What is the pathophysiology of cartilage-hair hypoplasia (CHH)?

Updated: Aug 06, 2019
  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

The genetic defect in cartilage-hair hypoplasia has been identified as a mutation in the gene for RNAase RMRP, mapped to 9p12. [4, 5, 6, 7, 8, 9, 10, 11, 12, 13] RMRP is a ribonucleoprotein present in the nucleus and mitochondria. RNAase RMRP has multiple functions: cleavage of the upstream 5.8S rRNA junction site necessary for ribosome assembly and associated with bone dysplasia; mRNA cleavage of cyclin B2 mRNA necessary for cell cycle progression, associated with susceptibility to cancer, immune deficiency, anemia, and hair hypoplasia; processing of mitochondrial RNA in the yeast RMRP ortholog; and interaction of RMRP and hTERT leads to an RNA-dependent RNA polymerase activity leading to siRNA altering gene expression. RMRP is required for cell growth, consistent with observations that a generalized defect in cell growth is observed in T cells, B cells, and fibroblasts. [5]

RMRP has 2 types of mutations. The first are insertions or duplications of 6-30 nucleotides that reside in the region between the TATA box and the transcription initiation site. [14] These mutations interfere with the transcription of the RMRP gene and are considered null mutations. Kavadas et al reported that mutations in the promoter region are associated with immune defects. [15] The second consists of single nucleotide substitutions and other changes that involve at most 2 nucleotides in highly conserved regions of the gene.These are considered leaky mutations and result in variable expression of the gene, which may explain the variable phenotype seen in cartilage-hair hypoplasia. These latter mutations result in variable expression of the gene, which may explain the variable phenotype seen in cartilage-hair hypoplasia. The most commonly found mutation in patients with cartilage-hair hypoplasia is 70A>G, which occurs in 30-50% of patients with cartilage-hair hypoplasia and causes an alteration in ribosomal processing. [10] RMRP mutations that reduce ribosomal RNA cleavage are associated with bone dysplasia; whereas, mutations that affect mRNA cleavage are associatedwith hair hypoplasia, immunodeficiency, and dermatologic abnormalities. [8]   Recently, it was observed that RMRP associates with the human telomerase catalytic subunit (hTERT). [16] The 3’ end of RMRP is essential for RNA dependent RNA polymerase acitivity of the RMRP-hTERT complex. 

Although the immune defect primarily affects the T-cell system, mutations of RMRP result in more generalized hematopoietic impairments. [17] In studies from Makitie et al, defective in vitro colony formation in all myeloid lineages was present, including erythroid, granulocyte-macrophage, and megakaryocyte colony formation. This suggests a common cell proliferation defect in cartilage-hair hypoplasia. How the recently identified genetic defects correlate with immunologic defects remains to be determined.


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