broad nasal tip

Al Kaissi Syndrome

Clinical Characteristics
Ocular Features: 

Reported facial dysmorphism features include periocular anomalies of ptosis, hypertelorism, down-slanting lid fissures, and epicanthal folds.  

Systemic Features: 

The phenotype is somewhat variable.  Intrauterine and postnatal growth retardation with hypotonia are common.   Moderate to severe intellectual disability is usually present and speech may be severely delayed.  The forehead is narrow, the nasal tip is broad, the nasal bridge is depressed, and the ears are low-set and posteriorly rotated.   Small hands and sometimes joint laxity are commonly present.  Cervical spine abnormalities including clefting, improper fusion, and segmentation anomalies are common.

Brain MRI may be normal but a small corpus callosum was present in some patients.

Genetics

Homozygous mutations in the CDK10 gene (16q24.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Windpassinger C, Piard J, Bonnard C, Alfadhel M, Lim S, Bisteau X, Blouin S, Ali NB, Ng AYJ, Lu H, Tohari S, Talib SZA, van Hul N, Caldez MJ, Van Maldergem L, Yigit G, Kayserili H, Youssef SA, Coppola V, de Bruin A, Tessarollo L, Choi H, Rupp V, Roetzer K, Roschger P, Klaushofer K, Altmuller J, Roy S, Venkatesh B, Ganger R, Grill F, Ben Chehida F, Wollnik B, Altunoglu U, Al Kaissi A, Reversade B, Kaldis P. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am J Hum Genet. 2017 Sep 7;101(3):391-403.

PubMed ID: 
28886341

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

Manitoba Oculotrichoanal Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been completely defined because of the limited number of families reported.    Colobomas, unilateral and bilateral, of the upper eyelids seems to be the most consistent finding. Clinical hypertelorism is also a common finding. Nasolacrimal duct obstruction, unilateral clinical anophthalmia, cryptophthalmos, and a cloudy cornea have also been reported.

Systemic Features: 

The anterior scalp hairline is abnormally low, sometimes extending to the eyebrows.  The anus is anomalous and may be stenotic in some cases.  The nasal tip is often broad and has a notch.  Several patients had omphaloceles.

Genetics

Autosomal recessive inheritance has been assumed as no direct transmission from parent to child has been reported, and most affected individuals (including sibs) have been found in an isolated population of Manitoba Indians with a high rate of consanguinity.  Homozygous deletions of exons 8-23 in FREM1 as well as simple 4bp deletions (9p22.3) have been found in several families confirming the presumed autosomal recessive mode of inheritance.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lid colobomas and anal stenosis should be repaired.

References
Article Title: 

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet. 2011 Jun;48(6):375-82.

PubMed ID: 
21507892
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