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J. W. Spranger M.D Postgrad Med J: first published as 10.1136/pgmj.53.622.480 on 1 August 1977. Downloaded from Postgraduate Medical Journal (August 1977) 53, 480-486. Metaphyseal chondrodysplasia J. W. SPRANGER M.D. Children's Hospital, Johannes Gutenberg University, Mainz Summary similar and might also be classified as metaphyseal Any review of the metaphyseal chondrodysplasias is disorders. complicated by their variety and mainly unknown pathogenesis. The more familiar types display con- (1) Commoner forms ofmetaphyseal chondrodysplasias siderable clinical and radiological diversity: even (Table 1) more so the rarer disorders which still require complete Hypophosphatasia definition, but differences in their mode of inheritance This is the only metaphyseal chondrodysplasia of make diagnostic precision mandatory. These dys- known pathogenesis, being caused by a deficiency of plasias present in infancy or in childhood, when the alkaline phosphatase, an enzyme which, in a patient, usually dwarfed, may be proportionate, so simplistic description, behaves as a pyrophosphatase, that some forms may be confused with rickets or other destroying pyrophosphate which itself inhibits lesions. Mental retardation is unusual, but the skin, tissue mineralization. In the absence or deficiency hair, nails and facies provide valuable diagnostic of the enzyme, pyrophosphate accumulates and features. interferes with normal tissue calcification. This by copyright. Radiological abnormalities mainly affect the phosphatase deficiency is variable in degree. metaphyses of the shortened limb bones, less often the skull, vertebrae, pelvis, ribs and. extremities, and sometimes their distribution may indicate the specific TABLE 1. The metaphyseal chondrodysplasias type of dysplasia. In a further complex group multiple 1. Well defined forms systems are involved, notably the pancreas, intestine Hypophosphatasia and lympho-reticular, causing malabsorption and Jansen type haematological or immunological disorders. Schmid type Vaandrager-Pefia type 2. Rarer forms (not well defined) http://pmj.bmj.com/ Rimoin & McAlister (1971) THE various metaphyseal chondrodysplasias are Van Creveld et al. (1971) intrinsic disorders of skeletal development, charac- Wiedemann & Spranger (1970) terized by abnormal radiographic appearances and, Kozlowski (1964) in most cases, by a disturbed histological structure Rosenblum & Smith (1965) of the metaphyses, the cause of which is unknown. Spahr & Spahr-Hartmann (1961) 3. With multi-system involvement The epiphyses and the vertebrae are only minimally Metaphyseal chondrodysplasia with malabsorption and affected. Their intrinsic nature implies that these neutropenia (Schwachman-Diamond syndrome) conditions are due to a defective growth potential McKusick type (cartilage hair hypoplasia) on October 2, 2021 by guest. Protected of cartilage and bone. They must be carefully Adenosine deaminase deficiency Metaphyseal chondrodysplasia with humoral immuno- distinguished from acquired secondary metaphyseal deficiency lesions such as those due to rickets, scurvy, trauma, etc., in which the growth potential of cartilage and bone is initially quite normal. These secondary metaphyseal changes are not included in the group Severe forms of hypophosphatasia are incompat- under review and, by convention, achondroplasia ible with life, perinatal death occurring in days, and hypochondroplasia are excluded, although both less often months, from respiratory failure. Less are radiologically and histologically somewhat severely affected patients may survive for varying periods, but hypercalcaemia gradually develops after the first weeks of life with failure to Correspondence: Professor J. W. Spranger, Children's thrive, Hospital, Johannes Gutenberg University, 6500 Mainz, episodic bouts of constipation, fever and nephro- Germany. calcinosis. If the infant survives the first year, Postgrad Med J: first published as 10.1136/pgmj.53.622.480 on 1 August 1977. Downloaded from Metaphyseal chondrodysplasia 481 spontaneous improvement takes place. Cranio- stenosis may occur with premature shedding of teeth and these may be the only clinical symptoms in mild cases. Microscopically, the only changes noted are the tongues of unmineralized cartilage or osteoid extending into the shafts of the long bones. It is important to note that the congenital lethal and the milder adult tarda forms have been observed in a single family and are hence expressions of a single gene mutation (Macpherson, Kroeker and Houston, 1972). The range of genetic variability is quite remarkable for an autosomal recessive con- dition, simulating that reported by Siggers (1977) for cartilage hair hypoplasia. Both liver and bone alkaline phosphatase are lowered, whilst the intestinal alkaline