Are bowing of long tubular bones and preaxial polydactyly signs of the Meekel syndrome? F. Majewski 1, H. StiJli3, T. Goecke 1, and H. Kemperdick 2 1 Institute of Human Genetics and 2Children's Hospital, University of Diisseldorf, 4000 Dtisseldorf, Federal Republic of Germany 2 Institute of Pathology, University of Erlangen, 8520 Erlangen, Federal Republic of Germany
Summary. We describe four cases with signs resembling those of Meckel syndrome. Two cases demonstrated postaxial polydactyly; one case, Preaxial polydactyly; and one case, pre- and postaxial polydactyly. Sinee there is at least one other reported case with preaxial polydactyly, it may be a rare sign of the Meckel syndrome. In all four cases, various degrees of bowing of the long tubular bones were observed. Since at least two cases exhibited typical Meckel syndrome and since in a few further reported cases X-ray examination revealed bowing of long tubular bones, this sign is considered to be a further, hitherto not well recognized sign of the Meckel syndrome, and not grounds for delineation of a new syndrome. A n extensive review of the literature revealed, that shortened and bowed extremities may be present in about one-sixth of all cases with Meckel syndrome.
Introduction Occipital encephalocele, cleft lip and palate, polycystic kidneys, and postaxial polydactyly are the main signs of the Meckel syndrome, transmitted by autosomal recessive inheritance (Mecke and Passarge 1971). This syndrome has been published in some 130 cases, but roentgenographic findings are rarely reported. Kemperdick et al. (1975) and Kozlowski et al. (1977) have been the only authors to publish roentgen films in a typical case. In each of these two cases the tibiae were bowed, broadened, and foreshortened; the other long tubular bones were unremarkable. It seems likely that this feature is a further, but poorly known sign of the Meckel syndrome. We report four cases with congenital bowing of long bones in addition to some signs of the Meckel syndrome.
Case reports Case 1. V., male, born 2 February 1981
The patient (Fig. 1) was the first child of nonconsanguineous young, healthy, parents. With a subsequent pregnancy the mother gave birth to a healthy child. Gestation was complicated by hydramnios; birth was by breech delivery in the 38th gestational week. Birth weight was 2200 g, length 44 cm, head circumference (OFC) 34 cm, Apgar score 3/6/5/6. We saw the baby at age 2 h. His skull appeared hydrocephalic, the fontanelles and sagittal suture being widely spaced. There was a tangerine-sized occipital encephalocele with a bony spur in Offprint requests to: F. Majewski
its cranial margin. The forehead was broad and somewhat bulging. The palpebral fissures were narrow and not slanted, the distance between the medial canthi being 21 m m and between the lateral canthi, 26 mm. The nose was unremarkable except for numerous milia. There was complete cleft palate and a small pedunculated fibroma at the right velum. The upper alveolar ridge was irregularly notched; there were three atypical frenula. The tongue was attached to the floor of the mouth. The chin was markedly receding. The ears were deepset and dysplastic. The right upper part of the thoracic cage appeared pushed in. The abdomen was unremarkable and not enlarged. He had male genitalia, but a very fiat scrotum, which did not contain testicles. His legs seemed to be somewhat shortened due to bowing of all long tubular bones. He had club feet bilaterally. Both big toes showed syndactylous doubling and were deviated medially. There was 50% cutaneous syndactyly of toes 2 and 3 on the left, the other toes being normally separated, but the 4th on the left was shortened. All toe nails were hypoplastic. Both thumbs were completely doubled, syndactylous, and deviated radially. On his left hand; the index finger was shortened; there was complete syndaetyly with the 3rd finger and complete syndactyly of fingers 4 to 6. The supernumerary 6th finger was hypoplastic, all nails of fingers 4 to 6 being separated. On his right hand, he showed 50% syndactyly of the shortened and radially deviated digits 2/3 and complete syndactyly of digits 4/5/6. The 6th ray was hypoplastic and had no nail; the nails of fingers 4/5 were separated. The main palmar creases were abnormal and the left proximal palmar crease was hypoplastic. There was a supernumerary crease distal to the distal transverse crease beyond digits 4 to 6. On the right hand, the proximal transverse crease ended in an abnormal bowed crease proximal to digits 5 and 6. The soles of his feet had no furrows at all. The newborn was cyanotic and moribund. Chest X-rays exhibited white lungs, with no visible heart shadow. The child died at age 6 h. Chromosome analysis with G-banding revealed a normal karyotype, 46,XY. Autopsy findings included a few small renal cysts next to the cortex, no enlargement of the kidneys, no congenital heart defect, but hematopericardium (due to puncture). Both testes were situated inguinally. In the middle portion of the bowed femur, the compacta was broadened and there was no visible spongiosa. The brain was abnormal, with micropolygyria, agenesis of corpus callosum, median cleft of the cerebellum and brain stem, and occipital encephalocele. On X-ray, (Figs.2 and 3), ribs 1-8 on the right appeared deformed and shortened. The pelvis and vertebral column
Fig. 1. Case 1. Occipital encephalocele, low-set ears, pre- and postaxial polysyndactyly of the hands, duplication of the big toes
Fig.2. Case 1. Lower extremities with bowing of all tubular bones
Fig.3a, b. Case 1. a Pre- and postaxial polysyndactyly of the right hand. b Preaxial polysyndactyly of the right foot
127 were unremarkable. The humerus, ulna, femur, tibia, and fibula were sharply bowed in their median parts, this bowing resembling a fracture in the left femur. In the median parts of the femora and tibiae, the cortex was broadened and appeared striped. The space of the spongiosa was markedly reduced in these areas, in which a notchlike deformity was present. X-rays of the feet exhibited preaxial polysyndactyly and five metatarsals bilaterally. X-rays of the hands demonstrated preand postaxial polysyndactyly with seven fingers and five metacarpals bilaterally.
