microcephalic osteodysplastic primordial dwarfism … dwarfism (mopd)are described,...

J Med Genet 1991; 28: 795-800

Microcephalic osteodysplastic primordial dwarfismtype I/III in sibs*

Peter Meinecke, Eberhard Passarge

AbstractThe clinical and radiological findings in a pairof sibs with microcephalic osteodysplasticprimordial dwarfism (MOPD) are described,a boy who survived for 5 years and his moreseverely affected younger sister, who died atthe age of6 months. Neuropathological studiesin this girl showed marked micrencephalywith severely hypoplastic, poorly gytatedfrontal lobes and absent corpus callosum. Ourobservation supports the hypothesis that typesI and III MOPD probably constitute a spec-trum ofone and the same entity and publisheddata together with this report are consistentwith autosomal recessive inheritance. Thepathogenesis of this condition is as yetunknown, but its characteristics indicate abasic defect affecting cell proliferation andtissue differentiation.

In 1982 Majewski and Goeckel re-evaluated micro-cephalic primordial dwarfism (including the illdefined 'Seckel syndrome') and consequently delin-eated a group of disorders which they term 'osteo-dysplastic primordial dwarfism types I, II, and III'.While type II is apparently a distinct disorder,shown by several examples,2-5 evidence is growingthat types I and III are one and the same disorder,"(Majewski, personal communication). Here we pre-sent a pair of sibs with this condition. This observa-tion supports the hypothesis that types I and IIImicrocephalic osteodysplastic primordial dwarfism

Abteilung Medizinische Genetik, Altonaer Kinder-krankenhaus, Bleickenallee 38, D-2000 Hamburg 50,Germany.Peter Meinecke

Institut fur Humangenetik, UniversitatsklinikumEssen, Germany.Eberhard PassargeCorrespondence to Dr Meinecke.

(MOPD) are one entity and makes autosomal reces-sive inheritance likely.

Case reportsThe proband (case 1) was referred to us in 1968 atthe age of 16 months for genetic diagnostic evalu-ation because of severe developmental retardationwith dwarfism and microcephaly. In 1974, we sawthe younger sister (case 2) who was then 1 monthold. At that time we recognised the striking similar-ity between our two patients and a probably auto-somal recessive condition described by Taybi andLinder,9 which they had termed 'cephalo-skeletaldysplasia'.

Case 1 was the first child of young, healthy, andnon-consanguineous parents. Their second preg-nancy had resulted in a normal girl. Case 2 was theproduct of the third pregnancy.

CASE 1This male infant was born spontaneously after anuneventful pregnancy at 38 weeks of gestation. Birthlength was 40 cm (- 5-2 SD), weight 1650 g (-4 SDfor age), and head circumference (OFC) was 27 cm(- 6-1 SD). Apgar score was 10. Apart from micro-cephaly and dwarfism, hypotrichosis, large eyes,deep set and small ears, and tapering of fingers werenoted. Initially the boy sucked poorly and he wastube fed for five weeks. Growth and weight gainwere poor and psychomotor development was sever-ely retarded. A first tooth was noted at 12 months ofage.When we saw the boy at 16 months (fig 1), his

length was 65 cm (-6 SD), weight 8500 g (3rd cent-ile for age), and OFC 36 cm (-8-4 SD). His strik-ingly small skull with closed fontanelles had a trigo-nobrachycephalic shape, scalp hair was sparse, hiseyes were slightly protruding, and the ears were lowset, small, and poorly differentiated. His arms andlegs appeared to be short, with short hands and feetwhich showed dorsal lymphoedema and short,tapering fingers and toes. The penis was small andthere was cryptorchidism bilaterally. Apart fromgeneralised hypotrichosis, the dry and hyperkerato-tic skin was slightly scaling. Psychomotor develop-ment was severely retarded. The boy was able to

Received for publication 26 November 1990.Revised version accepted for publication 26 March 1991.

*This article is dedicated to Professor Jurgen Spranger on theoccasion of his 60th birthday.

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Figure 1 Case 1 aged 16 months. Note microcephaly,sparse hair, dorsal lymphoedema of hands and feet, taperingfingers, and hypoplastic genitalia.

grasp toys but could not sit. He showed some socialcontact with his parents.TORCH titres were negative. Urinary amino acid

chromatography and mucopolysaccharides werenormal. Chromosomes (standard Giemsa stained)were normal. The boy's EEG was strikingly abnor-mal with generalised dysrhythmia and signs of con-vulsive potential.

