hepatosplenomegaly

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

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. 

This group of lysosomal deficiency diseases is probably the most common.  MPS I is clinically heterogeneous encompassing three clinical entities: Hurler, Hurler-Scheie, and Scheie.  In terms of clinical severity, Hurler is the most severe and Scheie is the mildest.  Infants generally appear normal at birth and develop the typical coarse facial features in the first few months of life.  Physical growth often stops at about 2 years of age.  Skeletal changes of dysostosis multiplex are often seen and kyphoscoliosis is common as vertebrae become flattened.  The head is large with frontal bossing and a depressed nasal bridge.  Cranial sutures, especially the metopic and sagittal sutures, often close prematurely.  The lips are prominent and an open mouth with an enlarged tongue is characteristic.  The neck is often short.  Odontoid hypoplasia increases the risk of vertebral subluxation and cord compression.  Joints are often stiff and arthropathy eventually affects all joints.  Claw deformities of the hands and carpal tunnel syndrome are common.  Most patients are short in stature and barrel-chested.

Cardiac valves often are thickened and endocardial fibroelastosis is frequently seen.  The coronary arteries are often narrowed.  Respiratory obstructions are common and respiratory infections can be serious problems.  Hearing loss is common.

Most patients reach a maximum functional age of 2 to 4 years and then regress.  Language is limited.  Untreated, many patients die before 10 years of age.

The lysosomal accumulation of glycosaminoglycans is responsible for the widespread signs and symptoms found in this disease.  Bone destruction in shoulders, hips and skull is often seen by the second decade of life and may become evident later in the knees and spine.  Early growth may be normal but eventually slows resulting in short stature.  Dysplasia of bones comprising these joints leads to stiffness and restricted movement.  The face is dysmorphic with coarse features.  Bone dysplasia and facial dysmorphism may be seen at birth.  Myelopathy and even tetraplegia can result from vertebral compression.  Intelligence is often normal although more severely affected individuals may have some cognitive defects.  Hepatosplenomegaly is common and compromised respiratory function can result in reduced physical stamina.  The tongue is usually enlarged.  Accumulation of dermatan sulfate in heart valves may produce insufficiency or restriction of outflow.

Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age.  Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly.  Hepatosplenomegaly is usually the first physical sign.  Hypotonia and pulmonary infections are common.  These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.

The less severe form of Niemann-Pick disease, type B, has a later onset and slower course.  Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood.  Mutations in the same gene are involved, however.  

Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized.  The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.

Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration.  Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.

Mild to severe developmental delays are common and mental retardation has been reported in some cases.  There is often 'pebbling' of the skin over the neck and chest.  Joint stiffness, short stature, and skeletal deformities are common.   Many have short necks, a protuberant abdomen, a broad chest, and facial coarseness.  Hepatosplenomegaly, hearing loss, hernias, and carpal tunnel syndrome are often present.  The skull is large with a J-shaped sella, the vertebral bodies are hypoplastic anteriorly, the pelvis and femoral heads are hypoplastic and the diaphyses are expanded.

A severe form, type A, has its onset in the first two to four years of life, with more rapid progression and death commonly by adolescence.  Many patients have obstructive pulmonary disease and heart failure.  The IDS deficiency is similar to that of type B which is less severe and compatible with life into the 7^th decade.  Intelligence is often normal in type B.