Hypophosphatasia

Clin. RadioL (1966) 17, 368-376

H Y P O P H O S P H A T A S I A

WILSON JAMES and BRIAN MOULE

From the Southern General Hospital, Glasgow

Hypophosphatasia is a condition characterised by bony changes resembling rickets. It is thought to be a basic enzymatic defect which is probably transmitted by an autosomal recessive gene. The radiological appearances in 5 patients are described and the clinical findings briefly discussed. The diagnostic triad which emerges, consists of clinical and radiological changes resembling severe rickets, a low serum alkaline phosphatase level and phosphoethanolamine in the urine.

HYPOPHOSPHATASIA was defined by Rathbun (1948) as a condition characterised by skeletal changes which resemble severe rickets histologically and to a lesser extent clinically and radiologically, and by low serum and tissue alkaline phosphatase levels. His patient was a male infant aged 3 weeks who had lost weight steadily since birth, became cyanosed on crying, and exhibited coarse, jerky movements of the arms and legs. There were long bone deformities; the ribs showed a 'rickety rosary' and the globular head felt 'like a balloon filled with water'. Radiographs showed marked ossification deficiency especially at the metaphyses of the long bones and in the skull vault. Rathbun recognised the significance of the decreased alkaline phosphatase levels; however, from a study of the literature it is evident that patients had been previously described, with labels such as 'atypical renal rickets' or 'hyperparathyroidism'.

Chown (1936) described 2 sisters, dying at 3 and at 6 months, similar to Rathbun's case, whom he considered to have renal rickets. The clinical and radiological findings of his second patient indicate that she had hypophosphatasia. The clinical features in case 1 were also typical; the radiographs were less so. No figures for alkaline phosphatase levels were given. The parents of these children were first cousins. Anspach and Clifton (1939) described a female infant who at 3 months suffered from anorexia, failure to gain weight, polyuria, tender limbs and joint swellings, and a bulging anterior fontanelle. At 9 months, a bony ridge had formed along the sagittal suture and radiographs showed rachitic changes in the long bones. The serum calcium was 16.2 m g ~ and serum phosphorus 2.3 m g ~ . At 2 years vision was impaired and skull radiographs showed the appearances of craniostenosis. At 4 years the child had become blind. Alkaline phosphatase levels were reported at 2 years, 2 years and 3 months and

4 years as 12, 2 and 1.5 Bodansky units respectively. They concluded that the child had hyperparathyroidism and apparently did not consider the low alkaline phosphatase levels as being significant. Macey (1940) reported a man of 36 who presented with 'pseudo' fractures of numerous bones, and a history of a rachitic condition in infancy. There was no serum phosphatase activity on 3 estimations. Less marked changes were found in his brother, with a serum phosphatase activity of under 1 unit. Macey appears to have been the first to comment on these low phosphatase levels.

Since Rathbun's report, others have published findings in similar cases and a well defined clinical entity has been established. The reported cases indicate that the condition is probably hereditary and that it is transmitted by an autosomal recessive gene because (I) There is a strong familial tendency. (Clausen 1952, e.g. reports 3 cases in one family.) (2) The sex incidence is approximately equal. (Of 50 cases collected from the literature 23 were male and 27 female.) (3) Low alkaline phosphatase levels are often found in parents and sibs without clinical evidence of disease, the carrier state being represented by adult persons with serum levels below 2 Bodansky units. (Rathbun et al., 1961.) Silverman (1962), however describes a family with documented hypophosphatasia in the father and 2 sons, suggesting that in this instance the inheritance is due to an autosomal dominant gene substitution. A further abnormality, an abnormal amino acid, phosphoethanolamine, in the urine of patients with hypophosphatasia, was demonstrated independently by Fraser et al. (1955) and by McCance et al. (1955). The whole subject and in particular the radiological aspects, has been exhaustively reviewed by Currarino et al. (1957).

The following 5 patients illustrate the clinical and radiological findings in 2 severely affected newborns, 2 less severely affected infants and one

368

H Y P O P H O S P H A T A S I A 369

chi ld . Cases 3 a n d 4 h a v e b e e n r e p o r t e d p r e v i o u s l y b y M a c D o n a l d a n d S h a n k s (1957).

