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Cartilage-hair hypoplasia

Cartilage-hair hypoplasia
Literature review current through: Jan 2024.
This topic last updated: Aug 11, 2023.

INTRODUCTION — Cartilage-hair hypoplasia (CHH; MIM #250250) is a skeletal dysplasia inherited as an autosomal recessive trait. CHH is sometimes also referred to as immunodeficiency with short-limbed dwarfism. It is caused by pathogenic variants in the ribonuclease mitochondrial ribonucleic acid (mRNA) processing (RMRP) gene [1]. Common features of the disorder include short stature; fine, sparse hair; varying degrees of immunodeficiency; Hirschsprung disease (HD); and a susceptibility to hematologic malignancies [2,3]. Persons with CHH have normal intelligence and achieve normal developmental milestones throughout childhood.

CHH is diagnosed clinically by observing fine and often sparse hair in an individual with short stature with disproportionally short limbs. Genetic analysis of the RMRP gene confirms the diagnosis. Immune-related complications (immunodeficiency, malignancy, and autoimmune disease) lead many to medical attention early in life and are a major cause of early mortality.

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of CHH. Other syndromic immunodeficiencies and skeletal dysplasias are discussed separately. (See "Syndromic immunodeficiencies" and "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders".)

EPIDEMIOLOGY — CHH is a rare disorder in the general population but exists with greater prevalence among the Old Order Amish and Finnish populations [4]. One Finnish study estimated an incidence of 1:23,000 [5]. Thus, any person with short stature and immunodeficiency with Amish or Finnish inheritance should be evaluated for CHH.

The carrier frequency of a point mutation in the RMRP gene (70 A>G) is estimated to be as high as 1 in 19 among the Old Order Amish [1].

The Old Order Amish are members of a larger Anabaptist group, which also included the Old Order Mennonites [6]. The Anabaptists fled religious persecution in Europe and eventually immigrated to America in the late 1600s. Members of the Old Order Amish sect are widely distributed throughout the United States, but approximately 70 percent are concentrated in four counties: Lancaster County, Pennsylvania; Holmes and Geauga Counties of Ohio; and LaGrange County, Indiana.

GENETICS AND PATHOGENESIS — CHH is an autosomal recessive disorder caused by pathogenic variants in the RMRP gene [1,7]. This gene encodes for the untranslated (long noncoding [lnc]) RNA component of a mitochondrial RNA-processing endonuclease (RNase mitochondrial RNA processing [MRP]), a protein-RNA complex that plays a role in nucleolar processing of ribosomal RNA (rRNA), cleavage of mitochondrial RNA (mRNA) in mitochondrial deoxyribonucleic acid (DNA) synthesis, and cleavage of cyclin B2 mRNA in cell cycle control.

The RMRP gene product functions as a nuclear reservoir for a group of lnc-RNAs with gene-silencing activity [8]. Gene targets of lnc-RNAs include those with functions related to bone and cartilage growth.

The RMRP 70 A>G pathogenic variant occurs in 30 to 48 percent of patients with CHH but is more common in the genetically isolated Amish and Finnish populations [1,4,9-11]. Numerous other pathogenic variants in the RMRP promoter region and gene have been identified in patients with CHH.

Phenotypic heterogeneity is great, even among patients homozygous for the RMRP 70 A>G pathogenic variant [3,7,12,13]. RMRP pathogenic variants that reduce rRNA cleavage are associated with bone dysplasia, whereas defects that decrease mRNA cleavage are associated with hair hypoplasia, immunodeficiency, and hematologic abnormalities [14]. The degree of reduced rRNA or mRNA cleavage correlates with the degree of phenotypic severity.

CLINICAL MANIFESTATIONS — CHH is a diverse disorder with varied clinical manifestations. Originally thought to be achondroplasia, CHH was first described as a distinct clinical entity among the Old Order Amish of Pennsylvania by Victor McKusick [2].

Somatic growth and musculoskeletal findings — The musculoskeletal system is most consistently affected in CHH. Short stature and short limbs with increased carrying angle at the elbow are universally found in persons with CHH (picture 1 and picture 2). Increased lumbar lordosis, ligamentous laxity, and scoliosis are common and age dependent [2,15-17].