Case 2: Sch., female, born 7 November 1980
Both parents were healthy and nonconsanguineous. The mother has a healthy child by another man. Gestation was complicated by a viral infection in the first weeks. Delivery was spontaneous in the 31st week of gestation; the newborn died shortly after birth. Birth weight was 2500 g, length 43 cm. There was marked turri- and hydrocephalus with bulging forehead and several defects of ossification of the calvaria. Microphthalmia and marked hypertelorism were present. The nose appeared short. There were multiple pedunculated skin appendages all over the face. The chin was markedly receded. The palate was completely cleft; the lips were intact. The ears were rudimentary, dysplastic, and low set, nearly at the level of the mouth. There was a polycystic hygroma colli, but no encephalocele. The sternum was missing, the apex of the heart being situated extrathoracically. The thorax was narrow; the abdomen, huge and protruding; the external genitalia were female (Fig. 4). All four extremities were shortened and bowed; she had club feet bilaterally. The big toe was doubled in both feet, with complete cutaneous syndactyly on the left and partial on the right. All other toes were short, with partial cutaneous syndactyly on the right and complete syndactyly of toes 3-5 on the left. All nails of the toes and fingers were rudimentary. There were five shortened fingers in both hands, all fingers being abnormally widely separated despite partial cutaneous syndactyly of digits 2/3 and 4/5 bilaterally. Autopsy revealed numerous internal malformations. The brain was abnormal, with broad and flat gyri. The lateral ventricles were enlarged; the corpus callosum was missing. The cerebellum was very small, with an abnormally polymicrogyric vermis, which was located like a supernumerary lobe between the hippocampal area of both temporal lobes. The foramen magnum was narrow. Both lungs were hypoplastic, and the ribs shortened. There was a diaphragmatic hernia on the left. The heart was located partially extrathoracically but otherwise showed no malformations. Both kidneys were large (10× 5 x 4 cm), with polycystic degeneration of Potter type 2a. There were multiple cysts in the pancreas also, and polymicrosplenia. Multiple leiomyomas were observed at the mesenterium commune. There was malrotation in the intestines and doubled anlagen of uterus and vagina; the ovaries appeared elongated. The caryotype (including G-banding) was normal, 46,XX, in cultured fibroblasts. Roentgenologic examinations revealed bowing of all long tubular bones, more marked in the lower than in the upper extremities. Each of the long tubular bones showed a notch in the midportion and triangular stripes in the cortex running to the apex of the bowing. This bowing was nearly rectangular in the left tibia and fibula (Figs. 5 and 6). The tibiae were neither broadened nor disproportionally shortened. There were six metatarsals on the right and five on the left, both big toes being doubled. The spine and pelvis corresponded with fetal age.
Fig. 4. Case 2, General appearance; note the protruding abdomen and the pedunculated masses all over the head.