CASE REPORTS

Case 1. R.B. Male infant, delivered by Caesarian section due to distress. Birth weight, 5 lb. 11 oz., length 19½ inches, head circumference 12½ inches. On 3rd day of life, started to have convulsive attacks of generalised stiffness lasting a few seconds. Settled after a few days and discharged 3 weeks after birth; head circumference now 13~ inches with some separation of sutures feeling rather soft posteriorly. Re- admitted at 2 months on account of failure to thrive and intermittent vomiting. Said to be a quiet baby who cried rarely but became 'jumpy' when picked up; he tended to be constipated and his head seemed an abnormal shape to the parents. Examination showed a 'flabby', poorly nourished baby; his skull circumference was 14½ inches and the anterior fontanelle bulged. There was palpable thickening of the ends of the long bones, especially the wrists.

Skeletal Survey: the diaphysis only of each long bone was adequately ossified, so that bones appeared short and thick, with a coarse trabecular pattern and unusually large soft tissue shadows between bone ends. Metaphyses showed markedly deficient ossification, with irregular expansion, fraying and extension into shaft of long processes of unossified tissue (Figs. 1 and 2). Similar changes present in ribs. Iliac bones: coarse trabeculation and poor ossification, with rather scalloped outlines. Pubic bones: poorly ossified. There was deficient ossification of the bones of the skull vault, with abnormally large 'space' between ossified

portions of parietal and frontal bones (Fig. 10). Spine: relatively normal. Diagnosis---either one of the bone dystrophies or hypophosphatasia, which was confirmed by serum alkaline phosphatase level less than 1 King Armstrong unit (3 separate occasions). Serum calcium: 11.8 mg%, serum phosphorus: 7'0 m g ~ . Diazo coupling method for detecting alkaline phosphatase in white cells: complete absence of enzyme in patient's neutrophils. Urine contained phosphoethanolamine.

In view of reports of beneficial effects of steroid therapy (Fraser and Laidlaw, 1956; Rathbun, 1959; Kretchmer, et aL, 1958) prednisolone, 5 rag. daily started but without clinical or radiological improvement; there was no weight gain; occasional attacks of vomiting and convulsions continued. Low grade pyrexia was noted. Chest deformity and respiratory difficulty increased; despite antibiotic therapy bronchopneumonia developed and patient died at 4 months. Serum alkaline phosphatase estimations in the mother and father; 6.0 and 9.0 King Armstrong units, respectively.

Case 2. S.H. Female infant, normal delivery. Birth weight, 5 lb. 7 oz., length 15½ inches, head circumference 13 inches. Obviously abnormal at birth; limbs short and deformed; dimples over the tibiae with skin apparently adherent to underlying bone (Fig. 3). Skull: vault felt soft and 'boneless'. Midwife who had carried out vaginal examination in 3rd stage of labour, noted that no sutures were definable and that head felt 'soft and squashy' at birth. Infant failed to thrive, fed poorly, vomited frequently; there were occasional convulsions and progressive dyspnoea

F~o. 1 Fio. 2 FIG. 1--Case I. Left upper limb. Deficient ossification with metaphyseal infractions, especially marked at the lower radius and ulna. FI6. 2--Case I. Lower limbs. Grossly irregular metaphyseal ossification. Note the 'cystic' appearance of the proximal tibial

metaphysis on the right side.

370 C L I N I C A L R A D I O L O G Y

FIG. 3 FIG. 4

FIG. 3--Case 2. Note the skin dimples over the tibiae, corresponding to pre-natal fractures. FIG. 4---Case 2. Right upper limb. Incomplete ossification with pre-natal fractures of radius

and ulna. Narrow ribs with cupping of the anterior ends.

F~G. 6

HYPOPHOSPHATASIA 371

?,

Fr~. 7 FIG. 7 Case 5. Knees. Irregular ossification of all metaphyses with translucent areas presumably due to unossified osteoid. The

epiphyses are virtually normal.

due to thoracic deformity. Bronchopneumonia developed and patient died at 3 months.

