I Med Genet 1995;32:39-43 Syndrome of the month Cartilage-hair hypoplasia 0 Makitie, T Sulisalo, A de la Chapelle, I Kaitila Cartilage-hair hypoplasia (CHH) or McKusick type metaphyseal chondrodysplasia (MIM No 250250)' is a rare autosomal recessive chon- drodysplasia with short limbed short stature, hypoplastic hair, and defective immunity and erythrogenesis.2' The major radiological ab- normalities are confined to the metaphyseal regions of the tubular bones.67 The disease is prevalent among the Old Order Amish in the United States and in the Finnish population.28 While genealogical data confirm autosomal re- cessive inheritance, segregation analysis shows a lack of affected persons among both the Amish and Finnish CHH families; this has been interpreted as a possible example of reduced penetrance.28 The CHH gene was recently as- signed to chromosome 9 by linkage analysis,9 and its localisation refined.'0 This has allowed prenatal diagnosis in four cases. IOA Department of Medical Genetics, Helsinki University Hospital, Haartmaninkatu 2B, SF-00290 Helsinki, Finland O Makitie I Kaitila Children's Hospital, Helsinki University Hospital, 00290 Helsinki, Finland O Makitie Department of Medical Genetics, PO Box 21, 00014 University of Helsinki, Finland T Sulisalo A de la Chapelle I Kaitila Folkhiilsan Institute of Genetics, 00250 Helsinki, Finland T Sulisalo A de la Chapelle Correspondence to: Dr Kaitila. Clinical description GROWTH FAILURE The growth failure has its onset prenatally; the shortness of limbs or stature or both was noticed neonatally in 76% and by the age of year in 98% of 108 Finnish CHH patients." All segments of the limbs are affected. The growth failure is progressive, owing in part to a weak or absent pubertal growth spurt; pubertal maturation is normal. Adult heights range from 103-7 cm to 149-0 cm with medians of 131 1 cm for males and 122 5 cm for females. 1 The growth failure is disproportionate with a long trunk in relation to the short limbs. The more severe the growth failure, the greater the disproportion." Proportionate short stature has been described in some CHH patients."213 Median relative weight is above the normal mean in childhood and is further augmented around puberty; most adult patients are clin- ically obese. The head circumference is close to normal at all ages." OTHER CLINICAL FEATURES The majority of affected persons have sparse, fine, and silky hair; the eyebrows, eyelashes, and body hair are similarly affected. In some patients, however, the hair appears normal. This was observed in 7% of the Finnish CHH patients.' Other clinical features include laxity of lig- aments, limited extension of the elbows, in- creased lumbar lordosis, bowing of the lower limbs, chest deformity (narrow thorax, Har- rison's grooves, prominent sternum, or asym- metry), and mild scoliosis (figs 1 and 2).' IMMUNE DEFICIENCY The defective cellular immunity is char- acterised by mild to moderate lymphopenia, decreased delayed hypersensitivity, and im- paired in vitro responsiveness of lymphocytes to PHA; humoral immunity is usually intact.""" A few patients with normal immunity" 1 or combined immuno- deficiency"7-2 have been reported. Defective cellular immunity results in suscepti- bility to and mortality from infections. The infection problems are most pronounced in early childhood but occasionally persist to adult age. Varicella infection has been fatal in a few cases. In the Finnish series impaired in vitro cellular immunity was observed in 88% of the patients.' Fifty-six percent had been unusually prone to infections. Six patients (6%) had died of primary infections. On the other hand, 44% of the patients had shown no unusual sus- ceptibility to infections even though deficient cellular immunity had been confirmed in half of them.' The incidence of malignancies is increased as observed in the Finnish series' and cases described earlier.22-24 Francomano et al2' re- ported an incidence of 10% of malignancies in 113 Amish CHH patients: lymphoma in three patients, leukaemia in two, skin neoplasms in five, ocular cancer in one, and bile duct car- cinoma in one patient.2' Among the Finnish patients the incidence was six out of 108 patients (6%): skin neoplasms in three patients, lymphoma in one, lymphosarcoma in one, and testicular tumour in one patient.' ANAEMIA Deficient erythrocyte production presents usu- ally as mild macrocytic anaemia in early child- hood with spontaneous recovery before adulthood.26 Occasionally, however, the patients have severe, even fatal, congenital hy- poplastic anaemia.4 132'2325-27 Sixty-seven out of 85 Finnish patients (79%) had been anaemic during childhood; in 14 patients (16%) the anaemia had been severe (lowest haemoglobin value 30-75 g/l) with a fatal course in six patients.5 39 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jm g .b m j.co m / J M e d G e n e t: first p u b lish e d a s 1 0 .1 1 3 6 /jm g .3 2 .1 .3 9 o n 1 Ja n u a ry 1 9 9 5 . D o w n lo a d e d fro m http://jmg.bmj.com/ Makitie, Sulisalo, de la Chapelle, Kaitila .X..X...r X~~.. 