Growth in cartilage-hair hypoplasia.

Cartilage-hair hypoplasia is an osteochondrodysplasia with short-limbed short stature. The cartilage-hair hypoplasia gene is exceptionally prevalent in Finland; more than 100 patients have been identified. We have analyzed the growth of 100 Finnish patients and present cartilage-hair hypoplasia-specific growth charts of height and weight for height. The disproportions were analyzed by sitting height, subischial leg height, sitting height:height ratio, and span-height difference. The stature was short at birth with a mean relative length of -3.0 SD. The median adult height was 131.1 cm (-7.9 SD, range 110.7 to 149.0 cm) for 15 males and 122.5 cm (-7.9 SD, range 103.7 to 137.4 cm) for 20 females. The progression of the growth failure was partly explained by weakness or absence of pubertal growth spurt. Weight for height was above normal median in childhood and increased further at puberty. Most of the adults were overweight. The adults' mean relative head circumference was -0.9 SD. Growth was disturbed both in the limbs and in the spine, more severely in the limbs. Adult height showed no correlation with the midparent height. The charts are useful for assessment of growth, prediction of adult height, detection of superimposed disorders, and evaluation of growth-accelerating therapy.     

Skeletal growth in cartilage-hair hypoplasia

Cartilage-hair hypoplasia is a metaphyseal chondrodysplasia with short-limbed short stature. In childhood radiographs the metaphyseal regions of the tubular bones are widened, scalloped and irregularly sclerotic. We have analyzed radiological characteristics and skeletal growth in 149 radiographic surveys of 82 Finnish patients. All extremity long bones were affected and short for age. The growth failure was progressive. In the adults the median relative lengths were for the humerus –6.3 SD, radius –8.6 SD, ulna –6.7 SD, femur –9.7 SD, tibia –8.7 SD, and fibula –6.8 SD. The severity of the metaphyseal changes correlated with the degree of the growth failure. The skeletal age was markedly retarded in 14% of the patients. Caudal widening of the interpediculate distance in the lumbar spine was observed in 90% of the patients, but it tended to be less than normal. The sagittal diameter of the spinal canal was normal in the cervical region but decreased in the lumbar region. Mild scoliosis was observed in one-fourth of the patients, and its incidence increased with age. Lumbar lordosis was moderately increased. Thoracic deformity was observed in 82% of the patients. The relative interorbital distance was increased with the median of +2.2 SD in the adults.     

Increased mortality in cartilage-hair hypoplasia

BACKGROUND—Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia with severe growth failure and impaired immunity. Impaired immunity may result in increased mortality.AIMS—To follow a cohort of 120 CHH patients for mortality from 1971 to 1995.METHODS—The overall and cause specific disease mortality rates in patients with CHH, and the disease mortality rate in 194 parents and 158 non-affected sibs were compared with the national rates.RESULTS—During follow up seven disease related deaths were observed versus 0.8 expected (standardised mortality ratio 9.3, 95% confidence interval 3.7 to 19). In most cases, the deaths were confined to the younger age groups and associated with defective immunity. The mortality of the parents and the non-affected sibs was similar to that in the general population.CONCLUSION—The study confirms increased mortality in patients with CHH attributable to defective immunity, especially in children.     

Diffuse lymphoplasmacytic bronchiolitis in cartilage-hair hypoplasia

Three children with cartilage-hair hypoplasia presented with chronic obstructive symptoms and bronchiolar wall thickening on high-resolution computed tomography scanning. In all children, surgical lung biopsy demonstrated diffuse dilated lymphoplasmacytic bronchiolitis. The bronchiolar wall was infiltrated by a lymphocyte sheath with plasma cell differentiation and dispersed secondary follicles. Clarithromycin substantially improved respiratory symptoms and pulmonary function, allowing children to return home.     

Increased mortality in cartilage-hair hypoplasia.

BACKGROUND: Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia with severe growth failure and impaired immunity. Impaired immunity may result in increased mortality. AIMS: To follow a cohort of 120 CHH patients for mortality from 1971 to 1995. METHODS: The overall and cause specific disease mortality rates in patients with CHH, and the disease mortality rate in 194 parents and 158 non-affected sibs were compared with the national rates. RESULTS: During follow up seven disease related deaths were observed versus 0.8 expected (standardised mortality ratio 9.3, 95% confidence interval 3.7 to 19). In most cases, the deaths were confined to the younger age groups and associated with defective immunity. The mortality of the parents and the non-affected sibs was similar to that in the general population. CONCLUSION: The study confirms increased mortality in patients with CHH attributable to defective immunity, especially in children.     