Metaphyseal dysplasia, with scalloped, flared, and sclerotic metaphyses, most frequently affects the lower extremities. The degree of metaphyseal abnormality correlates with growth velocity and final height [18].

One detailed radiographic study of 82 patients with CHH showed that long-bone growth was particularly abnormal and progressive in CHH [18]. In the same study, scoliosis was noted in 25 percent of patients overall and in 44 percent of adults [18]. Another series of 100 patients with CHH showed that relative limb growth rates declined rapidly in early childhood and the pubertal growth spurt was minimal to absent [19]. Appendicular skeletal growth was particularly abnormal, but axial skeletal dimensions were also affected among persons with CHH, indicating the global dysfunction of skeletal growth in this syndrome.

Analysis of the Finnish CHH cohort showed that most newborns were short but of normal weight for gestational age [16], with similar unpublished findings in the Amish CHH cohort. Median adult heights were 131 cm (51.6 in) and 122.5 cm (48.2 in) for males and females, respectively, in the Finnish cohort [20].

Growth velocity is generally normal for weight and length. However, most persons with CHH do not plot along "normal" percentiles. Head circumference is an exception in that normal measurements and growth velocity are the rule. Head measurements below the third percentile or those who do not follow a normal growth percentile should prompt further evaluations in a person with CHH. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Postnatal evaluation'.)

Many persons with CHH suffer arthralgias and progressive arthritis due to the metaphyseal abnormalities intrinsic to the disorder. However, the degree of metaphyseal abnormality does not appear to correlate with severity of symptomatic joint disease [18]. Some patients benefit from joint replacement surgery or arthroscopy, although a comprehensive analysis of these interventions and their benefit for CHH is lacking.

Gastrointestinal abnormalities — Gastrointestinal anomalies in CHH range from classic Hirschsprung disease (HD), to long segment disease, to total colonic aganglionosis [21]. Enterocolitis is commonly associated with HD in the setting of CHH. It is a potentially lethal complication due to the severity of the inflammation and the risk of bacterial translocation into the bloodstream with subsequent sepsis in an individual with immunodeficiency. (See 'Immunodeficiency' below and "Congenital aganglionic megacolon (Hirschsprung disease)".)

Hair abnormalities — Abnormal hair morphology is a hallmark of the CHH phenotype. Hair is fine but may vary in texture from patient to patient and even appear normal on gross inspection. However, hair shaft diameter in CHH is 50 to 67 percent smaller than normal hair when viewed under magnification [22]. CHH hair is more fragile than normal hair and weaker when subjected to tensile strength testing [23]. However, amino acid analysis reveals no difference in sulfur-containing amino acid composition compared with controls (disulfide bonds and sulfhydryl groups are major components of keratin in hair).

Immunodeficiency — Impairment of immune function is the greatest health risk among persons with CHH and represents the most common cause of premature death in this syndrome [24]. All persons with CHH are at risk for severe, frequent, and unusual infections irrespective of their laboratory findings.

Various host defense abnormalities are described in persons with CHH [3,16,25-31]. Cell-mediated immunodeficiency (combined immunodeficiency) is most commonly reported. In a series of 108 patients with CHH from Finland, 88 percent of patients had in vitro evidence of abnormal cellular immunity [16]. More than one-half had an increased susceptibility to infection, and 6 percent died of primary infections. (See "Combined immunodeficiencies: An overview".)

Fatal varicella infection has been described in a number of patients [2]. However, many persons from the Amish cohort have developed native immunity to varicella without serious sequelae. Patients may develop infections with organisms that signify a severe T cell defect, such a Pneumocystis carinii (P. jirovecii) pneumonia, cytomegalovirus pneumonitis, or severe oropharyngeal candidiasis [3].

Severe combined immunodeficiency (SCID) is known to occur in the setting of CHH [32-35]. SCID may present in classic fashion with alymphocytosis and severe humoral defects, with severe T and B cell functional defects, but quantifiable cell counts, or with an Omenn syndrome phenotype [3,7,32]. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

Sinopulmonary infections suggestive of humoral immunodeficiency are also common in CHH. In the Finnish cohort, 35 percent (7 of 20) of patients prospectively evaluated had defective humoral immunity, most frequently immunoglobulin A (IgA) deficiency. Some patients have hypogammaglobulinemia requiring immunoglobulin replacement. (See "Primary humoral immunodeficiencies: An overview".)

