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Home , Achondrogenesis, Achondroplasia, Chondrodystrophy, Dwarfism, Osteogenesis imperfecta

Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from Postgraduate Medical Journal (April 1977) 53, 204-211

The of the short-limbed dwarfs presenting at birth R. N. MUKHERJI P. D. Moss M.R.C.P., D.C.H. F.R.C.P., D.C.H. Department ofPaediatrics, Royal Infirmary, Blackburn, Lancashire

Summary Harris and Patton (1971) reviewed seventeen still- Attention is drawn to the fact that in a number of born or early neonatal deaths originally diagnosed types of short-limbed a precise diagnosis can as achondroplastics and showed that in ten of these be made in the neonatal period. Examples are given cases the diagnosis should have been thanatophoric and the prognostic and genetic implications are dis- dwarfism. This supports the view that achondro- cussed. It is important to be able to advise parents of plasia has been over diagnosed at birth and that the the likely outlook for the infant and of the genetic severely affected cases are, in fact, some other type implication. Early diagnosis is therefore not merely of lethal neonatal dwarfism. an academic exercise. Introduction This was first described under the title of anosteo- When Rathbun (1948) first described neonatal genesis (Parenti, 1936) as it was thought to be a he discussed three conditions of variety of . Fraccaro (1952)

differential diagnosis. These consisted ofosteogenesis first used the term 'achondrogenesis' because of by copyright. imperfecta, and renal hyperpara- marked retardation of . Parental con- thyroidism. Since then a number of other conditions sanguinity (Saldino, 1971) and multiple affected have been defined on a clinical, radiological and siblings (Houston, Awen and Kent, 1972) have been genetic basis (Tables 1 and 2). Such conditions are reported. The role ofteratogenic agents is speculative not excessively rare if sought. Ryan and Kozlowski as a case of achondrogenesis following maternal (1971) found nineteen cases of dysplasia in thalidomide ingestion has been described (Jurczok consecutive radiographs of 109 infants dead on and Schollmeyer, 1962). Hydramnios is a frequent delivery. When a case of neonatal hypophospha- of the pregnancy and achondrogenic

tasia occurred in the authors' unit they were able infants are usually premature and stillborn. It is a http://pmj.bmj.com/ to include thirteen conditions in the differential rare condition and is characterized at birth by diagnosis. They are here described together with extremely short limbs, large head, swollen abdomen, prognosis and genetic implications. poor ossification of generally and essentially no neck (Fig. 1). Harris, Patton and Barson (1972) Achondroplasia described two siblings under the title of 'pseudo- Achondroplasia is the prototype of true bone achondrogenesis with fractures' which is representa- dysplasia (Rubin, 1963) and it is the best described tive of a different type of achondrogenesis and form of neonatal dwarfism. Its incidence per one resembling the siblings described by Houston et al. on September 30, 2021 by guest. Protected million people was found to be fifteen in the United (1972). This particular variety is now known as States (Potter and Coverstone, 1948), twenty-three 'Harris and Houston' type of achondrogenesis in Denmark (Morch, 1941) and 283 in Northern (Fig. 2). The presence of fractures is the point of Ireland (Stevenson, 1957). It is inherited as an differentiation between the two types of this condi- autosomal dominant but over 90%/ of cases are tion. fresh especially with elderly parents (Barr and Forfar, 1973). Harris and Patton (1971) in their Asphyxiating thoracic dystrophy series found that the rate was not greater Jeune, Beraud and Carron (1955) first described than 1 in 100,000. Its incidence in twins is extremely this condition. It is characterized by extemely short rare. ribs, variable degree of shortening of limbs and Clinically the condition may be recognizable at fingers and occasionally by polydactyly. The thorax birth but often it is not, as the features of proximal is narrow and immobile. Hereditary nephritis leading limb shortening, large head, depressed nasal bridge to death has been reported (Shokeir, Houston and and prominent forehead may be poorly developed. Awen, 1971). Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from Diagnosis of short-limbed dwarfs at birth 205

