New Autosomal Recessive Syndrome of SevereMicrocephaly and Skeletal Anomalies IncludingPosterior Rib-Gap Defects

Alex Duval,1 Odile Boute,1 Louise Devisme,2 Anne S. Valat,3 and Sylvie Manouvrier1*1Consultation de Conseil Genetique, Hopital Jeanne de Flandre Chru, Lille, France2Laboratoire d’Anatomie Pathologie, Hopital Albert Calmette Chru, Lille, France3Service de Foetopathologie, Hopital Jeanne de Flandre Chru, Lille, France

We describe two female fetuses conceivedby a nonconsanguineous couple. The preg-nancies were interrupted at 31 and 26 weeksof gestation, respectively, because of severemicrocephaly. Postmortem X-ray and au-topsy studies showed in both fetuses: 1) se-vere intrauterine growth retardation; 2) fa-cial anomalies characterized by severe mi-crocephaly, sloping forehead, low set andposteriorly angulated ears, prominent eyes,down-slanting palpebral fissures, largenose, small mouth with full lips, and mildmicroretrognathia; 3) severe brain hypopla-sia that was more pronounced in the secondfetus; 4) severe rib hypoplasia with poste-rior rib-gap defects and in case 2 hypoplasiaof several bones (right clavicle, right radiusand ulna, several phalanges of hands andfeet); 5) contracture at large joints. No othervisceral malformations were observed, andchromosomes were normal in patient 2 andparents. This phenotype has some similari-ties with different syndromic entities but anidentical malformation syndrome seems notto have been described previously. Autoso-mal recessive inheritance is the most likelycause of this putative ‘‘new syndrome.’’ Am.J. Med. Genet. 80:429–434, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: microcephaly; brain hypo-plasia; rib hypoplasia; rib-gap defects; intrauterinegrowth retardation

INTRODUCTION

Severe congenital microcephaly has been noted inmany genetic syndromes and in nongenetic conditions.Several physiopathological processes are involved. No-tably it can be caused by severe developmental defectoccurring during brain development in some geneticentities. On the contrary, for purposes of genetic diag-nosis, the specificity of rib hypoplasia is high as thisdefect is seen in only few syndromes, especially whenassociated with rib-gap defects. Here, we present de-tails of two sib fetuses affected by a striking multiplecongenital anomalies (MCA) syndrome characterizedby these ribs anomalies and severe microcephaly ofprenatal onset. According to the family history, an au-tosomal recessive inheritance is likely for this putativenew syndrome.

CLINICAL REPORTS

We report on two female fetuses whose parents werereferred to us for genetic counseling. Mother and fatherwere healthy and nonconsanguineous and family his-tory was unremarkable. The mother was 27 years old.She had had two male twins with normal growth anddevelopment and two spontaneous miscarriages at 6and 8 weeks of gestation, respectively, occurring be-tween the birth of the two fetuses described here. Thepregnancies of the propositae were free of maternalinfections and drug exposure and were medically inter-rupted at 31 weeks and 26 weeks of gestation, respec-tively, because of severe microcephaly detected on ul-trasonography.

Fetus 1

Pregnancy was terminated at 31 weeks of gestation.This female fetus (Fig. 1B) presented with severe in-trauterine growth retardation (weight 850 g, median of25 weeks). Her craniofacial anomalies included severemicrocephaly (head circumference 18 cm, median of16.5 weeks) and a significant facial abnormality (Fig.2B). Contractures of knees and elbows were observed.The thorax was small and bell-shaped. Postmortem X-ray films showed posterior ‘‘gap defects’’ on the fourthand fifth right ribs and on the fifth left rib and gener-

*Correspondence to: Sylvie Manouvrier, Consultation de ConseilGenetique, Hopital Jeanne de Flandre Chru, 59037 Lille cedexFrance

Received 24 August 1998; Accepted 27 August 1998

American Journal of Medical Genetics 80:429–434 (1998)

© 1998 Wiley-Liss, Inc.

alized marked rib hypoplasia. Autopsy confirmed mi-crocephaly (brain weight was 47 g, median of 20 weeks)caused by severe hypoplasia of the frontal and occipitallobes; cerebellum and other cerebral lobes were normalwith normal cortical architecture. Histological study ofthe brain showed no specific abnormality. No other vis-ceral anomalies were observed.