Radiological findings resembled those of Case 1 (Figs. 4 and 11). Dr. W. Bourne reported 'The appearances are consistent with hypophosphatasia. If the serological findings fail to confirm this, they may be due to an unusual osteo- chondrodystrophy'. Diagnosis confirmed by serum alkaline phosphatase level of 1"6 King Armstrong units and phosphoethanolamine in urine. Serum calcium: 15-4 mg ~ , serum phosphorus: 4-8 nag ~.

Case 3. F.O'D. Male infant. Low forceps delivery, cyanosed at birth, continuing attacks of cyanosis and vomiting subsequently. There appeared to be no bone in vault of skull; skeletal survey: changes suggestive of hypophosphatasia, most marked in upper limbs and skull (Figs. 5 and 12). Alkaline phosphatase less than 1-5 King Armstrong units (3 occasions). Infant died at 15 days.

Case 4. G.MeK. Male infant. Normal delivery, healthy at birth. After first month, vomited intermittently and failed to thrive. Admitted at 6 months with acute diarrhoea and vomiting; died the following day. Examination showed widespread bony deformities; skull sutures widely separated (Figs. 6 and 13). Child was last of five siblings born to apparently healthy parents; only one survived and appeared to be normal. One died almost immediately after birth, diagnosis of achondroplasia made elsewhere. Alkaline phosphatase not estimated. Histological and radiological appearances make diagnosis of hypophosphatasia likely.

Case 5. R.B. Male aged 5 years. Brought to the Orthopaedic Clinic with 'fiat feet' and difficulty in running. Previous history: Spontaneous delivery. Intermittent vomiting for first 3 months with weight loss. Cut first tooth at one year; between 18 months and 2 years, shed 3 deciduous teeth. Remaining teeth showed marked caries; lost shortly afterwards. Began to walk at one year; parents thought feet were abnormal and he walked with feet ~urned

out. At 3 years, developed photophobia for strong light, which gradually decreased over the years. Headaches were troublesome. His intelligence was normal.

Examination showed flat feet, bilateral genu valgum deformity, swelling of ankles and flaring of lower ribs; the head seemed small. Skeletal survey: irregular calcification of all metaphyses of long bones, expansion of the anterior ends of the ribs and craniostenosis (Figs. 7, 8 and 14). No deciduous teeth present. Diagnosis, hypophosphatasia of childhood type, confirmed by serum alkaline phosphatase levels of 5-4 and 6.6 King Armstrong units. Trace of phosphoethanolamine in urine. Serum alkaline phosphatase estimations in the family showed :--mother 3'5 K.A. units, father 4.0 K.A. units, sister 10.6 K.A. units. All were clinically normal; no phosphoethanolamine was found in urine. There was a history of flat foot in the mother's family.

C L I N I C A L F E A L U R E S

Fraser (1957) and Currarino et al. (1957) divided r e p o r t e d cases in to 3 b r o a d genera l g roup ings , a c c o r d i n g to t he sever i ty and age at onse t : the i r c lass i f icat ions were r o u g h l y similar. As m o r e n e w pat ien ts a re r epo r t ed , these classes t e n d to over lap , bu t t hey still f o r m a c o n v e n i e n t m e t h o d o f descr i - b ing the va r i ous signs a n d s y m p t o m s a n d m a y be o f s o m e p r o g n o s t i c significance. I n genera l , t he ear l ier t he age at p r e sen t a t i on the m o r e severe a re the p resen t ing fea tures . Thus the n e w b o r n cases t e n d to be severe ly affected, the nex t g r o u p inc lude the less severe ly affected infants a n d c h i l d h o o d cases, a n d the last g r o u p con ta ins those few cases so far seen in adu l t life.


1. Neonates and Severely Affected Infants.--From studying these cases, it is evident that the pathological features were present in utero and indeed there are at least 3 cases recorded where pre-natal films show bony changes; Currarino et al., 1957; Fraser, 1957; Rosenthal et al., 1960. In our case No. 1 the changes were present on neonatal chest films. Often the skeletal deformities-- bowing, skin dimples, fractures, rickety rosary, metaphyseal swelling and the 'vault like a balloon' or a bulging anterior fontanelle are the presenting features in this group. Common symptoms are failure to thrive, vomiting, irritability, jerky movements, convulsions and intermittent pyrexia without evidence of infection. Less specific features include cyanosis, refusal of feeds, constipation and episodes of loud cries. The convulsive seizures appear to be fairly similar in the various patients. Rosenthal et al. (1960) described an abnormal E.E.G. pattern of hypsarrythmia in their patient.

