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Cartilage-Hair Hypoplasia 

Cartilage-Hair Hypoplasia
Cartilage-Hair Hypoplasia

Outi Mä kitie

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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


Frequency (%)

Short stature, –4 SD or <5th percentile


Hair hypoplasia




Propensity to infections


In vitro immunodeficiency


Hypoplastic childhood anemia


Gastrointestinal dysfunction


Hirschsprung’s disease


Defective spermatogenesis


Metaphyseal chondrodysplasia on childhood skeletal radiographs


Overall risk of malignancies (standardized incidence ratio)


Non-Hodgkin’s lymphoma (standardized incidence ratio)


Basal cell carcinoma (standardized incidence ratio)


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).


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