Fetus 2

Ultrasonography at 24 weeks showed severe intra-uterine growth retardation associated with severe mi-crocephaly (biparietal diameter of 38 mm, median of16.5 weeks; head circumference of 144 mm, median of18.5 weeks) and webbed neck with redundant skin (8mm). Pregnancy was interrupted at 26 weeks. Birthweight was 372 g (median of 21.5 weeks); length 26.5cm (median of 20.5 weeks), and head circumference 15cm (median of 19 weeks). This female fetus (Fig. 1A)presented with the same craniofacial anomalies as hersister with severe microcephaly (Fig. 2A). The hard pal-ate was intact but narrow and high-arched, the neckwas short, and the thorax was small and bell-shaped.Arthrogryposis with contractures of large joints was

also noted. Hands and feet were abnormal with shortfifth fingers, clinodactyly of the second right finger, andbilateral partial syndactyly of fourth-fifth toes. Post-mortem X-ray films, showed several skeletal anomalies(Fig. 3), thin ribs with posterior rib-gap defects, andhypoplasia of several long bones (right clavicle, rightradius, and ulna). Moreover, middle phalanges of fin-gers and proximal phalanges of great toes, which wereclinically present, appeared unossified or hypoplasticon X-ray films. The autopsy showed severe generalizedcerebral hypoplasia (weight 24.2 g, median of 18.5weeks) with predominant involvement of the frontaland occipital lobes. The external appearance of thebrain was abnormal and consistent with a gestationalage of 17 weeks. The cerebral hemispheres weresmooth, but the cortical structure was histologicallynormal for the gestational age with regular distribu-tion of neurons resulting in normal cortical layers, cor-responding to the diagnosis of ‘‘radial microbrain’’ ormicrolissencephaly, which is caused by a defect in neu-roblast multiplication [Kroon et al., 1996]. Other vis-cera were grossly and histologically normal. Ribs werepresent but underossified.

Fig. 1. The propositae at time of examination. A: case 2 (26 weeks of gestation); B: case 1 (31 weeks of gestation). Note severe microcephaly, bell shapedchest, and contracture of large joints.

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Routine chromosome analyses from peripheral bloodwere performed on this fetus and the parents by GTGbanding. The fetal karyotype was normal at the 400-band level. Parental chromosomes were also normalwith high resolution banding studies.

DISCUSSION

Both fetuses suffered from the same MCA syndromecharacterized by distinctive craniofacial anomalies in-cluding severe microcephaly, backward sloping fore-head, down-slanting palpebral fissures, prominenteyes, large nose, low-set and posteriorly angulatedears, small mouth with full lips, mild microretrogna-thia, short and webbed neck, bell-shaped chest andcontractures of large joints, and hypoplastic ribs withposterior rib-gap defects. Other skeletal anomalieswere also found in case 2, including hypoplasia of sev-eral long bones (right clavicle, right radius, and ulna),and radiographically absent or hypoplastic phalanges(middle phalanges of fingers, proximal phalanges ofgreat toes). Chromosomes were apparently normal. Inreviewing the cases, no diagnosis resulted from an ex-tensive search on the POSSUM and OSSUM Data-bases and literature. Although the combination of in-

trauterine growth retardation, severe microcephalycaused by marked cerebral hypoplasia, arthrogryposisand skeletal anomalies, including hypoplastic ribs withposterior rib-gap defects has not been described in anyother known syndromes, some need to be discussed(Table 1), because they are characterized by: 1) asso-ciation of microcephaly and rib anomalies, as in thecerebrocostomandibular syndrome (CCMS); 2) associa-tion of microcephaly of prenatal onset with severe ce-rebral hypoplasia and skeletal anomalies as in someskeletal dysplasias; and 3) other skeletal anomalies ofthe limbs affecting phalanges of hands and feet as inatelosteogenesis (AO).

Posterior rib-gap defects are associated with micro-cephaly in CCMS, which is a rare condition with mul-tiple defects involving especially posterior ribs andmandible. Fifty-three cases have been described so farworldwide [Hennekam and Goldschmeding, 1998; Vanden Ende et al., 1998]. Its cardinal manifestations (pos-terior rib-gap defects and severe micrognathia) aresimilar in all patients, however, variability of the rib-gap defects can be considerable. The number of ribsinvolved varies from a few to almost all and usuallyboth sides are affected, although not necessarily sym-

Fig. 2. A: case 2; B: case 1. Same facial appearance with microcephaly, sloping forehead, low set and posteriorly angulated ears, down-slantingpalpebral fissures, large nose, small mouth with full lips, and microretrognathia.

New AR Syndrome of Microcephaly and Rib-Gap 431

metrically. Hypoplastic and rudimentary ribs, as de-scribed in our cases, have also been observed. Microret-rognathia is severe with palatal anomalies in approxi-mately 90% of cases, mostly clefts (67%) or PierreRobin anomaly (66%). Microcephaly of postnatal onsetmay be present (40%), sometimes associated withstructural cerebral anomalies [Plotz et al., 1996]. So farthese have been detected in only three living patientsby ultrasound and CT scan, and they include largeporencephalic cyst and no definable ventricular systemor interhemispheric fissure in one case; agenesis of thecorpus callosum with ‘‘enhancement’’ of the right leaf ofthe tentorium and enlargement of both lateral ven-tricles in another, and ‘‘fluid filled supratentorial’’ com-partment in yet another [Clarke and Nguyen, 1985;Merlob et al., 1987; Burton and Oestreich 1988]. Ex-ceptionally, intrauterine growth retardation and ribanomalies could be seen by ultrasound examinationduring pregnancy, but usually prenatal diagnosis isvery difficult and probably restricted to families with apositive history for CCMS [Merlob et al., 1987]. Hori-zontal and vertical transmission in the familial casessuggest the possibility of genetic heterogeneity withboth autosomal-recessive and autosomal-dominant in-heritance. In the cases reported here, CCMS was dis-cussed because of micrognathia and small, bell-shapedchest with rib anomalies that can be similar. However,the syndrome described here contains more severe

