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Cartilage-Hair Hypoplasia - Anauxetic Dysplasia Spectrum Disorders

Includes: Anauxetic Dysplasia, Cartilage-Hair Hypoplasia, Metaphyseal Dysplasia without Hypotrichosis
Institute of Human Genetics
Friedrich-Alexander Universität Erlangen-Nürnberg
Erlangen, Germany

Initial Posting: .


Clinical characteristics.

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes:

  • Metaphyseal dysplasia without hypotrichosis (MDWH),
  • Cartilage-hair hypoplasia (CHH), and
  • Anauxetic dysplasia (AD).

CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature which is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility and often fine silky hair, immunodeficiency, anemia, impaired spermatogenesis, gastrointestinal dysfunction, and increased risk for malignancy. The most severe phenotype (AD), which has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.


Diagnosis of the CHH-AD spectrum disorders is based on clinical findings, characteristic radiographic findings, and in some cases, evidence of immune dysfunction, macrocytic anemia, and/or gastrointestinal problems. RMRP, encoding the untranslated RNA subunit of the ribonucleoprotein endoribonuclease complex, RNase MRP, is the only gene in which mutations cause the CHH-AD spectrum disorders. Molecular genetic testing confirms the diagnosis.


Treatment of manifestations:

  • In the newborn: hypoplastic anemia may require repeated blood transfusions; congenital megacolon or Hirschsprung disease may require surgical resection.
  • In childhood: surgery may be needed to fuse unstable cervical vertebrae and/or to treat progressive kyphoscoliosis that compromises lung function; corrective osteotomies may be required to treat progressive varus deformity associated with ligament laxity in the knees.
  • For those with immunodeficiency: treatment of underlying infections based on their type, location, and severity; consideration of prophylactic antibiotic therapy if neutropenia is present and/or immunoglobulin replacement therapy if IgG levels are low. Recurrent severe infections and/or the presence of severe combined immunodeficiency (SCID) and/or severely depressed erythropoiesis may warrant bone marrow transplantation.

Malignancies are treated in the usual manner.

Prevention of secondary complications: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia.


  • Skeletal dysplasia: clinical and, if warranted, radiographic monitoring of growth, joints of the lower extremities, and spine annually in childhood and as required in adulthood.
  • Infection: monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella infections.
  • Anemia: for those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, monitor for evidence of relapse.
  • Malignancy: no specific recommendations exist; it is advised that patients be checked on a regular basis for evidence of lymphomas and other associated malignancies.

Agents/circumstances to avoid: Administration of live vaccines when signs of abnormal immunologic function or SCID are present.

Evaluation of relatives at risk: Early diagnosis of relatives at risk for the CHH-AD spectrum allows early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, and malignancies).

Genetic counseling.

The CHH-AD spectrum is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic mutation carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.


Clinical Diagnosis

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum ranging from short stature without hypotrichosis with only radiographic evidence of metaphyseal dysplasia (MDWH) [Bonafé et al 2002] to short stature with hypotrichosis and variable metaphyseal dysplasia of the tubular bones (CHH) [McKusick et al 1965, Mäkitie & Kaitila 1993] to severe deforming short stature with metaphyseal, epiphyseal, and vertebral dysplasia (anauxetic dysplasia or AD) [Horn et al 2001, Thiel et al 2005].

Despite widely ranging associated findings, the diagnosis of the disorders in the CHH-AD spectrum can usually be established by the hallmark clinical and radiographic findings of short stature with metaphyseal dysplasia.

Main diagnostic criteria:

  • Mild to severe disproportionate short stature (final adult height <85 - 151 cm)
  • Presence of variable metaphyseal dysplasia with epiphyseal and vertebral dysplasia in the severe end of the spectrum
  • Bowed femora and tibiae
  • “Bullet”-shaped middle phalanges
  • Laxity of ligaments with joint hypermobility, but limited extension of the elbows
  • Fine, silky hair
  • Increased rate of infections and intestinal dysfunction

Clinical Findings by Phenotype (Frequency)

Cartilage-hair hypoplasia (CHH)

