Journal of Medical Genetics 1982, 19, 104-109

A new variant of spondylometaphyseal dysplasia withautosomal dominant mode of inheritanceJ M GARCIA-CASTRO, C M ISALES-FORSYTHE, AND P DIAZ DE GARAU

From the Department ofPediatrics, Medical Genetics Section, School of Medicine,University ofPuerto Rico, San Juan, Puerto Rico

SUMMARY Clinical and radiographic evaluation of an infant boy and his father revealed findingssuggesting a new variant of spondylometaphyseal dysplasia with an apparently autosomal dominantmode of inheritance. The main clinical findings included short stature and marked ligamentouslaxity in the infant. X-ray findings included severe and peculiar multiple metaphyseal involvementand striking vertebral undermineralisation in the infant, and platyspondyly in the father. However,all the epiphyses were normal. Laboratory studies were essentially normal except for an extremelyraised serum alkaline phosphatase in the infant. The uniqueness of these findings suggests a newvariant of the spondylometaphyseal dysplasias, distinct from the cases described initially byKozlowski et all and subsequent investigators.

The nosology of skeletal dysplasias is badly in needof elucidation. Among these, spondylometaphysealdysplasia is one of the most difficult to classify. In1967, Kozlowski et all differentiated this entityfrom that of Morquio, noting the differences inclinical, radiographic, and metabolic findings.Various authors have since reported other cases ofspondylometaphyseal dysplasia which were so variedin their manifestations that the possibility arises ofmultiple alleles in such a heterogeneous condition.27We recently had the opportunity to study a familysegregating for this gene. The proband was initiallyevaluated at one month of age, at which time thediagnosis of a chondrodystrophy was considered.Evaluation of his father confirmed the condition asa spondylometaphyseal dysplasia, with clinical andradiological findings quite distinct from the typesreported up to the present, with an autosomal domin-ant mode of inheritance.

Case reports

CASE 1The proband, a male, was born on 6.2.79 in SanJuan, Puerto Rico after an uneventful termpregnancy and delivery. The parents were non-consanguineous, with maternal and paternal ages atthe time of conception of 22 and 30 years, respec-tively. There was no history of maternal drugReceived for publication 23 May 1981

ingestion during pregnancy. Birthweight was 2466 gand length was 45-7 cm. He was diagnosed as anormal newborn at that time. At 3 days of age hedeveloped diarrhoea, subsequently diagnosed asbeing caused by pathogenic E coli, and because ofpersistence of symptoms after therapy he wasreferred to our institution. During this admissionwe were called for consultation on the presence ofsome dysmorphic features.On examination the following findings were

observed: naevus flameus over the left superioreyelid; prominent nasal bridge with a globular andbeaked tip to the nose; small mandible with a higharched palate; asymmetrical bell-shaped thorax withthe left side more prominent; asymmetrical place-ment of the nipples, the left being higher; no heartmurmurs; liver palpable 1 cm below the right costalmargin; normal male genitalia with a right inguinalhernia; cutis marmorata; hypotonia and normaldeep tendon reflexes. Both upper and lower extrem-ities were externally rotated with marked hyper-extension of the elbows and wrists, the latter beingalso extremely wide. Radial deviation of the handswith the thumb adducted over the palm and the fifthfinger overriding the others was present. The fingerswere thin and tapered distally. A most surprisingfinding was the degree of ligamentous laxity; theupper extremity could be rotated through almost3600 and the lower through 1800 with the utmostease and without any discomfort to the patient.

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A new variant ofspondylometaphyseal dysplasia with autosomal dominant mode of inheritance

Dermatoglyphic findings were not outstandingexcept for a distal loop hypothenar pattern bilaterallyand a t' right axial triradius.