anomalies than CCMS, and this diagnosis was rejectedfor several reasons: 1) in CCMS, microcephaly is mild,not always present and of postnatal onset; 2) althoughmild retrognathia was observed in both cases reportedhere, they did not have either Pierre Robin sequence ora cleft palate; and 3) other bone anomalies similar tothose observed here have never been described inCCMS. A severe case of CCMS has been recently de-scribed in a girl who died shortly after birth [Hen-nekam and Goldschmeding, 1998], but absence of anyrib ossification as well as normal brain autopsy makethis case different from ours.

Extreme microcephaly of prenatal onset with majorcerebral hypoplasia involving all lobes is rarely ob-served and has been reported in very few syndromes,including: seckel type of bird-headed dwarfism, whichcan be excluded because of its specific phenotype andevolution very dissimilar to those of the cases describedhere [Majewski and Goecke, 1982] and severe micro-cephalic dwarfism of prenatal onset (MOPD) types I,II, and III [Bass et al., 1975; Brizard et al., 1973; Ma-jewski et al., 1982a; Majewski et al., 1982b], which ap-pear to be separate entities in view of the differentosteodysplastic anomalies. Our patients showed somecharacteristic facial manifestations of MOPD (back-ward sloping forehead, protruding eyes, down-slantingpalpebral fissures, large nose, micrognathia, andlow set ears). Neuropathological studies in several

Fig. 3. X-rays of patient 2. Note hypoplastic ribs with posterior rib-gap defects, hypoplasia of right clavicle, right radius and ulna, absent or hypoplasticmiddle phalanges of fingers, and hypoplastic proximal phalanges of great toes.

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cases of MOPD typeI/III demonstrated several corti-cal anomalies such as micrencephaly with severelyhypoplastic, poorly gyrated frontal lobes, and absentcorpus callosum in a male baby who died at the age of33 days [Haan et al., 1989]. Short middle phalanges,like in our case 2, are classically observed in MOPDtype II. However, both present fetuses clearly do not fitthis diagnosis. They are not markedly dwarfed withdisproportionately short limbs as observed in MOPD.Moreover, thin ribs with rib-gap defects are not in-cluded in the clinical spectrum of these bone dyspla-sias.

Lastly, some of the observed skeletal anomalies ofhands and feet, other bone anomalies, or isolated facialcharacteristics are also present in other syndromes, al-though the main characteristics of these conditions arenot observed in our patients. Notably our second casehas some roentgenographic manifestations in commonwith AO type I, a perinatal lethal form of skeletal dys-plasia first described by Sillence et al. [1982] and Ma-roteaux et al. [1982]. It represents one of the rare neo-natal osseous dysplasias characterized by incompletebone formation. Thin and hypoplastic ribs as well asuneven ossification of most of the proximal and middlephalanges of hands and feet have been described in AOtype I. However, craniofacial anomalies as observed inpresent cases are not features of AO type I.

In conclusion, this sibship is of interest because thetwo affected fetuses presented with severe microceph-aly caused by extensive cerebral hypoplasia and severeintrauterine growth retardation, which were diagnosedat 31 and 26 weeks of gestation, respectively. Based onthe severity of these findings we think that prenatal

diagnosis could be made earlier. We suggest that thissibship represents a previously undescribed syndromeinherited as an autosomal recessive trait, although go-nadal mosaicism for a dominant mutation in one par-ent cannot be excluded.

ACKNOWLEDGMENT

We thank M. Le Merrer for excellent clinical assis-tance.

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TABLE I. Clinical Manifestations of Patients A and B Compared With Those Observed in theLiterature in CCMS and OPD

Manifestations Patient A Patient B CCMS MOPD AO type 1

IUGR (severe) + + − + +rhizomelic

IUGR (moderate) +/−

Microcephaly (prenatal onset) + + − + −Microcephaly (postnatal onset) 40%

Backward sloping forehead + + − + −Down-slanting palpebral fissures + + − + −Prominent eyes + + − + +Long/large nose + + − + −

Cleft and/or highly arched palate 91% 100%High vaulted and narrow palate

without clefting ? + +Micrognathia/retrognathia + + 100% + +Low set/retroverted ears + + − + +Short neck + + − + +Webbed neck/excess skin + + + + −Bell-shaped chest + + + − −

Thin/hypoplastic ribs + + + − −Rib-gap defect + + 98% − −

Absent/hypoplastic clavicle − + − + −Absent/hypoplastic radius − + − − +/−Absent/hypoplastic ulna − + − − +/−Contracture of large joints + + − + +Absent/small/short phalanges − + − + +

+, present; −, absent; +/−, inconstant; and when known estimated frequency in the literature [Van den Ende etal., 1998].

New AR Syndrome of Microcephaly and Rib-Gap 433

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