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Picture of the Month
Keith A. Knoell, MD;
Walter W. Tunnessen, Jr, MD
From the Department of Dermatology, University of Virginia Health Sciences Center, Charlottesville (Dr Knoell); and the American Board of Pediatrics, Chapel Hill, NC (Dr Tunnessen).
Arch Pediatr Adolesc Med. 2000;154:85-86.
A 7-YEAR-OLD developmentally and neurologically disabled boy developed numerous asymptomatic, flesh-colored papules on the skin of his chest, upper arms, and thighs over a 4-year period. His birth history was unremarkable. The family history was notable for the presence of a severe progressive neurological condition affecting a maternal uncle and a maternal male second cousin.
Findings on physical examination revealed striking dolichocephaly with coarse facial features. The forehead was prominent and the eyes symmetrically proptotic (Figure 1). Findings on oral examination showed an enlarged tongue and mild enamel defects of the teeth. The spleen was not palpable, but the liver edge was palpable 3 cm below the right costal margin. Severe claw-hand deformities were present (Figure 2) as well as a decreased range of motion of the elbows and knees and severe hip flexion contractures. The skin felt thickened and demonstrated hypertrichosis as well as groups of bilaterally symmetrical, firm, nontender, discrete, ivory-colored 0.3- to 0.5-cm-diameter papules over the chest, upper arms (Figure 3), scapulae, and thighs. No corneal clouding was present, but findings from auditory testing revealed a moderate to severe combined sensorineural and conductive hearing deficit.
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Figure 1.
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Figure 2.
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Figure 3.
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A biopsy of normal-appearing skin, obtained for enzyme studies, revealed an absence of iduronate sulfatase.
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Denouement and Discussion: Hunter Syndrome (Mucopolysaccharidosis IIA)
Figure 1. The head is dolichocephalic in shape with coarse facial features.
Figure 2. Claw hands and flexion contractures of the elbows are present.
Figure 3. Ivory-colored papules are present over the chest and upper arm.
Hunter syndrome is a rare (1 per 130,000 live-born males) X-linked, recessive disorder characterized by a deficiency of iduronate sulfatase. The enzyme deficiency results in the deposition and accumulation of the mucopolysaccharides dermatan and heparan sulfate in the brain and other tissues.1 Two clinical varieties of Hunter syndrome are recognized: mucopolysaccharidosis (MPS) IIA, resulting in severely affected males, and MPS IIB, a mild form of the disorder.2
CLINICAL MANIFESTATIONS
In MPS IIA, affected males demonstrate progressive physical and mental abnormalities by age 2 years, including progressive mental retardation, short stature, joint contractures, coarse facial features, hypertrichosis, prominent forehead and dolichocephaly, and thickening of the skin.
Additional features of the disorder include progressive deafness, macroglossia, dental deformities, and hernias. Thickening of the valve leaflets may result in the appearance of cardiac murmurs, ventricular enlargement, congestive heart failure, and arrhythmias. Visual loss may result from papilledema secondary to increased intracranial pressure from hydrocephalus. In addition to thickened skin, firm, ivory or skin-colored papules and nodules filled with acidic glycosaminoglycans may appear, often in reticular patterns over the chest, upper arms, and thighs.
As the deposition of mucopolysaccharides continues, affected males demonstrate progressive mental deterioration and aggressive, hyperactive behavior. In MPS IIB, somatic manifestations, although similar to MPS IIA, develop more slowly. Joint contractures and carpal tunnel syndrome may develop in adulthood and occasionally in childhood. Intelligence is normal, however.
PROGNOSIS AND MOLECULAR BASIS
The health of boys affected with MPS IIA progressively deteriorates, usually resulting in death between age 10 and 15 years.3 In MPS IIB, the milder variant of this disorder, survival into the fifth and sixth decades is not unusual.3
The gene for Hunter syndrome has been mapped to the Xq27/Xq28 region, distal to the fragile X mutation (FRAXA).4 The spectrum of severity of the disorder has been attributed to different mutations of the gene responsible, ranging from full deletions in more severely affected individuals to partial deletions or other gross rearrangements in those with milder phenotypes.5
DIAGNOSIS AND TREATMENT
The diagnosis of Hunter syndrome is made by demonstrating deficiency of the enzyme iduronate sulfatase in serum, white blood cells, or fibroblasts. The carrier status of females may be ascertained through linkage analysis studies or by measuring iduronate sulfatase activity in serum, leukocyte homogenates, or fibroblasts.6-7 Prenatal diagnosis by enzyme assay of amniotic cells or chorionic biopsies have also been used.8
The treatment of severe Hunter syndrome is mainly supportive. Bone marrow transplantation and gene therapy to halt progressive neurological and physical deterioration have been attempted, but results thus far have been disappointing.9-10
DIFFERENTIAL DIAGNOSIS
Hunter syndrome is most commonly confused with other types of MPS, particularly Hurler and Hurler-Scheie syndromes. In these disorders corneal clouding is a major feature, and skin papules do not occur. In addition, Hunter syndrome is the only MPS that is X-linked. The mucolipidoses may have similar phenotypic features. The flesh- to ivory-colored skin papules are quite characteristic of Hunter syndrome and seen in both variants. The papules offer a cutaneous diagnostic marker of the disorder.
AUTHOR INFORMATION
Accepted for publication March 16, 1999.
Corresponding author: Keith A. Knoell, MD, 1928 Powell Creek Ct, Charlottesville, VA 22911.
REFERENCES
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1. Finlayson LA. Hunter syndrome (mucopolysaccharidosis II). Pediatr Dermatol. 1990;7:150-152.
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2. Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of Hunter syndrome. J Med Genet. 1982;19:408-411.
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3. Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, Pa: WB Saunders Co; 1997:462.
4. Wilson PJ, Suthers GK, Callen DF, et al. Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome. Hum Genet. 1991;86:505-508.
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5. Hopwood JJ, Bunge S, Morris CP, et al. Molecular basis of mucopolysaccharidosis type II: mutations in the iduronate-2-sulphatase gene. Hum Mutat. 1993;2:435-442.
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6. Schroder W, Petruschka L, Wehnert M, et al. Carrier detection of Hunter syndrome (MPS II) by biochemical and DNA techniques in families at risk. J Med Genet. 1993;30:210-213.
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7. Bunge S, Steglich C, Lorenz P, et al. Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis: a 47, XXY male heterozygous for a missense point mutation. Prenat Diagn. 1994;14:777-780.
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8. Cooper A, Thornley M, Wraith JE. First-trimester diagnosis of Hunter syndrome: very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus. Prenat Diagn. 1991;11:731-735.
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9. McKinnis EJR, Sulzbacher S, Rutledge JC, Sanders J, Scott CR. Bone marrow transplantation in Hunter syndrome. J Pediatr. 1996;129:145-148.
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10. Maria BL, Medina CD, Hoang KB, Phillips MI. Gene therapy for neurologic disease: benchtop discoveries to bedside applications, 2: the bedside. J Child Neurol. 1997;12:77-84.
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SECTION EDITOR: WALTER W. TUNNESSEN, JR, MD
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