Fig. 5. Case 2. Full-body X-ray. Note angulation of the long tubular bones
Fig. 6. Case 2. Postmortem X-ray of the extremities. Note angulation of both femora, left tibia and fibula, both humeri, and left radius and ulna as well as preaxial polydactyly in the feet (visible on the right only)
Fig. 7a, b. Case 3. Lateral view with micro-anencephaly and occipital encephalocele, b Frontal view with bilateral CLP, protruding abdomen, omphalocele, and club feet Case 3. E., male, born 3 December 1981, Erlangen This infant was the first child of healthy, unrelated young parents. Routine ultrasonic examination revealed anencephalus in the fetus. Amniocentesis was done in the 16th and 21st weeks of gestation. Prenatal diagnosis revealed a normal male karyotype, 46,XY and a pathologically elevated level ofafetoprotein (207 900 ng/ml) in the anmiotic fluid. The parents refused abortion. The child was born spontaneously in the
36th week of gestation; he died intrapartum. Birth weight was 2800 g, length 37 cm, and OFC 28 cm. The child was extremely microcephalic with a large occipital encephalocele (Fig. 7). The os occipitale showed a 2- cm defect which extended to a cleft of the first vertebra. There was bilateral microphthalmia, marked hypertelorism, and slight antimongoloid slanting of the shortened palpebral fissures. The nose was fiat and broad. There was bilateral cleft lip and palate. The lower alveolar ridge exhibited multiple notches. The tongue was attached
Fig. 8. Case 3. Postmortem X-rays of lower extremities with bowing of all long tubular bones, most pronounced in the tibiae to the floor of mouth. The ears were dysplastic and poorly formed. The thorax was broad and short, the abdomen extremely protruding. There was an omphalocele, in 2 cm diameter, containing parts of the polycystic liver. There was a wide rectus diastasis with only some rudimentary muscle fibers in the lateral parts of the upper abdomen. All extremities were shortened and bowed, more markedly in the distal parts than in the proximal parts. There was rudimentary postaxial hexadactyly in the right hand; the left showed hexadactyly also, but the supernumerary finger was of intermediate type due to doubling of the whole 3rd ray. There was complete cutaneous syndactyly 5/6 in the right hand. Both feet were clubbed, but neither showed syndactyly nor polydactyly. Autopsy revealed hypoplasia of both lungs and total situs inversus. The aorta descended on the right side; the cranial and caudal vena cava were situated on the left. There was no heart defect. The liver was located in the left side, the spleen on the right. The liver was polycystic (mainly due to large ectasias of the bile ducts), as were both kidneys, pancreas, and ovaries. The spleen showed some notches, and there were several small supernumerary spleens. The external genitalia were female; the internal genitalia were ambiguous, with a rudimentary vagina, uterus bicornis, and rudimentary intraabdominal testicular anlagen. Both suprarenal glands were hypoplastic. There was marked intestinal malrotation, The karyotype was 46,XY. The brain was grossly malformed, with flat gyri. Classification of distinct brain areas was not possible histologically. There were numerous cavernous vessels with irregular calcifications. The encephalocele contained cavernous vessels, calcifications, and some areas of white matter as well as glial formations. X-ray examination demonstrated extreme microcephaly. Rib pairs 1-5 were bowed abnormally upward. The pelvis was
Fig. 9. Case 3. Hexadactyly of both hands, postaxial in the right and intermediate in the left
Fig. 10. Case 4. Postaxial polydactyly in the right foot. Note bowed tibia dysplastic and small. All long tubular bones were shortened, more obviously the forearms and lower legs. Both radii were broadened, shortened, and bowed, with a sharp bend in the midportion. Both femora were shortened and bowed, the cortex being triangularly thickened in the midportion. Both tibiae
130 Table 1. Signs in 114 cases with Meckel syndrome compared with those of 23 cases with Meckel syndrome plus shortened extremities and of our four observations Sign
Meckel syndrome plus shortened extremities
Perinatal death Occipital encephalocele Microcephaly Hydrocephalus Agenesis of corpus callosum Hypoplasia of cerebellum Eye malformations Dysplastic ears Cleft lip/alveolar ridge Cleft palate Cleft tongue Hypoplasia of mandible Congenital heart defect Hypoplasia of lungs Short ribs Malrotation Cysts of liver Cysts of pancreas Polycystic kidneys A- or hypoplasia of kidneys Umbilical hernia Malformed genitalia Short extremities Campomelia Postaxial polydactyly of hands of feet Hepta(octa-)dactyly Preaxial polydactyly Syndactyly Club feet
