Schmid metaphyseal chondro dysplasia (MCD) is characterized by short stature, bowed legs, coxa vara, metaphyseal changes on skeletal X-rays, and autosomal dominant inheritance. It is usually considered to be easily distinguished from the autosomal recessive cartilage-hair hypoplasia (CHH), in which the skeletal findings are typically more severe and frequently accompanied by hair abnormalities, defective immunity, and hematologic disturbances. However, as Ridanpää and colleagues report, this may not always be the case. Although many patients with Schmid MCD have heterozygous mutations of the COL10A1 (the gene encoding the type X collagen chain), some do not. In the study of 32 patients with a clinical diagnosis of Schmid MCD reported in this paper, COL10A1 mutations were identified in 12 patients. Even though they lacked the non-skeletal features of CHH, the 20 patients with no COL10A1 mutations were screened for mutations of the RMRP gene, which encodes the non-translated RNA component of the RNase mitochondrial RNA processing complex (RNase MRP) and which is mutated in patients with CHH.
Two of the Schmid MCD patients (both 5-year-old boys), one of Canadian descent, the other of French-Canadian descent, were found to be homozygous for a base substitution G for A at nucleotide 70 of RMRP. This is considered a worldwide “major” mutation for CHH. In one case, parents were found to be heterozygous for this mutation consistent with the recessive inheritance of CHH. Review of the clinical findings confirmed that both boys had normal hair, no excessive ligamentous laxity, and normal history of infections with normal immunological and hematological findings. One was the product of a consanguineous mating.
The authors also searched for mutations in another gene H1RNA, which encodes the RNA component of RNase P, which is structurally and functionally similar to RNase MRP. No mutations were identified. The authors concluded that these patients represent the mild end of the clinical spectrum of CHH, and caution that it should be considered in patients with clinical features of Schmid MCD in whom a COL10A1 mutation can not be found, especially if there is no family history for bone dysplasia.
Ridanpää M, Ward LM, Rockas S, et al. Genetic changes in the RNA components of RNase MRP and RNase P in Schmid metaphyseal chondrodysplasia. J Med Genet. 2003;40:741-746.
Editor’s Comment: This paper provides another example of disorders that resemble each other clinically but have different genetic origins. It also underscores why identification of causative mutations is important. As the authors note, it is unknown if mild cases of CHH, such as those reported here, carry the same risk for complications such as skin and lymphoid cancers as more severely affected CHH patients. However, they may well since they carry the same RMRP mutation making surveillance for such complications an essential component of their care.
William A. Horton, MD
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Current GGH - Vol. 24 No. 1
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