2. Less Severely Affected Infants.--The features are essentially similar except that they are later in onset and the prognosis is apparently better; symptoms come on gradually after a pre-natal period of relatively good health. Anorexia, vomiting, constipation and failure to thrive are the most frequent, often associated with pyrexia, irritability and hypotonia, convulsions, cyanosis and episodes of loud cries.

The s less bal of the cJ

fontanelle. A rickety rosary and swellings at the wrists and ankles are usually evident. The survivors tend to improve symptomatically, but deformities persist and often become worse. Walking is late and deformities such as genu valgum develop; stature tends to be short. An interesting feature of this group is the marked tendency toward the development of craniostenosis, with the formation of a sagittal ridge and a bony prominence at the position of the anterior fontanelle.

3. Cases of Late Onset.--This group presents mainly with features such as delayed onset of walking, poor gait, genu valgum, pains in the arms and legs and short stature. A previous history of a rachitic condition may be elicited and bony sequelae such as a rickety rosary, kyphoscoliosis and enlarged bone ends may still be present. Cranio- stenosis is not common but a distinctive feature is the prevalence of dental abnormalities such as caries and premature shedding of the deciduous teeth.

Several cases diagnosed in older children and adult life belong to this group, since the history goes back to childhood. Late features which may develop include osteoporosis, multiple pseudo fractures and rachitic deformities with lateral bowing of tibiae. It is therefore essential that bone

FIG. 8 FIG. 9

FIG. 8--Case 5. Ankles. Showing similar appearances to those in Fig. 7. Tilting of the epiphyseal plate. FIG. 9--Ankles. Late rickets in a 14-year-old Pakistani girl. For comparison with Fig. 8.

, H Y P O P H O S P H A T A S I A 373

dystrophies which do not conform to typical patterns should be investigated from the point of view of hypophosphatasia.

RADIOLOGICAL FEATURES The Long Bones.--These show the most obvious

changes. As in rickets the pathology is most evident at metaphyses where growth is most rapid, namely the wrists, knees, hips and proximal humeri. Defective, irregular ossification of the metaphysis is the most diagnostic feature of the disease. The provisional zone of calcification is nearly always absent and there is irregular widening of the epiphyseal plate (Figs. 1 and 2). These changes are seen in rickets, but the distinguishing feature in hypophosphatasia is the grossly irregular ossification which gives a 'frayed' or 'tufted' appearance. In rickets, the decalcification is usually regular and may give a 'ground glass' effect to the affected metaphysis. In foetal rickets the appearances are probably identical or very similar to hypophosphatasia (Maxwell and Turnbull, 1930). Metaphyseal cupping does occur in hypophosphatasia but this is due to 'excavation' of the diaphysis by unossified osteoid and the 'cup' is deeper than in rickets, where the effect is largely due to splaying of the extreme end of the metaphysis from muscle pull and weight bearing. A 'cystic' appearance may be simulated, particularly in the lateral projection of the femora and in the proximal fibula (Fig. 2). This may lead to suspicion of enchondroma when only one bone is examined. Marginal metaphyseal infractions are common, often producing small 'spurs' (Fig. 1). Where growth is less rapid, there is a more regular edge to the metaphysis, frequently showing as a zone of decreased density, with a proximal area of irregular sclerosis (lower ends of femora, Fig. 2).

Because of decalcification of a large part of the metaphysis, frequently only the diaphysis or part of the diaphysis is visualised on the radiograph. The long bones therefore appear very short with large 'gaps' between the bone ends (Figs. 2 and 4). In a severely affected infant, there may be hardly any ossified bone and it is such a case that is likely to be mistaken for an osseous dystrophy, such as osteogenesis imperfecta, since the characteristic metaphyseal changes are obscured. Irregular mineralisation also occurs in the diaphysis, producing coarse trabeculation with areas of decreased density and patchy sclerosis. Periosteal new bone formation is frequent and cortical thickening occurs along the concave aspects of long bones with bowing deformities. Congenital bowing deformities and congenital fractures of the shafts are frequent,

non-specific and identical with those thought to be due to faulty foetal posture (Caffey, 1961), and are often associated with skin dimples (Figs. 5 and 7).