a In two sibs there was no detailed description of extremities. The cases are taken from Alfieri (1946); Altmann et al. (1977); Aula et al. (1977); Babes (1904); Battaglia and Locatelli (1956); Brtickner (1869); Calmann (1893); Chemke et al. (1977); Crawford et al. (1978); Duncan et al. (1979); van Duyse (1900); Fitch and Pinsky (1973); F6rster (1862); Fried et al. (1971); Friedrich et al. (1979); Fryns et al. (1980); Gibb (1962); Giordano (1933,1936,1949); Gruber (1859); Gruber (1934); Holmes et al. (1976); Hsia et al. (1971); Joly (1866); Karjalainen et al. (1981); Kemperdick et al. (1975); Kozlowski et al. (1977); de Lange (1930); Lauras et al. (1976); Lenz (1966); Leschot et al. (1978); Levin (1895); Lundin and Olow (1961); Malpuech et al. (1979); Marshall et al. (1964); Mecke and Passarge (1971); Meckel (1822); Meitner (1961); von Meyenburg (1918)); Miller and Selden (1967); Moermann et al. (1982a, b); Mohr (1941); Nevin (1979); Naffah (1972); Nieberding (1887); Opitz and Howe (1969); Parisio (1951); Pohlmann (1935); Roscher (1933); Rfimler (1934); Schlenzka (1867); Schupmann (1842); Schurig et al. (1980); Seller (1978,1981); Shapiro (1977); Simopoulos (1967); Stockard (1920-21); Strassmann (1894); Teuscher (1926); Tucker et al. (1966); Virchow (1855); Voss (1866); Wackerle (1926); Walbaum et al. (1967); Walther and Leli~vre (1923); Wigand (1889); Witzel (1880); Wollenberg (1889); Zancla (1937) were markedly broadened, coarse, and sharply b o w e d in their midportion. T h e fibulae were b o w e d only slightly. T h e r e were five metacarpals and a complete sixth postaxial finger in the right hand. In the left hand, the 3rd metacarpal was doubled and V-shaped. All bony phalanges of the 6th finger in the left h a n d were of normal size. As in most long tubular bones, the cortex was triangularly thickened in the m i d p o r t i o n of all metacarpals (Figs. 8 and 9). Case 4. N.P., male, born 5 M a r c h 1973 This case (reported briefly by K e m p e r d i c k et al. 1975) was the second child of young, healthy, n o n c o n s a n g u i n e o u s parents of
Italian stock. Birth occurred spontaneously in the 38th week of gestation; the birth weight was 2950 g and length 45 cm. T h e head was microcephalic with a flat forehead and occipital meningocele. H e had left corneal clouding; his ears were dysplastic. T h e a b d o m e n was protruberant due to enlarged kidneys. T h e penis was short; no testes were palpable. T h e extremities were shortened; the feet were in equinovarus position; there was postaxial hexadactyly of all extremities and cutaneous syndactyly 3/4 in both feet. T h e boy died shortly after birth. C h r o m o s o m e analysis revealed a normal karyotype, 46,XY. A u t o p s y findings included polycystic and enlarged kidneys, hypoplasia of the bladder and ureters, hypoplasia of the aortic
131 valve, persistent ductus arteriosus, and aplasia of the caudal parts of the corpus callosum. Radiologic studies showed that the tibiae were shortened, broadened, and bowed in the midportion (Fig. 10). All other long tubular bones were without abnormalities. The right upper thoracic cage was deformed.
Discussion The main signs of Meckel syndrome are occipital encepbalocele, cleft lip and or palate, polycystic kidneys, postaxial polydactyly, and numerous other malformations (Table 1). Since Meckel's (1822) original description, more than 130 cases have been published. The disorder may even be more common, if cases with partial manifestations would be recognized as Meckel syndrome (Holmes et al. 1976). The phenotypic variability has been stressed recently by Fraser and Lytwyn (1981) and Seller (1981). The frequency distribution of the various malformations as given in Table 1 is probably biased since the majority of these cases are ascertained on the basis of the above-mentioned malformations. In addition, not all cases are documented sufficient to be sure that a sign not mentioned in the case description had really been looked for. Polycystic dysplasia is thought to be the only constant sign in the Meckel syndrome (Fraser and Lytwyn 1981). In our case 1, a few cortical cysts could be detected only microscopically. The same was true for case 3 of Moermann et al. (1982). In this case the kidneys were not enlarged, "slight cortical and medullary noncystic dysplasia" being detectable only microscopically. In Table 1, polycystic kidneys were tabulated in 92 of 98 classical cases with Meckel syndrome. Possibly microscopic examination of the kidneys in the few cases lacking renal cysts was not done accurately. Shortened or bowed extremities were mentioned in at least 23 cases (Table 2) with signs resembling those of the Meckel syndrome; however, X-ray examinations were done in only a few cases (see below). Except for preaxial polydactyly, nearly all other signs are present in the classicial cases of Meckel syndrome and those with short or bowed extremities. Though in almost