Granulocyte colony-stimulating factor-responsive chronic neutropenia in cartilage-hair hypoplasia

: Chronic neutropenia is common in children with cartilage-hair hypoplasia (CHH). The authors describe a 6-year-old with severe CHH, moderate neutropenia associated with serum IgG antibodies directed against Fcgamma-RIIIb (NA1/2), and frequent bacterial infections. In this patient, long-term administration of granulocyte colony-stimulating factor increased peripheral neutrophil counts and prevented recurrent hospitalizations for bacterial lower respiratory tract infections.     

Hirschsprung disease associated with severe cartilage-hair hypoplasia

Cartilage-hair hypoplasia is a chondrodysplasia with a high incidence of Hirschsprung disease. This study suggests that Hirschsprung disease is associated especially with severe cartilage-hair hypoplasia: the patients with Hirschsprung disease had severe growth failure and a higher incidence of alopecia, infections, malignancies, and childhood anemia than the patients with cartilage-hair hypoplasia who did not have Hirschsprung disease.     

Increased incidence of cancer in patients with cartilage-hair hypoplasia

OBJECTIVE: Previous reports have suggested an increased risk of cancer among patients with cartilage-hair hypoplasia (CHH). This study was carried out to further evaluate this risk among patients with CHH and their first-degree relatives. STUDY DESIGN: One hundred twenty-two patients with CHH were identified through 2 countrywide epidemiologic surveys in 1974 and in 1986. Their parents and nonaffected siblings were identified through the Population Register Center. This cohort underwent follow-up for cancer incidence through the Finnish Cancer Registry to the end of 1995. RESULTS: A statistically significant excess risk of cancer was seen among the patients with CHH (standardized incidence ratio 6.9, 95% confidence interval 2.3 to 16), which was mainly attributable to non-Hodgkin's lymphoma (standardized incidence ratio 90, 95% confidence interval 18 to 264). In addition, a significant excess risk of basal cell carcinoma was seen (standardized incidence ratio 35, 95% confidence interval 7.2 to 102). The cancer incidence among the siblings or the parents did not differ from the average cancer incidence in the Finnish population. CONCLUSIONS: This study confirms an increased risk of cancer, especially non-Hodgkin's lymphoma, probably attributable to defective immunity, among patients with CHH.     

Anaemia and macrocytosis—unrecognized features in cartilage-hair hypoplasia

Cartilage-hair hypoplasia is an autosomal recessive osteo-chondrodysplasia which results in short stature, sparse hair and impaired cell-mediated immunity. In a study of 88 Finnish patients we found episodes of anaemia and/or macrocytosis during childhood in 86% of the patients. The reticulocyte index was always low in relation to anaemia. Bone marrow examination revealed decreased erythropoiesis in six of eight anaemic patients studied. Anaemia was most prevalent and severe during infancy. Spontaneous recovery occurred before adulthood in all patients except in three infants with fatal hypoplastic anaemia. Sixty-two percent of the patients had had lymphopenia and 24% neutropenia. Presence of anaemia significantly correlated to severity of immunodeficiency and growth failure and to presence of neutropenia. Disordered erythrogenesis is an integral feature of cartilage-hair hypoplasia and may, together with growth failure and immunodeficiency, reflect a generalized defect in cellular proliferation.     

Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia

Cartilage-hair hypoplasia (CHH), an autosomal recessive chondrodysplasia, results in severe growth failure, sparse hair and impaired cellular immunity. Lymphocyte subpopulations and proliferative responsiveness in mitogen stimulation were analysed in 35 patients of whom 31% had an increased incidence of infections the year prior to the evaluation. Of the patients, 57% had a decreased CD4+ cell count which led to a decreased total count of T-lymphocytes in 52% and a subnormal CD4+/CD8+ cell ratio in 32%. The B-lymphocyte count was usually normal. The natural killer cell count was above reference values in 40% of the patients. The lymphocyte stimulation indices as studied with phytohaemagglutinin , Concanavalin A and pokeweed mitogen were subnormal in 69%, 69% and 83% of the patients, respectively. The numbers of lymphocytes, T-lymphocytes and CD4+ cells, and the pokeweed mitogen stimulation index, but not the other measured parameters, correlated significantly with the proness to infections during the preceding year. However, the correlation was reverse with higher counts in the patients who had had recurring infections. The observed significant correlations may reflect immunological stimuli caused by recurring infections. Conclusion The presently used parameters of cellular immunity poorly predict the clinical outcome of an individual cartilage-hair hypoplasia patient. All patients, irrespective of their in vitro immunological competence, have to be carefully followed because of possibility of serious infections and malignancies. Received: 25 November 1997 / Accepted: 2 March 1998     

Combined immunodeficiency and vaccine-related poliomyelitis in a child with cartilage-hair hypoplasia.

