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 a CHH-AD spectrum disorder is established in a proband with characteristic clinical and radiographic findings. 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: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia; 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 for progressive varus deformity of the lower extremities; treatment of underlying infections based on their type, location, and severity; immediate high-dose intravenous acyclovir for varicella infection; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; recurrent severe infections, severe combined immunodeficiency (SCID), and/or severely depressed erythropoiesis may warrant hematopoietic stem cell transplantation; physiotherapy and other acute and long-term medical management for bronchiectasis per pulmonologist; red blood cell transfusions for severe anemia with iron chelation as needed; standard treatments for malignancies, congenital megacolon, Hirschsprung disease, and intestinal malabsorption; nutritional evaluation in those with short bowel syndrome; hormonal induction as needed for pubertal maturation; developmental and educational support as needed.

Surveillance: Monitor growth using CHH-specific growth curves; clinical and (if warranted) radiographic examination of joints of the lower extremities and spine annually in childhood and as required in adulthood; annual clinical and radiographic examination of the spine in individuals with AD. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella infection, then monitor annually; laboratory assessment for those with suspected infection; laboratory assessment of immune function with frequency based on initial lab results; assess the frequency of respiratory tract infections at each visit; high-resolution CT examination for those with suspected bronchiectasis and lung MRI to monitor bronchiectasis. For those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, complete blood count every six months. Clinical and laboratory examination for manifestations of malignancy annually in children and as needed in adults; abdominal ultrasound every one to two years in children and as needed in adults. Assess pubertal development annually throughout adolescence; assess for hypogonadism in those with pubertal delay. Developmental and cognitive assessment as needed in those with AD throughout childhood.

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

Pregnancy management: Fetal growth is generally unaffected; therefore, planned cæsarean section should be considered in term pregnancies in affected women due to cephalopelvic disproportion.

Genetic counseling.

CHH-AD spectrum disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RMRP pathogenic variant, each sib of an affected individual has at conception 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. Once the RMRP pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal and preimplantation genetic testing for CHH-AD spectrum disorders are possible.

Suggestive Findings

A CHH-AD spectrum disorder should be suspected in a proband with:

• Mild-to-severe disproportionate short-limbed short stature
• Presence of variable metaphyseal dysplasia, with epiphyseal and vertebral dysplasia at 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 elbow
• Fine, silky hair
• Increased rate of infections or intestinal dysfunction or anemia

Establishing the Diagnosis

The diagnosis of a CHH-AD spectrum disorder 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: (1) 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. (2) Identification of biallelic RMRP variants of uncertain significance (or of one known RMRP pathogenic variant and one RMRP variant of uncertain significance) does not establish or rule out the diagnosis.

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 phenotypes of CHH-AD spectrum disorders are 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
• At the severe end, the rare anauxetic dysplasia (AD), the most pronounced skeletal phenotype

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

Disproportionate short-limb short stature is usually evident in the newborn period 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. Final adult height range is <85 cm to 151 cm. 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 immunoglobulin G and undetectable immunoglobulin A 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 later 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]. Bronchiectasis is reported in 29%-52% of individuals with CHH; however, clinical relevance and progression of bronchiectasis can be insignificant [Vakkilainen et al 2021]. Individuals with CHH and combined immunodeficiency are at risk for chronic bronchiectasis [Toiviainen-Salo et al 2008], which may also develop in individuals with mild immunodeficiency [Kostjukovits et al 2017a]. Chronic viral infections with bocavirus and norovirus have been reported [Kainulainen et al 2014]. Impaired cellular immunity persists into adulthood. Fatal enteroviral meningoencephalitis has been reported in a child with CHH [Vatanavicharn et al 2010]. Cutaneous granulomas can be caused by vaccine-strain rubella virus in individuals with CHH [Buchbinder et al 2019]. Anti-TNF-α therapy has been used successfully in the treatment of cutaneous and visceral granulomas. However, fatal progressive multifocal leukoencephalopathy caused by JC (John Cunningham) virus has been described during treatment with anti-TNF-α antibodies. Hematopoietic stem cell transplantation resulted in disappearance of granulomas in two of three transplanted individuals [Moshous et al 2011].

Autoimmune complications. Clinical autoimmunity is common, and its spectrum is broad in individuals with CHH [Vakkilainen et al 2018]. Autoimmune complications and a form of severe allergic reaction have been rarely observed in individuals with 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 individuals [Mäkitie et al 1992b]. Severe and persistent anemia resembling that of Diamond-Blackfan syndrome is seen in about 6% of affected individuals [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]. In individuals requiring repeated transfusions iron chelation is successful and well tolerated when needed [Taskinen et al 2013]. A single case report demonstrated the efficacy of an mTOR inhibitor in the treatment of anemia in an individual with CHH [Del Borrello et al 2022].

