be imperforate and a rectovaginal fistula and cryptorchidism have been reported.  Long bones may be malformed as well and most patients are short in stature. Delayed dentition, enamel dysplasia, and abnormal cusp morphology are often present.  Cardiac septal defects may be seen.

Genetics

Homozygous mutations in LONF1 (19p13.3) segregate with the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no general treatment available and infants sometimes die from laryngeal obstruction in the first days of life.   Individual anomalies may be surgically correctable in selected individuals.  Occasional infants are stillborn but one patient died an accidental death at 14 years of age. 

References
Article Title: 

CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease

Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, Mikita N, Thilagavathi J, Lee J, Sarafianos S, Benkert A, Koehler A, Zhu A, Trovillion V, McGlincy M, Morlet T, Deardorff M, Innes AM, Prasad C, Chudley AE, Lee IN, Suzuki CK. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet. 2015 Jan 8;96(1):121-35.

PubMed ID: 
25574826

IFAP (BRESHECK) Syndrome

Clinical Characteristics
Ocular Features: 

The eyelashes and eyebrow hair is sparse or completely absent.  Keratitis with secondary photophobia is often seen during infancy and progresses to corneal vascularization and scarring, sometimes resembling trachomatous disease.  Cataracts do not seem to be part of this syndrome unlike some other genodermatoses.

Systemic Features: 

Dry, scaly skin and alopecia are usually evident at birth.  There is marked absence of hair throughout the body.  The skin is generally ichthyotic and erythematous, with continuous lamellar desquamation of surface skin.  Generalized follicular hyperkeratosis is present on the scalp, dorsal surface of the limbs and on the abdomen.  Most patients are completely bald.

In some patients the skin, hair and corneal disease is accompanied by severe internal anomalies such as kidney dysplasia, brain anomalies and mental retardation, Hirschsprung disease, cleft palate, external ear malformations, cryptorchidism, and skeletal deformities, a combination of signs that some have called BRESEK/BRESHECK syndrome.  Depending upon how extensive the organ involvement, the prognosis is usually guarded and patients may not live beyond early childhood. 

It is uncertain if IFAP refers to a single disorder or if two disorders are involved (see Genetics).

Genetics

This is generally considered to be an X-linked recessive disorder most likely due to mutations in MBTPS2, at least in patients considered to have the BRESHECK condition.  Female carrier may have some similar skin and hair signs albeit to a lesser degree than males.

Since the amount of MBTPS2 activity has been shown to vary with different mutations, it is possible that all cases of IFAP with or without the added BRESHECK findings are part of the clinical spectrum of a single disorder (variable expressivity).  

Other genodermatoses with severe keratitis are KID syndrome (148210) and Hereditary Mucoepithelial Dysplasia (158310).

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

No effective treatment is known.

References
Article Title: 

MBTPS2 mutation causes BRESEK/BRESHECK syndrome

Naiki M, Mizuno S, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A. 2012 Jan;158A(1):97-102.

PubMed ID: 
22105905

IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response

Oeffner F, Fischer G, Happle R, Konig A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casano A, Weirich C, Grzeschik KH. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet. 2009 Apr;84(4):459-67.

PubMed ID: 
19361614

Microphthalmia with Limb Anomalies

Clinical Characteristics
Ocular Features: 

Patients have either microphthalmia or anophthalmia which may be present unilaterally or bilaterally.  The MRI in several patients has revealed complete absence of the globes, optic nerves, chiasm, and optic tracts.  The eyelashes are often sparse with shortened palpebral fissures and broad lateral eyebrows.

Systemic Features: 

Global developmental delays, failure to thrive, and mild to moderate mental retardation are common.   Syndactyly, polydactyly, and oligodactyly with hypoplasia of the long bones are present to a variable degree.  Synostosis in the digits, ankles, and wrist is often seen.  A split hand (lobster-claw deformity) is variably present.  Other anomalies such as the kidneys (horseshoe kidney), undescended testes, anomalous venous circulation and deformed vertebrae have been reported.  The midface is often flattened.  A high palate, cleft lip, and mild scoliosis may be seen.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the SMOC1 gene (14q24.2) but there is some evidence of genetic heterogeneity as the disorder has been mapped to 10p11.23 in several families.  However, no causative mutations were found in this region.  Consanguinity among parents is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment in most cases for the ocular malformations.  Some of the limb anomalies may be surgically correctable.

References
Article Title: 

SMOC1 is essential for ocular and limb development in humans and mice

Okada I, Hamanoue H, Terada K, Tohma T, Megarbane A, Chouery E, Abou-Ghoch J, Jalkh N, Cogulu O, Ozkinay F, Horie K, Takeda J, Furuichi T, Ikegawa S, Nishiyama K, Miyatake S, Nishimura A, Mizuguchi T, Niikawa N, Hirahara F, Kaname T, Yoshiura K, Tsurusaki Y, Doi H, Miyake N, Furukawa T, Matsumoto N, Saitsu H. SMOC1 is essential for ocular and limb development in humans and mice. Am J Hum Genet. 2011 Jan 7;88(1):30-41.

