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Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders

, MD, PhD and , MD.

Author Information
, MD, PhD
Children's Hospital
University of Helsinki and Helsinki University Hospital
Folkhälsan Research Center
Helsinki, Finland
, MD
Children's Hospital
University of Helsinki and Helsinki University Hospital
Folkhälsan Research Center
Helsinki, Finland

Initial Posting: ; Last Update: August 13, 2015.

Summary

Clinical characteristics.

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

  • Metaphyseal dysplasia without hypotrichosis (MDWH)
  • Cartilage-hair hypoplasia (CHH)
  • 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/testing.

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 pathogenic variants cause the CHH-AD spectrum disorders. Molecular genetic testing confirms the diagnosis.

Management.

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 in AD; 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 and/or immunoglobulin replacement therapy. 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.

Surveillance:

  • 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 infection.
  • 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; regular examination for evidence of lymphomas, basal cell carcinomas, and other associated malignancies is advised.

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 carrier of a pathogenic variant, 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 pathogenic variants in the family have been identified.

GeneReview Scope

Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders: Included Phenotypes
  • Cartilage-hair hypoplasia (CHH)
  • Metaphyseal dysplasia without hypotrichosis (MDWH)
  • Anauxetic dysplasia (AD)

For synonyms and outdated names see Nomenclature.

Diagnosis

There are no formal diagnostic criteria for CHH, as individuals present with highly variable phenotypes.

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].

Newborn screening for severe combined immunodeficiency (SCID) using detection of T-cell receptor excision circles is able to identify some of the individuals with CHH prior to recognition of other findings [Kwan et al 2013].

Suggestive Findings

Cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders should be suspected in individuals with:

  • Mild to severe disproportionate short-limbed 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

Especially when accompanied by:

  • Short tubular bones
  • Bowed femora and tibiae
  • “Bullet”-shaped middle phalanges, cone-shaped epiphyses and premature epiphyseal fusion on hand radiographs
  • Laxity of ligaments with joint hypermobility, but limited extension of the elbows
  • Fine, silky hair
  • Increased rate of infections or intestinal dysfunction or anemia

Clinical Findings by Phenotype

Cartilage-hair hypoplasia (CHH)

  • Disproportionate short-limb short stature (present in 100% of affected individuals; prenatal onset in 76%-93%)
  • Short fingers and toes
  • Bowed femora and tibiae (present in 77%)
  • Laxity of ligaments with hypermobility of joints (in 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
  • Cutaneous and visceral granulomas [Moshous et al 2011, McCann et al 2014]

Metaphyseal dysplasia without hypotrichosis (MDWH)

  • Clinical features similar to CHH, but with normal hair
  • Absence of immunodeficiency, anemia, and intestinal manifestations

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

Note: Radiographic findings tend to be highly variable.

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, most prominent changes at the knees
  • Distal metaphyses: wide, flared, occasionally scalloped with cystic areas; poor ossification with trabeculation
  • Epiphyseal changes: absent or mild in the femoral head
  • Vertebral bodies: normal or mild biconvexity with increased height, lumbar lordosis, reduced widening of interpediculate distance in the lumbar spine

Metaphyseal dysplasia without hypotrichosis (MDWH)

  • Similar to those in CHH

Anauxetic dysplasia (AD)

  • Vertebral bodies: late-maturing 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

Establishing the Diagnosis

The diagnosis of cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) is established in a proband by detection of biallelic pathogenic variants in RMRP on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and genomic testing.

  • Single-gene testing. Sequence analysis of RMRP is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Sequencing should cover both the transcribed region and the promoter region.

    Targeted analysis for the common g.70A>G pathogenic variant can be performed first in individuals of Finnish or Amish ancestry.

    Note: This noncoding RNA spans only 268 bp; therefore, targeted testing by sequence analysis is likely to result in analysis of the entire gene.
  • A multi-gene panel that includes RMRP and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of CHH-AD. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    For issues to consider in interpretation of genomic test results, click here.

Table 1.

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

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
RMRPTargeted analysis~50%-100% 3
Sequence analysis 4~100% 5
Gene-targeted deletion/duplication analysis 6Unknown, none reported 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

The founder variant g.70A>G is present in 100% of Old Order Amish, 92% of Finnish, and 48% of non-Finnish individuals with CHH [Ridanpää et al 2002, Ridanpää et al 2003, Rider et al 2009].

