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Cartilage-Hair Hypoplasia 

Cartilage-Hair Hypoplasia
Chapter:
Cartilage-Hair Hypoplasia
Author(s):

Outi Mä kitie

DOI:
10.1093/med/9780195389838.003.0037
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Description

Cartilage-hair hypoplasia (CHH), or metaphyseal chondrodysplasia, McKusick type (MIM 250250), is an autosomal recessive skeletal dysplasia in which immunodeficiency is a constant feature (McKusick et al., 1965). Skeletal dysplasias comprise a large group of clinically distinct and genetically heterogeneous conditions characterized by abnormalities in patterning, linear growth, differentiation, and maintenance of the human skeleton, beginning during the early stages of fetal development and evolving throughout life. In the 2006 revision of the International Nosology and Classification of Genetic Skeletal Disorders, 372 different conditions were listed in 37 groups defined by molecular, biochemical, and/or radiographic criteria (Superti-Furga and Unger, 2007). The metaphyseal chondrodysplasias constitute a subgroup of bone dysplasias with eight distinct disorders.

CHH is a pleiotropic skeletal dysplasia with symptoms arising also from several nonskeletal tissues (Makitie et al., 1995; Makitie and Kaitila, 1993; McKusick et al., 1965). In the original description of CHH, McKusick et al. observed an increased propensity to infections, caused by viruses in particular. Since then the defective immunity in CHH has been confirmed by clinical and laboratory studies (Makitie et al., 1998, 2000b; Polmar and Pierce, 1986). The disease-causing gene, RMRP, RNA component of mitochondrial RNA processing endoribonuclease, was identified in 2001, and a number of mutations have been found (Ridanpaa et al., 2001, 2002). However, the pathogenic mechanisms of the pleiotropic features, including the immunodeficiency, have remained elusive.

CHH is prevalent among the Amish in the United States and among the Finns in Europe, but affected families have been observed in most Caucasian and Asian populations (Nakashima et al., 2003; Ridanpaa et al., 2002).

Clinical Manifestations

Nonimmunological Features

The clinical features include growth failure and hair hypoplasia (Makitie and Kaitila, 1993; Makitie et al., 1995), anemia (Juvonen et al., 1995; Makitie et al., 1992b), intestinal neuronal dysplasia or Hirschsprung’s disease (HD) (Makitie et al., 2001a), defective spermatogenesis (Makitie et al., 2001c), and risk of malignancies (Makitie et al., 1999) (Table 37.1 and Fig. 37.1).

Table 37.1 Pleiotropic Features in Cartilage-Hair Hypoplasia

Feature

Frequency (%)

Short stature, –4 SD or <5th percentile

100

Hair hypoplasia

93

Immunodeficiency

56

Propensity to infections

56

In vitro immunodeficiency

88

Hypoplastic childhood anemia

79

Gastrointestinal dysfunction

18

Hirschsprung’s disease

9

Defective spermatogenesis

100

Metaphyseal chondrodysplasia on childhood skeletal radiographs

100

Overall risk of malignancies (standardized incidence ratio)

7.0

Non-Hodgkin’s lymphoma (standardized incidence ratio)

90

Basal cell carcinoma (standardized incidence ratio)

33

The marked short-limbed, short stature is due to metaphyseal dysplasia. The growth failure has its onset prenatally and progresses with age. In Finnish patients the mean birth length was 45.8 cm for boys and 44.9 cm for girls (range, 38–51 cm), and the median adult height was 131.2 cm (range, 110–158 cm) for males and 122.5 cm (range, 103–137 cm) for females (Makitie et al. 1992a; Makitie and Kaitila, 1993).

The radiographic skeletal abnormalities include short and broad tubular bones with splaying and an irregular metaphyseal border of the growth plate (Fig. 37.2). The costochondral junctions are similarly splayed and irregular; the vertebrae are usually normal. These findings develop and are diagnostic by the age of 6 to 9 months. In adults the tubular bones remain short and thick but are otherwise unspecific (Makitie and Kaitila, 1993; Makitie et al., 1995).

Figure 37.2 Radiographs showing the characteristic features.

Figure 37.2
Radiographs showing the characteristic features.