all affected siblings, shortened extremities are observed as well, we do not think that there is enough evidence to suspect an entity different from Meckel syndrome. X-ray examination in cases with Meckel syndrome has been reported in only four cases (Battaglia and Locatelli 1956; Fitch and Pinsky 1973; Kemperdick et al. 1975; Kozlowski et al. 1977). All authors mentioned a shortened and bowed tibia in their cases. Only Kozlowski et al. (1977) and Kemperdick et al. (1975) (see Fig. 10) published X-ray films. In both cases the tibiae, which were shortened and broadened, were bowed in the midportion of the diaphysis. In our cases there was great variation of bowing of tubular bones. In our case 4, only the tibiae were shortened and bowed, all other long tubular bones being normal. In case 1 all long tubular bones were bowed in their midportion. This bowing was more obvious in the lower extremities than in the upper. In cases 2 and 3 we noted similar bowing of all long tubular bones; in case 2 this bowing was nearly rectangular in the left tibia and fibula (Fig. 5). Pelvis and spine were unremarkable in all cases, as were the metaphyses of all tubular bones. Although not present in cases 1 and 2, broadened tibiae was a sign in cases 3 and 4. In case 3 the femora seemto be broadened also (Fig. 8). The tibiae were nearly identical in cases 3 and 4 and in the case ofKozlowski et al. (1977). W e think that bowing of the midportion of one or more long tubular bones is a further, hitherto unknown sign of the Meckel syndrome,
Table 2. Cases with signs of the Meckel syndrome and shortened and/ or bowed extremities Author
Giordano (1936) Battaglia and Locatelli (1956) Marshall et al. (1964) Hsia et al. (1971)
2 2 1
m MT? 1 m MT?) m 0
m m, f, m
Fitch and Pinsky (1973) & Kemperdick et al. (1975) Kozlowski et al. (1977) Seller (1978) Moermann et al. (1982a, b)
a ? f m}
0 1 0
+? 6 1
26.6% Affected siblings (without probands)
m, male; f, female; a, ambiguous; ?, sex unknown; MT, monozygous twins; &, parental consanguinity; }, siblings rather than a reason to delineate a new syndrome. Nearly onesixth of the cases with Meckel syndrome are probably affected in the same way. Our case 1 exhibited preaxial polysyndactyly of all extremities and postaxial polydac!yly of both hands. Case 2 demonstrated preaxial polydactyly of both feet only, whereas cases 3 and 4 had postaxial polydactyly only. Postaxial polydactyly was reported in almost all cases with Meckel syndrome. Usually there was hexadactyly; only a few cases with hepta- or octadactyly were observed. Wigand (1889) was the only author to report unilateral preaxial polydactyly of one hand in an otherwise typical case of Meckel syndrome. Since in our case 2 the preaxial type ofpolydactyly became evident only after repeated and careful X-ray examinations, we think that preaxial polydactyly may have been overlooked in some previously reported cases and that preaxial polydactyly is a further hitherto unrecognized sign of the Meckel syndrome. Meitner (1961) reported a case very similar to our case 1: This case exhibited microphthalmia, cleft lip and palate, agenesis of the corpus callosum, congenital heart defect, and pre- and postaxial polysyndactyly of all extremities. Both femora were noted to be bent sharply in their midportion. Since there were no X-rays and since this case exhibited neither encephalocele nor polycystic kidneys, we are not sure whether this case and ours suffered from the same condition. Pre- and postaxial polysyndactyly is a feature in the Mohr syndrome (Pfeiffer et al. 1972), the acrocallosal syndrome (Schinzel 1982), the Greig cephalopolysyndactyly syndrome
132 ( D u n c a n et al. 1979), and the short rib-polydactyly syndrome, type Majewski (Motegi et al. 1979). However, in all these syndromes, encephalocele and bowing of long tubular bones were not observed. Bowing of long tubular bones is possibly an unspecific sign of a great n u m b e r of conditions, especially c a m p o m e l i c dysplasia (Hall and Spranger 1980). T h e presence of polydactyly and encephalocele as well as polycystic kidneys and several other internal malformations clearly separates Meckel syndrome f r o m other conditions with congenital bowing of long tubular bones. Since n o n e of our cases occurred with oligohydramnios and since the kidneys were not enlarged in our case 1, we do not think bowing of the long bones was caused by mechanical factors. A u t o s o m a l recessive inheritance has b e e n established for the Meckel syndrome. A m o n g the cases with shortened extremities, affected siblings and consanguinity of parents were reported. W i t h o u t counting the probands, there were 26.6% affected siblings (Table 2). T h u s recessive inheritance is likely in these families also.
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