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.
6.

Testing that identifies exon or whole-gene deletions/duplications not 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.

7.

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

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]. The natural history has been extensively reported particularly in Finnish individuals with CHH.

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 mechanisms for phenotypic variability are incompletely understood. Individuals with identical pathogenic variants in RMRP can have discordant phenotypes. Phenotypic variability regarding skeletal and immunologic features, hair hypoplasia, and hematologic complications is marked even within families, and CHH and MDWH phenotypes may occur in the same family.

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 individuals 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 alopecia including scalp hair and eyelashes, eyebrows, and body hair.

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. Early reports on fatal varicella infection conflict with the more recent publications on larger cohorts of individuals with CHH with mostly uncomplicated varicella disease [McKusick et al 1965, Mäkitie et al 1998]. Severe respiratory disease (e.g., lymphoplasmacytic bronchiolitis) has been reported in children [Bailly-Botuha et al 2008]. Chronic viral infections with bocavirus and norovirus have been reported [Kainulainen et al 2014]. Impaired cellular immunity persists into adulthood.

Deficient humoral immunity has also been observed in several individuals and can result in severe combined immunodeficiency (SCID) [Mäkitie et al 2000, Horn et al 2010]. Individuals with CHH and combined immunodeficiency are at particular risk for chronic bronchiectasis [Toiviainen-Salo et al 2008]. Fatal enteroviral meningoencephalitis has been reported in a child with CHH [Vatanavicharn et al 2010].

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]. Cutaneous and visceral granulomatous inflammatory lesions have been described in five individuals with CHH [Moshous et al 2011, McCann et al 2014].

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 in 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% of the cohort (14/123) followed for 39 years had developed malignancies [Taskinen et al 2008]. Kaplan-Meier estimate gave a probability of a cancer event (excluding basal cell carcinoma) of 41% by age 65 years.

Nine of the 14 malignancies were diagnosed in persons age 15-44 years. Of the 14 who developed malignancies, nine have died; median time to death was three months after initial diagnosis of the malignancy. Underlying pathogenic variants in RMRP and severity of preceding immunodeficiency varied and did not correlate with risk of malignancy.

The most frequently observed cancers are non-Hodgkin lymphoma, followed by squamous cell carcinoma, leukemia, and Hodgkin lymphoma; non-aggressive basal cell carcinoma was also common. Rarely, two or more malignancies are observed in one individual.

Intestinal problems

  • Newborn period. Hirschsprung disease with short-segment or total colon aganglionosis is observed in 7%-8% of those with CHH, especially infants with the severe forms of CHH [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. Intestinal problems have not been described in AD or MDWH.

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 pathogenic variant and the expected effect on the protein do not apply. Thus, genotype-phenotype correlation depends on the position of the pathogenic variant in the transcript and the proposed effect on the transcript folding and RNA/protein interaction.

The milder phenotypes are usually caused by either of the following:

  • Compound heterozygous or homozygous pathogenic variants within the transcript resulting in little to intermediate effect on function of the RNase MRP (complex formed of the RMRP transcript and other proteins)
  • Compound heterozygosity for one pathogenic variant within the transcript and one pathogenic variant in the promoter region.

AD is caused by either of the following:

  • Compound heterozygous or homozygous biallelic pathogenic variants that severely alter function
  • Compound heterozygosity for:
    • One pathogenic variant within the transcript that severely alters the RNase MRP function
      AND
    • A hypomorphic (reduced function) allele (e.g., pathogenic variant leading to an unstable transcript)

Nomenclature

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].

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

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

Prevalence

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

Skeletal dysplasia. 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].

Metaphyseal dysplasia. Several forms of metaphyseal chondrodysplasia, such as Schmid dysplasia (OMIM 156500), Jansen dysplasia (OMIM 156400), and Shwachman-Diamond syndrome, have short stature and radiographic metaphyseal abnormalities resembling those observed in CHH. The molecular basis of these conditions is known [Warman et al 2011]. Schmid dysplasia and Jansen dysplasia are autosomal dominant while Shwachman-Diamond syndrome and CHH are autosomal recessive conditions.