TABLE 1. Clinical differences Part of limbs Associated Type Family history Antenatal involved abnormalities Inheritance Achondroplasia (mutant) - - Proximal Enlarged head, de- Autosomal pressed nasal bridge, dominant hands and feet short and broad

Achondrogenesis Parental consan- Hydramnios Both proximal Large head, essentially Autosomal guinity and distal no neck, swollen recessive abdomen

Asphyxiating thoracic - - Distal Extremely short ribs, Autosomal distal narrow and immobile recessive thorax, polydactyly, hereditary nephritis Chondrodysplasia punctata - - Proximal and Flexion contracture of Autosomal distal joints, cataracts, recessive ectodermal changes, mental deficiency Chondro-ectodermal - - Distal Thoracic dystrophy, Autosomal dysplasia (Ellis-Van polydactyly, con- recessive Creveld syndrome) genital heart, ecto- dermal changes

Diastrophic - - Distal Marked talipes equino- Autosomal by copyright. varus, resembles arthrogryposis, 'hitch- hiker' thumb Homozygous achondro- Both parents -Proximal Large head, depressed Autosomal plasia achondroplastic nasal bridge, frontal dominant bossing, early death Hypophosphatasia Parental consan- X-ray diagnostic Proximal and Soft skull bones, Autosomal guinity distal marked angulation recessive and deformities of http://pmj.bmj.com/ long bones Lymphopenic agamma- - - Proximal Features of achondro- Not known globulinaemia with short- plasia, lymphopenia, limbed dwarfism agammaglobulin- aemia, early death dwarf - - Proximal and narrow Metatrophic Long thorax, Autosomal on September 30, 2021 by guest. Protected distal caudal appendage, recessive swollen joints Osteogenesis imperfecta Blue sclera X-ray diagnostic Proximal and Soft skull, blue sclera Autosomal distal dominant recessive Spondylo-epiphyseal - - Proximal and Myopia, retinal detach- Autosomal dysplasia congenita distal ment, cataract, cleft dominant palate Thanatophoric dwarf Parental consan- Hydramnios, Proximal Redundant skin folds, Autosomal guinity weak fetal move- limbs abducted and recessive ments, stillbirth, externally rotated, X-ray diagnostic large head with frontal prominence Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from 206 R. N. Mukherji and P. D. Moss TABLE 2. Radiographic differences Type Spine Limbs Pelivs Thorax, ribs Skull Achondroplasia Narrow inter- Proximal bones Narrow sacrum Thorax long and Large vault, (mutant) pedicular distance short, ball and and sciatic notch narrow small base and of lower lum- socket appear- foramen magnum bar vertebrae ance of meta- physes Achondrogenesis Poorly mineralized Marked shorten- Poorly mineralized Short ribs, clavicles Poorly mineral- and ossified ing, poorly disproportionately ized, otherwise mineralized long normal Asphyxiating thoracic Normal Variable short- Hypoplastic iliac Extremely short Normal dystrophy ening hook-shaped horizontal ribs sciatic notch Chondrodysplasia Punctate calcifica- Both proximal and -Normal Craniostenosis punctata tions of inter- distal shortening, vertebral discs puncatate calcifi- cations ofjoint capsules and epiphyses Chondro-ectodermal Normal Short distal bones, Reduced height of Short ribs Normal dysplasia (Ellis-Van hypoplastic bones Creveld syndrome) terminal phalanges, carpal and tarsals fused into solid masses

Diastrophic dwarf Hypoplastic Hypoplastic first Acetabular dys- Long thorax Normal by copyright. cervical verte- metacarpal plasia brae Homozygous Flattening of Markedly short Small iliacs Short ribs Large, small base achondroplasia vertebrae Hypophosphatasia Normal Appearance of Normal Marked costo- Little or no bone severe chondral bead- material ing dwarf Flat vertebrae mark- Normal Metatrophic Metaphyses Crescent-shaped Long thorax, http://pmj.bmj.com/ edly flared, iliac crests short ribs enlarged and irregular Osteogenesis imper- Shallow vertebrae Thick-thin bones, Normal Deformities Poorly ossified fecta stunted, deformed Spondylo-epiphyseal Hypoplastic odon- Short, bowing of Small iliac wings Bell-shaped thorax Normal displasia congenita toid femora Thanatophoric dwarf Flat vertebrae, Markedly short, Short iliacs Short ribs, wide Enlarged, short on September 30, 2021 by guest. Protected deep discs bowing of anterior ends base, premature fusion of coronal and lamboidal sutures