Discrimination between severe and more moderate forms of immunodeficiency in CHH is difficult and often not discernible with routine laboratory methods. However, persons with CHH who have severe lymphopenia and immunoglobulin defects should be considered as high risk for infection susceptibility. An additional confounding feature is that many patients with CHH who have lymphopenia do not suffer recurrent infections [3].

Malignancy — Mortality in CHH is increased primarily owing to greater infection susceptibility in children and a higher incidence of hematologic malignancy among adults [24,36,37]. Extended follow-up of a Finnish cohort of 123 patients revealed 14 cases of cancer, with an expected incidence of two based upon population-based data [37]. Half of the malignancies were of B cell origin. Non-Hodgkin lymphoma was most common (n = 9), followed by squamous cell carcinoma (n = 3), leukemia (n = 1), and Hodgkin lymphoma (n = 1). Nine of the 14 cases occurred in patients between the ages of 15 and 44 years. An update of the Finnish registry outcomes (n = 160 patients with CHH) showed that 16 developed lymphoma over a 63-year span and that 38 percent of lymphomas were of diffuse large cell B cell type [38]. In addition, outcomes were poor, with only five surviving. Late diagnosis may have contributed to suboptimal outcomes. Multiple additional malignancies have also been reported in CHH patients [27,37]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

Persons with CHH also display a unique predisposition to the development of basal cell carcinoma [27,37]. In the same Finnish cohort described above, an additional 10 patients had basal cell carcinoma of the skin, with an expected number of 0.3 cases for the population [37]. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)

Autoimmunity — Autoimmune disease is reported among persons with CHH, including immune-mediated thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), enteropathy, thyroid disease, and juvenile idiopathic arthritis (JIA) [3,25,39]. Additionally, those patients with CHH and autoimmune disease may have greater risk for death and serious bacterial infections, but serum positivity for autoantibodies does not necessarily correlate with disease [40]. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Classification of juvenile idiopathic arthritis".)

Pulmonary findings — Pulmonary complications reported in patients with CHH include mild to severe bronchiectasis [41] and chronic obstructive symptoms with diffuse dilated lymphoplasmacytic bronchiolitis that improves with antibiotic therapy [26]. Patients with bronchiectasis more often have a humoral immunodeficiency and worse growth failure. Estimates from registry data suggest that persons with CHH and chronic respiratory symptoms have a prevalence of bronchiectasis in excess of 50 percent [41]. Subsequent analysis of a random sampling of Finnish patients (n = 34) revealed that 10 patients (29 percent) had bronchiectasis confirmed by high-resolution computed tomography scan (HRCT) with a lower lobe predominance [42]. Follow-up of 16 patients with CHH and bronchiectasis (median interval of 6.8 years) revealed generally lower serum immunoglobulin M (IgM) levels but stable lung imaging findings, suggesting that infrequent pulmonary imaging may be acceptable for those with CHH, bronchiectasis, and stable clinical findings [43]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Pregnancy, obstetric, and gynecologic considerations — A systematic evaluation of gynecologic health in CHH noted that females in the cohort were concerned about pregnancy and fertility in relation to their skeletal dysplasia, although study results showed that females with CHH typically had normal pregnancies without fertility issues [44]. Another study found that CHH may predispose females to cervical cancer at a higher rate than the general population because of greater susceptibility to human papilloma virus (HPV) infection [45]. These studies underscore the need for females with CHH to be followed carefully for routine gynecologic health and pregnancy and also to be provided condition-specific anticipatory guidance. A subsequent study of 42 pregnancies among 14 CHH females showed that most pregnancy outcomes were favorable but that cephalo-pelvic disproportion was common and warranted consideration for cesarean delivery [46].