  • Individuals with Schmid dysplasia have short stature and skeletal manifestations (metaphyseal dysplasia especially in the proximal femur) but lack extraskeletal manifestations. Schmid dysplasia is caused by mutation of COL10A1.
  • Jansen dysplasia is caused by activating pathogenic variants in the PTH/PTHrP receptor and is associated with short stature and skeletal changes with hypercalcemia and hypercalciuria [Savoldi et al 2013].
  • In Shwachman-Diamond syndrome skeletal features are usually milder while exocrine pancreatic insufficiency, neutropenia, and failure to thrive are the principal manifestations [Levin et al 2015]. Shwachman-Diamond syndrome is caused by mutation of SBDS.

Other considerations:

  • 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]. Pathogenic variants 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 (OMIM 603554). 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. Pathogenic variants in RAG1, RAG2, or DCLRE1C are causative; inheritance is autosomal recessive.
  • Congenital neutropenia. Isolated congenital neutropenia can be caused by pathogenic variants in ELANE, HAX1, GFI1, WAS [Klein 2009], or G6PC3; congenital neutropenia that occurs as part of a syndrome can be caused by pathogenic variants 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 congenital neutropenia associated with other systemic disorders.

Management

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, IgM, and IgG subclasses
  • CD3, 4, 8, 19, 16/56
  • Post-vaccine titers
  • Other 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

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

Consultations

  • Orthopedic. Evaluation for complications of joint laxity, lumbar lordosis, chest deformity, scoliosis, and varus deformity of the lower extremities
  • Immunologic. For further assessment and treatment if above testing is abnormal or if the child has infections, and to determine the vaccination program and the approach to varicella prophylaxis
  • Hematologic. For further assessment and treatment if above testing is abnormal
  • Pulmonary. Evaluation for evidence of respiratory disease
  • Gastroenterologic. Evaluation for congenital megacolon if clinical observation is suggestive
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Skeletal dysplasia

  • Corrective osteotomies may be warranted in late childhood or adolescence for excessive varus deformity of the lower extremities [Riley et al 2015].
  • 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.

Short stature. Treatment with recombinant growth hormone has not shown any sustained benefit in individuals with CHH and cannot be recommended [Obara-Moszynska et al 2013].

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

  • Immediate antiviral treatment with intravenous high-dose acyclovir must be considered at the first symptoms of varicella infection to prevent complications.
  • Consider prophylactic antibiotic therapy if the individual has recurrent infections or if neutropenia/severe lymphopenia is present. Consider also immunoglobulin replacement therapy if immunoglobulin or IgG subclass levels are low, or if vaccine responses are inadequate.
  • Individuals with bronchiectasis need proper management of infectious exacerbations and physiotherapy. Consider also long-term treatment with inhaled antibiotics or oral macrolide [Altenburg et al 2015].
  • 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]. HSCT has resulted in normalization of T-lymphocyte numbers and function, resolution of autoimmune manifestations, and catch-up growth, probably due to reduced infections. Overall survival rates have been reported at 63% for unrelated donor transplants and as high as 80% for matched siblings. HSCT should be considered in selected individuals with CHH with recurrent infections and autoimmune manifestations or bone marrow dysplasia for whom a well-matched donor is available [Bordon et al 2010].
  • Anti-TNFa therapy has been used successfully in the treatment of cutaneous and visceral granulomas. However, fatal progressive multifocal leukoencephalopathy caused by JC virus has been described during treatment with anti-TNFa antibodies. HSCT resulted in disappearance of granulomas in two out of three transplanted individuals [Moshous et al 2011].

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]. In individuals requiring repeated transfusions iron chelation is successful and well tolerated when needed [Taskinen et al 2013].
  • 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.

Surveillance

Skeletal dysplasia

  • Children with CHH require annual measurement of linear growth and body proportions; comparison with published disease-specific growth curves [Mäkitie et al 1992a] is helpful.
  • Pubertal development should be monitored during yearly follow-up visits and hypogonadism excluded if puberty is significantly delayed.
  • Clinical assessment for deformities of the lower extremities and joints is appropriate. Radiographic evaluation and orthopaedic consultation is necessary if symptomatic misalignment, restricted knee or hip mobility, or symptomatic joint laxity is present.
  • Individuals with AD require annual clinical and radiographic monitoring of the spine.

Anemia

  • 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: (1) No data are available on the likely timing of recurrence of anemia after successful treatment; (2) severe anemia in adolescents and adults with CHH can be the presenting symptom of malignancy and may require extensive investigations with bone marrow evaluation and imaging studies.