Patients previously described with cartilage-hair hypoplasia, a distinctive form of short-limbed dwarfism, have been found to have deficient cell-mediated immunity with intact antibody-mediated immunity. The patient with cartilage-hair hypoplasia described in the present report is unusual in that she had both deficient antibody-mediated immunity and deficient cell-mediated immunity. In addition, she developed severe, vaccine-related paralytic poliomyelitis. This complication suggests that live viral vaccines should not be administered to children with short-limbed dwarfism until the form of short-limbed dwarfism is established and immunologic evaluation is performed when indicated.     

Deficiencies in humoral immunity

B cell immune deficiencies are characterized by inadequate production of antibodies and/or low levels of one or more classes of immune globulins (IgG, IgA, IgM) or IgG sub-classes. They include: 1) severe deficiencies involving all the immune globulins (Bruton agammaglobulinemia, variable hypogammaglobulinemia); 2) selective deficiencies in immune globulins (IgA deficiency, IgM deficiency, deficiencies in IgG sub-classes, dysgammaglobulinemias); 3) transient infantile hypogammaglobulinemia; 4) B cell immune deficiencies with normal gammaglobulin levels. Symptoms of B cell immune deficiencies are variable but respiratory manifestations are usually more prominent than the other features that include digestive disorders, fungal infections, autoimmune conditions, joint manifestations, and severe bacterial or viral infections (pneumococcus, meningococcus, enterovirus). Management of IgM and IgA deficiencies rests on antimicrobial agents and non-specific measures. The prognosis of the other B cell immune deficiencies has improved dramatically since effective replacement immune globulin therapy has become available; this treatment combined with antimicrobial therapy and chest physiotherapy can usually prevent development of bronchiectases. The main risk is chronic enteroviral neuromeningeal infection.     

Growth hormone treatment in cartilage-hair hypoplasia: effects on growth and the immune system

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by metaphyseal chondrodysplasia with severe growth retardation and impaired immunity. We studied the effects of growth hormone treatment on growth parameters and the immune system in four children with CHH. The effects of growth hormone on growth parameters are the most prominent in patients with the mildest growth retardation. However, the effects are temporary and last only for 1 year. There is no gain in final height. Serum immunoglobulins did not change during growth hormone treatment. We conclude that growth hormone treatment is not beneficial in children with CHH.     

Bone marrow transplantation in cartilage-hair hypoplasia: Correction of the immunodeficiency but not of the chondrodysplasia

Abstract We diagnosed cartilagehair hypoplasia (CHH) in a female child with prenatal-onset short stature, metaphyseal chondrodysplasia, and severe combined immunodeficiency leading to recurrent, severe respiratory tract infections. The patient required several hospital admissions during her 1st year of life and failed to thrive in spite of antimicrobial therapy and hypercaloric nutrition. Bone marrow transplantation (BMT) from an HLA-identical sister was performed at age 16 months after conditioning with busulphan and cyclophosphamide, using 9×10⁸ nucleated bone marrow cells/kg body weight. Graft-versus-host disase prophylaxis consisted of cyclosporine and methotrexate. The post-transplantation period was uneventful. She developed full and sustained chimerism as demonstrated by DNA analysis of granulocytes and mononucleated cells on days 44, 69 and 455 post BMT. Cellular immunity was completely reconstituted at 4 months, humoral immunity at 15 months post BMT. The patient is alive and well 24 months post BMT without medication, but the radiological osseous changes persist, and longitudinal growth remains markedly below the 10th percentile for CHH standards; her height at age 3 years 4 months is 66 cm.Conslusions In this patient with unusually severe CHH, bone-marrow transplantation has fully corected the immune deficiency but has had no influence on the course of the chondrodysplasia.     

Defective in-vitro colony formation of haematopoietic progenitors in patients with cartilage-hair hypoplasia and history of anaemia

Cartilage-hair hypoplasia (CHH) is a metaphyseal chondrodysplasia with short-limbed short stature. The CHH gene has been recently mapped to chromosome 9, and a generalized defect in cellular proliferation has been suggested. Immunological and haematological abnormalities are common findings in CHH. In the present study erythroid, megakaryocyte, and granulocyte-macrophage colony formation in vitro by progenitors from bone marrow and blood was investigated in eight patients with CHH. All patients showed decreased erythroid and megakaryocyte colony formation. Only one patient had a normal granulocyte-macrophage growth, while the others showed decreased numbers of colonies. The defect in colony formation did not correlate with the haemoglobin concentration, platelet count or neutrophil count. The impaired growth was not caused by a decreased number of progenitors as shown by erythroid cultures. The erythroid progenitors were incapable of colony formation in culture conditions sufficient for colony formation by normal progenitors. In a more effectively stimulated culture assay the number of erythroid progenitors was normal or increased.Conclusion The present study shows defective in vitro colony formation in all myeloid lineages in patients with CHH, which is in accordance with the suggestion of a common cell proliferation defect in CHH.