Alternative titles; symbols
SNOMEDCT: 73123008; ICD10CM: E76.03; ORPHA: 579, 93474; DO: 0060222;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p16.3 | Mucopolysaccharidosis Is | 607016 | Autosomal recessive | 3 | IDUA | 252800 |
A number sign (#) is used with this entry because Scheie syndrome is caused by homozygous or compound heterozygous mutation in the gene encoding alpha-L-iduronidase (IDUA; 252800) on chromosome 4p16.
The mucopolysaccharidoses are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function.
Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with 3 major recognized clinical entities: Hurler (MPS IH; 607014), Hurler-Scheie (MPS IH/S; 607015), and Scheie (MPS IS) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (McKusick, 1972).
McKusick et al. (1972) suggested that the Hurler syndrome might be called MPS IH and the Scheie syndrome MPS IS.
Stiff joints, clouding of the cornea most dense peripherally, survival to a late age with little if any impairment of intellect, and aortic regurgitation are features of the Scheie syndrome, which was earlier thought (McKusick et al., 1965) to be a separate entity designated MPS V.
The manifestations of Scheie syndrome are so mild that the diagnosis is often not considered until adulthood. The diagnosis is often made between 10 and 20 years of age with onset of symptoms commonly occurring after the age of 5 years (Neufeld and Muenzer, 2001).
The second case of Emerit et al. (1966) was probably Scheie syndrome. The parents were second cousins. The facies and hands were characteristic and aortic regurgitation with tricuspid atresia and situs inversus were present. The sisters, aged 47 and 55, reported by Koskenoja and Suvanto (1959) probably had this condition. The case of Poulet (1968) with 2 affected cousins was probably Scheie syndrome.
Fischer et al. (1999) described combined aortic and mitral stenosis in a patient with the clinical diagnosis of Ullrich-Scheie syndrome. The patient was short (161 cm). He was of normal intelligence with a high school degree. At age 23 years, recurrent syncope led to the diagnosis of severe aortic valve stenosis which was successfully treated by replacement of the calcified valve with a St. Jude prosthesis. Clouding of the cornea was found. In his thirties he developed weakness in the legs which was found to be due to compression of his spinal cord by severe thickening of the epidermal tissues from segments C1 through T1. Spinal cord decompression was required. At the age of 35, a stenotic mitral valve was replaced, again by a St. Jude prosthesis.
Head and Neck
The face is relatively normal without the coarsening seen in the other mucopolysaccharidoses. The face is broad with mandibular prognathism and full cheeks. The nasal bridge is flat and the nose and nares are broad. The neck is short (Whitley, 1993).
Corneal clouding is common in adults with Scheie syndrome and is often the presenting complaint (Whitley, 1993). The corneal clouding is progressive, leading to significant visual impairment. Other ophthalmologic problems include glaucoma (Quigley et al., 1975) and retinal degeneration (Neufeld and Muenzer, 2001).
Cardiovascular Features
Aortic and mitral valvular disease is a feature in Scheie syndrome (Whitley, 1993). Butman et al. (1989) reported the first successful combined aortic and mitral valve replacement in an adult female patient with severe aortic and mitral stenosis due to Scheie syndrome.
Gross et al. (1988) described the echocardiographic abnormalities in 2 sisters with Scheie syndrome. The 19-year-old sister had clinical evidence of mild aortic stenosis. Her echocardiogram revealed a markedly thickened left coronary cusp of the aortic valve and abnormal mitral valve. Cardiac catheterization confirmed aortic stenosis and regurgitation with well-preserved left ventricular function. The younger, 14-year-old sister had similar echocardiogram findings with the exception that the noncoronary aortic cusp was thickened and immobile.
Respiratory Features
Perks et al. (1980) reported 2 brothers with Scheie syndrome and sleep apnea. The 18-year-old brother presented with a 2-year history of daytime sleepiness and noisy breathing during sleep. Sleep study revealed 320 apneic episodes, 7% obstructive and 3 mixed. The apnea was associated with EEG changes suggestive of cerebral hypoxia. He underwent tracheostomy, which produced symptomatic improvement. The 25-year-old brother was less severely affected and had a total of 58 apneic episodes: 24% obstructive, 33% mixed, and 43% central.
Musculoskeletal System
Dysostosis multiplex can be present but is usually mild. Joint involvement is marked in the hand with a claw-hand deformity. Patients also have genu valgum, stiff, painful feet, and pes cavus (Neufeld and Muenzer, 2001).