Laboratory findings included normal blood counts,urine analysis, serum electrolytes, blood ureanitrogen, and fasting blood glucose. Screening forurinary amino-acids and mucopolysaccharides wasalso normal. Serum calcium and phosphorus levels

FIG 1 Case I at one month of age. Anteroposteriorview demonstrating lack of mineralisation of thevertebral bodies.

were 2.4 mmol/l and 1 7 mmol/l, respectively, bothwithin normal limits. Serum alkaline phosphataselevels, however, were increased to 468 U/l.The most important findings were obtained from

the x-ray studies. There was complete absence ofmineralisation of all the vertebral bodies (fig 1), andabnormal metaphyses at the glenoid, proximal anddistal humerii, radii, ulnae, femora, tibiae, andfibulae. The metaphyses, particularly the distal radiiand femora, showed widening and severe lack of

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FIG 2 Case I at one month of age: (a) severeproximal and distal involvement of the metaphyses ofthe upper extremity. Note particularly the abnormalityat the glenoid; (b) blown-out and irregular metaphysesof the lower extremities, accompanied by marked tibiaevarum.

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JM Garcia-Castro, CM Isales-Forsythe, andP Diaz de Garau

mineralisation, producing a blown-out appearance(fig 2a, b). All of the epiphyses examined werenormal.

Re-evaluation at one year of age revealed delayedmotor developmental milestones: he could hold hishead without difficulty, prop himself up with hisarm, remain seated when seated, and stand withsupport, but he could not sit or stand by himself orcrawl. However, his intellectual development seemedadequate: he was alert, recognised his parents, andhad a normal vocabulary for his age.

His recumbent length was 69 5 cm with a sittingheight of 42 e 5 cm. His weight was 8 kg and the headcircumference was 46 - 2 cm. Inner and outer canthaldistances were 2 * 5 and 7 *2 cm, respectively. Physicalfindings were similar to those already described. Hestill had marked ligamentous laxity. Radiographic-ally there was an improvement from the previousfilms in that the vertebral bodies, as well as themetaphyses, showed some ossification. Recentfilms taken at 2 years of age (fig 3a, b, c) showed aneven greater improvement, and his motor andintellectual development was normal for his age.He had not had any major medical problems.

CASE 2The patient's father, born on 15.1.48, was found tobe similarly affected. He was the penultimate ofnine sibs, none of whom has the dysplasia. Hepresented with short stature, his height being

FIG 3 Case I at 26 months of age. Some visualisationof the vertebral bodies is now possible in the antero-posterior (a) and lateral (b) projections. (c) Improved,but still abnormal, x-ray of the lower extremities;slight bowing of the femora is present.

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A new variant of spondylometaphyseal dysplasia with autosomal dominant mode of inheritance

144 0 cm, symphysis pubis to floor was 71 - 3 cm, andsitting height was 813 cm. He was also barrel-chested and had severe genu valgum and pelvic tiltowing to a very shortened left leg (68 2 cm vs82- 7 cm on the right) which had been operated uponwhen he was 13 years old. Details of this surgicalprocedure were not available. The patient describedan osteotomy being performed to correct the

FIG 4 Case 2. Lateral view of vertebral column ofaffected adult showing slight thoracic platyspondyly withcephalad progression.

curvature of the femur. In addition, there wasalmost complete accidental amputation of the lefthand. Dermatoglyphs, as in his son, were notinformative except for a distal loop hypothenarpattern and a t' axial triradius on the right. Bilateralsensorineural hearing loss was documented, 68 dbon the right and 73 db on the left, which he statedhad been present since birth. X-ray studies demon-strated a spondylometaphyseal dysplasia. The

I/i

FIG 5 Case 2. (a) Abnormal modelling of theproximal end of the humerus; (b) widened distal endof the radius with unusual persistence of the epiphysealline offusion; (c) abnormal modelling of the distalfemora and shortening of the left femur, probably theresult of an osteotomy performed when the patient was13 years old. Femoral necks are shortened also.

)

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vertebral bodies showed slight platyspondyly of themid-thoracic vertebrae with cephalad progression(fig 4). No scoliosis or kyphosis was present.Abnormal modelling was seen of the proximalhumerii, distal radii and ulnae, proximal and distalfemora (fig 5a, b, c), and distal tibiae and fibulae.Femoral necks were short and wide. It is interestingto note that the epiphyseal line of fusion at the lowerend of the radius was still visible (fig 5b).

Laboratory findings included normal screeningfor urinary amino-acids and mucopolysaccharidesand normal serum calcium (2. 1 mmol/l), phosphorus(1 - 0 mmol/l), and alkaline phosphatase (53 U/1).

