heart defects

Septal defects involving both the atrium and the ventricle are consistently present.  Pulmonary valve abnormalities are present in some patients.

Posteriorly rotated pinnae and a small mouth with a thin upper lip have been observed.  Camptodactyly and clinodactyly are common.  Some patients have mild microcephaly.

Global developmental delay is a consistent feature manifest as delays in walking and speech and eventual intellectual disability.  Feeding difficulties are common.  Hypotonia and hypermobile joints are often noted.  Imaging of the brain may reveal agenesis of the corpus callosum, incomplete formation of the inferior vermis, and leukomalacia of periventricular tissue.

Onset of symptoms commonly begins in infancy with severe hypotonia while developmental delays soon become evident as most children do not achieve normal milestones.  The amount of cognitive impairment is variable.  Congenital cardiac defects, ichthyosis, and hypertrichosis may be present.  The skin over the dorsum of the hands and feet often appears dark.  Ataxia is sometimes present and MRIs may reveal vermal and cerebellar hypoplasia.

Facial dysmorphism is common.  Low-set malformed ears, low hairline, depressed nasal bridge, redundant facial skin, decreased subcutaneous tissue, large mouth, thin lips, and long face have been noted.

There is considerable variation in clinical manifestations and longevity varies from infancy to adulthood.

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.

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions.  Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia.  There may be some healing of the skin defects.  The corpus callosum is sometimes absent.  Diaphragmatic hernias are often present.  Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects.   Preauricular pits and hearing loss have been found in some patients.  Patients may be short in stature and some have nail dysplasia.  GU and GI anomalies may be present.