Chondro-ectodermal dysplasia are shortened rather than the proximal (Fig. 3) and This condition was described in 1940 by Ellis polydactyly of fingers and toes is commonly found. and Van Creveld. It is a complex dysplasia in which skeletal defects are associated with ectodermal Chondrodysplasia punctata anomalies affecting hair, teeth and nails, and con- These infants are recognizable at birth as dwarfs genital heart disease is common. The shortening of with short limbs. Radiologically punctate calcifica- limbs in this condition is the reversal of achondro- tions are found in the epiphyses, joint capsules, plasia in that it is the distal parts of the limbs which trachea, larynx, hyoid, intervertebral discs and in Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from Diagnosis of short-limbed dwarfs at birth 207

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FIG. 2. 'Harris and Houston' type of achondrogenesis. by copyright.

FIG. 1. A stillborn infant with achondrogenesis showing oedematous soft tissue, virtual absence of ossification of bones and micromelia. http://pmj.bmj.com/ rhizomelic type proximal limb bone shortening (Fig. 4). Diastrophic dwarf This term was coined by Lamy and Maroteaux (1960) for achondroplastic-like dwarfs with twisted lower extremities and varying degrees of . The other abnormalities described are contracture on September 30, 2021 by guest. Protected ofjoints, dislocation of hips, knees, radial heads and superficial resemblance to arthrogryposis. The long bones are short. The thumbs are displaced proxim- ally and the first metacarpal bone is hypoplastic. The hypoplasia of the mid-cervical vertebrae is a characteristic radiographic feature. Homozygous achondroplasia This is extremely rare and is lethal. The affected infant dies within the first few days or weeks of life. The overall body proportions of the infant are mid- way between those of a thanatophoric dwarf and FIG. 3. Three-day-old infant with chondro-ectodermal those of an infant with classical achondroplasia dysplasia.dyslaia Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from 208 R. N. Mukherji and P. D. Moss

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PE; . '.JSAl http://pmj.bmj.com/ Hypophosphatasia FIG. 5. Two-day-old infant with homozygous achon- This is an autosomal recessive condition. droplasia. The term 'hypophosphatasia' was used for the first time by Rathbun (1948) to designate an osteo- Lymphopenic agammaglobulinaemia with short-limbed blastic condition with low serum alkaline phospha- dwarfism tase. There are three salient features-abnormal McKusick and Cross (1966) first described a mineralization of bone, increased urinary excretion patient with Swiss-type agammaglobulinaemia and on September 30, 2021 by guest. Protected of phosphoethanolamine and diminished alkaline a skeletal disorder resembling achondroplasia but phosphatase activity. Fraser (1957) described three they thought the sketetal disorder had no relation- different categories depending on the age of onset: ship to the agammaglobulinaemia. A few months newborn, infants and children. The newborn type is later Davis (1966) described a newborn female infant the most severe (Figs 6 and 7) and carries the worst with achondroplasia and Swiss-type agammaglo- prognosis. Hypercalcaemia is a common complica- bulinaemia. He concluded that because of the rarity tion presumably due to accumulation of calcium in of both conditions their concurrence was due to the blood as it fails to be incorporated into bone genetic association and not simply to chance. The because of absent or low subsequent recognition of isolated cases of this activity. Dent (1956) maintained that the hyper- nature (Fulginiti et al., 1967; Alexander and Dunbar, calcaemia in hypophosphatasia was due to hyper- 1968) have given support to Davis's assumption. sensitivity to vitamin D. This hypercalcaemia can be complicated by nephrocalcinosis which can con- Metatrophic dwarf tribute to some of the fatal outcome. This term 'metatrophic' (which means 'variable') Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from i: "· ..~

