Mucopolysaccharidosis, Type Ix

A number sign (#) is used with this entry because of evidence that mucopolysaccharidosis type IX can be caused by compound heterozygous mutation in the HYAL1 gene (607071) on chromosome 3p21. One such patient has been reported.

Clinical Features

Natowicz et al. (1996) described the clinical, pathologic, and biochemical findings in a child with short stature and multiple periarticular soft-tissue masses who proved to have a storage disease of hyaluronan (hyaluronic acid) due to a genetic deficiency of hyaluronidase. Genetic deficiencies of most of the lysosomal enzymes that catalyze the degradation of glycosaminoglycans had been previously identified, with the exception of hyaluronidase, a lysosomal endoglycosidase that catalyzes the degradation of hyaluronan. The patient was a 14-year-old girl who had a normal early medical history except for frequent episodes of otitis media and a 'ganglion' that had been excised from her left wrist when she was 6 months old. At the age of 7.5 years, a soft-tissue mass over the lateral aspect of her left ankle had been removed. During the next year, additional periarticular masses developed involving the proximal right second finger, the left popliteal fossa, the left inferior patella, and the right and left lateral malleoli. At the age of 9.5 years, the patient had the first of several episodes of transient, painful swelling of the periarticular masses, and generalized cutaneous swelling. These episodes accompanied or followed exertion or a febrile illness and were self-limited, resolving spontaneously within a period of 72 hours. Between the ages of 8.5 and 14 years, her growth rate declined from about the 15th percentile to below the 5th percentile, some of the periarticular masses enlarged, and new masses and right-foot pain developed. She was 145.5 cm tall (less than 5th percentile) at the age of 14 years.

Natowicz et al. (1996) noted mildly dysmorphic craniofacial features with a flattened nasal bridge, bifid uvula, and a submucosal cleft palate. There was full range of motion of all joints and no scoliosis, kyphosis, adenopathy, or organomegaly. Magnetic resonance imaging (MRI) of the left knee at the age of 10 years revealed a nodular synovium, a popliteal cyst, and a large joint effusion. Computed tomography (CT) and MRI of hip joints at the age of 12 years demonstrated the presence of masses and erosions and also revealed bilateral joint effusions and a possible cyst of the right trochanteric bursa. The patient had no plasma hyaluronidase activity, and a mixing experiment provided no evidence of an inhibitor of enzyme activity. The plasma hyaluronidase activity of the patient's father and mother was 30% and 53% of normal, respectively, and 2 of her grandparents also had low or intermediate levels of enzyme activity. Plasma concentrations of hyaluronan were very high in the patient, but normal in the father and mother. The descriptions of hyaluronidase deficiency in this family are consistent with autosomal recessive inheritance. Natowicz et al. (1996) noted that plasma hyaluronidase activity was normal in 56 patients with 25 different lysosomal storage disorders, and there was no marked elevation of the plasma hyaluronan concentration in 16 patients with other storage diseases.

Natowicz et al. (1996) suggested that the accumulation of nodular aggregates of histiocytes around and in joints may be the result of the failure of catabolism of hyaluronan by hyaluronidase. The histiocytic predominance at these sites might be the result of the hyaluronan-induced aggregation of macrophages. The marked intracellular storage of substrate and macrophages was presumably due to the receptor-mediated internalization of hyaluronan by these cells, in conjunction with the enzymatic deficiency. The lesser involvement of fibroblasts (and of the skin) and, possibly, other tissues may be due to less efficient internalization of hyaluronan, the delivery of hyaluronan to the lymphatic system, or other enzymatic or nonenzymatic degradative pathways. Natowicz et al. (1996) stated: 'It is curious that the periarticular aggregates of histiocytes caused bone erosions detected only the acetabula. Activated macrophages secrete a variety of cytokines that can stimulate localized osteoclastic activity.'

Molecular Genetics

To determine the molecular basis of MPS IX, Triggs-Raine et al. (1999) analyzed 2 candidate genes tandemly distributed on chromosome 3p21.3 that encode proteins with homology to a sperm protein with hyaluronidase activity. These genes, HYAL1 and HYAL2 (603551), encode 2 distinct lysosomal hyaluronidases with different substrate specificities. They found that the patient with hyaluronidase deficiency originally reported by Natowicz et al. (1996) was a compound heterozygote for 2 mutations in the HYAL1 gene: a 1412G-A mutation that introduced a nonconservative amino acid substitution (glu268 to lys; 607071.0001) in a putative active site residue, and a complex intragenic rearrangement, 1361del37ins14 (607071.0002), that resulted in a premature termination codon. They showed that these 2 hyaluronidase genes, as well as the adjacent HYAL3 gene (604038), had markedly different tissue expression patterns, consistent with differing roles in the metabolism of hyaluronan. The findings in relation to these 3 genes explained the unexpectedly mild phenotype of MPS IX and predicted the existence of other hyaluronidase deficiency disorders.

Nomenclature

The hyaluronan form of mucopolysaccharidosis is designated mucopolysaccharidosis type IX (MPS9).

A form of mucopolysaccharidosis had earlier been designated mucopolysaccharidosis VIII (MPS VIII; MPS8), DiFerrante syndrome, or glucosamine-6-sulfate sulfatase deficiency, but the phenotype was later found to be based on incorrect data (see HISTORY). These designations are no longer used for a form of mucopolysaccharidosis.

History

Ginsburg et al. (1977) described a patient with a form of mucopolysaccharidosis that combined clinical and biochemical features of the Morquio and Sanfilippo syndromes. The patient was a 5-year-old male with short stature, mental retardation, excessive coarse hair, hepatomegaly, only mild dysostosis multiplex, and hypoplasia of the odontoid. The cornea was unaffected. Both keratan sulfate and heparan sulfate were excreted in the urine. Circulating lymphocytes stained with toluidine blue showed a peculiar ring-shaped metachromasia underlying the cell membrane. Unlike Morquio syndrome, cultured fibroblasts accumulated (35)S and showed delayed wash-out of (35)S. Heparan sulfate and keratan sulfate have in common a sulfated N-acetylglucosamine. Sulfated N-acetylgalactosamine is limited to keratan sulfate. Ginsburg et al. (1977) suspected the existence of 2 hexosamine sulfatases, one (deficient in MPS IV, or Morquio syndrome) specific for sulfate attached to galactosamine, and one specific for sulfate attached to glucosamine. Although they stated that the latter sulfatase was deficient in their patient, DiFerrante (1980) subsequently found that N-acetylglucosamine-6-sulfate sulfatase was normal. Scientific fraud in his laboratory was suspected. The designation for the disorder based on the article by Ginsburg et al. (1977), mucopolysaccharidosis VIII (MPS VIII), was retired and the next-described MPS was designated MPS IX.