Carpal tunnel syndrome, a common complication in the mucopolysaccharidoses, probably results from a combination of excessive lysosomal storage in the connective tissue of the flexor retinaculum and a deformity secondary to the underlying skeletal dysplasia. Wraith and Alani (1990) performed nerve conduction studies on 18 patients with various forms of mucopolysaccharidoses and mucolipidosis III. All 5 patients with MPS IS were found to have carpal tunnel syndrome.
Lumbar-sacral spondylolisthesis may be present and may be associated with spinal cord compression (Wraith, 1995).
Nervous System
Intelligence is normal (Neufeld and Muenzer, 2001). Pachymeningitis cervicalis (compression of the cervical cord secondary to glycosaminoglycan in the dura) occurs in MPS IS, although less commonly than in MPS IH/S.
Wiesmann and Neufeld (1970) found no cross-correction of Scheie and Hurler fibroblasts with those from Sanfilippo (see 252900) and Hunter (309900) patients. Both disorders showed deficiencies of alpha-L-iduronidase.
Fujibayashi et al. (1984) found that residual alpha-L-iduronidase activity in Hurler fibroblasts is heat-stable whereas that in Scheie fibroblasts is heat-labile.
Schuchman and Desnick (1988) reported the presence of cross-reactive immunologic material (CRIM) in individuals from each of the 3 MPS I subtypes. Furthermore, they identified effector compounds that enhanced the residual activities in subtype extracts into the heterozygote range. The polyclonal antibody with which this work was done, however, is under suspicion because of the findings of Scott et al. (1990) that it gave a fallacious result when used for the mapping of the IDUA gene in somatic cell hybrids.
Autosomal recessive inheritance of MPS IS was suggested by early reports of affected sibs born to normal parents (McKusick et al., 1965). McKusick's prototypic case of Scheie syndrome was subsequently shown to be a genetic compound of an allele that in the homozygote causes Hurler syndrome (252800.0001) and another allele (252800.0004) with a splicing mutation associated with residual enzyme activity.
Lowry and Renwick (1971) reported the frequency of Scheie syndrome to be 1 in 500,000 births.
Yamagishi et al. (1996) defined the IDUA mutations in 19 Japanese MPS I patients, including 2 pairs of sibs, with various clinical phenotypes; Hurler syndrome, 6 cases; Hurler/Scheie syndrome, 7 cases; Scheie syndrome, 6 cases. Two common mutations accounted for 42% of the 38 alleles in these patients. One was a novel 5-bp insertion between the T at nt704 and the C at nucleotide 705 (704ins5; 252800.0014), which was seen only in the Japanese population. The other was a missense mutation, R89Q (252800.0015), which is seen also in Caucasians, although uncommonly. No Japanese patient was found to carry the W402X (252800.0001) or Q70X (252800.0002) alleles, the 2 most common MPS I mutations in Caucasians. Homozygosity for the 704ins5 mutation was associated with a severe phenotype; homozygosity for the R89Q mutation was associated with a mild phenotype. Compound heterozygosity for these 2 mutations produced an intermediate phenotype. Haplotype analysis using polymorphisms linked to IDUA locus demonstrated that each of these 2 common mutations occurred on a different specific haplotype, suggesting that individuals with each of these common mutations derived from a common founder. The mild-intermediate-severe phenotypic relationships of the 2 common Japanese mutations fulfill the prediction of McKusick et al. (1972).
Bunge et al. (1995) identified 13 novel and 7 previously reported mutations of the IDUA gene, covering 88% of mutant alleles and 86% of genotypes, in a total of 29 patients with MPS I of differing clinical severity.
In a mutation analysis of 85 mucopolysaccharidosis type I families, including 7 families with Scheie syndrome, Beesley et al. (2001) identified 165 of the 170 mutant alleles. Despite the high frequency of W402X (252800.0001) and Q70X (252800.0002), the identification of many novel mutations unique to individual families further highlighted the genetic heterogeneity of MPS I.
Horton and Schimke (1970) described brother and sister, aged 13 and 11, with features like pseudo-Hurler polydystrophy (mucolipidosis III) but with mucopolysaccharides (both chondroitin sulfate B and heparitin sulfate) in the urine in amounts about 10 to 15 times normal. Intelligence was normal. These patients were subsequently shown to have alpha-iduronidase deficiency. The clinical phenotype suggested the Hurler-Scheie compound. Horton (1980) stated that valvular heart disease has been a problem in both sibs, who presumably have Scheie syndrome.
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