genital 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

LEOPARD Syndrome

Clinical Characteristics
Ocular Features: 

Ocular hypertelorism is a characteristic of all forms of the LEOPARD syndrome.  The lid fissures may be downward slanting.  Combined with the inverted triangle facies, the appearance is similar to that of the Noonan syndrome (163950).

Systemic Features: 

This is a multisystem disorder manifest in skin, heart, skeletal, genital, neurologic and auditory systems.  Generalized lentiginosis is characteristic but they may not be present until age 4 or 5 years following the appearance of cafe-au-lait spots.  Some patients have patchy scalp hair loss.  The facies bears some resemblance to the Noonan syndrome but usually without the short, webbed neck.  Sensorineural hearing loss is found in 20% of individuals.  Cardiac conduction defects, pulmonic stenosis, and hypertrophic cardiomyopathy are often (85%) present.  Cognitive defects are present in 30% of patients and some individuals have been described as mentally retarded.  Juvenile behavior may be evident in the presence of normal intelligence.  Hypospadias, cryptorchidism, and gonadal infantilism have been seen in some patients.  The ears are often malformed (87%).  Thoracic skeletal anomalies have been described in 75% of patients.  Although somatic growth is described as slow, short stature is present in less than half of patients.

Rare patients without lentigines are said to resemble the Noonan syndrome (163950) in appearance.

Genetics

Heterozygous mutations in the PTPN11 gene (12q24) are most frequently responsible for this autosomal dominant disorder.  The same gene is mutated in more than half of patients with the Noonan syndrome (NS1)(163950) with which it is allelic.  Other mutations that cause what is called LEOPARD syndrome are RAF1 and BRAF.

Other types of LEOPARD syndrome such as LEOPARD syndrome 2 (611554) are far more rare but also share mutations with Noonan syndrome (RAF1 mutations in Noonan syndrome 5) (611553) and LEOPARD syndrome 3 (613707) with mutations in BRAF similar to that seen in NS7 (613706).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Assistive hearing devices, especially cochlear implants, may be helpful.  Special education can be of value in more mildly affected individuals.Treatment of cryptorchidism is similar to that of other children.

References
Article Title: 

CHARGE Syndrome

Clinical Characteristics
Ocular Features: 

Both ocular and systemic abnormalities are highly variable, even within families.  Among the most common ocular features are unilateral or bilateral ocular colobomas (80%).  These involve the iris most frequently but they may extend into the posterior chamber and rarely involve the optic nerve.  A significant number of patients with uveal colobomas have an associated microphthalmia.  The lid fissures often slant downward.  A few patients have congenital cataracts, optic nerve hypoplasia, persistent hyperplastic vitreous, and strabismus.

Systemic Features: 

A wide variety of systemic anomalies have been reported.  Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively.  Tetralogy of Fallot is considered by some to be the most common heart malformation.  Growth and mental retardation are found in nearly 100%.  The pinnae are often set low and hearing loss is common.  Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%.  Choanal atresia is found in at least 57% of patients.  This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups.  Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients.  The most common cranial nerve defects involve numbers IX, X, VIII, and V.  Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males.  One-third of patients have limb anomalies and many have short digits.  The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.

Infant and childhood morbidity is high with feeding difficulties a major cause of death.

Genetics

Many cases occur sporadically but family patterns consistent with autosomal dominant inheritance are common as well.  Advanced paternal age may be a factor in de novo cases.  Sequence variants of multiple types have been reported in the CHD7 gene (8q12.1-q12.2) in more than 90% of familial patients.  The gene product is a DNA –binding protein that impacts transcription regulation via chromatin remodeling.

Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has been considered to be allelic to CHARGE syndrome but may be the same disorder since mutations in CHD7 are responsible and many patients have other features characteristic of the syndrome described here.

Several patients with classical features of the CHARGE syndrome and de novo mutations in the SEMA3E gene (7q21.11) have also been described.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is lesion dependent but focused on airway, feeding, and cardiac defects at least initially.  Regular ophthalmologic and audiologic evaluations are recommended beginning in infancy.  Evidence for hypogonadism should be evaluated if puberty is delayed.  Nutrition must be monitored especially in those with serious feeding problems.  Hearing devices, with speech, occupational, and education therapy may be required.

References
Article Title: 

Gorlin-Chaudhry-Moss Syndrome

Clinical Characteristics
Ocular Features: 

Orbital hypoplasia, short, abnormally slanted (up or down) lid fissures, and sometimes lid notching (colobomas?) are characteristic facial features as are bushy eyebrows and synophrys.  Lacrimal duct stenosis has been noted.  The eyes are described as 'small' but no ophthalmological examination has been performed to document microphthalmia or other ocular anomalies.  No mention is made of visual problems.

Systemic Features: 

Premature closure of the coronal suture and midface hypoplasia lead to striking brachycephaly.  The scalp hairline is low and scalp hair is abundant and coarse.  In fact, hypertrichosis is seen throughout the body.  Hypo- and microdontia with irregularly spaced teeth and a high arched palate are common features.  Clefts of the soft palate has been observed.  The ears can be small and rotated posteriorly.  The labia majora are hypoplastic as are the distal phalanges of the fingers and toes.  Mild syndactyly of the second and third fingers and toes have been described.  The nails may be abormally small.  Conductive hearing loss may be present.  Growth and psychomotor development seem to be normal although some patients have been described to have a 'stocky' build.  The facial features tend to coarsen over time.

Genetics

Autosomal recessive inheritance has been suggested but nothing is known about the gene locus.  All 5 reported patients have been female.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 
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