Granuloma — Epithelioid cell granulomatous inflammation was seen in 19 percent (4 of 21) of patients in one series [47]. All four patients had infiltrative skin lesions, and one also had visceral organ involvement. One patient had spontaneous resolution of granulomas at 17 years of age. The other three patients had partial regression of lesions with anti-tumor necrosis factor (TNF) therapy in addition to cyclosporine. However, one of these patients died from viral progressive multifocal leukoencephalopathy. The granulomatous inflammation resolved completely in another of these patients after undergoing successful hematopoietic cell transplantation (HCT).

Other features — Dramatic clinical heterogeneity is observed within CHH sibships. This phenotype diversity within families makes presymptomatic diagnosis of immunodeficiency challenging, even when a previous sibling had immune problems. Similar findings are noted in other populations with different RMRP pathogenic variants [48].

LABORATORY FINDINGS — Almost all persons with CHH will have some abnormal immune studies. However, there is not a clear pattern of immunodeficiency among people with CHH [3,13,22,49-51]. Absolute lymphocyte counts and T cell counts for age are generally low, delayed-type hypersensitivity responses are often impaired, and neutropenia is also reported [3]. Lymphocyte proliferation to mitogens is generally suboptimal compared with controls [3]. However, abnormal in vitro proliferation and lymphopenia do not necessarily indicate that a given individual will have a severe immunodeficiency. (See "Laboratory evaluation of the immune system".)

Telomere length is significantly shorter in T and natural killer (NK) cells of patients with CHH [52,53]. The mechanism linking telomere homeostasis and ribonuclease mitochondrial RNA (mRNA) processing (RMRP) function is not clear. This finding may relate to the abovementioned proliferative impairments and cytopenias seen in the condition. Testing of telomere length is a potential biomarker for cellular immunodeficiency that can be performed once the diagnosis of CHH is made.

Antibody defects are also common in patients with CHH [3,54]. Hypogammaglobulinemia may be transient or persist throughout life. Selective IgA deficiency is described in some patients and may be a marker for severe immunodeficiency in CHH [3]. An individual with more than one immunoglobulin isotype deficiency should be considered high risk for infectious complications. Humoral immune defects, including specific antibody deficiency, may occur alone or in combination with cellular defects [55]. In the latter case, the provisional diagnosis is severe combined immunodeficiency (SCID) until proven otherwise. (See "Primary humoral immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview".)

Anemia is also common among persons with CHH and may warrant hematopoietic cell transplantation (HCT) for marrow failure [55]. One retrospective study of 88 patients found a history of macrocytic or normocytic anemia in 73 percent during the childhood years [56]. Severe anemia is rare; however, autoimmune hemolytic anemia (AIHA) and Diamond-Blackfan syndrome are reported in the setting of CHH [3,25,49]. Thrombocytopenia is also reported. (See "Overview of causes of anemia in children due to decreased red blood cell production".)

DIAGNOSIS — Clinical findings of short-limbed dwarfism and fine hair without manifestations of another skeletal dysplasia suggest the diagnosis of CHH. Thus, all persons with short-limbed dwarfism and clinical or laboratory evidence of immunodeficiency should be evaluated for CHH. The diagnosis is probable in a patient with short stature and Finnish or Old Order Amish heritage. Analysis for RMRP sequence variants can confirm the diagnosis in a patient with skeletal dysplasia and associated clinical findings [1,4].

Some infants with CHH come to medical attention through T cell receptor excision circle (TREC) based newborn screening [57,58]. These infants can contract early-life viral infections that are not cleared and cause death. As such, all infants with CHH who present with an abnormal severe combined immunodeficiency (SCID) newborn screen are presumed to have a clinically significant T cell deficiency and should be evaluated for hematopoietic cell transplantation (HCT) candidacy. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

Radiographic findings are helpful in the work-up of an individual with suspected skeletal dysplasia. The metaphyseal ends are abnormal in CHH and appear as scalloped, irregular surfaces (image 1) that may contain cystic areas on routine radiographs [18]. Metaphyseal changes vary depending upon the bone studied but are universally abnormal in an individual with CHH.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CHH includes other autosomal recessive skeletal dysplasias and disorders of short stature with or without immune dysfunction. Often, the following conditions cannot initially be distinguished from one another in an infant; therefore, involvement of a clinical geneticist is prudent upon suspecting a skeletal dysplasia. (See "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders".)

