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Cartilage-hair hypoplasia (CHH)

Written2007-10Pia Hermanns, Brendan Lee
Department of Molecular, Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza Room 635E, Mail Stop 225, Houston, TX 77030, USA

(Note : for Links provided by Atlas : click)


Other namesMetaphyseal chondrodysplasia, McKusick type
Atlas_Id 10105
Genes implicated inRMRP  
Inheritance Autosomal rezessive


Note CHH was first described in the Amish, an isolated religious group in the USA by Victor McKusick in 1965. It is a multi-systemic disorder characterized by short stature, blond fine sparse hair, but this may be quite variable, and defective cellular immunity predominantly affecting T-cell mediated responses. Patients may have severe combined immunodeficiency, requiring bone marrow transplantation or they may be asymptomatic. Gastrointestinal dysfunctions are frequently observed such as mal-absorption or Hirschsprung's disease.
The incidence of CHH in the Amish is 1.5 in 1,000 births, whereas in Finland it is 1 in 18,000 to 23,000 live births.
Phenotype and clinics The metaphyses of tubular bones are widened, scalloped and irregularly sclerotic. Delayed ossification and trabeculation of the long bones are also characteristic findings on X-rays. All long bones are affected. The relative length of the humerus, ulna, radius, tibia and fibula decreases rapidly in early childhood and again at puberty. Relatively short and broad phalanges of the hands are observed.
Neoplastic risk A predisposition to certain cancers primarily lymphomas has been reported.
Treatment - Disproportionate short stature: Treatment with growth hormone is likely not beneficial in children with CHH. Surgical bone lengthening is occasionally considered.
- Orthopedic problems: The lumbar lordosis and ligamentous laxity can cause joint pains of the lower spine, the knees and ankles.
- Immunodeficiency: The cellular immunity may be defective whereas the humoral immunity is usually intact. However, there are a few cases that have combined immune deficiency.
- Vaccination: immunization with live vaccines is contraindicated in patients with impaired cellular immunity.
- Anemia: Patients with severe anemia (5% of CHH patients) require repeated transfusions. A few cases might need lifelong transfusions and/or bone marrow transplantation.
- Gastrointestinal dysfunction: This can present with signs of malabsorption, diarrhea, celiac disease, and failure to thrive. This requires symptomatic treatment. It also may present as Hirschsprung's disease that can be surgically corrected.
- Malignancies: Patients should be monitored closely, since they have a higher risk of developing lymphomas and leukemias.
Prognosis Adult height ranges between 111 and 151 cm in males and between 104 and 137 cm in females. No more than 20% of CHH patients exhibit recurrent and severe infections. These patients show evidence of immune deficiency in vivo and in vitro.

Genes involved and Proteins

Note CHH is mainly caused by mutations in the RMRP gene, but a Uniparental Disomy of 9p13 has been reported as well in one CHH patient.
Gene NameRMRP (RNA component of mitochondrial RNA processing endoribonuclease)
Alias RNase MRP
Location 9p13.3
Note RMRP is the RNA component of the RNase MRP protein complex. It functions as an RNA and is not translated into a protein.
Transcription In vitro analysis of the RMRP promoter revealed that the four described promoter elements are sufficient for RMRP transcription. It is transcribed by the DNA dependent RNA polymerase III and is encoded in the nucleolus. The complex is localized primarily in the nucleolus and to a lesser extend in the mitochondria. Studies in yeast revealed multiple functions of this protein complex. RNase MRP is involved in mitochondrial DNA replication by cleaving the RNA primer starting mitochondrial replication and is also involved in the RNA primer formation itself. In addition it plays a role in cell cycle progression at the end of mitosis. RNase MRP cleaves the 5'UTR of the CLB2 gene thus causing a rapid CLB2 degradation, which leads to a cell cycle progression. If CLB2 is not cleaved cell cycle will be arrest. The best understood function is its processing of pre-ribosomal RNAs. It cleaves the pre-ribosomal RNA at the A3 site thus helping in the maturation of the short and active form of the 5.8S rRNA.
Expression Strong ubiquitous expression in mouse embryos (E9.5 to E18.5 have been tested) and in adult animals. In bone Rmrp is more strongly expressed in hypertrophic chondrocytes and pericondrium than in the zone of proliferating chondrocytes. There is also very strong expression in the epiphysis.
In Xenopus laevis oocytes RMRP is stronger expressed in developmental stages with a higher content of mitochondria.
Function The RNase MRP complex is highly conserved among a variety of different species (human, mouse, rat, cow, frog, yeast and plants).
Homology The functional analysis of the RNase MRP endoribonuclease is complicated by the fact, that eight proteins are shared by a related ribonucleoprotein complex, called RNase P. RNase P is also a ribonucleprotein endoribonuclease and is mainly involved in rRNA precursor maturation.
Note The most frequently found mutation among CHH patients is a 70 A to G transition mutation with an ancient founder origin established in Finland, a country where the disorder is uncommonly frequent. In fact it is the only mutation found in Amish CHH patients.
Over 93 different mutations have been described in CHH patients. These include promoter duplications, triplications and insertions exclusively between the TATA box and the transcription start site. These mutations decrease the RMRP transcription efficiency. Single base pair substitutions are spread out over the entire RMRP transcript. Also small deletions of and insertions in the transcribed region of the gene have been observed as well. These mutations might influence the secondary structure of the RNA, the binding of the proteins to the RNA or the RNA stability.
In addition many polymorphisms and rare sequence variants have been observed. This is remarkable considering the very small size of the RMRP gene.

To be noted

So far no complete deletion of the entire RMRP gene has been observed. This suggests that complete loss of RMRP function might be incompatible with life. This is also supported by the fact that the knock out in yeast is lethal.


Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia.
Berthet F, Siegrist CA, Ozsahin H, Tuchschmid P, Eich G, Superti-Furga A, Seger RA
European journal of pediatrics. 1996 ; 155 (4) : 286-290.
PMID 8777921
RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.
Bonafé L, Schmitt K, Eich G, Giedion A, Superti-Furga A
Clinical genetics. 2002 ; 61 (2) : 146-151.
PMID 11940090
The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis.
Cai T, Aulds J, Gill T, Cerio M, Schmitt ME
Genetics. 2002 ; 161 (3) : 1029-1042.
PMID 12136008
Phalangeal cone-shaped epiphyses of the hand: their natural history, diagnostic sensitivity, and specificity in cartilage hair hypoplasia and the trichorhinophalangeal syndromes I and II.
Giedion A
Pediatric radiology. 1998 ; 28 (10) : 751-758.
PMID 9799296
Radiologic changes in infancy in McKusick cartilage hair hypoplasia.
Glass RB, Tifft CJ
American journal of medical genetics. 1999 ; 86 (4) : 312-315.
PMID 10494084
RMRP mutations in cartilage-hair hypoplasia.
Hermanns P, Tran A, Munivez E, Carter S, Zabel B, Lee B, Leroy JG
American journal of medical genetics. Part A. 2006 ; 140 (19) : 2121-2130.
PMID 16838329
Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia.
Hirose Y, Nakashima E, Ohashi H, Mochizuki H, Bando Y, Ogata T, Adachi M, Toba E, Nishimura G, Ikegawa S
Journal of human genetics. 2006 ; 51 (8) : 706-710.
PMID 16832578
Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease.
Ko DC, Milenkovic L, Beier SM, Manuel H, Buchanan J, Scott MP
PLoS genetics. 2005 ; 1 (1) : 81-95.
PMID 16103921
T cell subsets and T cell function in cartilage-hair hypoplasia.
Kooijman R, van der Burgt CJ, Weemaes CM, Haraldsson A, Scholtens EJ, Zegers BJ
Scandinavian journal of immunology. 1997 ; 46 (2) : 209-215.
PMID 9584003
Hirschsprung's disease in cartilage-hair hypoplasia has poor prognosis.
Mäkitie O, Heikkinen M, Kaitila I, Rintala R
Journal of pediatric surgery. 2002 ; 37 (11) : 1585-1588.
PMID 12407544
Bulletin of the Johns Hopkins Hospital. 1965 ; 116 : 285-326.
PMID 14284412
RNase MRP RNA and human genetic diseases.
Martin AN, Li Y
Cell research. 2007 ; 17 (3) : 219-226.
PMID 17189938
A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia.
Muñoz-Robles J, Allende LM, Clemente J, Calleja S, Varela P, Gonzalez L, de Pablos P, Paz E, Morales P
Immunobiology. 2006 ; 211 (9) : 753-757.
PMID 17015150
RMRP mutations in Japanese patients with cartilage-hair hypoplasia.
Nakashima E, Mabuchi A, Kashimada K, Onishi T, Zhang J, Ohashi H, Nishimura G, Ikegawa S
American journal of medical genetics. Part A. 2003 ; 123 (3) : 253-256.
PMID 14608646
The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases.
Ridanp M, Jain P, McKusick VA, Francomano CA, Kaitila I
American journal of medical genetics. Part C, Seminars in medical genetics. 2003 ; 121 (1) : 81-83.
PMID 12888988
Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.
Ridanp M, Sistonen P, Rockas S, Rimoin DL, Mäkitie O, Kaitila I
European journal of human genetics : EJHG. 2002 ; 10 (7) : 439-447.
PMID 12107819
Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia.
Ridanp M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Mäkitie O, Kaitila I, de la Chapelle A
Cell. 2001 ; 104 (2) : 195-203.
PMID 11207361
Uniparental disomy in cartilage-hair hypoplasia.
Sulisalo T, Mäkitie O, Sistonen P, Ridanp M, el-Rifai W, Ruuskanen O, de la Chapelle A, Kaitila I
European journal of human genetics : EJHG. 1997 ; 5 (1) : 35-42.
PMID 9156319
Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator.
Thiel CT, Horn D, Zabel B, Ekici AB, Salinas K, Gebhart E, Rüschendorf F, Sticht H, Spranger J, Müller D, Zweier C, Schmitt ME, Reis A, Rauch A
American journal of human genetics. 2005 ; 77 (5) : 795-806.
PMID 16252239
Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum.
Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A
American journal of human genetics. 2007 ; 81 (3) : 519-529.
PMID 17701897
The natural history of severe anemia in cartilage-hair hypoplasia.
Williams MS, Ettinger RS, Hermanns P, Lee B, Carlsson G, Taskinen M, Mäkitie O
American journal of medical genetics. Part A. 2005 ; 138 (1) : 35-40.
PMID 16097009
Cartilage-hair hypoplasia syndrome: increased apoptosis of T lymphocytes is associated with altered expression of Fas (CD95), FasL (CD95L), IAP, Bax, and Bcl2.
Yel L, Aggarwal S, Gupta S
Journal of clinical immunology. 1999 ; 19 (6) : 428-434.
PMID 10634217


This paper should be referenced as such :
Hermanns, P ; Lee, B
Cartilage-hair hypoplasia (CHH)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6):481-484.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes RMRP

External links

OrphanetCartilage-hair hypoplasia
Other databaseCartilage-hair hypoplasia (GARD)
Genes implicated inRMRP   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

REVIEW articlesautomatic search in PubMed
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