The characteristic hair hypoplasia in CHH presents as fair, thin, and sparse hair growth. However, variation is marked and individuals with normal hair have been observed (Bonafe et al., 2002; Makitie and Kaitila, 1993; Makitie et al., 1995; Verloes et al., 1990).

Gastrointestinal problems, such as neuronal dysplasia of the intestine, are common in CHH. Congenital HD was found in 13 of 147 Finnish patients with CHH (9 percent), all of whom had an overall severe form (Makitie et al., 2001a). Eight patients had the classic form of HD with rectosigmoid involvement, two had long-segment colonic disease, and three had total colonic aganglionosis. Six of the patients had episodes of enterocolitis, two with colonic perforations prior to the first surgery; 11 patients had postoperative enterocolitis and some died of enterocolitis-related septicemia (Makitie et al., 2002).

Defective erythrogenesis in early childhood presenting as refractory hypoplastic anemia is a common feature in CHH and was found in 54 of 74 Finnish patients (73 percent). In approximately 6 percent of CHH patients severe anemia is persistent and resembles Diamond-Blackfan anemia (Makitie et al., 1992b, 2000a; Williams et al., 2005). Thrombocytopenia and autoimmune hemolytic anemia have also been reported (Ashby and Evans, 1986; Berthet et al., 1996).

Immunological Features

McKusick et al. (1965) observed an increased rate of infections in patients with CHH. Varicella occasionally resulted in a prolonged and severe disease with hemorrhagic vesicles, high fever, and even fatality. They showed in two Amish patients mild to moderate lymphopenia, decreased delayed hypersensitivity, and impaired lymphocyte responses to mitogens, whereas immunoglobulin concentrations and antibody synthesis were normal (Lux et al., 1970). Subsequent studies confirmed cell-mediated immune deficiency to be an integral feature of CHH (Pierce and Polmar, 1982; Pierce et al., 1983; Polmar and Pierce, 1986; Ranki et al., 1978; Rider et al., 2009; Trojak et al., 1981; Virolainen et al., 1978). The absolute lymphocyte count was about half that of normal controls. The results of allogeneic stimulations indicated an intrinsic T-cell defect, whereas antigen-presenting cells were not affected. The IL-2 production by CHH lymphocytes was reduced, but exogenous IL-2 did not correct the defect in proliferation (Kooijman et al., 1997; Pierce and Polmar, 1982; Pierce et al., 1983; Polmar and Pierce, 1986).

In the Finnish patients, a reduction of 50 percent in the CD4+ cell count and a reduction of 30 percent in the CD4+/CD8+ cell ratio have been reported. The B-lymphocyte count was usually normal, whereas the NK-cell count was often elevated (Makitie et al., 1998). On the basis of increased expression of Fas (CD95), CD95L, and Bax, and decreased expression of Bcl-2 and inhibitor of apoptosis protein (IAP) in both CD4+ and CD8+ cells, it has been suggested that the lymphopenia might be due to increased apoptosis of these cells (Yel et al., 1999). In another study, the levels of mRNA encoding c-myc, IL-2Rα‎, IL-2, and IFN-γ‎ were decreased in stimulated CHH lymphocytes, whereas those of other early activation gene products, such as c-fos and c-jun, were not impaired, suggesting a lymphocyte intracellular signaling defect (Castigli et al., 1995). Transcriptional profiling of CHH patient RNAs identified several upregulated and downregulated genes that play a role in the immune system, cell-cycle regulation, and signal transduction (Hermanns et al., 2005).

In contrast to earlier studies, we found that one third of the Finnish CHH patients also had partially defective humoral immunity presenting as isolated IgA and IgG subclass deficiencies (Makitie et al., 2000b; Toiviainen-Salo et al., 2008). Impaired antibody production has been observed (Rider et al., 2009). Several CHH patients with combined immune deficiency have been reported also from other populations (Guggenheim et al., 2006; Kavadas et al., 2008; Rider et al., 2009).