Anauxetic dysplasia (AD) – Features of AD (MIM #607095) include severe spondyloepimetaphyseal dysplasia, mild intellectual disability, and hypodontia. Immunodeficiency has not been reported in these patients.

Metaphyseal dysplasia without hypotrichosis – Metaphyseal dysplasia is mild in patients with metaphyseal dysplasia without hypotrichosis (MDWH; MIM #250460). Immunodeficiency has not been reported in these patients.

Kyphomelic dysplasia (KD) – Features of KD (MIM #211350) include metaphyseal dysplasia, combined immunodeficiency, facial dysmorphisms, and rib abnormalities.

Shwachman-Diamond syndrome – This syndrome with metaphyseal dysplasia has associated hematologic abnormalities, such as neutropenia and exocrine pancreatic dysfunction (MIM #260400). (See "Shwachman-Diamond syndrome".)

Ectodermal dysplasia with immunodeficiency – The features associated with this syndrome include abnormal teeth, hair, and eccrine sweat glands and immunodeficiency with dysgammaglobulinemia and recurrent infections (MIM #300921). (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia and immunodeficiency'.)

Growth hormone insensitivity with immunodeficiency – This syndrome of postnatal growth failure and recurrent infections is associated with pathogenic variants in signal transducer and activator of transcription 5b (STAT5B) (MIM #604260). (See "Growth hormone insensitivity syndromes", section on 'Abnormal growth hormone receptor signal transduction'.)

Schimke immunoosseous dysplasia – Skeletal anomalies, such as spondyloepiphyseal dysplasia, and associated cellular immune dysfunction are reported (MIM #242900). This syndrome is also associated with immune complex nephritis. (See "Syndromic immunodeficiencies", section on 'Schimke immunoosseous dysplasia'.)

Ellis-van Creveld (EVC) syndrome – Persons with this autosomal recessive skeletal dysplasia have postaxial polydactyly and a high incidence of congenital heart disease but do not have associated immune defects (EVC; MIM #225500 [59]. Additional distinguishing features of EVC syndrome include dysplastic nails and natal teeth [59,60].

MANAGEMENT — Optimal management of CHH, similar to that for any complex genetic disease, requires a medical home base where the patient can be seen promptly for acute illnesses, managed longitudinally for chronic problems, and monitored for the manifold problems associated with this syndrome. Surveillance for immunodeficiency, malignancy, and autoimmune disease is important for all people with CHH and should be part of every clinical visit.

Immunization — Infants should be evaluated for immunodeficiency and have close surveillance for infections (algorithm 1). Administration of live-attenuated vaccines (table 1) is not recommended without first demonstrating normal T cell responses. However, lymphocyte subset values and other immunologic parameters for age (such as lymphocyte proliferation to mitogens and antigens, specific immunoglobulin G [IgG] titers, and quantitative immunoglobulins) are typically abnormally low in patients with CHH, even in those not subsequently identified with an immunodeficiency.

It is the author's opinion that clear cutoff values cannot reliably distinguish the immunocompetent individual with CHH within the first six months of life, although patients with severe combined immunodeficiency (SCID) can be identified. Live vaccines should not be administered to patients with suspected SCID. The author follows all infants with CHH and no evidence of SCID until at least one year of age to confirm that there is no clear evidence of a combined immunodeficiency or T cell dysfunction (ie, the patient is immunocompetent) before administering live-attenuated virus vaccines. A study of Finnish patients with CHH reported no adverse events among 50 patients who received live vaccines, suggesting that some persons can safely receive live vaccines [61]. Other routine vaccinations are recommended for persons with CHH according to the standard schedule. (See "Severe combined immunodeficiency (SCID): An overview" and "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