  • Disproportionate short-limb short stature (100%; prenatal onset: 76%-93%)
  • Short fingers and toes
  • Bowed femora and tibiae (77%)
  • Laxity of ligaments with hypermobility of joints (87%)
  • Limited extension of the elbows (83%)
  • Lumbar lordosis, chest deformity (~50%)
  • Blonde, sparse, fine silky hair (89%-93%)
  • Impaired lymphocyte proliferation and T-lymphocyte function (88%) with increased rate of:
    • Infection in infancy and childhood (35%-65%)
    • Severe varicella infection (11%)
    • Severe combined immunodeficiency
  • Macrocytic, hypoplastic anemia in early childhood (79%)
  • Lymphomas; leukemia; neoplasms of the skin, eye, and liver (6%-11%)
  • Congenital megacolon or Hirschsprung disease (7%-8%)
  • Intestinal malabsorption with diarrhea and failure to thrive

Metaphyseal dysplasia without hypotrichosis (MDWH)

  • Clinical features similar to CHH, but with normal hair

Anauxetic dysplasia (AD)

  • Prenatal onset of extreme short-limb short stature (100%)
  • Barrel chest with hyperlordosis and kyphoscoliosis
  • Dislocated hips
  • Atlantoaxial subluxation leading to cervical spine compression
  • Facial features: midfacial hypoplasia and macroglossia
  • Dental abnormalities
  • Mild intellectual disability

Radiographic Findings by Phenotype *

Cartilage-hair hypoplasia (CHH)

  • Short and thick tubular bones
  • Short and bullet-shaped metacarpals and phalanges with cone shaped epiphyses
  • Metaphyseal dysplasia of all tubular bones
  • Distal metaphyses: wide, flared, occasionally scalloped with cystic areas; poor ossification with trabeculation
  • Epiphyseal changes: mild in the femoral head
  • Vertebral bodies: mild biconvexity with increased height and lumbar lordosis

Metaphyseal dysplasia without hypotrichosis (MDWH)

  • Similar to those in CHH

Anauxetic dysplasia (AD)

  • Vertebral bodies: late-maturating, ovoid with concave dorsal surfaces in the lumbar region; dislocation in the cervical spine
  • Femora: small capital femoral epiphyses with hypoplastic femoral necks
  • Iliac bodies: hypoplastic
  • Acetabulae: shallow
  • Metacarpals: short with widened shafts (I and V)
  • Phalanges: very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges

* Note: Radiographic findings tend to be highly variable.


To identify impaired immune function (lymphocyte proliferation, lymphopenia, and/or severe combined immunodeficiency) [Kavadas et al 2008] and/or neutropenia [Klein 2009]:

  • Complete blood count (CBC) with differential
  • Specific screening for CD3, 4, 8, 19, and 16/56 lymphocytes
  • Immunologic parameters:
    • Allogeneic lymphocyte cytotoxicity (ALC)
    • T-cell receptor excision circles (TREC) analysis
    • T-cell repertoire
    • Proliferation response to PHA
    • Proliferation response to anti-CD3
    • Measurement of the serum immunoglobulins IgG, IgA, IgM, and IgE

Molecular Genetic Testing

Gene. RMRP, encoding the untranslated RNA subunit of the ribonucleoprotein endoribonuclease complex, RNase MRP, is the only gene in which mutations cause the cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders [Ridanpää et al 2001].

Clinical testing

  • Sequence analysis. Sequence analysis of the 267-bp coding region of the single exon of RMRP and the promoter region identifies mutations in up to 100% of individuals with the clinical diagnosis of a CHH-AD spectrum disorder. RMRP mutations occur in either the RMRP transcript or the promoter region (between the TATA box and the transcription starting site). Mutations include:
    • Point mutations or smaller deletions/duplications within the transcribed region
    • Insertions, duplications, or triplications between the TATA box and the transcription starting site.
  • Deletion/duplication analysis. Although theoretically possible, no large deletions/duplications involving exonic or noncoding regions have been observed to date. Thus, the clinical usefulness of such testing is unknown.

Table 1.