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FIG. 7. Day-old infant with neonatal hypophosphatasia FIG. 9. Osteogenesis imperfecta congenita. showing demineralization simulating severe rickets. Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from 210 R. N. Mukherji and P. D. Moss

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FIG. 10. Spondylo-epiphyseal dysplasia congenita show- ing shortening of ribs and long bones, flattening of thoracic vertebrae posteriorly and hypoplastic odontoid. FIG. 11. Thanatophoric dwarf. was defined by Maroteaux, Spranger and Wiedemann metaphyses. The associated clinical abnormalities (1966) for a condition characterized by variation in are: severe myopia, retinal detachment, cataracts, http://pmj.bmj.com/ the clinical picture with age. Initially they super- deafness and cleft palate. Roaf, Longmore and ficially resemble achondroplastics with limbs shorter Forrester (1967) reported four cases of a syndrome than trunk; later, the proportions reverse with more comprising bone dysplasia, retinal detachment and shortening of the trunk than limbs and bear resem- deafness. These were probably cases of spondylo- blance to Morquio's disease. The skeletal radio- epiphyseal dysplasia. There are six types of spondylo- graphs show expansion of all the metaphyses, epiphyseal dysplasia distinguishable on clinical,

shortening of long bones which become dumb-bell genetic and radiological grounds. It is inappro- on September 30, 2021 by guest. Protected shaped and flattening of vertebral bodies (Fig. 8). priate to discuss all here. The skeletal radiograph (Fig. 10) shows the abnormalities that are found in Osteogenesis imperfecta congenita the congenital variety. This condition in the majority of cases results from sporadic mutation and is inherited as auto- Thanatophoric dwarf somal dominant. The severe neonatal type indicates a Maroteaux, Lamy and Robert (1967) first reported recessive mode of inheritance. It is characterized by this condition which is the commonest cause of multiple fractures of long bones which consequently neonatal deaths amongst short-limbed dwarfs. The become deformed, angulated and short (Fig. 9). title means 'death bearing'. Harris and Patton (1971) reviewed seventeen stillborn and early neonatal Spondylo-epiphyseal dysplasia congenita deaths originally diagnosed as achondroplasia and This condition was first described by Spranger and showed that in ten of these the diagnosis should have Wiedemann (1966). It selectively affects vertebrae, been thanatophoric dwarf. The clinical appearance is epiphyses of long bones and occasionally adjacent characteristic (Fig. 11) and consists of very short Postgrad Med J: first published as 10.1136/pgmj.53.618.204 on 1 April 1977. Downloaded from Diagnosis of short-limbed dwarfs at birth 211 limbs, redundant skin folds, limbs held in abduction neonatal dwarfism. Journal of the Canadian Association of and external a head and Radiologists, 23, 45. rotation, large depressed JEUNE, M., BERAUD, C. & CARRON, R. (1955) Dystrophie nasal bridge. thoracique asphyxiante de caractere familial. Archives francaises de pediatrie, 12, 886. Conclusions JEUNE, M., BERAUD, C. & CARRON, R. (1962) Zur frage des It is make an and gehauften Auftretens von Extremitatenmissbildungen bei now possible to early precise Neugeborenen. Geburtshilfe und Frauenheilkunde, 22, diagnosis in a number of different types of short- 400. limbed dwarfs. This is of importance for prognosis JURCZOK, F. & SCHOLLMEYER, R. (1962) Zur Frage des and genetic counselling. gehauften Auftretens von Extremitatenmissbildungen bei Neugeborenen, Geburtshilfe und