Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition.

Key words: India, Metaphyseal chondrodysplasia, RMRP mutation, Skeletal dysplasia.

Following extraction of DNA from blood of the sibs and their parents, the RMRP gene was amplified by polymerase chain reaction (PCR) [1]. The complete transcript of the RMRP gene as well as 200 base pairs of the promoter region was sequenced. Thereby the novel RMRP mutations c.94_96dupAGT and c.99C>T (Fig. 1) as well as the previously described polymorphisms g. 58T>C; g.-48C>A and g.+7T>C (all homozygous), were identified in both patients. Both siblings were compound heterozygous for the mutations. The correct segregation of the mutations was proven by subcloning and sequencing of the PCR products. Analysis of the parents confirmed their carrier status. The father had a c.99C>T mutation whereas the mother had the duplication (c.94_96dupAGT). The father was homozygous for the polymorphisms and the mother was heterozygous.

Fig 1. Sequencing of the RMRP gene after subcloning; results of the boy. (a) The paternal allele carries a c.99C>T nucleotide substitution within the RMRP gene. (b) The maternal allele carriers a duplication of 3 nucleotides (c.94_96dupAGT) within the RMRP gene. Both patients were compound heterozygous for the novel RMRP mutations c.99C>T and c.94_96dupAGT.

CHH is a rare disease with known carrier frequencies of 1:19 among the Amish and 1:76 among the Finnish population [3]. The phenotype of CHH is variable. Laxity of ligaments, incomplete extension at the elbows, cone shaped epiphyses of the phalanges [1], rounded distal epiphyses, prominent sternum, chest deformity [5], mild scoliosis, increased lumbar lordosis and bowing of the lower limbs are described. The affected siblings reported in this study, had most of the clinico-radiographic findings suggestive of CHH.

The RMRP gene encodes the untranslated RNA component of the RNase MRP complex. This ribonucleoprotein complex cleaves RNAs and is thereby involved in the replication of mitochondrial DNA [6], processing of the 5.8 S ribosomal RNA [7] and control of cell cycle progression at the end of mitosis [8]. Mutations in the RMRP gene lead to a wide spectrum of recessive skeletal dysplasias with different degrees of short stature. The molecular analysis of the RMRP gene in the affected siblings identified two novel mutations, c.94_96dupAGT and c.99C>T. We conclude that these were pathogenic as they were inherited from unaffected parents, both carrying one of the mutations. In addition, the mutations were not identified in 100 controls [9]. The functional importance could be explained by the localization of both mutations in an evolutionary conserved part of the transcript [9]. They might alter a very important stem-loop structure [10].

After having confirmed the diagnosis by molecular analysis, the prospective treatment was discussed. Unlike most CHH patients, these sibs did not have a history of recurring infections or other signs of immunodeficiency. As the clinical outcome of CHH patients can only be poorly predicted, they should be carefully followed up because of the possibility of serious infections and malignancies.

Acknowledgments: We acknowledge the support of Dr Andreas Zankl, Dr Sheila Unger and the ESDN clinical-radiographic review panel (www.esdn.org). We thank Dr Pia Hermanns, who was involved in the RMRP mutation analysis and the interpretation of the data. We thank Dr Suresh S of the Fetal Care Research Foundation for his encouragement.

Contributors: KR: did the molecular analysis, was involved in the interpretation of the data, drafted the manuscript together with AIV and revised the manuscript; AIV: drafted the manuscript initially; SJ: managed the case and will act as the guarantor. The final manuscript was approved by all authors.

Funding: None.

Competing interests: None stated.

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