- Nicholas L Rider, DO
Nicholas L Rider, DO
- Associate Professor of Pediatrics, Allergy and Immunology
- Baylor College of Medicine
Cartilage-hair hypoplasia (CHH; MIM #250250) 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 mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene . Common features of the disorder include short stature, fine sparse hair, varying degrees of immunodeficiency, Hirschsprung disease (HD), and a susceptibility to hematologic malignancies [2,3]. Individuals with CHH have normal intelligence and achieve normal developmental milestones throughout childhood.
CHH is diagnosed clinically by observing fine and often sparse hair in an individual with short stature with disproportionally short limbs. Genetic analysis of the RMRP gene confirms the diagnosis. Immune-related complications (immunodeficiency, malignancy, and autoimmune disease) lead many to medical attention early in life and are a major cause of early mortality.
This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of CHH. Other syndromic immunodeficiencies are discussed separately. (See "Syndromic immunodeficiencies".)
CHH is a rare disorder in the general population but exists with greater prevalence among the Old Order Amish and Finnish populations . Thus, any person with short stature and immunodeficiency with Amish or Finnish inheritance should be evaluated for CHH.
One Finnish study estimated an incidence of 1:23,000 . The carrier frequency of a point mutation in the ribonuclease mitochondrial RNA-processing gene (RMRP 70 A>G) is estimated to be as high as 1 in 19 among the Old Order Amish .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Ridanpää M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 2001; 104:195.
- MCKUSICK VA, ELDRIDGE R, HOSTETLER JA, et al. DWARFISM IN THE AMISH. II. CARTILAGE-HAIR HYPOPLASIA. Bull Johns Hopkins Hosp 1965; 116:285.
- Rider NL, Morton DH, Puffenberger E, et al. Immunologic and clinical features of 25 Amish patients with RMRP 70 A-->G cartilage hair hypoplasia. Clin Immunol 2009; 131:119.
- Ridanpää M, Jain P, McKusick VA, et al. The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Am J Med Genet C Semin Med Genet 2003; 121C:81.
- Mäkitie O. Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients. J Med Genet 1992; 29:652.
- Kraybill D. Concise Encyclopedia of Amish, Brethren, Hutterites and Mennonites, Johns Hopkins Universtiy Press, Baltimore 2010.
- Roifman CM, Gu Y, Cohen A. Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome. J Allergy Clin Immunol 2006; 117:897.
- Rogler LE, Kosmyna B, Moskowitz D, et al. Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia. Hum Mol Genet 2014; 23:368.
- Huang W, Thomas B, Flynn RA, et al. Corrigendum: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 2016; 533:130.
- Ridanpää M, Sistonen P, Rockas S, et al. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP. Eur J Hum Genet 2002; 10:439.
- Bonafé L, Dermitzakis ET, Unger S, et al. Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. PLoS Genet 2005; 1:e47.
- Hermanns P, Tran A, Munivez E, et al. RMRP mutations in cartilage-hair hypoplasia. Am J Med Genet A 2006; 140:2121.
- Hirose Y, Nakashima E, Ohashi H, et al. Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia. J Hum Genet 2006; 51:706.
- Notarangelo LD, Roifman CM, Giliani S. Cartilage-hair hypoplasia: molecular basis and heterogeneity of the immunological phenotype. Curr Opin Allergy Clin Immunol 2008; 8:534.
- Thiel CT, Mortier G, Kaitila I, et al. Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Am J Hum Genet 2007; 81:519.
- Mäkitie O. [Cartilage-hair hypoplasia--a Finnish growth disorder]. Duodecim 1993; 109:1638.
- Mäkitie O, Kaitila I. Cartilage-hair hypoplasia--clinical manifestations in 108 Finnish patients. Eur J Pediatr 1993; 152:211.
- Riley P Jr, Weiner DS, Leighley B, et al. Cartilage hair hypoplasia: characteristics and orthopaedic manifestations. J Child Orthop 2015; 9:145.
- Mäkitie O, Marttinen E, Kaitila I. Skeletal growth in cartilage-hair hypoplasia. A radiological study of 82 patients. Pediatr Radiol 1992; 22:434.
- Mäkitie O, Perheentupa J, Kaitila I. Growth in cartilage-hair hypoplasia. Pediatr Res 1992; 31:176.
- Mäkitie O, Sulisalo T, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia. J Med Genet 1995; 32:39.
- Mäkitie O, Heikkinen M, Kaitila I, Rintala R. Hirschsprung's disease in cartilage-hair hypoplasia has poor prognosis. J Pediatr Surg 2002; 37:1585.
- Lux SE, Johnston RB Jr, August CS, et al. Chronic neutropenia and abnormal cellular immunity in cartilage-hair hypoplasia. N Engl J Med 1970; 282:231.
- Coupe RL, Lowry RB. Abnormality of the hair in cartilage-hair hypoplasia. Dermatologica 1970; 141:329.
- Mäkitie O, Pukkala E, Kaitila I. Increased mortality in cartilage-hair hypoplasia. Arch Dis Child 2001; 84:65.
