Mucopolysaccharidosis (Hunter, Hurler, also discussion of Fragile X)

The findings of coarse facies, macrocephaly, and hepatosplenomegaly, as described for the child in the vignette, are suggestive of a lysosomal storage disease. This class of disorders typically results from deficient enzyme activity and the consequent lysosomal accumulation of its substrate. The disorders include the lipidoses (eg, Tay-Sachs disease), glycoproteinoses, mucolipidoses, and mucopolysaccharidoses.

Because the substrates for the lysosomal storage disorders are large molecules that do not diffuse readily through the body, the affected sites can be predicted based on the usual tissues in which the substrate is used. For example, a defect in the storage of mucopolysaccharides, which are major constituents of connective tissue, results in a combination of coarse facies, corneal clouding, organomegaly, joint stiffness, dysostosis multiplex, hernias, short stature, and in some disorders, mental retardation. The phenotype of each disorder is determined by the specific enzyme deficiency and the resultant pattern of degradation products that accumulate.

The diagnosis of the mucopolysaccharidoses (MPSs), such as would be suspected for the child in the vignette, can be confirmed by measuring the urinary excretion of mucopolysaccharides. However, the definitive diagnosis is made by determination of the specific enzymatic activity in isolated leukocytes or cultured skin fibroblasts. Prenatal diagnosis of each of the MPSs by the measurement of specific enzyme activity in fetal cells or by the incorporation of labeled substrates into cultured amniotic cells is available. Carrier status can be identified in individuals who have a positive family history by determination of the appropriate enzyme activity in isolated leukocytes or serum. In addition, the molecular bases of some of the MPSs are known, allowing for more specific molecular identification of carriers after the mutant alleles in the family have been characterized.

MPS type IH (Hurler disease) is one of the more severe MPSs that results from the deficiency of alpha-L-iduronidase activity. It is characterized by progressive organ involvement and mental retardation that lead to death, usually in the first decade. Patients appear normal at birth and have accelerated growth in the first year followed by deceleration and short stature. The diagnosis usually is made by 2 years of age when organomegaly, corneal clouding, coarse features, enlarged tongue, and joint stiffness all are apparent. Developmental delay appears between 12 and 28 months of age and is followed by subsequent regression. Other complications include hearing loss, chronic respiratory infections, cardiac insufficiency due to valvular disease, and increased intracranial pressure. 

Hurler (crouched down, hurling a L-id, but can't see where it lands and can't hear when it lands)

Hunter (also crouched down, but not as much since He is a Hunter, who grabs a spear with a claw hand and can see and hear his prey.

MPS type IS (Scheie disease) and MPS type IH/S (Hurler-Scheie disease) are milder disorders that also result from allelic mutations in the alpha-L-iduronidase gene, but they are characterized by a less severe clinical course, presumably due to the presence of a higher level of residual enzymatic activity. MPS type II (Hunter syndrome), which is inherited in an X-linked recessive pattern, is notable for the absence of corneal clouding and the presence of severe and mild forms with and without mental impairment. MPS types IIIA, IIIB, IIIC, and IIID (the Sanfilippo syndromes) result from one of four enzyme deficiencies and are characterized by behavioral problems, seizures, and less severe somatic manifestations, with survival reported into the third decade. Children who have MPS type IV (Morquio syndrome) have normal intelligence and severe skeletal findings that sometimes are confused with the spondyloepiphyseal dysplasias. The most clinically significant complication of this disorder is upper cervical spinal cord compression due to atlantoaxial instability. Patients who have MPS type VI (Maroteaux-Lamy disease) have a somatic phenotype similar to Hurler disease, but they have normal intelligence.

- MPS 1H (Hurler): organomegaly, coarse features, joint stiffness, developmental regression, death in 1st decade
- MPS 1S (Scheie) 1H/S (Sheie-Hurler):milder disease
- MPS 2 (Hunter): X-linked, no corneal clouding, severe/mild, +/- MR
- MPS 3 (Sanfilippo): less severe somatic stuff, but behavior problems/seizures, survival into 20s
- MPS 4 (Morquio): severe skeletal findings, normal intelligence
- MPS 5 ?
- MPS 6 (Maroteaux-Lamy): like Hurler, but nl intelligence

Hurler is badness, Hunter in boys only, Sanfillipo seizes, Morquio morphs his skeleton

Fragile X mental retardation can present with global developmental delay, and some patients may be macrocephalic, but it is not associated with organomegaly. Chromosomal abnormalities typically result in a combination of growth retardation, mental retardation, and congenital defects. Hypothyroidism can share some characteristics with the mucopolysaccharidoses, including coarse features and retardation,  but organomegaly is not typical. Infants who have congenital infections that lead to retardation and organomegaly usually present in the first year of life, and coarse facies are not characteristic.

Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR,
Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of
Inherited Disease. 7th ed. New York, NY: McGraw-Hill, Inc;
Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991; 60:257-280