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].
  • Laboratory markers for immunodeficiency may fluctuate in children with CHH, thus emphasizing the need for regular yearly follow up [Kainulainen et al 2014].
  • Bronchiectasis should be suspected especially in subjects with frequent respiratory tract infections and combined immune deficiency; high-resolution computed tomography should be used for diagnosis [Toiviainen-Salo et al 2008].

Malignancy

  • Although no specific recommendations exist, it is advised that children be checked on a regular basis (once yearly) by their pediatrician or primary healthcare provider for lymphomas and other associated malignancies by careful clinical examination and routine blood tests.
    • Skin should be inspected for abnormal changes, lymph nodes for enlargement, and abdomen for hepatomegaly, splenomegaly, or other abnormalities. Abdominal ultrasound is recommended at a regular one- to two-year interval, as well as yearly laboratory tests including blood counts with differential, LDH, and uric acid.
  • As no clinical parameters predict susceptibility to malignancy in adults, ongoing regular follow up beyond adolescence is recommended, including routine physical examination and laboratory testing for early detection of malignancy, as described above. The frequency of follow-up visits need to be determined on an individual basis.

Agents/Circumstances to Avoid

Routine immunizations with inactivated vaccines are considered safe in persons with CHH. However, immunization with live vaccines 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). Relatives at risk should be tested if clinical features, especially short stature, are present; completely asymptomatic individuals need not be tested.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variants in the family are known;
  • Radiographic evaluation and RMRP sequence analysis if the pathogenic variants in the family are not known.

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

Varicella vaccine is being investigated for children with CHH who have not had varicella. Search ClinicalTrials.gov for access to information on this and other clinical studies for a wide range of diseases and conditions.

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 individual are obligate heterozygotes (i.e., carriers of one RMRP pathogenic variant).
  • According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [Mäkitie et al 1999].

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. The type of RMRP pathogenic variants cannot, in general, predict the severity of the resulting phenotype; thus, intrafamilial variability has been observed.
  • According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [Mäkitie et al 1999].

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 of an RMRP pathogenic variant).

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members requires prior identification of the RMRP pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the RMRP pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

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.

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 most centers would consider decisions about prenatal testing to be 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 RMRP pathogenic variants have been identified.

Resources

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
    Email: info@lpaonline.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
RMRP9p13​.3Not applicableFinnish Disease Database (RMRP)
Resource of Asian Primary Immunodeficiency Diseases (RMRP)
RMRP

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)

157660MITOCHONDRIAL RNA-PROCESSING ENDORIBONUCLEASE, RNA COMPONENT OF; RMRP
250250CARTILAGE-HAIR HYPOPLASIA; CHH
250460METAPHYSEAL DYSPLASIA WITHOUT HYPOTRICHOSIS
607095ANAUXETIC DYSPLASIA

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 90 different pathogenic variants have been described [Ridanpää et al 2001, Bonafé et al 2005, Hermanns et al 2006, Martin & Li 2007, Thiel et al 2007].

Most pathogenic variants are in conserved regions of the RMRP transcript. Pathogenic variants 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 pathogenic variants have been observed in compound heterozygosity with pathogenic variants within the transcript.

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

The decrease in rRNA cleavage caused by some pathogenic variants 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 variants can be quite variable, depending on the functional impairment resulting from the specific combination of pathogenic variants. Further, other factors influence phenotypic variability as evidenced by significant phenotypic variability between affected siblings.

Table 2.

Selected RMRP Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
g.70A>GNot applicableNG_017041​.1

Note on variant classification: Variants listed in the table have been provided by the authors. 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​.hgvs.org). 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 into a highly complex secondary structure and combines with at least ten proteins to form 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. RMRP also forms a complex with telomerase reverse transcriptase catalytic subunit (TERT), which may play a role in cellular senescence [Maida et al 2009].

Abnormal gene product. None

References

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Chapter Notes

Author History

Svetlana Kostjukovits, MD (2015-present)
Outi Mäkitie, MD, PhD (2015-present)
Christian T Thiel, MD; Friedrich-Alexander Universität (2011-2015)

Revision History

  • 13 August 2015 (me) Comprehensive update posted live
  • 15 March 2012 (me) Review posted live
  • 3 February 2011 (ct) Original submission
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