- Ashby GH, Evans DI. Cartilage hair hypoplasia with thrombocytopenic purpura, autoimmune haemolytic anaemia and cell-mediated immunodeficiency. J R Soc Med 1986; 79:113.
- Bailly-Botuha C, Jaubert F, Taam RA, et al. Diffuse lymphoplasmacytic bronchiolitis in cartilage-hair hypoplasia. J Pediatr 2008; 152:429.
- Eisner JM, Russell M. Cartilage hair hypoplasia and multiple basal cell carcinomas. J Am Acad Dermatol 2006; 54:S8.
- Ferber B, Bruckheimer E, Schlesinger Y, et al. Kingella kingae endocarditis in a child with hair-cartilage hypoplasia. Pediatr Cardiol 1997; 18:445.
- Mäkitie O, Kaitila I, Savilahti E. Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Eur J Pediatr 1998; 157:816.
- Polmar SH, Pierce GF. Cartilage hair hypoplasia: immunological aspects and their clinical implications. Clin Immunol Immunopathol 1986; 40:87.
- Saulsbury FT, Winkelstein JA, Davis LE, et al. Combined immunodeficiency and vaccine-related poliomyelitis in a child with cartilage-hair hypoplasia. J Pediatr 1975; 86:868.
- Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999; 340:508.
- Castigli E, Irani AM, Geha RS, Chatila T. Defective expression of early activation genes in cartilage-hair hypoplasia (CHH) with severe combined immunodeficiency (SCID). Clin Exp Immunol 1995; 102:6.
- Guggenheim R, Somech R, Grunebaum E, et al. Bone marrow transplantation for cartilage-hair-hypoplasia. Bone Marrow Transplant 2006; 38:751.
- Steele RW, Britton HA, Anderson CT, Kniker WT. Severe combined immunodeficiency with cartilage-hair hypoplasa: in vitro response to thymosin and attempted reconstitution. Pediatr Res 1976; 10:1003.
- Mäkitie O, Pukkala E, Teppo L, Kaitila I. Increased incidence of cancer in patients with cartilage-hair hypoplasia. J Pediatr 1999; 134:315.
- Taskinen M, Ranki A, Pukkala E, et al. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet A 2008; 146A:2370.
- Toiviainen-Salo S, Kajosaari M, Piilonen A, Mäkitie O. Patients with cartilage-hair hypoplasia have an increased risk for bronchiectasis. J Pediatr 2008; 152:422.
- Moshous D, Meyts I, Fraitag S, et al. Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF-α mAbs. J Allergy Clin Immunol 2011; 128:847.
- Kavadas FD, Giliani S, Gu Y, et al. Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations. J Allergy Clin Immunol 2008; 122:1178.
- Harris RE, Baehner RL, Gleiser S, et al. Cartilage-hair hypoplasia, defective T-cell function, and Diamond-Blackfan anemia in an Amish child. Am J Med Genet 1981; 8:291.
- Mäkitie O, Juvonen E, Dunkel L, et al. Anemia in children with cartilage-hair hypoplasia is related to body growth and to the insulin-like growth factor system. J Clin Endocrinol Metab 2000; 85:563.
- Ranki A, Perheentupa J, Andersson LC, Häyry P. In vitro T- and B-cell reactivity in cartilage hair hypoplasia. Clin Exp Immunol 1978; 32:352.
- Mäkitie O, Kaitila I, Savilahti E. Deficiency of humoral immunity in cartilage-hair hypoplasia. J Pediatr 2000; 137:487.
- Mäkitie O, Rajantie J, Kaitila I. Anaemia and macrocytosis--unrecognized features in cartilage-hair hypoplasia. Acta Paediatr 1992; 81:1026.
- MCKUSICK VA, EGELAND JA, ELDRIDGE R, KRUSEN DE. DWARFISM IN THE AMISH I. THE ELLIS-VAN CREVELD SYNDROME. Bull Johns Hopkins Hosp 1964; 115:306.
- Ruiz-Perez VL, Tompson SW, Blair HJ, et al. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet 2003; 72:728.
- Berthet F, Siegrist CA, Ozsahin H, et al. Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia. Eur J Pediatr 1996; 155:286.
- Bordon V, Gennery AR, Slatter MA, et al. Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation. Blood 2010; 116:27.
- Ip W, Gaspar HB, Kleta R, et al. Variable phenotype of severe immunodeficiencies associated with RMRP gene mutations. J Clin Immunol 2015; 35:147.
- Guðmundsdóttir ES, Bjarnason G, Magnússon J. [Hirschprung' disease in Iceland 1969-1998.]. Laeknabladid 2001; 87:987.
- GENETICS AND PATHOGENESIS
- CLINICAL MANIFESTATIONS
- Somatic growth and musculoskeletal findings
- Gastrointestinal abnormalities
- Hair abnormalities
- Pulmonary findings
- Other features
- LABORATORY FINDINGS
- DIFFERENTIAL DIAGNOSIS
- Hematopoietic cell transplantation
- Monitoring for complications
- SOCIETY GUIDELINE LINKS