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 that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, 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. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in RMRP by molecular genetic testing can confirm the diagnosis and allow for family studies.

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. Pubertal maturation may be delayed and may require hormonal induction.
• For those with immunodeficiency. Treatment of underlying infections based on their type, location, and severity; immediate antiviral treatment with intravenous high-dose acyclovir for varicella; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; physiotherapy and acute and long-term medical management for bronchiectasis. Recurrent severe infections and/or the presence of severe combined immunodeficiency (SCID) and/or severely depressed erythropoiesis may warrant bone marrow transplantation.
• Malignancies. Treat 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. Individuals with AD require annual clinical and radiographic monitoring of the spine.
• 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.
• Immunodeficiency/infection. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella. Annual evaluation after age two years. High-resolution CT examination for those with features suggestive of bronchiectasis.
• Malignancies. No specific recommendations exist; regular examination for evidence of lymphomas, basal cell carcinomas, and other associated malignancies is advised.
• Endocrinology. Monitor pubertal maturation.

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 for early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, 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.

Suggestive Findings

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

Establishing the Diagnosis

The diagnosis of CHH-AD is established in a proband with the above Suggestive Findings including clinical and characteristic radiographic findings. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic (or likely pathogenic) variants in RMRP by molecular genetic testing (see Table 1) can confirm the diagnosis and allow for family studies.

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CHH-AD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with short stature and/or immune deficiency are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes three phenotypes:

• Metaphyseal dysplasia without hypotrichosis (MDWH);
• Cartilage-hair hypoplasia (CHH), with metaphyseal dysplasia and hypotrichosis; and
• At the severe end, the rare anauxetic dysplasia (AD), with the most pronounced skeletal phenotype.

The mechanisms for phenotypic variability are incompletely understood (see Genotype-Phenotype Correlations).

Disproportionate short-limb short stature is the hallmark finding and is usually recognized in the newborn and occasionally prenatally. Proportionate short stature has been observed in some individuals [van der Burgt et al 1991, Mäkitie & Kaitila 1993]. Normal growth in childhood has also been reported [Klemetti et al 2017]. 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.

Immunodeficiency may manifest as lymphopenia and defects in T-lymphocyte function and/or proliferation [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 [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. Individuals with CHH and combined immunodeficiency are at particular risk for chronic bronchiectasis [Toiviainen-Salo et al 2008], which may, however, develop even in individuals with mild immunodeficiency [Kostjukovits et al 2017a]. 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]. Individuals with CHH demonstrate broad autoantibody reactivity compared to healthy controls [Biggs et al 2017].

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. There are isolated reports of uterine carcinoma and vocal cord carcinoma [Kostjukovits et al 2017b]. 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.

Delayed puberty. Girls with CHH may have hypogonadotropic or normogonadotropic hypogonadism with no spontaneous pubertal development [Holopainen et al 2018].

Additional findings observed in some persons with AD [Horn et al 2001]:

• Atlantoaxial subluxation with fatal cervical compression
• Mild intellectual disability

Genotype-Phenotype Correlations

The CHH-AD spectrum includes a range of phenotypes. RMRP is not translated into a protein; thus, genotype-phenotype correlation depends on the position of the pathogenic variant in the transcript and the proposed effect on transcript folding and RNA/protein interaction (see Molecular Genetics).

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 OR
• 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, McKusick type was first described in the Old Order Amish population by McKusick and his colleagues [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 1:1,000-2:1,000 (carrier frequency 1:10) and in Finland with an incidence of 1:23,000 (carrier frequency 1:76) [Mäkitie 1992, Mäkitie & Kaitila 1993].

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 evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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 sibs. 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 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; lifelong 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].

Endocrine. Pubertal maturation may be delayed and may require hormonal induction.

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 annual 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 orthopedic 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.

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 immunodeficiency; high-resolution computed tomography should be used for diagnosis [Toiviainen-Salo et al 2008]; lung MR examination is recommended for follow up [Kostjukovits et al 2017a].

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.

Malignancy

• Children. Although no specific recommendations exist, it is advised that children be evaluated annually by their pediatrician or primary health care 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.
• Adults. 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 needs to be determined on an individual basis.

Endocrinology. Monitor pubertal maturation.

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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

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; intrafamilial variability in disease severity 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 affected individual's reproductive partner also has CHH-AD spectrum disorder or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in RMRP.

Other family members. Each sib of the proband's parents has a 50% chance of being a carrier of an RMRP pathogenic variant.

Carrier 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the RMRP pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a CHH-AD spectrum disorder are possible.

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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Author History

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

Revision History

• 6 August 2020 (aa) Revision: added NEPRO and POP1 in the Differential Diagnosis
• 24 May 2018 (sw) Comprehensive update posted live
• 13 August 2015 (me) Comprehensive update posted live
• 15 March 2012 (me) Review posted live
• 3 February 2011 (ct) Original submission