Malignancies. Extended follow up of persons with CHH revealed that about 11% of the cohort (14/123) followed for 39 years developed malignancies [Taskinen et al 2008]. A 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 malignancy diagnosis. Underlying pathogenic variants in RMRP and severity of preceding immunodeficiency varied and did not correlate with the 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.

A case series of 16 individuals with CHH and lymphoma revealed that the most common lymphoma type was diffuse large B cell lymphoma [Kukkola et al 2022]. Mortality due to lymphoma is high in individuals with CHH (11/16, 69%), probably due to the advanced stage of lymphoma at the time of diagnosis. In almost all surviving individuals with CHH and lymphoma, the diagnosis was made either during routine follow up or after evaluation for nonspecific mild symptoms. Other CHH-related manifestations were poor predictors of lymphoma development, implying that all individuals with CHH should be regularly screened for malignancy.

Intestinal issues

• Newborn period. Hirschsprung disease with short-segment or total colonic aganglionosis is observed in 7%-8% of those with CHH, especially infants with a more severe CHH phenotype [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 poor weight gain. Although most intestinal manifestations occur in the first two years of life, they can occur later in childhood. Intestinal issues have not been described in individuals with 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 the function of RNase MRP (see Molecular Pathogenesis)
• 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 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 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 [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 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 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 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

There is no cure for CHH-AD spectrum disorders.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

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 severe combined immunodeficiency [Rider et al 2009].

Note: (1) Routine immunizations with inactivated vaccines are safe in persons with CHH. (2) No serious adverse events have been recorded after immunization with live viral vaccines in individuals of Finnish ancestry with CHH. (3) Individuals with CHH generate humoral and cellular immune response to live viral vaccines. Immunization with live vaccines may be considered in selected individuals with CHH without immunodeficiency or with clinically mild immunodeficiency [Vakkilainen et al 2020a].

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 molecular genetic testing 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

Despite significant short stature in women with CHH and other potential CHH-related effects on pregnancy outcome, most pregnancies lead to a term cæsarean section delivery. Fetal growth is generally unaffected; therefore, planned cæsarean section should be considered in term pregnancies due to cephalopelvic disproportion [Holopainen et al 2020].

Therapies Under Investigation

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 presumed to be heterozygous for an RMRP pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an RMRP pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• According to previous evaluations, heterozygotes (carriers) are not at increased risk for cancer and are asymptomatic [Mäkitie et al 1999].

Sibs of a proband

• If both parents are known to be heterozygous for an RMRP pathogenic variant, each sib of an affected individual has at conception 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 clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
• 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 a CHH-AD spectrum disorder or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in RMRP (see Family planning).

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 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.
• Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a CHH-AD spectrum disorder should be considered, particularly if both partners are of the same ethnic background. A high incidence of CHH has been reported in the Old Order Amish population, with a prevalence of 1-2:1,000 (carrier frequency of 1:10), and in Finland, with an incidence of 1:23,000 (carrier frequency of 1:76) [Mäkitie 1992, Mäkitie & Kaitila 1993].

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 and preimplantation genetic testing for a CHH-AD spectrum disorder are possible.

Ultrasound examination. If the RMRP pathogenic variants have not been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk may also be possible through fetal ultrasound studies at 16-18 weeks' gestation.

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.

Molecular Pathogenesis

RMRP encodes the untranslated RNA subunit of the ribonucleoprotein endoribonuclease complex RNase MRP [Ridanpää et al 2001]. The RMRP transcript consists of 267 bp with a type 3 promoter, a PSE element, a TATA box, and transcription factor binding sites upstream of the transcription initiation site. 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 B1 mRNA (encoded by CCNB1) needed in cell cycle regulation progression. RNase MRP also forms a complex with telomerase reverse transcriptase catalytic subunit (encoded by TERT), which may play a role in cellular senescence [Maida et al 2009].

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

RMRP pathogenic variants may affect both mRNA and rRNA cleavage and thus cell cycle regulation and protein synthesis (see Thiel et al [2007] and references therein). 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.

Mechanism of disease causation. Loss of function

RMRP-specific laboratory technical considerations. RMRP is an intronless gene encoded by nuclear DNA. The RMRP RNA transcript is not translated into a protein.

Author History

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

Revision History

• 11 May 2023 (sw) Comprehensive update posted live
• 6 August 2020 (aa) Revision: added NEPRO and POP1 to 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

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