Radiological findingsAt the age of 3 weeks, the strikingly small skull (fig2) showed a steep, sclerotic base, particularly smalland sloping frontal bones, a well ossified occipitalbone, and large orbits. The clavicles were relativelylong and there were only 11 pairs of ribs. The spineshowed mild platyspondyly. The iliac wings wererounded, and there were nearly horizontal, irregularacetabular roofs (fig 3). Both femora showed mildbowing of their shafts and there was no ossificationof the epiphyses in the knee region. Calcaneus andtalus were present. Joint spaces were strikingly nar-row.The hands (fig 4) and feet were small, the first

metacarpals were slightly short, and the proximal

Figure 2 Case 1 aged 3 weeks. Note small skull withparticularly small and sloping frontal bones.

phalanges of the big toes were particularly short androunded.

Clinical courseThere are only sparse data for the following yearsbecause the parents declined follow up visits. As faras we know, the boy remained dwarfed and micro-cephalic with severely retarded psychomotor de-velopment. At 51 years, the patient died at homefrom an acute aphthous stomatitis complicated bypurulent tonsillitis with high fever and vomiting.Necropsy was not performed.

CASE 2This female infant (fig 5) was born at term after anuneventful pregnancy. Her length was 36 cm(-9 SD), weight 1400 g (-5-5 SD for age), andOFC 26 cm (-7-5 SD). Apgar score was 10. Cranio-facial anomalies included a microcephalic skull withsloping forehead, prominent occiput, and a very

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Microcephalic osteodysplastic primordial dwarfism type I/III in sibs

Figure 3 Case 1 aged 3 weeks. Note nearly horizontal andirregular acetabular roofs, narrow joint spaces, and lack ofepiphyseal ossification of the femora.

Figure 4 Hand of case 1 aged 3 weeks.

small anterior fontanelle; large, slightly protrudingeyes with upward slanting palpebral fissures; broad,flat nasal bridge and broad nasal tip with prominentcolumella; and short, poorly structured philtrumand moderate micrognathia. The ears were low set,small, and poorly modelled. The neck was short.External female genitalia were normal. The limbsappeared to be short, in particular her hands withproximally placed thumbs and tapering fingers.Rockerbottom feet showed dorsal lymphoedema.She had generalised hypotrichosis and a dry, hyper-keratotic, and scaling skin. Dermatoglyphics showedbilateral single palmar crease, palmar axial triradiusin the t' position, and ulnar loops on all fingertips.

Laboratory studies including urinary amino acidsand mucopolysaccharides excretion gave normal re-sults. G banded chromosomes were normal.

Radiological findingsAt birth, she had a strikingly small skull (fig 6) with asteep and sclerotic cranial base, small and slopingfrontal bone, and a well ossified occipital bone with aprotuberance (bathrocephaly).A so-called 'babygram' (fig 7) showed long clav-

icles, poor ossification of the sternum, and only 11pairs of ribs which were dorsally narrow. The spinewas abnormal with moderate platyspondyly andcoronal clefts of lumbar vertebral bodies (fig 8). Theiliac wings were rounded with horizontal, irregularacetabular roofs. The long tubular bones ofher armsand legs were short and poorly modelled. In addi-tion, the cortices of both humeri were unusuallythick. Bilateral malposition of the proximal radiussuggested dislocation of the radial heads. Both handsshowed ulnar deviation and there were rockerbot-tom feet bilaterally. The first metacarpals wereslightly short and the proximal phalanges of the bigtoes were particularly short and rounded. While thetalus and the calcaneus showed immature ossifica-tion, there was otherwise a total lack of epiphysealossification.

Re-examination at 5 months showed that the skullwas still strikingly small, the long tubular bonesremained undermodelled, and bone age was mark-edly delayed.

Clinical courseFeeding was uncomplicated but weight gain wasslow. During the neonatal period a few seizures werenoted which ceased after treatment with phenobar-bital. At the age of 6 months, length was 45 cm(-8 SD), weight 3815 g (3rd centile for age), andOFC was 32 cm (-7 SD). The girl was able tofollow objects with her eyes, but otherwise psycho-motor development was severely retarded. At 6

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Figure 5 Case 2 at birth. Note microcephaly with sloping forehead and prominent occiput, low set and dysmorphic ears,short limbs, and hypotrichosis.