Summary of Molecular Genetic Testing Used in the Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
RMRPSequence analysisCoding and promoter region 2~100%
Deletion / duplication analysis 3Whole-gene deletionsUnknown, none reported 4

The ability of the test method used to detect a mutation that is present in the indicated gene


Examples of mutations detected by sequence analysis include point mutations, small intragenic deletions/insertions within the transcribed region and insertions, duplications, or triplications between the TATA box and the transcription starting site.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


To date, no deletions or duplications involving RMRP as causative of cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders have been reported.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Examine for the clinical and radiologic features that strongly suggest the diagnosis of a CHH-AD spectrum disorder.
  • Sequence analysis of RMRP identifies two causative mutations in the great majority of probands with a presumed diagnosis of a CHH-AD spectrum disorder, thus confirming the clinical diagnosis.
  • Deletion/duplication analysis is recommended if no mutation or only one mutation in RMRP is identified in an affected individual by sequence analysis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Characteristics

Clinical Description

Cartilage-hair hypoplasia (CHH) was described as a metaphyseal osteochondrodysplasia presenting with short-limbed dwarfism and fine, sparse, light-colored hair, anemia, and immunodeficiency among the Old Order Amish [McKusick et al 1965]. More recently, anauxetic dysplasia (AD), a rare and severe form of autosomal recessive spondylometaepiphyseal dysplasia, was added to the phenotypic spectrum [Horn et al 2001, Thiel et al 2005].

It is now recognized that the condition comprises a spectrum that includes metaphyseal dysplasia without hypotrichosis (MDWH); CHH with metaphyseal dysplasia and hypotrichosis; and, at the severe end, the rare AD with the most pronounced skeletal phenotype. The natural history has been extensively reported particularly in Finnish patients with CHH.

Disproportionate short-limb short stature is the hallmark finding; on occasion proportionate short stature is observed [van der Burgt et al 1991, Mäkitie & Kaitila 1993]. Growth failure is progressive and associated with the degree of disproportion. Lumbar lordosis and scoliosis may contribute to the short stature.

Marked inter- and intrafamilial variability of short stature has been observed. Growth curves for Finnish patients with CHH have been published. Final adult height ranges from 104 to 151 cm in CHH (median: 131 cm in males; 122 cm in females) and less than 85 cm in AD [Mäkitie et al 1992a, Mäkitie & Kaitila 1993, Horn et al 2001].

Laxity of ligaments with joint hypermobility is marked especially in the hands and feet. The laxity of lateral ligaments of the knees contributes to the varus deformity of the lower extremities.

Fine silky hair. Sparse hair, reduction of the diameter of the hair shaft, and loss of the central pigmented core of the hair shaft contribute to the distinctive appearance of the hair. About 15% of affected persons have complete primary baldness.

Deficient cellular immunity may manifest as lymphopenia and defects in T-lymphocyte function and/or proliferation [Mäkitie et al 1998, Kavadas et al 2008]. Sometimes defects in B-lymphocyte proliferation with low IgG and undetectable IgA are observed. Although deficient cellular immunity is present in most affected individuals (88%), an increased rate of infection is noted in only 35%-65%, usually during infancy and childhood. The risk of life threatening varicella infections has been reported to be increased; however, this needs further clarification [Notarangelo et al 2008]. Severe respiratory disease (e.g., lymphoplasmacytic bronchiolitis) has been reported in children [Bailly-Botuha et al 2008]. Impaired cellular immunity persists into adulthood.

Deficient humoral immunity has also been observed on occasion and can result in severe combined immunodeficiency (SCID) [Mäkitie et al 2000, Horn et al 2010]. Patients with CHH and SCID are at particular risk for chronic bronchiectasis [Toiviainen-Salo et al 2008].

Autoimmune complications. In rare instances autoimmune complications and a form of severe allergic reaction have been observed in CHH; however, the pathophysiology is still unknown [Bacchetta et al 2009, Narra & Shearer 2009].

Anemia. Deficient erythropoiesis may lead to mild to severe macrocytic anemia. Mild anemia is seen in about 80% of those with CHH and resolves spontaneously in childhood in most cases [Mäkitie et al 1992b]. Severe and persistent anemia resembling that of Diamond-Blackfan syndrome is seen about 6% [Williams et al 2005]. About 50%-75% of those with severe anemia require lifelong transfusions or bone marrow transplantation (see Management); on occasion spontaneous resolution is observed [Williams et al 2005].

Malignancies. Extended follow-up of persons with CHH revealed that about 11% (14/123) develop malignancies [Taskinen et al 2008]. The most frequently observed cancers are non-Hodgkin lymphoma, followed by squamous carcinoma, leukemia, and Hodgkin lymphoma; typically non-aggressive basal cell carcinoma was excluded. Rarely, two or more malignancies were observed in one individual. Nine of the 14 cancers were diagnosed in persons age 15 to 44 years. Of the 14 who developed malignancies, nine have died; median age at death was only three months after initial diagnosis of the malignancy.