The epiphyses are small and appear late in severe cases. They too are irregularly calcified, with an abnormal trabecular architecture and may have a 'ring' appearance (Fig. 2). The epiphyseal plates are often tilted: with weight bearing, deformities arise such as genu valgum. This is particularly evident in older patients where the epiphyseal plate and provisional zone of calcification have reformed, with irregular wavy margins (Figs. 7 and 8). Similar changes are seen in the ribs, particularly anteriorly; the shafts tend to be narrow and poorly formed (Fig. 4).

The Spine.--No consistent changes are reported in the spine, apart from generalised loss of bone density and occasionally 'fluffy' ill defined margins. Poor definition of the bone edges and sometimes a scalloped appearance is a feature of the flat bones, particularly the ilium. Caffey (1961) reports a case with universal vertebra plana which he thinks may have been due to hypophosphatasia.

The Skull.--The pathological changes found in the skull in this condition are probably unique. Large areas of uncalcified osteoid are found in the membranous bones in the regions adjoining the sutures and to a lesser extent at the base (Figs. 10, 11, 12 and 13). Radiologically the 'sutures' appear to be very wide in the less severe cases (Figs. 10 and 13) or there may be little ossified bone apart from the base, in the more severely affected patient (Figs. 11 and 12). Paradoxically, the sutures are not separated but are prematurely closed, as is seen in some of the survivors of the infant group who subsequently 'develop' craniostenosis (or rather where a craniostenosis already present becomes obvious when the osteoid is subsequently mineralised) (Fig. 14).

The Teeth.--Premature loss of the deciduous teeth as in Case 5 is a very rare condition in children. It occurs in severe pink disease, in local bone disease such as osteitis or eosinophilic granuloma, in hereditary ectodermal dysplasia (Illingworth & Gardiner, 1955) and in hypophosphatasia. Other findings described in hypophosphatasia are hypoplasia of the teeth, enlarged pulp spaces, irregular calcification and severe caries (Sobel, et al., 1953; Ritchie, 1964). The permanent teeth appear to be affected to a much lesser degree (Currarino et al., 1957).

Adults.--A few adults with hypophosphatasia have been reported. As well as residual effects of the lesions described above, with accompanying deformities, pseudo fractures have occurred in the


FIG. 10 FIG. 11

FIG. 12 Fro. 13

FIG. 10--Case 1, FIG. l l - -Case 2, FiG. 12--Case 3, and FIC. 13--Case 4. Showing deficient ossification of the bones of the vault and 'wider sutures'.

femora and other bones with generalised rarefaction of bone, the appearances resembling osteomalacia. Ectopic calcification around the joints and in tendons and intervertebral ligaments is also described (Bethune and Dent, 1960).

Diagnosis.--The condition is so uncommon that the radiologist may be the first to suggest the diagnosis. The diagnosis is easily made, provided that it is considered. Radiologically, the differential diagnosis can be divided into 3 broad sub-groups:

1. Rickets and osteomalacia. 2. Osseous dystrophies. 3. Others.

Classical rickets is unlikely to be found in a neonate, so that the appearance of metaphyseal lesions, suggestive of, but not typical of rickets should immediately suggest hypophosphatasia. Maxwell and Turnbull (1930) described 2 cases of foetal rickets which occurred in osteomalacic mothers; in one, scurvy was probably also present. Such cases are unlikely to be encountered today. In the more severely affected infants with extensive uncalcified osteoid tissue, the very short visible parts of the diaphysis are likely to suggest an osteodystrophy such as the 'boneless' type of osteogenesis imperfecta, but the appearances will

H Y P O P H O S P H A T A S I A 375

Fie. 14

Case 5. Skull. Showing the features of craniostenosis.