A number of patients with chronic, severe, and even fatal infections due to viruses, bacteria, and fungi have been reported (Berthet et al., 1996; Castigli et al., 1995; Guggenheim et al., 2006; Hong, 1989; Kainulainen et al., 2008; Lux et al., 1970; Polmar and Pierce, 1986; Saulsbury et al., 1975; Steele et al., 1976). CHH patients, particularly those with defective humoral immunity, have an increased risk for bronchiectasis (Toiviainen-Salo et al., 2008). Despite severe clinical presentations in occasional patients, most patients do clinically relatively well (Makitie et al., 1998, 2000b; Rider et al. 2009).

Molecular Basis

On the basis of molecular linkage studies on Finnish multiplex CHH families, the disease-causing gene was mapped to 9p12 in 1993 (Sulisalo et al., 1993). The location was refined by disequilibrium analysis; finally, the mutated gene, RMRP, was detected through physical mapping and sequencing (Ridanpaa et al., 2001). Several RMRP mutations have been detected (Bonafé et al., 2005; Ridanpaa et al., 2002). Most are base substitutions, insertions, or short duplications that alter conserved nucleotide sequences in the transcribed region. Insertions or duplications in the promoter region between the TATA box and the site of initiation of transcription, or in the 5′ end of the transcribed region, are also common.

The most common CHH-causing mutation is 70A > G, found in 92 percent of Finnish CHH patients and probably all Amish patients (Ridanpaa et al., 2003). The same mutation accounts for 48 percent of the mutations among patients from other parts of Europe, North and South America, the Near East, and Australia (Ridanpää et al., 2001, 2002).

The human RMRP gene encodes the 267 bp RNA molecule of the RNase MRP complex, which consists of protein components and the RNA molecule. Thus, unlike most of the known disease-associated genes, the RMRP is an untranslated gene. The RNase MRP is a ribonucleoprotein endoribonuclease involved in the processing of precursor ribosomal RNA and in priming of the RNA for mitochondrial DNA replication. It has been suggested that the RNase MRP also carries other important biological functions, such as control of cell proliferation (Clayton, 2001; Maida et al., 2009). In situ hybridization experiments have indicated the presence of RNase MRP in both mitochondria and nucleoli, the majority being localized to the latter. The pathogenetic mechanisms of the RMRP mutations are still unknown.

Treatment and Prognosis

Children with CHH should not be vaccinated with live or attenuated bacteria or viruses. Antibiotic and antiviral treatment of infections, as well as prophylactic antibiotics, should be recommended on a case-by-case basis. Immunoglobulin treatment is indicated in patients with combined immune deficiency.

Profound T-cell deficiency similar to that seen in severe combined immunodeficiency has been demonstrated in some patients with CHH. Anecdotal CHH patients with such severe presentation have undergone bone marrow transplantation with successful long-term reconstitution of immunity; no improvement was observed in longitudinal growth, however (Berthet et al., 1996; Guggenheim et al., 2006)

Patients with CHH have significantly increased mortality rates compared with their parents and nonaffected siblings (Makitie et al., 2001b). While infections predispose younger children to premature death, malignancies predominate as the cause of death in the older age groups (Makitie et al., 1999, 2001b). A recent follow-up study including 123 Finnish CHH patients identified 14 cases of cancer (standardized incidence ratio [SIR] 7.0). Non-Hodgkin’s lymphoma was the most frequent cancer type (9 patients, SIR 90.2). Nine of the 14 cancers were diagnosed in patients less than 45 years of age. In addition, 10 patients had basal cell carcinoma of the skin (SIR 33.2) (Taskinen et al., 2008). Kaplan-Meier estimation of cancer events gave a probability of a cancer event (excluding basal cell carcinoma) of 41 percent by the age of 65 years (Taskinen et al., 2008).