4 ..... i i! @ :':..A'......e...tWW;5Nfijff ; gfiff;fffffffg;; j2gffff ; gaffgfff ff;~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.......... Figure I Six CHH patients, front view. Age and absolute and relative values of height (from left to right): (1) 3 6 years, 74 5cm (-68 SD); (2) 35 years, 84-3cm (-41 SD); (3) 55 years, 94 8cm (-41 SD) (4) 105 years, 113 2cm (-4-7SD); (5) 15-2years, 123-9cm (-6 1 SD); (6) 28-7years, 134-2cm (-5-8SD). INTESTINAL MANIFESTATIONS There have been several descriptions of CHH patients with congenital megacolon (Hirsch- sprung's disease) 2416212228-31 The Finnish series included eight patients (7%) with con- genital megacolon.5 These cases clearly indicate increased prevalence of Hirschsprung's disease among CHH patients. Intestinal malabsorption was suspected in six Amish patients who had diarrhoea and failure to thrive in the first two years of life.2 However, primary malabsorption was not observed in any of the 108 Finnish CHH patients; instead, gastrointestinal infection was confirmed in two patients with symptoms suggesting mal- absorption.5 These and other reported cases3233 suggest that primary malabsorption is only ex- ceptionally associated with CHH; mimicking symptoms may reflect an underlying gastro- intestinal infection. ORTHOPAEDIC PROBLEMS Orthopaedic problems in CHH are rare com- pared with many other chondrodysplasias. Lig- amentous laxity and increased lumbar lordosis may cause arthralgic pains in the knees, ankles, or lumbar region of the spine. Bow legs may necessitate corrective osteotomy (in 14% of the Finnish patients).' Radiographic features The tubular bones are short for age and their metaphyseal ends are flared, scalloped, and irregularly sclerotic, often with cystic areas (fig 3); the epiphyses are less affected.67 The meta- physeal changes are most pronounced in the knees and ankles; the hips are only mildly affected (fig 4). The metaphyseal irregularities disappear after the closure of the epiphyseal plates but the ends remain somewhat flared and angulated. The spine shows only minor abnormalities: the vertebral bodies are usually normal and caudal widening of the inter- pediculate distances, though less obvious than normal, is present in most patients (fig 5). Lumbar lordosis is increased and further ac- 'U.K~~~~~~~1 ME E,1|W ,| AF_Se.tlM |--. F I _ _ 1_F l:NNEW liSS|C~~~~~~~-.MmWg ~aal_;:lm Figure 2 Six CHH patients, side view. Same patients as in fig 1. Note the variation in the degree of disproportion, hair hypoplasia, lumbar lordosis, and chest deformity. 40 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jm g .b m j.co m / J M e d G e n e t: first p u b lish e d a s 1 0 .1 1 3 6 /jm g .3 2 .1 .3 9 o n 1 Ja n u a ry 1 9 9 5 . D o w n lo a d e d fro m http://jmg.bmj.com/ Cartilage-hair hypoplasia Figure 3 Radiograph of the legs of a 9 year old boy. The metaphyseal ends are flared and irregularly sclerotic. Note the excessive distal length of the fibula. Figure 4 Radiograph of the hips of a 9 year old boy (same patient as in fig 3) showing only mild metaphyseal involvement in the proximal femora. Figure 5 Constant interpediculate distances of 17mm at the levels offirst, third, and fifth lumbar vertebrae. The moderate lumbar lordosis (520) is accentuated by a horizontally tilted sacrum (male, 9 5 years). centuated by a horizontally tilted sacrum (fig 5).7 Differential diagnosis Most of the 150 different osteochondro- dysplasias result in disproportionate short stat- ure and progressive problems in the joints and spine. The clinical features of CHH resemble those of hypochondroplasia (MIM 14600)1 which, however, is a dominantly inherited con- dition and does not present with abnormal hair. It is easily differentiated from CHH by normal metaphyses in childhood skeletal radiographs. Murk Jansen (MIM 156400) and Schmid (MIM 156500) metaphyseal dysplasias are dominantly inherited conditions and result in severe growth failure but patients have normal immunity and erythrogenesis; these are easily distinguished from CHH. Recently, a type X collagen mutation was reported as the cause of Schmid chondrodysplasia.34 Shwachman-Bod- ian syndrome (MIM 260400), an autosomal recessive condition with metaphyseal in- volvement, is associated with pancreatic in- sufficiency, malabsorption, and leucopenia; the mild skeletal changes are most evident in the proximal femora. Epidemiology CHH was originally described among the Old Order Amish, a religious isolate in the United States.2 At least 113 Amish CHH patients have been recognised25; the incidence is estimated at 1-2: 1000 corresponding to a carrier fre- quency of 1:10.2 Another accumulation of the disease has been observed among Finns with 120 patients in a population of 5 million; the incidence is estimated at 1:23 000 live births and the carrier frequency at 1 :76.8 The number of diagnosed patients among other populations is low: 13 patients have been reported among the French, eight among the Dutch, seven among the British, and sporadic cases among the Germans, Danes, Algerians, Italians, Pol- ish, Spanish, and Mexicans.35 Whether this is because of underdiagnosis, under-reporting, or low incidence cannot be determined with cer- tainty. Mapping of the gene for CHH by linkage and linkage disequilibrium analysis Assignment of the CHH gene to the proximal part of 9p was accomplished by