PubMed ID: 
21194678

A locus for ophthalmo-acromelic syndrome mapped to 10p11.23

Hamanoue H, Megarbane A, Tohma T, Nishimura A, Mizuguchi T, Saitsu H, Sakai H, Miura S, Toda T, Miyake N, Niikawa N, Yoshiura K, Hirahara F, Matsumoto N. A locus for ophthalmo-acromelic syndrome mapped to 10p11.23. Am J Med Genet A. 2009 Mar;149A(3):336-42.

PubMed ID: 
19208380

Iridogoniodysgenesis and Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Megalocornea, congenital glaucoma, a concave iris with stromal atrophy and corectopia, and deep anterior chambers are typical ocular features.  High myopia has been reported and retinal detachments have been observed.  Glaucoma control can be difficult to achieve and there is a significant risk of cataracts and phthisis bulbi following surgery.  Posterior embryotoxon has not been observed.

Systemic Features: 

Facial features seem to be consistent.  The forehead is wide, the nose appears broad with a large nasal tip and broad nares although the bridge appears narrow.  The philtrum is long and wide.  The ears may appear large and the neck is short.  The thorax is abnormally wide and the nipples are widely spaced and umbilicated.  The long bones are slender with thin cortices and wide metaphyses.  There is generalized osteopenia.  Vertebral bodies are cuboid-shaped with narrow vertebral canals and enlarged apophyses

Genetics

Two non-consanguineous families each with 3 sibs have been reported suggesting autosomal recessive inheritance.  Nothing is known about the mutation or its locus.

The ocular features may resemble Rieger or Axenfeld anomaly but these are inherited in autosomal dominant patterns and the skeletal features are dissimilar.       

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Vigorous treatment of glaucoma is indicated but successful control, even with surgery, is difficult to achieve.

References
Article Title: 

Keratoconus Posticus Circumscriptus

Clinical Characteristics
Ocular Features: 

The posterior corneal surface has area(s) of excavation (indentation) associated with overlying opacification.  The lens-corneal separation is reduced and iridocorneal adhesions are often present.  The clinical picture has been described as ‘posterior conical cornea’ or posterior keratoconus.

Systemic Features: 

The neck is short and has webbing.  The facies appear ‘coarse’, the posterior hairline is low, the nose is prominent, digits are short, and the vertebral anomalies may lead to scoliosis.  Individuals are short of stature and brachydactyly is often present.  Developmental delays and mental retardation are usually features.  Other variable anomalies have been reported.

Genetics

Autosomal recessive inheritance seems most likely in view of the family patterns.  Based on the few families reported, it is uncertain if this is a single entity with variable expression or a combination of disorders.  No gene or locus has been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond surgical repair of the cleft lip and palate or scoliosis is available.  Peripheral iridotomies have been done in the presence of shallow anterior chambers.

References
Article Title: 

Goldenhar Syndrome Spectrum

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this syndrome.  Upper eyelid colobomas and ocular dermoids or lipdermoids are the primary ocular signs (lower lid colobomas are more common in Treacher Collins-Franceschetti syndrome [154500]).  The caruncles may be dysplastic, displaced or even bilobed.  Iris, optic nerve and chorioretinal colobomas also occur.  Microphthalmia is uncommon.  All ocular features are usually unilateral but are bilateral in a minority of cases.

Systemic Features: 

The facial asymmetry (hemifacial microsomia) can be a striking feature.  The side with microsomia may have a malformed external auricle, preauricular tags, pretragal fistulas, and microtia or even atresia of the external auditory canal.  A wide variety of other anomalies are often found including left lip and palate, mandibular hypoplasia, vertebral anomalies, facial nerve paralysis, congenital heart defects, and conductive hearing loss.  Mental deficits are often present along with features of the autism spectrum in 11%.

Genetics

Most cases are sporadic but other family patterns support autosomal recessive and autosomal dominant inheritance with the latter being the most common.  A locus at 14q32 has been associated with OAVS but so far no mutant gene has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some patients benefit from scoliosis and cosmetic surgery.  Assistive hearing devices can be helpful and children especially should be monitored for physical and cognitive development.

References
Article Title: 

Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients

Beleza-Meireles A, Hart R, Clayton-Smith J, Oliveira R, Reis CF, Venancio M, Ramos F, Sa J, Ramos L, Cunha E, Pires LM, Carreira IM, Scholey R, Wright R, Urquhart JE, Briggs TA, Kerr B, Kingston H, Metcalfe K, Donnai D, Newman WG, Saraiva JM, Tassabehji M. Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015 Sep;58(9):455-65.

PubMed ID: 
26206081
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