clinodactyly

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

Cleft Palate, Psychomotor Retardation, and Distinctive Facial Features

Clinical Characteristics
Ocular Features: 

The facial dysmorphism is present at birth together with the cleft palate.  Downslanting lid fissures, widely spaced eyes, and ptosis may be present.  Eyebrows have been described as sparse in one patient.  Strabismus and ocular apraxia are present in some children. 

Systemic Features: 

Three patients have been reported, one of whom also had a second deletion in a gene implicated in the Kabuki syndrome.  This individual had hypertrichosis and synophyrys whereas the others had sparse eyebrow and temporal hair.  The teeth are malformed with some conically shaped and widely spaced.  The forehead is prominent and the fingers are tapered and brachydactylous with 5th finger clinodactyly.

There are significant delays in achieving developmental milestones.  Hypotonia has been described.  Speech and walking in particular may be delayed for several years.   Physical growth may be delayed as well.  A variety of brain anomalies have been seen in some but not all individuals.  Hypospadius and cryptorchidism have been described.  All children reported have palatal anomalies.

Genetics

Heterozygous mutations in the KDM1A gene have been identified in two patients.  In another report a single patient had an out-of-frame 3-nucleotide deletion in the ANKRD11 gene (as sometimes found in Kabuki syndrome) plus a mutation in the KDM1A gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, Rauch A, Saenz MS, Boltshauser E, Patterson KE, Nickerson DA, Bamshad MJ. Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet Med. 2015 Dec 10. doi: 10.1038/gim.2015.161. [Epub ahead of print].

PubMed ID: 
26656649

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

Microphthalmia, Syndromic 6

Clinical Characteristics
Ocular Features: 

Ultrasound evaluation reveals globe size to vary widely from extremely small (6 mm) to normal axial length. Clinical anophthalmia is often diagnosed.  Both anophthalmia and microphthalmia may exist in the same individual. True anophthalmia has been confirmed in some patients in which no ocular tissue was detectable with ultrasound examination.  In such cases the optic nerves and chiasm are often missing as well.  Iris colobomas are common and these may extend posteriorly.  Myopia is sometimes present.

The ERG reveals generalized rod and cone dysfunction in some eyes, but may be normal in others. In many eyes the ERG is nonrecordable. Cataracts are frequently present.

Systemic Features: 

Digital and hand anomalies are common.  The hands are often described as broad and the thumbs may be low-placed.  The nails can appear dysplastic and postaxial polydactyly is often present.  Mild webbing of the fingers has been reported as well.  Microcephaly and the cranium can be misshapen. A high arched palate is often present and clefting has also been noted.  Micrognathia may be present. Some evidence of physical growth retardation is often evident.

Pituitary hypoplasia is not uncommon and may be associated with hypothyroidism and cryptorchidism with hypospadias, and a small or bifid scrotum.

The brain anomalies vary considerably.  Many patients have mild to moderate developmental delays with some learning difficulties. Sensorineural hearing loss is often present. Hypoplasia of the vermis, thinning of the corpus callosum, widening of the lateral ventricles, and occasional generalized cortical atrophy, at least in older individuals, have been described.

Genetics

This is an autosomal dominant condition caused by a point mutation in BMP4 (bone morphogenetic protein-4) (14q22-q23).  A number of chromosomal deletions involving this gene have also been identified in individuals who have this syndrome but since contiguous genes such as OTX2 and SIX6 may also be involved, the phenotype is more likely to be associated with other anomalies including genital hypoplasia, pituitary hypoplasia, absence of the optic nerves and/or chiasm, developmental delay, digital malformations, and cerebellar dysplasia.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataracts can be removed in selected individuals with potential visual function.  Socket prostheses should be considered in anophthalmia and extreme microphthalmia.  Low vision devices, Braille, and mobility training should be initiated early when appropriate.  Hearing evaluations should be done as soon as practical.

Learning specialists and special education facilities should be available for selected patients.  Polydactyly, syndactyly, skull, and cleft palate repairs may be indicated.

References
Article Title: 

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways

Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK. Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet. 2008 Feb;82(2):304-19.

PubMed ID: 
18252212

Feingold Syndrome 1

Clinical Characteristics
Ocular Features: 

Short, narrow palpebral fissures have been reported (73%).  The fissures may be up slanting and epicanthal folds have been noted.   

Systemic Features: 

The face can appear asymmetrical and triangular and the head is small in 89% of individuals.  Micrognathia is usually present and the lips appear full.  The nasal bridge is broad and the nostrils are anteverted.  The ears are often low-set and rotated posteriorly.  Syndactyly of the toes is common (97%) and the fingers are often anomalous (particularly 5th finger clinodactyly and brachydactyly) with hypoplastic thumbs.  Shortening of the 2nd and 5th middle phalanx of the fingers is especially common.  True short stature is uncommon but 60% are below the 10th centile.  Rare individuals have a sensorineural hearing loss.

Tracheoesophageal fistulas are often present, together with atresia of the duodenum and sometimes the esophagus as well.  Cardiac, renal, and vertebral malformations are seen in a minority of patients.

Intelligence may be normal but more often is below average and learning difficulties are often present.

Genetics

This is an autosomal dominant disorder secondary to mutations in the MYCN gene (2p24.3).

MYCN is up regulated in some patients with retinoblastoma (180200).

Feingold syndrome 2 (614326) is caused by hemizygous deletions of the MIR17HG gene but no ocular signs have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for the syndrome but surgery can be important for some of the external and internal malformations. Special education and treatment of hearing loss are important.

References
Article Title: 

Genotype-phenotype correlations in MYCN-related Feingold syndrome

Marcelis CL, Hol FA, Graham GE, Rieu PN, Kellermayer R, Meijer RP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer AP. Genotype-phenotype correlations in MYCN-related Feingold syndrome. Hum Mutat. 2008 Sep;29(9):1125-32.

PubMed ID: 
18470948
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