Figure 6 Case 2 at birth. Note small neurocraniumand bathrocephaly.

months, she died suddenly at home from unex-plained causes.

Necropsy findingsNecropsy showed no internal malformations apartfrom brain abnormalities. Neuropathological studies

Figure 7 Case 2 at birth. Note 11 pairs of ribs, roundediliac wings with horizontal, irregular acetabular roofs, andshort, poorly modelled tubular bones of arms and legs.

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Microcephalic osteodysplastic primordial dwarfism type I/III in sibs

Figure 8 Case 2 at birth. Note moderate platyspondylyand coronal clefts of lumbar vertebral bodies.

(courtesy of Dr H Klein, Bremen) showed markedmicrencephaly (brain weight 180 g) with poorlygyrated telencephalon and particularly hypoplastic,nearly lissencephalic frontal lobes. The corpus callo-sum was absent (fig 9). Histologically, there weresigns of severely arrested differentiation of thecerebral cortex and extremely reduced mass de-velopment of the white matter, whereas the brain-stem and spinal cord showed normal architecture.

DiscussionFeatures common to this pair of sibs are primordialdwarfism, severe microcephaly, and a variety ofexternal characteristics, such as large and protrudingeyes, deep set, small, and poorly differentiated ears,micrognathia, short neck, short limbs, dorsal lym-phoedema of the hands and feet, tapering fingers,and dry, scaling skin with strikingly sparse hair. Inaddition, psychomotor development is severelyretarded.

Radiologically, both patients show a markedlysmall neurocranium, relatively long clavicles, 11pairs of ribs only, rounded iliac wings with hori-zontal acetabular roofs, short and poorly modelledtubular bones, unusually narrow joint spaces, andmarkedly retarded epiphyseal maturation. Apart

from severe microcephaly, neuropathological find-ings include strikingly arrested brain maturation,expressed by very hypoplastic frontal lobes, poorgyration of the cortex, absent corpus callosum, andhistologically poor differentiation of the cortex andthe white matter.Our observation in sibs indicates a considerable

spectrum of phenotypic and prognostic variability ofthis condition. In case 1, the birth length was -5-2SD, whereas it was -9 SD in case 2. The radiolo-gical changes were also more severely expressed incase 2 as shown by more pronounced platyspondyly,coronal clefts of vertebral bodies, thin ribs, andmarked shortening of the first metacarpals. Thevariable prognosis is shown by the short survival of 6months in case 2, whereas case 1 died at the age of 5jyears, and is the oldest documented patient with thiscondition. Thus, considerable intrafamilial variab-ility has to be expected in this disorder in keepingwith the well known interfamilial variability in mic-rocephalic osteodysplastic primordial dwarfism(MOPD).With regard to the nosology ofMOPD, Majewski

et al'0 felt that mainly radiological characteristicsrather than clinical ones would allow the distinctionbetween types I and III MOPD. While commonfeatures in both types are severe intrauterine dwarf-ism, severe microcephaly, and similar facies, in typeI dwarfism was more disproportionate with short

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Figure 9 Case 2. Lateral view of the micrencephalic brain(above) and coronal section (below). Note hypoplastic,lissencephalic frontal lobes and absent corpus callosum.

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and bowed humeri and femora, the skull was notdolichocephalic, the pelvis was less 'dysplastic', andthere were no medial spurs of the ischial bones. Onthe other hand, type III is thought to be character-ised by a dolichocephalic skull, elongated clavicles,platyspondyly, marked 'dysplasia' of the pelvis, andenlargement of the proximal femoral metaphyses.The present pair of sibs share characteristics of

