strabismus

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

No systemic disease has been found. 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4^th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

The facial features are reported to be characteristic but there are few distinctive signs.  The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip.  Smiles have been described as 'grimacing'.  It is common for the columella to protrude beyond the alae nasi.  The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties.  The ears may be rotated posteriorly.  The anterior hairline can appear low.

Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially.  However, the distal phalanges of all fingers may be broad as well.  Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life.  Hypotonia is a feature.  Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.

Developmental delays are common.  Infancy and childhood milestones are often delayed.  Many patients have cognitive delays and some are mildly retarded.  Postnatal growth is subnormal and obesity is common.  A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus.  Renal abnormalities occur frequently and almost all males have undescended testes.  Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system.  Other problems are constipation and hearing loss.

In the congenital form, hypotonia, generalized weakness, mental retardation and respiratory insufficiency are often present.  There is a great deal of clinical heterogeneity among patients.  Those with mild disease may have only cataracts and mild myotonia with a normal life expectancy.  Those with more severe disease (classical myotonic dystrophy) have these signs plus marked muscle weakness and wasting.  Cardiac conduction defects with secondary arryhthmias are a significant cause of mortality. Such patients tend to become disabled in adulthood.  Symptoms become evident in the second decade or later.  Deep muscle pain is common and can be severe.  Distal muscle weakness usually begins before facial muscle weakness is apparent.  Myotonia often involves the tongue while proximal muscle weakness can cause dysphagia and dysarthria.  Such patients may also suffer respiratory distress. Reproductive fitness is reduced in males who can have gonadal atrophy.  Frontal balding is common.  Some age-related cognitive decline occurs.

Over 60% of patients have a hearing impairment and more than half of these have auditory brainstem response abnormalities.  Vestibular hypesthesia is present in 37.5%.

The facial features are considered to be distinctive, characterized by a broad, square face, prominent forehead, broad nasal bridge, and midface hypoplasia.  These and other features appear more pronounced with age as in the size of the jaw which is underdeveloped in infancy and eventually becomes prognathic.  Most patients have developmental delays, speech and motor deficits, cognitive impairments and behavioral abnormalities.  Hypotonia, hyporeflexia, failure to thrive, lethargy, and feeding difficulties are common in infants.  Older individuals have REM sleep disturbances with self-destructive behaviors, aggression, inattention, hyperactivity, and impulsivity.  Short stature, hypodontia, brachydactyly, hearing loss, laryngeal anomalies, and peripheral neuropathy are common. Seizures are uncommon.

The behavioral profile of this syndrome can resemble that of autism spectrum disorders although symptoms of compulsivity are more mild.

A related developmental disorder known as Potacki-Lupski syndrome (610883) involving the same locus on chromosome 17 has a similar behavioral profile.  Ocular and systemic malformations may be less severe though.

This is a syndrome of multiple congenital anomalies.  Among these are dwarfism, micrognathia, hard palate anomalies, hypotonia, anomalies of the external genitalia, polysyndactyly, microcephaly, and mental retardation.  It has been suggested that many individuals have a characteristic behavioral profile consisting of cognitive delays, hyperreactivity, irritability, language deficiency, and autism spectrum behaviors.  Some individuals exhibit aspects of self destructive behavior.  Tissue levels of cholesterol are low.