hypertension

This is a progressive disorder in which psychomotor regression and loss of speech develop by 1 to 2 years of age, often appearing as the first sign of abnormalities.  Cognitive impairment can progress to profound intellectual disability.  Older patients have limb and truncal ataxia and experience frequent falls.  Muscle tone in the limbs is increased and children often exhibit dyskinesia, dystonia, and axial hypotonia.  General muscle weakness is often present.  No abnormalities have been seen on brain imaging.

Some patients develop a nephropathy with renal insufficiency, hypertension, and hyperechogenic kidneys though deterioration of the renal disease is slow.  Renal biopsy in one patient revealed tubulointerstitial nephritis but no individuals have reached end-stage renal failure.

The facial features are unusual.  The nose appears long and may have a broad nasal root.  The lips are full and the lower jaw is prominent. Evidence of developmental delay has been reported in one patient.

The scrotum can be edematous at birth and sometimes contains large hydroceles.  Hair is sparse in infancy but within a few years alopecia is complete.  Telangiectases on the scalp, scrotum, and limbs are evident at several years of age.  Pulmonary vascular congestion and lymphangiectasia may be present in some individuals antenatally.  Renal failure, sometimes with hypertension can occur at any time from early childhood to young adulthood.  Renal biopsy has shown histologic features consistent with membranoproliferative glomerulonephritis and thrombotic microangiopathy.  This may be preceded by proteinuria in infants as young as 2 years. 

Slow somatic growth and neural development are usually noted in the first few years of life.  Young children may acquire some independence and motor skills but progressive neurologic deterioration is relentless with loss of milestones and eventual development of mental retardation or dementia.  Patients often appear small and cachectic, with a 'progeroid' appearance.  The hair is thin and dry, and the skin is UV-sensitive but the risk of skin cancer is not increased.  Sensorineural hearing loss and dental caries are common.  Skeletal features include microcephaly, kyphosis, flexion contractures of the joints, large hands and feet, and disproportionately long arms and legs.  Perivascular calcium deposits are often seen, particularly in various brain structures while the brain is small with diffuse atrophy and patchy demyelination of white matter.  Peripheral neuropathy is characterized by slow conduction velocities.  Poor thermal regulation is often a feature. 

Type A is considered the classic form of CS.  Neurological deterioration and atherosclerotic disease usually lead to death early in the 2^nd decade of life but some patients have lived into their 20s.  

Clinical symptoms typically have their onset during the second decade of life.  These commonly (in 35% of patients) result from the presence of a cerebellar hemangioblastoma while overall more than 60% eventually develop this malignancy.  Up to 40% of patients develop renal cell carcinomas and these are a major cause of death.   However, benign and malignant tumors may appear in many organs including the adrenal glands, pancreas, and spinal cord.  Pheochromocytomas occur in 20-35% of individuals and may be bilateral and multifocal.  These can induce an erythrocythemia. Endolymphatic sac tumors occur in about 10% of patients.  Cystic lesions are often associated with the tumors, especially in the pancreas.

Several subtypes have been proposed based on the pattern of malignancies and the types of mutations found in patients.