eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology
Cartilage-Hair Hypoplasia
Updated: May 19, 2009
Introduction
Background
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.1 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.
Hair of a patient with cartilage-hair hypoplasia (left) compared with that of a typical individual. The hair of the patient with cartilage-hair hypoplasia has a smaller diameter because the central core is absent.
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.2 The genetic defect in cartilage-hair hypoplasia has been confirmed to be mutations in the RMRP gene.
Pathophysiology
The genetic defect in cartilage-hair hypoplasia has been identified as a mutation in the gene for RNAase RMRP, mapped to 9p12.3 RMRP is a ribonucleoprotein present in the nucleus and mitochondria. RNase RMRP has 2 functions: cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of preribosomal RNA (pre-rRNA). RMRP also plays a role in ribosomal RNA production and may have a role in nuclear DNA replication. 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. In 2005, a study reported that different RMRP gene mutations led to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell-cycle regulation.4
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. The second consists of single nucleotide substitutions and other changes that involve at most 2 nucleotides in highly conserved regions of the gene. The 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 causes an alteration in ribosomal processing.
Although the immune defect primarily affects the T-cell system, mutations of RMRP result in more generalized hematopoietic impairments.5 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.
Frequency
United States
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.6 A recent study examined the temporal trends of primary immunodeficiency diseases.7
International
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.8
Mortality/Morbidity
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.9 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.10 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.
Race
First reported among Amish children, the disorder has also been reported in other groups throughout the United States, Europe, Asia, and Mexico.
Sex
Cartilage-hair hypoplasia is inherited as an autosomal recessive disorder with equal male-to-female frequency.
Age
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.9,8 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.
Clinical
History
The clinical findings in cartilage hair-hypoplasia (CHH) are outlined below.9,11,12,13,5 The predominant features include disproportionate short-limbed stature, hair hypoplasia, and immunodeficiency.
The frequency of reported features is as follows:1
- Short limbed/short stature - 100%
- Hair hypoplasia - 93%
- Immunodeficiency - 56%
- Propensity to infections - 58%
- In vitro immunodeficiency - 86%
- Hypoplastic childhood anemia - 79%
- GI dysfunction - 18% (Hirschsprung disease - 9%)
- Defective spermatogenesis - 100%
- Metaphyseal chondrodysplasia - 100%
- Risk of malignancies - 6.9%
- Non-Hodgkin lymphoma - 90%
- Basal cell carcinoma - 35%
Disproportionate short-limbed dwarfism is the most prominent feature in cartilage hair-hypoplasia; it is due to metaphyseal dysplasia. The limbs and ribs are most affected, with sparing of the spine and skull. Radiographic studies reveal short and thick tubular bones, with splaying and irregular metaphyseal borders of the growth plates. The costochondral junctions are similarly affected. These radiographic abnormalities develop by age 6-9 months and are diagnostic. In addition, the hair is characteristic in cartilage hair-hypoplasia; it is fair, thin, and sparse, beginning in the newborn period. GI problems occur in approximately 18% of patients with cartilage hair-hypoplasia. Hirschsprung disease is the most common disorder.
Recently, defective spermatogenesis that affects the number and function of sperm has been identified in all 11 patients with cartilage hair-hypoplasia in one study. Hypoplastic anemia of childhood has been reported in approximately 79% of patients with cartilage hair-hypoplasia and may be life-threatening. It usually resolves by age 2-3 years.
Most individuals with cartilage hair-hypoplasia have limited susceptibility to infections. However, life-threatening varicella infections may occur. Individuals with cartilage hair-hypoplasia occasionally have infections with common pathogens observed in T-cell immunodeficiency, such as Candida species, P carinii, and cytomegalovirus (CMV). Individuals with severe combined T- and B-cell immunodeficiency have more serious infections and are susceptible to graft versus host disease. In some patients with cartilage hair-hypoplasia, a predominant B-cell immunodeficiency with increased susceptibility to bacterial sinopulmonary infections is reported.14,5 Individuals with cartilage hair-hypoplasia are at increased risk for leukemia and lymphoma. Both Hodgkin lymphoma and non-Hodgkin lymphoma have been reported.
Physical
Abnormal physical findings of cartilage hair-hypoplasia are present at birth.9,15 Head size is within the normal reference range, hands are short and pudgy, and skin forms redundant folds around the neck and extremities. Hair of the scalp, eyebrows, and eyelashes at birth is light in color, fine, and sparse and lacks a central pigmented core (see Media file 1).
Hair of a patient with cartilage-hair hypoplasia (left) compared with that of a typical individual. The hair of the patient with cartilage-hair hypoplasia has a smaller diameter because the central core is absent.
Physical findings include the following:
- Growth - Short-limb dwarfism, average adult height 107-157 cm (40-60 in)
- Skin - Hypopigmentation
- Nails - Dysplasia
- Hair - Fine, sparse, light-colored hair on the scalp, eyebrows, and eyelashes; body hair similarly affected; hair darkens with age
- Teeth - Notched incisor, microdontia, doubling of lower premolar lingual cusps
- Limbs - Short hands, brachydactyly, bowleg
- Joints - Hypermobility, hyperflexibility, possible limitation of motion affecting elbow extension
- Spine - Mild platyspondylia, lumbar lordosis
- Thorax - Flaring of lower rib cage, Harrison grooves
- GI -Malabsorption, celiac syndrome, Hirschsprung disease, anal stenosis, esophageal atresia
Causes
Cartilage-hair hypoplasia is an autosomal recessive inherited disorder. In 2001, mutations of the RMRP gene in the RNA component of the gene for RNase MRP on chromosome band 9p12 were identified as the genetic defect in Finnish patients with cartilage-hair hypoplasia.6 RNase MRP has 2 functions: (1) cleavage of RNA in mitochondrial DNA synthesis and (2) nucleolar cleaving of pre-rRNA.
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References
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Further Reading
Keywords
cartilage-hair hypoplasia, CHH, short-limb dwarfism, metaphyseal dysplasia, spondyloepiphyseal dysplasia, immunodeficiency, metaphyseal chondrodysplasia McKusick type, T-cell immunodeficiency, isolated B-cell immunodeficiency, varicella infection, severe combined immunodeficiency, SCID, leukemia, lymphoma, graft versus host disease, non-Hodgkin lymphoma, basal cell carcinoma, anal stenosis, esophageal atresia, treatment, diagnosis
