Cartilage-hair hypoplasia (CHH), which is Online Mendelian Inheritance in Man (OMIM) disease number 250250, is an autosomal recessive inherited disorder that results in short-limb dwarfism associated with T-cell and B-cell immunodeficiency.  Cartilage-hair hypoplasia and other short-limb dwarfism phenotypes are associated with metaphyseal or spondyloepiphyseal dysplasia. Cartilage-hair hypoplasia is a variant of short-limb dwarfism in which fine sparse hair is also present.
The immunodeficiency in cartilage-hair hypoplasia may be an isolated T-cell immunodeficiency, isolated B-cell immunodeficiency, or combined T-cell and B-cell immunodeficiency.
Although originally described by McKusik et al in 1964 in Amish children and known as metaphyseal chondrodysplasia McKusick type, cartilage-hair hypoplasia has been described in non-Amish persons throughout the United States, Europe, and Mexico.  The genetic defect in cartilage-hair hypoplasia has been confirmed to be mutations in the RMRP gene.
The genetic defect in cartilage-hair hypoplasia has been identified as a mutation in the gene for RNAase RMRP, mapped to 9p12. [3, 4, 5, 6, 7, 8, 9, 52, 56] 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. 
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.  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.  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.  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.  Recently, it was observed that RMRP associates with the human telomerase catalytic subunit (hTERT).  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.  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.
Cartilage-hair hypoplasia is a rare defect. It has been described in both Amish and non-Amish populations. In the Amish, the gene frequency was reported to be 1 per 1340 population with a carrier rate of 1 per 19 population.  A recent study examined the temporal trends of primary immunodeficiency diseases. 
In Finland, the frequency of cartilage-hair hypoplasia was reported to be 1 case per 23,000 live births, with a carrier rate of 1 case per 76 live births. 
Persons with cartilage-hair hypoplasia may be subject to infections with opportunistic microorganisms, principally life-threatening varicella infections. In one report, approximately 88% of 108 Finnish patients with cartilage-hair hypoplasia had defective cellular immunity and 56% had increased susceptibility to infections.  Individuals with more severe impaired cellular immunity are more susceptible to malignancies, especially leukemia and lymphoma. In their series, the incidence rate of malignancies was 6%. The risk of infections and malignancies correlates with the severity of impaired T-cell immunity.
However, cartilage hair-hypoplasia is a rare cause of severe combined immunodeficiency (SCID). In a large series of 108 patients with SCID, only one patient with cartilage hair-hypoplasia was identified.  Individuals with cartilage hair-hypoplasia and SCID have a greater susceptibility to opportunistic infections, such as Pneumocystis carinii pneumonia and graft versus host disease, and may succumb to overwhelming infections in infancy.
First reported among Amish children, the disorder has also been reported in other groups throughout the United States, Europe, Asia, and Mexico.
Cartilage-hair hypoplasia is inherited as an autosomal recessive disorder with equal male-to-female frequency.
The predominant clinical feature of cartilage-hair hypoplasia is short-limb dwarfism evident at birth. The onset of dwarfism may be detected in utero, manifesting as shortening and bowing of the femur.
The onset of increased susceptibility to recurrent infections and severity of infections is somewhat more variable in cartilage-hair hypoplasia.
In two studies, increased susceptibility to infections was reported in only 31-56% of individuals with cartilage-hair hypoplasia. [15, 14] In addition, infections may be limited to varicella and may occur in early childhood. Thus, immunodeficiency in individuals with cartilage-hair hypoplasia varies, often with limited susceptibility to infections, and many children with cartilage-hair hypoplasia may live healthy lives.
Children with cartilage-hair hypoplasia that causes SCID present in early infancy with susceptibility to overwhelming and opportunistic infections.
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