a random search for linkage in 14 Finnish families.9 Sub- sequently, linkage to the same locus was shown in a large series of Amish families.'0 No signs of heterogeneity within or between the two populations were detected. As there were no recombinations within the highly polymorphic marker D9S163 (lod score 26-30 at 0=0) CHH could be placed in the vicinity ofD9S 163 in the 4 cM interval between markers D9S165 and D9S50. As both the Finnish and Amish populations had few found- ers and have remained highly isolated, it could be assumed that the number of ancestral mut- ations would be small, possibly with a single 41 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jm g .b m j.co m / J M e d G e n e t: first p u b lish e d a s 1 0 .1 1 3 6 /jm g .3 2 .1 .3 9 o n 1 Ja n u a ry 1 9 9 5 . D o w n lo a d e d fro m http://jmg.bmj.com/ Mdkitie, Sulisalo, de la Chapelle, Kaitila mutation accounting for the majority of the patients in each population. Haplotype analyses and linkage disequilibrium studies confirmed this assumption.'0 Moreover, the strength of linkage disequilibrium was used to assess the distance between D9S163 and CHH by a re- cently developed method.36-3' The current best estimate of this distance is 0-3 cM.39 Genetics and penetrance Genetic studies among Amish and Finnish fam- ilies have confirmed the recessive mode of in- heritance in CHH.28 However, segregation analyses showed a slightly lower number of affected members than expected according to the recessive hypothesis. This has been ex- plained by reduced penetrance or by the loss of affected children in utero or in infancy.2835 The mapping of CHH and availability of closely linked polymorphic markers provide a tool to examine the question of penetrance. If reduced penetrance were responsible for the unexpectedly low proportion of affected chil- dren in CHH sibships, healthy persons with haplotypes identical to their affected sibs should be found. Such a phenomenon was looked for in a total of 66 unaffected sibs but was not found.910 This finding is indeed credible as reduced penetrance appears to be very rare in recessively inherited disorders. Several other mechanisms might account for the observed under-representation of affected children,40 which is more pronounced in the Amish2 than in the Finnish series.8 The haplotype analyses done in unaffected sibs appear to exclude not only reduced penetrance, but also genetic heterogeneity.910 Remaining explanations are uniparental disomy, monosomy owing to de- letion, biased ascertainment of families, early lethality in a fraction of homozygotes, and gam- etic selection. Prenatal diagnosis As CHH may in some cases be severe or even fatal, some families with an affected child have requested prenatal testing for CHH. The pre- cise mapping of the CHH gene with respect to several highly polymorphic DNA markers provides an excellent opportunity for accurate predictive testing based on the segregation of those markers in families with a previous history of CHH. Four prenatal determinations have so far been done; in three cases the fetus was predicted to be unaffected, and in one case an affected fetus was predicted.l"A In all cases the outcome was as predicted. Hypotheses regarding the pathogenesis The pathogenesis of the disorder remains un- known. However, since previous studies have established defective cellular proliferation of T and B lymphocytes and fibroblasts,4 and defective erythrogenesis,26 it is suggested that the clinical manifestations (growth failure, sparse hair, recurrent infections, anaemia, Hirschsprung's disease) in CHH may result from a generalised defect of cellular pro- liferation. It is intriguing to note that a gene causing isolated Hirschsprung's disease located on chromosome 10 has recently been cloned.4 42 It follows that one of the pleiotropic effects of the CHH gene, Hirschsprung's dis- ease, arises either by a different mechanism from that in the isolated form of the disease, or by the interaction of the two genes. Additional studies are needed to elucidate further the mo- lecular mechanisms in the pathogenesis of CHH. The solution will probably have to await the cloning and characterisation of the gene itself. These studies have been supported by the Academy of Finland, the Sigrid Juselius Foundation, the March of Dimes Birth Defects Foundation, the Human Growth Foundation, the Pai- vikki and Sakari Sohlberg Foundation, the Finnish Medical Foundation, the University of Helsinki, and the Foundation for Paediatric Research. 1 McKusick VA. Mendelian inheritance in nman. Baltimore: Johns Hopkins University Press, 1991. 2 McKusick VA, Eldrige R, Hostetler JA, Ruangwit U, Ege- land JA. Dwarfism in the Amish. II. Cartilage-hair hy- poplasia. Bull johns Hopkins Hosp 1965;116:285-326. 3 Virolainen M, Savilahti E, Kaitila I, Perheentupa J. Cellular and humoral immunity in cartilage-hair hypoplasia. Pediatr Res 1978;12:961-6. 4 Polmar SH, Pierce GF. Cartilage hair hypoplasia: im- munological aspects and their clinical implications. Clin Immunol Immunopathol 1986;40:87-93. 5 Makitie 0, Kaitila I. Cartilage-hair hypoplasia clinical manifestations in 108 Finnish patients. 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