CARTILAGE–HAIR HYPOPLASIA SYNDROME
Synonym: McKusick-type metaphyseal chondrodysplasia
Key features
Fine, sparse, hypopigmented hair
Short-limbed dwarfism with metaphyseal dysostosis
Doughy skin with abnormal elastic tissue
Defective cell-mediated and (in a minority of patients) humoral immunity
Cartilage–hair hypoplasia (CHH) syndrome is a pleiotropic autosomal recessive disorder that occurs most commonly in Amish individuals and Finns. The condition results from mutations in RMRP which encodes the RNA component of a ribonucleoprotein endoribonuclease, RNase MRP; the latter cleaves RNA primers responsible for DNA replication in mitochondria and processes pre-rRNA in the nucleolus. Impaired telomerase activity leading to decreased telomere length in lymphocytes may also have a pathogenic role in the immune deficiency associated with CHH.
Affected individuals are most likely to visit the dermatologist for their fine, sparse, hypopigmented hair, although they may also have soft, doughy skin with degenerated elastic tissue. The short-limbed dwarfism results from metaphyseal dysostosis, and ligamentous laxity is often observed. Most patients have some degree of defective cellmediated immunity, which predisposes them to severe varicella and herpes simplex viral (HSV) infections. Approximately a third of patients also have abnormal humoral immunity, most frequently an IgA or IgG deficiency, which increases their susceptibility to recurrent respiratory tract infections that can lead to bronchiectasis. Occasionally, affected individuals present with severe combined immunodeficiency and an Omenn syndrome-like phenotype with erythroderma, eosinophilia, chronic diarrhea, lymphadenopathy, and hepatosplenomegaly
(see below). Neutropenia and anemia can develop due to autoimmunity or bone marrow hypoplasia. Hirschsprung disease, other autoimmune disorders, and impaired spermatogenesis represent additional manifestations of CHH. Patients also have an increased risk of developing non-Hodgkin lymphoma and BCCs.
Hematopoietic stem cell transplantation, which can restore function of the immune system and bone marrow, should be considered in patients with severe immunodeficiency or cytopenias.