be 'atypical' especially in the skull, pelvis and spine. According to Caffey (1961) the changes in the childhood group are identical with those seen in juvenile rickets, or metaphyseal dysostosis. We have had the opportunity of seeing only one case of hypophosphatasia in childhood (Case 5) and the appearances are certainly very like late rickets (Fig. 9). Similarly, the occurrence of an unexplained osteoporosis or osteomalacia in an adult, particularly if there is a history of a rachitic condition, or orthopaedic deformities, or of dental trouble at an earlier age, should give rise to suspicion. Again, the finding of craniostenosis, particularly without evidence of mental defect or increased intra- cranial pressure, indicates the need for further investigation. It is important to make the diagnosis as early as possible, not only from the point of view of investigating the natural history of the disease, but also because the survivors are prone to develop craniostenosis. However, it may be that craniostenosis is present from the beginning, despite the paradoxical radiological appearances and that active surgery to relieve this condition is indicated (Anspach and Clifton, 1939).

DISCUSSION

Rathbun's suggested name for this condition, 'hypophosphatasia', is descriptive of a basic enzymatic defect and yet makes no claim as to aetiology. It is therefore to be preferred, on grounds

both of simplicity and accuracy to 'osteo dysmeta- morphosis foetalis' (Engfeldt and Zetterstrom, 1954) and 'osteoblastic dysplasia' (Schlesinger, et al., 1955). The estimated incidence of hypophosphatasia is about 1 : 100,000 live births in the Toronto area (Fraser, 1957).

Although there is some difference of opinion in detail, in general the histological appearances in reported cases is closely similar to or identical with rickets, with distortion of the metaphyseal line, poor alignment of cartilage columns and irregular and excessive laying down of pre-osseous tissues. However, at least in the neonatal and severely affected infant groups, these features are markedly exaggerated as compared with rickets of all types. Another indication of the relative severity of the changes is the failure of mineralisation of osteoid in the base and vault of the skull, a change which is not described even in foetal rickets. In severely affected neonates, a low grade nephritis with calcified deposits and casts in the tubules may be found.

The diagnostic feature of the disease is, by definition, the low level of alkaline phosphatase activity in serum and tissues. Decreased activity also occurs in scurvy, achondroplasia, osteogenesis imperfecta, hypothyroidism and idiopathic hypercalcaemia. In these conditions the deficiency is moderate, whereas in hypophosphatasia the level varies from 0-40~ of the lower limit of normal (Rathbun, 1948). Classical rickets arises as a result of inadequate


calcium deposition on a normal organic bone matrix, due to Vitamin D deficiency. It is postulated that in hypophosphatasia there exists a primary disturbance in the metabolism of bone matrix, so that the matrix is not 'calcifiable' (Fraser, et al., 1955). An inhibitory agent to alkaline phosphatase has not so far been demonstrated in the serum, nor is there evidence of increased excretion of the enzyme nor the absence of an activator, so that at present the low level should be considered to be due to decreased production. It would be convenient if a direct connection between the low alkaline phosphatase level and the absence of calcification in the matrix could be demonstrated, but the association is not so simple. Very low phosphatase levels may exist in the parents and siblings of patients, without concurrent evidence of clinical abnormality.

The almost invariable presence of phosphoethanolamine in the urine serves further to distinguish hypophosphatasia from other conditions and it has been suggested that this substance is in some way connected with alkaline phosphatase (Lanman, 1955). Fraser (1957) believes that very small amounts may be found in the urine of normal adults whose serum alkaline phosphatase is at the lower limit of normal and also in the urine in cases of coeliac disease, scurvy and hypothyroidism.

Aeknowledgements.--We are grateful to the following for permission to publish and for access to clinical details and radiographs: Case 1. Drs. W. Tennent and H. McC. Giles, Birmingham. Case 2. Drs. W. I. H. Bourne and H. W. E. Jones, Wolverhampton. Cases 3 and 4. Drs. A. M. MacDonald, R. A. Shanks and S. P. Rawson, Glasgow. Case 5. Mr. N. J. Blockey and Dr. S. P. Rawson, Glasgow. We are also indebted to Miss Margaret D. Simpson for typing the manuscript.

REFERENCES

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BETHUNE, J. E. & DENT, C. E. (1960). Amer. J. Med. 28, 615. CAFFEY, JOHN (1961). Pediatric X-ray Diagnosis, p. 1040.