Frauenheilkunde, 22, 400. Acknowledgments LAMY, M. & MAROTEAUX, P. (1960) Diastrophic nanism. The authors are grateful to Dr R. Harris and the Journal of Presse Medicale, 68, 1977. Clinical for permission to reproduce two figures McKusIcK, V.A. & CROSS, H.E. (1966) Ataxia telangiectasia (Figs 2 and 11). They gratefully acknowledge permission from and Swiss type agammaglobulinaemia. Journal of the Dr R. M. Saldino for the illustrations (Figs 1, 3, 4, 5, 8, 10) American Medical Association, 195, 739. obtained from Medical , and photography MAROTEAUX, P., LAMY, M. & ROBERT, J.M. (1967) Le published by Radiography Markets Divisions, Eastman nanisme thanatopore. Presse Medicale, 75, 2519. Kodak Company. MAROTEAUX, P., SPRANGER, J. & WIEDEMANN, H.R. (1966) The authors would like to thank Mrs M. E. Hunt for her Der metatropische Zwergwuchs. Archiv fur Kinderheil- invaluable help in typing the manuscript. kunde, 173, 211. MORCH, E.T. (1941) Chondrodystrophic Dwarfs in Denmark. References Ejnar Munksgaard, Copenhagen. ALEXANDER, W.J. & DUNBAR, J.S. (1968) Unusual bone PARENTI, G.C. (1936) La anosteogenesi (una varieta della changes in thymic alymphoplasia. Annals of Radiology, osteogenesi imperfetta). Pathologica. Genova, 28, 447. 11, 389. POTTER, E.L. & COVERSTONE, V.A. (1948) BARR D.G.D. & FORFAR, J.O. (1973) Textbook of Paedia- foetalis. American Journal of Obstetrics and Gynecology, trics. Churchill Livingstone, London and Edinburgh. 56, 790. DAVIS, J.A. (1966) A case of Swiss type of agammaglo- RATHBUN, J.C. (1948) 'Hypophosphatasia'. New develop- bulinaemia and achondroplasia. British Medical Journal, mental anomaly. American Journal of Diseases of Children, 2, 1371. 75, 822. by copyright. DENT, C.E. (1956) Bone structure and metabolism. In: Ciba ROAF, R., LONGMORE, J.B. & FORRESTER, R.M. (1967) A Foundation Symposium, p. 266. Churchill, London. childhood syndrome of bone dysplasia, retinal detachment ELLIS, R.W.B. & VAN CREVELD, S. (1940) Syndrome charac- and deafness. Developmental Medicine and Child , terized by ectodermal dysplasia, polydactyly, chondro- 9, 464. dysplasia and congenital morbus cordis: report of 3 cases. RUBIN, P. (1963) Achondroplasia versus pseudoachondro- Archives of Disease in Childhood, 15, 65. plasia. Radiologic Clinics of North America, 1, 621. FRACCARO, M. (1952) Contributo allo studio delle malattie RYAN, J. & KOZLOWSKI, K. (1971) Australian Radiation del mesenchima osteopoitico: l'achondrogenesi. Folia Records, 15, 213. hereditaria et pathologica (Milano) 1, 190. SALDINO, R.M. (1971) Lethal short limbed dwarfism: achon- FRASER, D. (1957) Hypophosphatasia. American Journal of drogenesis and thanatophoric dwarfism. American Journal Medicine, 730. of Roentgenology, 112, 185. http://pmj.bmj.com/ FULGINITI, V.A., HATHAWAY, W.E., PEARLMAN, D.S. & SHOKEIR, M.H.K., HOUSTON, C.S. & AWEN, C.F. (1971) KEMP, C.H. (1967) Agammaglobulinaemia and achon- Asphyxiating thoracic chondrodystrophy. Association with droplasia. British Medical Journal, 2, 1371. renal disease and evidence for possible heterozygous ex- HARRIS, R. & PATTON, J.T. (1971) Achondroplasia and pression. Journal of , 8, 107. thanatophoric dwarfism in newborn. Clinical Genetics, 2, SPRANGER, J. & WIEDEMAN, H.R. (1966) Dysplasia spondylo- 61. epiphysaria congenita. Helvetica paediatrica acta, 21, 598. HARRIS, R., PATTON, J.T. & BARSON, A.J. (1972) Pseudo- STEVENSON, A.C. (1957) Achondroplasia: an account of the achondrogenesis with fractures. Clinical Genetics, 3, 435. condition in Northern Ireland. American Journal of C.F. & H.P. Fatal Human 8. HOUSTON, C.S., AWEN, KENT, (1972) Genetics, 9, on September 30, 2021 by guest. Protected