phosphatase may be either normal or elevated. Clinically normal heterozygotes can be identified by a slightly reduced serum alkaline phosphatase and may also have increased urinary excretion ofphosphoethanolamine. It is important to note that the clinical and radio- graphic features of hypophosphatasia have been observed in patients with a normal level of blood alkaline phosphatase. This has been described as 'pseudo-hypophosphatasia', but there is at least one by copyright. family described in which the various features of FIG. 1. Metaphyseal chondrodysplasia, Jansen type. The hypophosphatasia occurred with normal or low tubular bones are severely shortened with striking meta- levels of serum alkaline phosphatase (Mehes et al., physeal irregularities, normal appearing epiphyses and very wide physes. There are no major differential 1972). Thus, so-called 'pseudo-hypophosphatasia' diagnostic problems. may not be a nosological entity. Metaphyseal chondrodysplasia-Jansen type This is well known and is inherited as an auto- somal dominant. The original patient reported by considered possible. The Schmid type is commoner Jansen (1934) has been re-examined, and at 44 years than the Jansen type, and at least fifty-one cases of age is stated to be in a remarkably good state of have been reported since the original paper by http://pmj.bmj.com/ health and running a drug store (De Haas, De Boer Schmid in 1949. In the Mainz Bone Dysplasia and Griffioen, 1969). Register there are nine cases of the Schmid type to With advancing age the metaphyseal abnormalities only three of the Jansen type. tend to disappear with fusion of the epiphyses, but This is a comparatively benign condition without the bones remain short and deformed (Fig. 1). The major complications, with a normal life span and an early skull changes consist of a peculiar reticular adult height of 130-160 cm. Its main clinical signi- pattern of the calvaria. Later there is a severe ficance is that it may be confused with, and some- degree of sclerosis with hyperostosis of the skull times treated as vitamin D-resistant rickets. on October 2, 2021 by guest. Protected base, but the mandible may be small and there may The most striking radiographic abnormalities be persistent metaphyseal irregularities. One case are well marked metaphyseal changes in the proximal reported by Ozonoff (1969) was described with these rather than the distal femora (Fig. 2)-quite the changes but did not have the Jansen type of meta- opposite of the distribution found in cartilage hair physeal chondrodysplasia, so that the early meta- hypoplasia (Fig. 3). Furthermore, in the Schmid physeal appearances should not be regarded as type there is much less coxa vara and osteotomies entirely diagnostic. are inadvisable as the spontaneous prognosis is very favourable. Metaphyseal chondrodysplasia-Schmid type As mentioned above, the radiological changes of This well-defined disorder is also transmitted as an metaphyseal chondrodysplasia may be closely autosomal dominant, although in some patients simulated by rickets (Fig. 4) and to a lesser degree by who are children of clinically and radiologically scurvy (Fig. 5) or by traumatic damage (Fig. 6) normal parents, a recessive inheritance must be including the so-called 'battered child'. Postgrad Med J: first published as 10.1136/pgmj.53.622.480 on 1 August 1977. Downloaded from 482 J. W. Spranger W\::i. ',.g; d,}''f .'^ 1S~~~~~~~~~1~ i.w.' _-Ek f;'.;.>.' .' _Bv A 4/ .?. J. .:: FIG. 2. Metaphyseal chondrodysplasia, Schmid type. The by copyright. metaphyscal changes are as severe in the proximal as in I K the distal femora. The femoral necks are in varus posi- tion. Both fcaturcs help to differentiate the Schmid from the McKusick type (cartilage hair hypoplasia) of meta- physeal chondrodysplasias. The changes in this patient FIG. 3. Metaphyseal chondrodysplasia, McKusick type are rather marked; they maybe milder in other instances. (cartilage hair hypoplasia). The metaphyseal changes are more pronounced in the distal than in the proximal femora. J Metaphyseal chondrodysplasia-Vaandrager type This disorder is fairly well defined, although very Vaandrager type with a normal spine and also an rare, and first described by Vaandrager (1960) who autosomal recessive or hump-backed variant with http://pmj.bmj.com/ reported monozygous twins with peculiar meta- distinct spinal changes. physeal changes. Radiographically, there are longi- tudinal radiolucent areas extending deeply into the (2) Metaphyseal chondrodysplasia-other rarer types diaphyses, the ends of the more severely afflicted (Table 1) bones being expanded. The spine is normal, and the These appear to be nosological entities, but as yet severity of the long bone changes is again variable. not adequately described.
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