New York: Year Book Medical Publishers. CrIOWN, B. (1936). Brit. J. Surg., 23, 552. CLAUSEN, S. W. (1952). Amer. J. Dis. Child., 83, 411. CURRARINO, G., NEUHAUSER, E. B. D., REYERSBACH, G. C.

& SOBEL, E. H. (1957). Amer. J. Roentgenol., 78, 392. ENGFELDT, B. • ZETTERSTROM, R. (1954). J. Pediat., 45, 125. FRASER, D. (1957). Amer. J. Med., 22, 730. FRASER, D. (1961). J. Amer. Med. Ass., 176, 281. FRASER, D. & LAIDLAW, J. C. (1956). Lancet, 1, 553. FRASER, D., YENDT, E. R. & CHVdSXIE, F. H. E. (1955).

Lancet, 1,286. ILLINGWORTrI, R. S. & GARDINER, J. H. (1955). Arch. Dis.

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Acad. Sci., 75 (1), 279. LANMAN, J. T. (1955). J. Pediat. 47 (4), 509. MCCANCE, R. A., FAIRWEATHER, D. V., BARRETT, A. M.

& MORRtSON, A. B. (1956). Quart. J. Med., 25, 523. MCCANCE, R. A., MORRISON, A. B. & DENT, C. E. (1955).

Lancet, 1, 131. MACDONALD, A. M. & SHANKS, R. A. (1957). Arch. Dis.

Childh., 32, 304. MACEY, H. B. (1940). Proc. Mayo Clin., 15, 789. MAXWELL, J. P. (1934). Proc. Roy. Soc. Med., 28, 265. MAXWELL, J. P. & TURNBULL, H. M. (1930). J. Path. Bact.,

33, 333. RATHBUN, J. C. (1948). Amer. J. Dis. Child., 75, 822. RATHBUN, J. C. (1959). Heh'. Paediat. Acta, 14, 548. RATHBUN, J. C., MACDONALD, J. W., ROBINSON, H. M. C.

& WANKHN, J. M. (1961). Arch. Dis. Childh., 36, 540. IOTCIaIE, G. McL. (1964). Arch. Dis. Childh., 39, 584. ROSENTHAL, I. M., BONTING, S. L., HOGAN, W. & PIRANI,

C. L. (1960). Amer. J. Dis. Child., 99, 185. SCHLESINGER, B., LUDER, J. & BODIAN, M. (1955). Arch. Dis.

Childh. 30, 265. SILVERMAN, J. L. (1962). Arch. intern. Med., 110, 191. SOBEL, E. H., CLARK, L. C., FOX, R. P. & ROBINOW, M.

(1953). Pediatrics, 11,309.

B O O K R E V I E W

The Year Book of Radiology (1965-1966 Year Book Series). Radiological Diagnosis edited by JortN FLOYD HOLT and WALTER M. WHITEHOUSE. Radiation Therapy edited by HOWARD B. LATOURETTE.

Year Book Medical Publishers Incorporated, 35 East Wacker Drive, Chicago. Distributed in the United Kingdom by Lloyd-Luke (Medical Books) Ltd., 49 Newman Street, London, W.1.

The 1965-1966 Year Book of Radiology maintains the high standard set by its predecessors. About 300 recent articles in diagnostic radiology and some 150 papers in radiotherapy are abstracted and the reader is presented with an easily read synopsis of current developments in these fields. The selection of articles for inclusion is generally made with care, but this reviewer would again suggest the constructive

criticism of article selection made here in a review of the 1964-1965 Year Book.

Particularly useful abstracts deal with trans-uterine infusion into the foetus with erythroblastosis, trans-placental rubella infection of the new born, a review of 2,320 lumbar discographies, and about 60 different articles concerned with angiography. In the therapy section, some outstanding articles are allotted 2 or 3 pages of text and are therefore considered in rather more detail. The greater number of diagnostic articles probably precludes this treatment, but the editors might consider adopting this policy for the exceptional paper in the radiodiagnostic section.

The Year Books of Radiology provide compulsive reading for all engaged in the field: they are essential reading for the higher radiological examinations. They must rank very high in priority in any departmental library.

R. G. GRAINGER

Hypophosphatasia

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