both types I and III. Our case 1 could be classified astype I MOPD, whereas case 2 would better fit typeIII, as postulated by Majewski et al.10 Thus ourobservation supports the hypothesis of Winter et a!6that types I and III MOPD probably constitute oneand the same entity. The same conclusion has beenreached by Haan et al7 and by Meinecke et a!8 on thebasis of isolated patients. It is not yet clear whetherthe patients originally described by Taybi andLinder,9 named 'cephalo-skeletal dysplasia', as wellas the patients published later by Thomas andNevin" and by Lavollay et al'2 belong to the samedisorder. However, clinically and radiologically thesimilarity among these patients, in particular withthe observation of Majewski et a1,'0 who classifiedthem as type III MOPD, is so convincing that wethink this is one and the same entity. Agreeing thatthere is a 'type II' MOPD, as proposed by Majewskiet a!4 on the basis of their observations and thepreviously published patients of Brizard et a!2 andAnoussakis et al,3 it would now be reasonable toclassify MOPD into type I (including the publishedcases of 'cephalo-skeletal dysplasia') and type II.Thus, the designation 'type III' can be omitted forthe time being.There is now sufficient evidence for a genetic

aetiology of this condition. Parental consanguinity9 13and occurrence among sibs of different sex9 (thisreport) corresponds to autosomal recessive inherit-ance. The gene has not yet been localised.The pathogenesis of this condition is unknown.

Impaired maturation of ectodermal, neural, andmesenchymal structures indicates a basic defectwhich preferentially affects cell proliferation andtissue differentiation. Noticeable is an almost totallack of early embryonic anomalies. Further studies

should involve thorough histological and electronmicroscopical investigations of neural tissues as wellas in cultured cells. This group of disorders mightresult from mutations of genes that are important inthe embryonic and fetal development of neural dif-ferentiation and proliferation.

We are grateful to Dr Elke Schaefer, paediatricradiologist in Hamburg, for diagnostic evaluation ofthe radiographs. We also thank Professor Gunschera(Bremen) for kindly providing radiographs of thesepatients.

1 Majewski F, Goecke T. Studies of microcephalic primordialdwarfism. I. Approach to a delineation of the Seckel syn-drome. Am J Med Genet 1982;12:7-21.

2 Brizard J, Mimouni M, Seneze J, Thoyer-Rozat J. Sur un casde nanisme extreme a debut intra-uterin vraisemblablementdu type Seckel. Ann Pediatr 1973;20:655-60.

3 Anoussakis C, Liakakos D, Zervos N, Karpathios T. Lesnanismes congenitaux avec dysmorphie. II. Le nanisme con-genital a tete d'oiseau (type Virchow-Seckel). Pidiatrie1974;29:261-7.

4 Majewski F, Ranke M, Schinzel A. Studies of microcephalicprimordial dwarfism. II. The osteodysplastic type II ofprimordial dwarfism. Am J Med Genet 1982;12:23-35.

5 Verloes A, Lambrechts L, Senterre J, Lambotte C. Micro-cephalic osteodysplastic dwarfism (type II-like) in siblings.Clin Genet 1987;32:88-94.

6 Winter RM, Wigglesworth J, Harding BN. Osteodysplasticdwarfism: report of a further patient with manifestationssimilar to those seen in patients with types I and III. Am JMed Genet 1985;21:569-74.

7 Haan EA, Furness ME, Knowles S, et al. Osteodysplasticprimordial dwarfism: report of a further case with manifesta-tions similar to those of types I and III. Am J Med Genet1989;33:224-7.

8 Meinecke P, Schaefer E, Wiedemann HR. Microcephalic osteo-dysplastic primordial dwarfism: further evidence for identityof the so-called types I and III. Am J Med Genet 1991;39:232-6.

9 Taybi H, Linder D. Congenital familial dwarfism with cepha-loskeletal dysplasia. Radiology 1967;89:275-81.

10 Majewski F, Stoeckenius M, Kemperdick H. Studies of micro-cephalic primordial dwarfism. III. An intrauterine dwarfwithplatyspondyly and anomalies of pelvis and clavicles - osteo-dysplastic primordial dwarfism type III. Am J Med Genet1982;12:37-42.

11 Thomas PS, Nevin NC. Congenital familial dwarfism withcephalo-skeletal dysplasia (Taybi-Linder syndrome). AnnRadiol 1976;19:187-92.

12 Lavollay B, Faure C, Filipe G, Branca G, Huet de Barochet Y.Nanisme familial congenital cephalo-squelettique (syndromede Taybi-Linder). Arch Fr Pediatr 1984;41:57-60.

13 Majewski F, Spranger J. Case report 49. Syndrome Identifica-tion 1976; IV:17-21.

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microcephalic osteodysplastic primordial dwarfism … dwarfism (mopd)are described,...

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