Intestinal problems

  • Newborn period. Hirschsprung disease with short-segment and total colon aganglionosis is observed in 7%-8% of those with CHH, especially infants with the severe forms [Mäkitie et al 2001a].
  • Infancy. When Hirschsprung disease has been excluded, malabsorption secondary to gastrointestinal infections can occur in the first two years of life [Mäkitie et al 1995]. The main findings are “celiac syndrome” with diarrhea and failure to thrive. Although most intestinal manifestations occur in the first two years of life, they can occur later in childhood.

Impaired spermatogenesis. Because of a defect in cell proliferation, males with CHH have defects in sperm concentration, motility, morphology, and immunology [Mäkitie et al 2001b]. Testicles are smaller than normal for age and pubertal status; however, serum concentrations of testosterone, inhibin B, and gonadotropins are within the normal range in most individuals.

Additional findings observed in some persons with AD:

Genotype-Phenotype Correlations

The CHH-AD spectrum includes a range of phenotypes. Because RMRP is not translated into a protein and exists only as a single-exon transcript, standard correlations between the position of a mutation and the expected effect on the protein do not apply. Thus, a clear genotype-phenotype correlation depends on the position of the mutation in the transcript and the proposed effect on the transcript folding and RNA/protein interaction.

The milder phenotypes are caused either by

  • Compound heterozygous or homozygous biallelic point mutations within the transcript resulting in little to intermediate effect on function of the RNase MRP (complex formed of the RMRP transcript and other proteins);

    or by
  • Compound heterozygosity for one point mutation within the transcript and one pathologic variant in the promoter region.

AD is caused either by

  • Compound heterozygous or homozygous biallelic mutations that severely alter function;

    or by
  • Compound heterozygosity for:


Cartilage hair hypoplasia (CHH) or metaphyseal chondrodysplasia, type McKusick was first described by McKusick and his colleagues in the Old Order Amish population [McKusick et al 1965].

Patients with normal hair and metaphyseal dysplasia, called metaphyseal dysplasia without hypotrichosis (MDWT), were reported by Bonafé et al [2002].

Anauxetic dysplasia was named after the Greek “not to permit growth” [Horn et al 2001].


About 700 individuals are currently known to have a CHH-AD spectrum disorder [Kaitila, personal communication]. The most severe form, AD, is extremely rare: fewer than ten affected individuals have been reported.

Affected individuals have been reported in most populations; however, a high incidence of CHH was noted in the Old Order Amish population with a prevalence of 1:1000-2:1000 (carrier frequency 1:10) and in Finland with an incidence of 1:23,000 (carrier frequency 1:76) [Perheentupa 1972, Norio et al 1973, Mäkitie 1992, Mäkitie & Kaitila 1993].

Differential Diagnosis

More than 200 skeletal dysplasias associated with short stature have been identified. The diagnosis is made based on clinical history and physical and skeletal radiographic findings (including prenatal-onset short stature when relevant) as indicated in the Nosology and Classification of Genetic Skeletal Disorders 2010 [Warman et al 2011].

Several forms of metaphyseal chondrodysplasia, such as Schmid dysplasia, Jansen dysplasia, and Swachman-Bodian-Diamond syndrome, have short stature and radiographic metaphyseal abnormalities similar to those observed in CHH. The molecular basis of these conditions is known [Warman et al 2011].

In individuals with only the mild skeletal dysplasia of the CHH-AD spectrum the differential diagnosis includes the following:

  • Kyphomelic dysplasia. The main characteristics are disproportionate short stature with bowing of the femora.
  • Schimke immunoosseous dysplasia. The main features are short stature caused by a short trunk, characteristic facies, cellular immune deficiency, and vascular problems. In the presence of recurrent infections, milder forms of the Schimke immunoosseous skeletal dysplasia could be confused with CHH [Baradaran-Heravi et al 2008]. Mutations in SMARCAL1 are causative; inheritance is autosomal recessive.
  • Combined immunodeficiency syndromes. In contrast to CHH, most immunodeficiency syndromes do not show skeletal abnormalities.
  • Omenn syndrome. CHH and Omenn syndrome both include short stature and hematologic and immunologic changes; however, Omenn syndrome is more severe and includes ichthyosiform skin changes and septicemia. Mutations in RAG1 or RAG2 are causative; inheritance is autosomal recessive.
  • Congenital neutropenia. Isolated congenital neutropenia can caused by mutations in ELANE, HAX1, GFI1, or WAS [Klein 2009]; congenital neutropenia that occurs as part of a syndrome can be caused by mutations affecting glucose metabolism or lysosomal function. The additional skeletal phenotype associated with defects in ribosomal genes like RMRP should distinguish CHH from isolated congenital neutropenia or that associated with other systemic disorders.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorder, the following evaluations are recommended:

