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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Cancer Prone Disease Section
Review
Cartilage-hair hypoplasia (CHH)
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
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Kprones/CartilageHairHypoID10105.html
DOI: 10.4267/2042/38617
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Treatment
Identity
Other names: Metaphyseal
McKusick type
Inheritance: Autosomal rezessive.
- 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.
chondrodysplasia,
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.
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.
Neoplastic risk
A predisposition to certain
lymphomas has been reported.
cancers
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6)
primarily
481
Cartilage-hair hypoplasia (CHH)
Hermanns P, Lee B
(violet), an octamer (olive green), a proximal sequence
element (PSE) (turquoise) and a TATA box (red).
Genes involved and Proteins
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.
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.
RMRP (RNA component of
Mitochondrial RNA-Processing
endoribonuclease)
Location: 9p13
DNA/RNA
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
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6)
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Cartilage-hair hypoplasia (CHH)
Hermanns P, Lee B
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.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6)
Mutations
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.
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Cartilage-hair hypoplasia (CHH)
Hermanns P, Lee B
hypoplasia variant with only skeletal manifestations and
reveals a high density of single-nucleotide polymorphisms. Clin
Genet 2002;61(2):146-151.
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.
Cai T, Aulds J, Gill T, Cerio M, Schmitt ME. The
Saccharomyces cerevisiae RNase mitochondrial RNA
processing is critical for cell cycle progression at the end of
mitosis. Genetics 2002;161(3):1029-1042.
Mäkitie O, Heikkinen M, Kaitila I, Rintala R. Hirschsprung's
disease in cartilage-hair hypoplasia has poor prognosis. J
Pediatr Surg 2002;37(11):1585-1588.
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This article should be referenced as such:
Hermanns P, Lee B. Cartilage-hair hypoplasia (CHH). Atlas
Genet Cytogenet Oncol Haematol.2008;12(6):481-484.
Bonafé L, Schmitt K, Eich G, Giedion A, Superti-Furga A.
RMRP gene sequence analysis confirms a cartilage-hair
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6)
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