Discussion

The classification of the spondylometaphysealdysplasias, among many clinically similar bonedysplasias, was begun by Kozlowski et al in 1967.'An autosomal dominant mode of inheritance is

clearly indicated in our cases, and a de novomutation in our case 2 is highly likely because no

other family members are affected, except for hisson (case 1), which argues against limited penetranceof the gene, and because of his birth order, thepenultimate, when his father and mother were 49 and37 years old, respectively.The x-ray findings observed clearly establish this

condition to be a spondylometaphyseal dysplasia.In contrast to some of the other spondylometa-

physeal dysplasias, this one can be diagnosed duringthe first month of life, probably at birth, by clinicaland x-ray findings, and perhaps even prenatally. Theligamentous laxity as well as the extremely unusualx-ray findings of lack of ossification of the vertebralbodies and of the metaphyses, with normal serumCa and P and raised serum alkaline phosphataselevels on repeated samplings, clearly excludes thepossibility of hypophosphatasia8 and distinguishes itfrom the other cases of spondylometaphyseal dys-plasia so far recorded.Also of interest in our case 2 was the presence of

congenital auditory deficit, a finding not describedin other reported cases of spondylometaphysealdysplasia, but observed in metaphyseal chondro-dysplasia of the Jansen type.9 Whether or not thisis a specific finding in this syndrome remains to bedetermined. So far we have not been able to docu-ment hearing loss in our case 1, but it might still betoo early to detect. Intellectual impairment is not afeature of this condition, though motor develop-mental milestones might be somewhat delayed. Thishas been reported in other cases.3 5 We speculatethat this motor delay might be in part the result ofossification delay and ligamentous laxity. The poorossification would seem to make the bone moresensitive to stress and other forms of stimuli, asperceived by osseous nerve terminals, which couldin turn retard muscular development as a defencemechanism.10 This is a temporary delay untiladequate mineralisation takes place, as is observedin our adult case 2, where no gross impairment offunction is present except what might be caused bythe short stature and unequal length of the lowerextremities. This might have been the result of earlysurgery, since unequal length of the legs, if present,is only minimal in our case 1. We expect that ourcontinued surveillance of this patient will clarifysome of these issues.

We are grateful to Dr Pierre Maroteaux for thecritical reading of the manuscript, to Mr Alvin APeralta for the audiometric studies, to Mr Angel LRivera for the x-ray work, to Mrs Luz Carlota Reyesde Torres and Karen Tossas for technical assistance,and to the house-staff of the Hospital Universitariode Ninios, who introduced us to this family.

References

Kozlowski K, Maroteaux P, Spranger J. La dysostosespondylom6taphysaire. Presse Med 1967;75:2769-74.

2 Grenier B, Castaing J, Laugier J, Michel J, Desbuquois G.Deux cas familiaux de dysplasie spondylom6taphysaire.Arch Fr Pediatr 1969;26:1015-26.

3 Schmidt BJ, Becak W, Becak ML, et al. Metaphysealdysostosis. Review of literature: study of a case withcytogenetic analysis. J Pediatr 1963 ;63 :106-12.

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A new variant ofspondylometaphyseal dysplasia with autosomal dominant mode ofinheritance

4 Diamond LS. Spondylometaphyseal dysplasia (Braziliantype). Birth Defects 1974;X(12):412-5.

5Lie SO. Spondylometaphyseal dysplasia (unclassified

form). Birth Defects 1974;X(12):416-8.6 Murdoch JL, Walker BA. A "new" form of spondylo-

metaphyseal dysplasia. Birth Defects 1969;V(4):368-70.7Maloney FP. A distinctive type of spondylometaphyseal

dysplasia (SMED) in two brothers and a third unrelatedmale. Birth Defects 1969;V(4):360-7.

8 Rathbun JC. Hypophosphatasia. A new developmental

anomaly. Am J Dis Child 1948;75:822-3 1.

I Jansen M. Uber atypische Chondrodystrophie (Achon-droplasie) und iuber eine noch nicht beschriebene ange-

borene Wachstumstorung. Z Orthop Chir 1934;61 :255-86.Johnson LC. The kinetics of skeletal remodeling. Struc-tural organization of the skeleton. Birth Defects 1966 ;II(1).

Requests for reprints to Dr Jose M Garcia-Castro,Instituto de Genetica Medica, GPO Apartado 1764,San Juan, Puerto Rico 00936.

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