Cartilage-hair hypoplasia (CHH)

Other names	Metaphyseal chondrodysplasia, McKusick type
Inheritance	Autosomal rezessive

Clinics

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 Hirschsprung¹s 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 Hirschsprung¹s 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 Name	RMRP (RNA component of Mitochondrial RNA-Processing endoribonuclease)
Location	9p13

DNA/RNA
Note	RMRP is the RNA component of the RNase MRP protein complex. It functions as an RNA and is not translated into a protein.
	The RMRP gene is an intronless gene, that is 267 bp long (blue). The promoter region contains a SP1 binding site (violet), an octamer (olive green), a proximal sequence element (PSE) (turquoise) and a TATA box (red).

Protein
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.

Mutations

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.

Bibliography

DWARFISM IN THE AMISH. II. CARTILAGE-HAIR HYPOPLASIA.

MCKUSICK VA, ELDRIDGE R, HOSTETLER JA, RUANGWIT U, EGELAND JA

Bulletin of the Johns Hopkins Hospital. 1965 ; 116 : 285-326.

PMID 14284412

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

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

Uniparental disomy in cartilage-hair hypoplasia.

Sulisalo T, Mˆ§kitie O, Sistonen P, Ridanpˆ§ˆ§ 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

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

Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia.

Mˆ§kitie O, Kaitila I, Savilahti E

European journal of pediatrics. 1998 ; 157 (10) : 816-820.

PMID 9809821

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

Increased incidence of cancer in patients with cartilage-hair hypoplasia.

Mˆ§kitie O, Pukkala E, Teppo L, Kaitila I

The Journal of pediatrics. 1999 ; 134 (3) : 315-318.

PMID 10064668

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

Anemia in children with cartilage-hair hypoplasia is related to body growth and to the insulin-like growth factor system.

Mˆ§kitie O, Juvonen E, Dunkel L, Kaitila I, Siimes MA

The Journal of clinical endocrinology and metabolism. 2000 ; 85 (2) : 563-568.

PMID 10690856

[The role of immune deficiency in cartilage-hair hypoplasia]

Mˆ§kitie O, Kaitila I, Pukkala E, Teppo L, Savilahti E

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PMID 11988965

Deficiency of humoral immunity in cartilage-hair hypoplasia.

Mˆ§kitie O, Kaitila I, Savilahti E

The Journal of pediatrics. 2000 ; 137 (4) : 487-492.

PMID 11035826

Hirschsprung disease associated with severe cartilage-hair hypoplasia.

Mˆ§kitie O, Kaitila I, Rintala R

The Journal of pediatrics. 2001 ; 138 (6) : 929-931.

PMID 11391344

Impaired spermatogenesis: an unrecognized feature of cartilage-hair hypoplasia.

Mˆ§kitie OM, Tapanainen PJ, Dunkel L, Siimes MA

Annals of medicine. 2001 ; 33 (3) : 201-205.

PMID 11370774

Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia.

Ridanpˆ§ˆ§ M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Mˆ§kitie O, Kaitila I, de la Chapelle A

Cell. 2001 ; 104 (2) : 195-203.

PMID 11207361

RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.

Bonafˆ© 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.

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PMID 12136008

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Mˆ§kitie O, Heikkinen M, Kaitila I, Rintala R

Journal of pediatric surgery. 2002 ; 37 (11) : 1585-1588.

PMID 12407544

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.

Ridanpˆ§ˆ§ M, Sistonen P, Rockas S, Rimoin DL, Mˆ§kitie O, Kaitila I

European journal of human genetics : EJHG. 2002 ; 10 (7) : 439-447.

PMID 12107819

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.

Ridanpˆ§ˆ§ 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

Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease.

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PMID 16103921

Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia.

Hermanns P, Bertuch AA, Bertin TK, Dawson B, Schmitt ME, Shaw C, Zabel B, Lee B

Human molecular genetics. 2005 ; 14 (23) : 3723-3740.

PMID 16254002

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, Rˆºschendorf F, Sticht H, Spranger J, Mˆºller D, Zweier C, Schmitt ME, Reis A, Rauch A

American journal of human genetics. 2005 ; 77 (5) : 795-806.

PMID 16252239

The natural history of severe anemia in cartilage-hair hypoplasia.

Williams MS, Ettinger RS, Hermanns P, Lee B, Carlsson G, Taskinen M, Mˆ§kitie O

American journal of medical genetics. Part A. 2005 ; 138 (1) : 35-40.

PMID 16097009

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

A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia.

Muˆ±oz-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

RNase MRP RNA and human genetic diseases.

Martin AN, Li Y

Cell research. 2007 ; 17 (3) : 219-226.

PMID 17189938

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

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Contributor(s)

Written	10-2007	Pia Hermanns, Brendan Lee
		Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza Room 635E, Mail Stop 225, Houston, TX 77030, USA

Citation

This paper should be referenced as such :

Hermanns P, Lee B . Cartilage-hair hypoplasia (CHH). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Kprones/CartilageHairHypoID10105.html

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indexed on : Mon May 12 18:13:38 2008

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