Hematopoietic cell transplantation — Those with concerning clinical or immunologic features suggestive of an SCID should be evaluated for hematopoietic cell transplantation (HCT) as early as possible. HCT is curative for SCID in the setting of CHH, and associated autoimmunity also resolves after transplantation [3,62-64]. However, HCT does not improve the musculoskeletal or growth features of the syndrome. Risk stratification for serious immunodeficiency is difficult unless the patient has alymphocytosis and classic SCID presentation. Thus, determining who will benefit from HCT is not always clear. However, a study of Amish patients with CHH noted that absent T cell receptor excision circle (TREC) values on newborn screening related to more severe immunodeficiency and need for HCT [58]. Transplantation before the development of serious infections, significant organ damage, or malignancy improves survival for those patients who clearly have combined immunodeficiency [63]. (See "Severe combined immunodeficiency (SCID): An overview" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

Monitoring for complications — Careful attention to bowel function during the first year of life is prudent. Hirschsprung disease (HD) is common in CHH. Some patients with CHH present outside of the newborn period with only mild constipation, with the diagnosis of HD established near six months of age [65]. Any bloody stools in an infant with CHH should prompt an evaluation for HD and associated enterocolitis because enterocolitis may be the heralding sign of HD. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

Growth monitoring in CHH is essential. CHH-specific growth charts are not readily available, but monitoring with standard growth charts is still useful to ensure steady progress. Delayed or diminished head growth is not typical in CHH and warrants further evaluation. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Postnatal evaluation' and "Normal growth patterns in infants and prepubertal children", section on 'Evaluation of growth'.)

Because adults may present with severe bronchiectasis [41], we recommend routine surveillance for obstructive lung disease with periodic spirometry and/or pulmonary function testing. Any chronic pulmonary infections or significant abnormalities of pulmonary function warrant further investigation with computed tomography (CT) of the chest.

Surveillance for musculoskeletal disease, such as scoliosis, symptomatic genu and ankle varus, and arthritides later in life, should be part of routine evaluations of CHH patients. Surgical correction may be needed for symptomatic scoliosis or large-joint arthritis. Some patients benefit from joint replacement surgery or arthroscopy, although a comprehensive analysis of these interventions and their benefit for CHH is lacking.

PROGNOSIS — Persons with CHH have normal intelligence and achieve normal developmental milestones throughout childhood. Lifespan can be shortened in patients with CHH secondary to a significant immunodeficiency in childhood or lymphoma and leukemia in adulthood. Severe bronchiectasis may also dramatically shorten lifespan of persons with CHH [41]. Analysis of 120 Finnish CHH patients between 1971 and 1995 revealed a standardized mortality ratio (SMR; the ratio of observed to expected deaths) of 380 for infectious complications in childhood (less than age 14 years) and an SMR of 52 for hematologic malignancies among persons older than 15 years [24]. Extended follow-up of the Finnish cohort (n = 123) reported patients living into the seventh decade, indicating that normal duration of life is possible for persons with CHH [37].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Genetics – Cartilage-hair hypoplasia (CHH) is a rare, autosomal recessive form of short-limb dwarfism (metaphyseal chondrodysplasia) that is caused by defects in the ribonuclease mitochondrial ribonucleic acid (mRNA) processing (RMRP) gene. (See 'Introduction' above and 'Epidemiology' above and 'Genetics and pathogenesis' above.)

Clinical manifestations – CHH has varied clinical manifestation, including fine, sparse hair; cellular and humoral immunodeficiencies; Hirschsprung disease (HD); hematologic and skin malignancies; autoimmune disease; and bronchiectasis. The immunologic complications associated with CHH are variable, and onset is not consistent. (See 'Clinical manifestations' above.)

Diagnosis – The diagnosis is suspected in patients with typical clinical and radiologic features and is confirmed with mutation analysis of the RMRP gene. Both are necessary to make a diagnosis of CHH. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis includes other autosomal recessive skeletal dysplasias. (See 'Differential diagnosis' above.)

Management – Management of CHH includes monitoring for and treating infections, gastrointestinal abnormalities, malignancy, autoimmune disease, and pulmonary complications. Hematopoietic cell transplantation (HCT) is a treatment option in patients with severe combined immunodeficiency (SCID) due to CHH. (See 'Management' above.)

Prognosis – Lifespan can be shortened in patients with CHH secondary to a significant immunodeficiency in childhood or lymphoma and leukemia in adulthood. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 3916 Version 19.0

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