References

Ashby GH, Evans DI. Cartilage hair hypoplasia with thrombocytopenic purpura, autoimmune haemolytic anaemia and cell-mediated immunodeficiency. J R Soc Med 1986;79: 113–114.Find this resource:

Berthet F, Siegrist CA, Ozsahin H, et al. Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia. Eur J Pediatr 1996;155: 286–290.Find this resource:

Bonafé L, Dermitzakis LT, Unger S, et al. Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. PLoS Genet 2005;1(4):e47.Find this resource:

Bonafé L, Schmitt K, Eich G, et al. RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet 2002;61: 146–151.Find this resource:

Castigli E, Irani AM, Geha RS, Chatila T. Defective expression of early activation genes in cartilage-hair hypoplasia (CHH) with severe combined immunodeficiency (SCID). Clin Exp Immunol 1995;102: 6–10.Find this resource:

Clayton DA. A big development for a small RNA. Nature 2001;410: 29–31.Find this resource:

Guggenheim R, Somech R, Grunebaum E, et al. Bone marrow transplantation for cartilage-hair-hypoplasia. Bone Marrow Transplant 2006;38: 751–756.Find this resource:

Hermanns P, Bertuch AA, Bertin TK, et al. Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hum Mol Genet 2005;14: 3723–3740.Find this resource:

Hong R. Associations of the skeletal and immune systems. Am J Med Genet 1989;34: 55–59.Find this resource:

Juvonen E, Makitie O, Makipernaa A, et al. Defective in-vitro colony formation of haematopoietic progenitors in patients with cartilage-hair hypoplasia and history of anaemia. Eur J Pediatr 1995;154: 30–34.Find this resource:

Kainulainen L, Waris M, Söderlund-Venermo M, et al. Hepatitis and human bocavirus primary infection in a child with T-cell deficiency. J Clin Microbiol 2008;46: 4104–4105.Find this resource:

Kavadas FD, Giliani S, Gu Y, et al. Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations. J Allergy Clin Immunol 2008;122: 1178–1184.Find this resource:

Kooijman R, van der Burgt CJ, Weemaes CM, et al. T cell subsets and T cell function in cartilage-hair hypoplasia. Scand J Immunol 1997;46: 209–215.Find this resource:

Lux SE, Johnston RB Jr, August CS, et al. Chronic neutropenia and abnormal cellular immunity in cartilage-hair hypoplasia. N Engl J Med 1970;282: 231–236.Find this resource:

Maida Y, Yasukawa M, Furuuchi M, et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 2009;461: 230–235.Find this resource:

Makitie O, Heikkinen M, Kaitila I, Rintala R. Hirschsprung’s disease in cartilage-hair hypoplasia has poor prognosis. J Pediatr Surg 2002;37: 1585–1588.Find this resource:

Makitie O, Juvonen E, Dunkel L, et al. Anemia in children with cartilage-hair hypoplasia is related to body growth and to the insulin-like growth factor system. J Clin Endocrinol Metab 2000a;85: 563–568.Find this resource:

Makitie O, Kaitila I. Cartilage-hair hypoplasia—clinical manifestations in 108 Finnish patients. Eur J Pediatr 1993;152: 211–217.Find this resource:

Makitie O, Kaitila I, Rintala R. Hirschsprung disease associated with severe cartilage-hair hypoplasia. J Pediatr 2001a;138: 929–931.Find this resource:

Makitie O, Kaitila I, Savilahti E. Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Eur J Pediatr 1998;157: 816–820.Find this resource:

Makitie O, Kaitila I, Savilahti E. Deficiency of humoral immunity in cartilage-hair hypoplasia. J Pediatr 2000b;137: 487–492.Find this resource:

Makitie O, Perheentupa J, Kaitila I. Growth in cartilage-hair hypoplasia. Pediatr Res 1992a;31: 176–180.Find this resource:

Makitie O, Pukkala E, Kaitila I. Increased mortality in cartilage-hair hypoplasia. Arch Dis Child 2001b;84: 65–67.Find this resource:

Makitie O, Pukkala E, Teppo L, Kaitila I. Increased incidence of cancer in patients with cartilage-hair hypoplasia. J Pediatr 1999;134: 315–318.Find this resource:

Makitie O, Rajantie J, Kaitila I. Anaemia and macrocytosis—unrecognized features in cartilage-hair hypoplasia. Acta Paediatr 1992b;81: 1026–1029.Find this resource:

Makitie O, Sulisalo T, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia. J Med Genet 1995;32: 39–43.Find this resource:

Makitie OM, Tapanainen PJ, Dunkel L, Siimes MA. Impaired spermatogenesis: an unrecognized feature of cartilage-hair hypoplasia. Ann Med 2001c;33: 201–205.Find this resource:

McKusick VA, Eldridge R, Hostetler JA, et al. Dwarfism in the Amish. II. Cartilage-hair hypoplasia. Bull Johns Hopkins Hosp 1965;116: 231–272.Find this resource:

    Nakashima E, Mabuchi A, Kashimada K, et al. RMRP mutations in Japanese patients with cartilage-hair hypoplasia. Am J Med Genet A 2003;123A:253–256.Find this resource:

    Pierce GF, Brovall C, Schacter BZ, Polmar SH. Impaired culture generated cytotoxicity with preservation of spontaneous natural killer-cell activity in cartilage-hair hypoplasia. J Clin Invest 1983;71: 1737–1743.Find this resource:

    Pierce GF, Polmar SH. Lymphocyte dysfunction in cartilage hair hypoplasia. II. Evidence for a cell cycle-specific defect in T cell growth. Clin Exp Immunol 1982;50: 621–628.Find this resource:

    Polmar SH, Pierce GF. Cartilage hair hypoplasia: immunological aspects and their clinical implications. Clin Immunol Immunopathol 1986;40: 87–93.Find this resource:

    Ranki A, Perheentupa J, Andersson LC, Hayry P. In vitro T- and B-cell reactivity in cartilage hair hypoplasia. Clin Exp Immunol 1978;32: 352–360.Find this resource:

    Ridanpaa M, Jain P, McKusick VA, et al. The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Am J Med Genet C Semin Med Genet 2003;121C:81–83.Find this resource:

    Ridanpaa M, Sistonen P, Rockas S, et al. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major 70A—>G mutation of the untranslated RMRP. Eur J Hum Genet 2002;10: 439–447.Find this resource:

    Ridanpaa M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 2001;104: 195–203.Find this resource:

    Rider NL, Morton DH, Puffenberger E, et al. Immunologic and clinical features of 25 Amish patients with RMRP 70 A–>G cartilage hair hypoplasia. Clin Immunol 2009;131: 119–128.Find this resource:

    Saulsbury FT, Winkelstein JA, Davis LE, et al. Combined immunodeficiency and vaccine-related poliomyelitis in a child with cartilage-hair hypoplasia. J Pediatr 1975;86: 868–872.Find this resource:

    Steele RW, Britton HA, Anderson CT, Kniker WT. Severe combined immunodeficiency with cartilage-hair hypoplasia: in vitro response to thymosin and attempted reconstitution. Pediatr Res 1976;10: 1003–1005.Find this resource:

    Sulisalo T, Sistonen P, Hastbacka J, et al. Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis. Nat Genet 1993;3: 338–341.Find this resource:

    Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A 2007;143: 1–18.Find this resource:

    Taskinen M, Ranki A, Pukkala E, et al. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet A 2008;146A:2370–2375.Find this resource:

    Toiviainen-Salo S, Kajosaari M, Piilonen A, Makitie O. Patients with cartilage-hair hypoplasia have an increased risk for bronchiectasis. J Pediatr 2008;152: 422–428.Find this resource:

    Trojak JE, Polmar SH, Winkelstein JA, et al. Immunologic studies of cartilage-hair hypoplasia in the Amish. Johns Hopkins Med J 1981;148: 157–164.Find this resource:

    Verloes A, Pierard GE, Le Merrer M, Maroteaux P. Recessive metaphyseal dysplasia without hypotrichosis. A syndrome clinically distinct from McKusick cartilage-hair hypoplasia. J Med Genet 1990; 27: 693–696.Find this resource:

    Virolainen M, Savilahti E, Kaitila I, Perheentupa J. Cellular and humoral immmunity in cartilage-hair hypoplasia. Pediatr Res 1978;12: 961–966.Find this resource:

    Williams MS, Ettinger RS, Hermanns P, et al. The natural history of severe anemia in cartilage-hair hypoplasia. Am J Med Genet A 2005;138: 35–40.Find this resource:

    Yel L, Aggarwal S, Gupta S. Cartilage-hair hypoplasia syndrome: increased apoptosis of T lymphocytes is associated with altered expression of Fas (CD95), FasL (CD95L), IAP, Bax, and Bcl2. J Clin Immunol 1999;19: 428–434.Find this resource: