Cartilage-hair hypoplasia (CHH)

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Cartilage-hair hypoplasia (CHH)

Identity

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.

REVIEW articles	automatic search in PubMed
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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