Testing. Blood survey for macrocytic anemia and immunodeficiency [Rider et al 2009]:

  • Complete blood count with differential cell count
  • Serum concentration of IgG, IgA, and IgM
  • CD3, 4, 8, 19, 16/56
  • Post-vaccine titers

Imaging. Full skeletal survey including views of the cervical spine to identify cervical vertebral abnormalities and to assess the risk for atlantoaxial subluxation


  • Orthopedic. Evaluation for complications of joint laxity, lumbar lordosis, chest deformity, scoliosis, and varus deformity of the lower extremities
  • Pulmonary. Evaluation for evidence of respiratory disease
  • Gastroenterologic. Evaluation for congenital megacolon if clinical observation is suggestive
  • Medical genetic

Treatment of Manifestations

Skeletal dysplasia. Corrective osteotomies may be warranted in late childhood or adolescence for excessive varus deformity of the lower extremities

In persons with AD, surgery may be needed to fuse malformed cervical vertebrae in infancy and to correct or prevent the progression of kyphoscoliosis.

Orthopedic surgery may be complicated by low bone density.

Immunodeficiency and infection. The treatment of infections in individuals with immunodeficiency is based on their type, location, and severity.

Immediate antiviral treatment must be considered in first symptoms of varicella infection to prevent complications.

Consider prophylactic antibiotic therapy if the patient has recurrent infections or if neutropenia is present, and/or immunoglobulin replacement therapy if immunoglobulin or IgG subclass levels are low.

Patients with bronchiectasis need long-term antibiotic treatment and physiotherapy.

Recurrent severe infections and/or the presence of severe combined immunodeficiency (SCID) may warrant bone marrow transplantation / hematopoietic stem cell transplantation (HSCT) [Guggenheim et al 2006].

Anemia. Treatment of severe anemia secondary to depressed erythropoiesis may require repeated red cell transfusions in infancy and childhood; life-long transfusions or bone marrow transplantation are rarely needed [Williams et al 2005].

Although steroid treatment has been effective in treating anemia in some persons with CHH, the available data are not sufficient to recommend this therapy in general, especially considering the potential side effects of immune suppression and growth retardation.

Malignancy. No specific recommendations for the treatment of the observed malignancies are available. Non-Hodgkin lymphoma often has a poor prognosis with conventional cytotoxic protocols [Taskinen et al 2008].

Prevention of Secondary Complications

If a cervical spine abnormality and/or instability is identified, special care should be exercised when general anesthesia is administered.


Skeletal dysplasia. Children with CHH require annual measurement of linear growth and assessment for deformities of the lower extremities and joints. Individuals with AD require annual clinical and radiographic monitoring of the spine.


  • Observe for clinical signs of anemia starting from the time of the initial diagnosis until early adolescence.
  • Follow RBC, hematocrit, and hemoglobin levels in those in remission after treatment for anemia at least every six months or when clinical signs of anemia reappear. Note: No data are available on the likely timing of recurrence of anemia after successful treatment.

Immunodeficiency and infection. As no clinical parameters predict susceptibility to infection in children, ongoing follow-up by physicians with experience in this condition is recommended, including routine physical examination and laboratory testing for early detection of infection. Particularly in the first two years of life, children with normal initial immunologic assessment should be monitored for recurrent infections, especially life-threatening varicella infections [Notarangelo et al 2008, Rider et al 2009].

Malignancy. Although no specific recommendations exist, it is advised that children be checked on a regular basis by their pediatrician or primary healthcare provider for lymphomas and other associated malignancies.

As no clinical parameters predict susceptibility to malignancy in adults, ongoing follow-up by physicians with experience in this condition is recommended, including routine physical examination and laboratory testing for early detection of malignancy.

Agents/Circumstances to Avoid

Although recent data suggest that routine immunizations (including live vaccines) are safe in persons with CHH, immunization should be carefully considered in those with CHH and evidence of abnormal immunologic function, and should be avoided in those with CHH and SCID [Rider et al 2009].

