Alternative titles; symbols
SNOMEDCT: 26745009; ICD10CM: E76.02; ORPHA: 579, 93476; DO: 0111389;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p16.3 | Mucopolysaccharidosis Ih/s | 607015 | Autosomal recessive | 3 | IDUA | 252800 |
A number sign (#) is used with this entry because Hurler-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), Scheie (MPS IS; 607016), and Hurler-Scheie (MPS IH/S) 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).
Roubicek et al. (1985) presented 5 patients with alpha-L-iduronidase deficiency and a phenotype atypical for both Hurler and Scheie syndromes. They felt that the genetic compound explanation was acceptable for some cases, but that others must represent different mutations.
The clinical features of Hurler-Scheie syndrome include short stature, corneal clouding, joint stiffening, umbilical hernia, dysostosis multiplex, hepatosplenomegaly, and little to no intellectual dysfunction. Onset of symptoms occurs between ages 3 and 8 years. Survival to adulthood is typical (Neufeld and Muenzer, 2001).
Head and Neck
The facial features somewhat resemble those of Hurler syndrome. The nasal bridge is depressed and there is micrognathia. The mouth is usually broad. Corneal clouding and abnormal electroretinogram are characteristic findings (Whitley, 1993).
Cardiovascular Features
Gross et al. (1988) studied 4 Hurler-Scheie patients clinically and echocardiographically. Their ages ranged from 5 to 11 years. Of the 4 patients, 3 had insignificant auscultatory findings and 1 had evidence of moderate mitral regurgitation with a diastolic flow rumble. Echocardiogram revealed thickening of the mitral valve leaflets and a dilated left atrium and left ventricle. The others all had thickening of the mitral valve leaflets and a dilated left atrium and left ventricle. The others all had thickened mitral valves. One patient with increasing upper airway obstruction had discrete bulging of the interventricular septum into the left ventricular outflow tract. Cardiac catheterization revealed mild pulmonary hypertension and tracheostomy was performed.
Respiratory Features
Frequent respiratory infections, limited chest expansion, and difficulties with endotracheal intubation are all features of MPS IH/S (Whitley, 1993). Tracheal stenosis was reported in a 23-year-old woman with MPS IH/S who died during attempted endotracheal intubation (Wassman et al., 1982).
Semenza and Pyeritz (1988) studied respiratory complications in 3 patients with MPS IH/S. All had tongue enlargement and nasopharyngeal obstruction. Tonsillar hypertrophy was found in two-thirds of the patients. One patient studied by polysomnography was found to have obstructive sleep apnea.
Shapiro et al. (1985) described a patient with MPS IH/S with severe scoliosis and a history of marked snoring and restless sleep. Tonsillectomy and adenoidectomy provided little change in symptomatology. Polysomnogram revealed obstructive sleep apnea with oxygen saturation ranging from 61 to 87%.
Musculoskeletal System
The radiographic features of Hurler-Scheie syndrome are intermediate in the spectrum of dysostosis multiplex. Schmidt et al. (1987) described the radiologic changes in 2 patients with MPS type I H/S. Radiologic findings revealed enlargement of the sella in 1 patient and basilar skull impression in the other. Sclerosis and thickening of the base of the skull was observed in both patients. They showed irregularities of the acromial joints and acetabula, hypoplasia of the inferior portion of the iliac bones, and flared iliac wings. The flat femurs had short metaphyses and were held in valgus position. The skeletal changes of the spine and hands were minimal.
Joint stiffness is a common feature of all the MPS disorders with the exception of Morquio syndrome (253000; 253010). The joint function abnormalities probably result from a combination of the metaphyseal deformities and thickened joint capsules secondary to glycosaminoglycan deposition and fibrosis (Neufeld and Muenzer, 2001).
Progressive lumbar gibbus or kyphosis is commonly seen in the MPS disorders (Neufeld and Muenzer, 2001). Semenza and Pyeritz (1988) described 3 patients with MPS IH/S. Two patients had thoracic hyperkyphosis and scoliosis. Two patients were studied for cervical spine involvement such as odontoid hypoplasia or c1-2 subluxation. Neither had evidence of abnormality.
Nervous System
Mental function is often preserved, but some patients have intellectual decline with age (Whitley, 1993).
Pachymeningitis cervicalis (compression of the cervical cord secondary to glycosaminoglycan in the dura) occurs in MPS IH/S. However, communicating hydrocephalus appears to be uncommon. Spondylolisthesis of the lower spine can lead to spinal cord compression and myelopathy (Neufeld and Muenzer, 2001).
Winters et al. (1976) described a case of alpha-L-iduronidase deficiency that differed from the Hurler and Scheie syndromes and may represent the Hurler-Scheie compound. The female patient died at age 25 years. She was 10 years old before she was noted to be academically slow. She could not perform normally in physical education. Although she was graduated from high school at age 20, she never received a grade higher than D in high school. In the last 5 years of life remarkable coarsening of her facial features occurred. She presented to medical attention because of acute paranoia. Autopsy findings were described.
Psychosis was also described by Dugas et al. (1985) in a 17.5-year-old patient with MPS IH/S.
Other Features
Schiro et al. (1996) described grouped papules on the extensor surface of the upper portions of the arms and legs as an initial presenting feature in a 5-year-old boy with Hurler-Scheie syndrome. Other physical findings included progressive flexion contractures and mild developmental delay.
The IDUA enzyme deficiency in Hurler-Scheie compound fibroblasts is intermediate between that in Hurler and Scheie syndromes (Fujibayashi et al., 1984).
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.
Jensen et al. (1978) observed brother and sister, children of first-cousin Pakistani parents, with the Hurler-Scheie phenotype, including receding chin. The parental consanguinity suggested that their alpha-L-iduronidase deficiency was due to homozygosity for an allele at that locus, not compound heterozygosity. The same is true in the 2 families with first-cousin parents reported by Kaibara et al. (1979), in each of which 2 sibs had the Hurler-Scheie phenotype.
Bunge et al. (1995) confirmed that Hurler-Scheie syndrome is an autosomal recessive disorder.
Wang et al. (2009) reported 2 brothers with intermediate MPS I diagnosed at ages 4 years and 3 months, respectively. Both were cognitively normal, even though both had white matter abnormalities and ventricular dilatation on brain MRI, which were more severe in the older brother. Treatment with intravenous enzyme replacement therapy (ERT) resulted in progressive improvement in brain MRI findings in both patients. The findings suggested that ERT may improve brain MRI abnormalities in patients with MPS, even though ERT had previously been thought not to cross into the brain. Wang et al. (2009) offered some explanations, including lessening of somatic GAG accumulation, repair of damaged brain endothelium, and possibly small amounts of enzyme being able to permeate the brain.
Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.
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.
Lee-Chen and Wang (1997) identified a homozygous T364M mutation (252800.0018) of the IDUA gene in a 10-year-old Chinese patient with Hurler-Scheie syndrome. Lee-Chen et al. (1999) identified the molecular lesion in an 18-year-old patient with intermediate phenotype classified as the Hurler-Scheie syndrome: short stature, mild coarse face, corneal clouding, and skeletal deformities with atlantoaxial dislocation. The patient showed normal intelligence based on excellent performance in school. As a result of loss of mobility, she was wheelchair-bound and educated at home. She was found to be homozygous for an R619G mutation (252800.0017).
In a mutation analysis of 85 mucopolysaccharidosis type I families, 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.
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).
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