Cartilage-hair hypoplasia

Related gene: RMRP

Inheritance pattern: Autosomal recessive

Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia inherited as an autosomal recessive trait. CHH is sometimes also referred to as immunodeficiency with short-limbed dwarfism. It is caused by variants in the ribonuclease mitochondrial RNA-processing (RMRP) gene. Common features of the disorder include short stature with short limbs; fine, sparse, fragile hair; varying degrees of immunodeficiency; Hirschsprung disease (HD) with associated enterocolitis; increased risk of bone marrow failure; and susceptibility to blood cancers. Individuals with CHH have normal intelligence and achieve normal developmental milestones throughout childhood. 

Impairment of immune function is the greatest health risk among persons with CHH. Cell-mediated immunodeficiency is most commonly reported. Individuals may develop severe infections like Pneumocystis jirovecii pneumonia, cytomegalovirus (CMV) pneumonitis, or severe oropharyngeal candidiasis. Sinopulmonary infections suggestive of humoral immune deficiency are also common, requiring Ig replacement therapy. Among adults, there is higher incidence of hematologic malignancy including lymphoma, squamous cell carcinoma, and leukemia. Autoimmune disease, like autoimmune hemolytic anemia, immune thrombocytopenia, and juvenile idiopathic arthritis, is also reported in the disease. Granulomatous inflammation of the skin and visceral organ is present and responsive to various immune-suppressive medications. 

There is not a clear pattern of immunodeficiency among people with CHH, and they may have variable cellular and humoral deficiency. Surveillance for immunodeficiency, malignancy, and autoimmune disease is important for all with CHH. Administration of live, attenuated vaccines is not recommended without first demonstrating normal T cell responses. Hematopoietic stem cell transplantation (HSCT) reverses the immune defect for SCID in the setting of CHH, and associated autoimmunity also resolves after transplantation. However, HSCT does not improve the musculoskeletal or growth features of the syndrome. Transplantation before the development of serious infections, significant organ damage, and/or malignancy improves survival for those individuals.