Evaluation of Relatives at Risk

Early diagnosis of relatives (i.e., sibs) at risk for CHH-AD spectrum disorders is important for early recognition and management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No issues are known; however, experience is limited.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Location of the RMRP mutations cannot, in general, predict the severity of the resulting phenotype; thus, intrafamilial variability has been observed.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with CHH-AD spectrum disorder has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an RMRP disease-causing mutation.

Other family members. Each sib of the proband’s parents has a 50% chance of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Ultrasound examination. Prenatal diagnosis may also be possible through fetal ultrasound studies at 16 to 18 weeks’ gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like CHH-AD spectrum disorders) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Phone: 49-761-270-34450
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Cartilage-Hair Hypoplasia - Anauxetic Dysplasia Spectrum Disorders : Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Cartilage-Hair Hypoplasia - Anauxetic Dysplasia Spectrum Disorders (View All in OMIM)


Normal allelic variants. RMRP is an intronless gene encoded by nuclear DNA. The RMRP transcript itself consists of only 267 bp with a type 3 promoter, a PSE element and a TATA box, and transcription factor binding sites upstream of the transcription initiation site. As the RMRP transcript is not translated into a protein there are no normal allelic variants at the amino acid level.

Pathologic allelic variants. More than 90 different mutations have been described to date [Ridanpää et al 2001, Bonafé et al 2005, Hermanns et al 2006, Thiel et al 2007].

Most mutations are in conserved regions of the RMRP transcript. Pathogenic mutations within the transcribed region affect either (1) evolutionary highly conserved nucleotides that are likely to alter the secondary structure through mispairing in stem regions or (2) RNA/protein interaction forming the RNase MRP complex.

Occasionally insertions, duplications, or triplications in the promoter region increase the distance between regulatory elements (i.e., the TATA box and the transcription start site). An increase of 24 to 26 bps between the regulatory elements leads to promoter inefficiency and reduced RMRP transcript levels [Ridanpää et al 2001, Nakashima et al 2007]. Such mutations have been observed in compound heterozygosity with mutations within the transcript.

The founder mutation g.70A>G is present in 100% of Old Order Amish, 92% of Finnish, and 48% of non-Finnish patients with CHH.

The decrease in rRNA cleavage caused by some mutations strongly correlates with the degree of bone dysplasia [Thiel et al 2007], whereas the disruption of the rRNA cleavage function correlates with the degree to which additional features including hair hypoplasia, immunodeficiency, anemia, and susceptibility to cancer are present. However, the actual phenotype in persons with compound heterozygous RMRP transcript mutations can be quite variable, depending on the functional impairment resulting from the specific combination of mutations.

Table 2.

Selected RMRP Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
g.70A>GNot applicableNR_003051​.3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Normal gene product. RMRP encodes the untranslated RNA subunit of the ribonucleoprotein endoribonuclease complex RNase MRP [Ridanpää et al 2001]. The mRNA transcript folds to a highly complex secondary structure and forms with at least ten proteins the mitochondrial RNA processing ribonuclease, RNase MRP, which is localized in the nucleolus and in mitochondria [Welting et al 2004, Hermanns et al 2005, Thiel et al 2005, Thiel et al 2007, Welting et al 2008]. This complex is involved in: (1) 5.8S rRNA cleavage leading to mature 5.8S rRNA (a necessary step to complete ribosome assembly); and (2) cleavage of cyclin B mRNA (CCNB1) needed in cell-cycle regulation progression.

Abnormal gene product. None


Literature Cited

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Chapter Notes

Author Notes

The author focuses on the research on genetic causes of short stature. By means of traditional methods including linkage analysis we have identified and further characterized the underlying genetic causes of anauxetic dysplasia, microcephalic osteodysplastic primordial dwarfism type Majewski (MOPD II), and short-rib polydactyly syndrome type Majewski. Besides the identification of genetic causes of rare skeletal dysplasias, we now focus on the genetics of idiopathic short stature using novel approaches such as whole-genome copy number analysis and whole-exome sequencing.


I would like to especially thank my former PI Prof. Dr. Anita Rauch, now chair of the Institute of Medical Genetics in Zurich, Switzerland.

Revision History

  • 15 March 2012 (me) Review posted live
  • 3 February 2011 (ct) Original submission
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