American Journal of Medical Genetics 17:827-834 (1984)

Lethal Multiple Pterygium Syndrome

N. Van Regemorter, P. Wilkin, Y. Englert, N. El Khazen, S. Alexander, F. Rodesch, and J. Milaire

Centre de Genetique de Bruxelles (N, V: R.), Departement de Gynecologie, H6pital Saint Pierre, Bruxelles (P. W., YE., N. E. K.), Departement de Gynecoiogie, Hbpital Erasme, Bruxelles (S.A., F. R.), Service d’Anatomie et d’Embryologie Humaine Universite Libre de Bruxelles (J. M.), Brussels, Belgium

We report on two fetuses with a lethal form of multiple-pterygium syndrome born to first cousins. The two pregnancies aborted spontaneously in the 2nd trimester, the fetuses, 10-1 1 weeks of embryonic age, showing multiple pterygia and multi- ple cartilaginous fusions. One had cleft lip and palate. In both cases the niicro- scopic anatomy of the placenta showed villi with scalloped border and intravillous trophoblastic invaginations.

Key words: Multiple pterygium syndrome, consanguinity, placental histology, cleft lip, autosomal recessive

INTRODUCTION

Two spontaneously aborted fetuses with multiple pterygia are described. The parents are first cousins between 20 and 25 years old, of Moroccan origin. They have had three additional pregnancies that resulted in intrauterine death during the first trimester of gestation, but no information about the embryos is available. There was no history of any congenital abnormality in their family.

CLINICAL REPORTS Fetus 1

This was the product of the first pregnancy and was followed ultrasonographi- cally from the 17th week after the last menstrual period (LMP) when absence of fetal movements was noticed. Ultrasound measurements (biparietal diameter 25 mm, transthoracic diameter 17 mm) corresponded to those of the 13th week of gestation;

Received for publication February 2, 1983; revision received August 15, 1983.

Address reprint requests to Dr N. Van Regemorter, Centre de GCnetique U.L.B., Avenue Winston Churchill 246, B-I180 Bruxelles, Belgium.

0 1984 Alan R. Liss, Inc.

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fetal heart rhythm was normal. The second ultrasound examination at 19 weeks post- LMP showed normal fetal growth (biparietal 32 tnm, transthoracic diameter 20 mm, transabdominal diameter 22 mm) but total absence of limb and body movements. At 24 weeks post-LMP, fetal death was observed. Ultrasound measurements (biparietal 34 mm, transthoracic diameter 32 mm, transabdominal diameter 34 mm) corre- sponded to growth equivalent to about 16 weeks of gestation. Moderate hydrainnios was noticed. The pregnancy was terminated.

The fetus, a male, weighed 130 gm and measured 12.5 cm (embryonic age, 14- 15 weeks) and had bilateral cleft of lip and of palate (Fig. 1). Photographs and roentgenograms (Figs. 2-4) demonstrated the presence of antecubital and axillary pterygia. The presence of popliteal pterygia could not be ruled out. Roentgenograms demonstrated the presence of spatulated ribs with bilateral multiple fractures, spatu- lated clavicles, short 1st and 5th metacarpals, and wider distal end than proximal end of the metacarpals. At autopsy, no visceral anomalies were observed.

The placenta was immature with signs of retention dating from at least 1 month after fetal death. Numerous large chorial villi with scalloped borders were covered by one layer of syncytiotrophoblasts and one nearly continuous layer of cytotropho- blasts. The stroma was poorly vascularized. The center of the villi presented some edema and contained numerous Hotbauer cells and accumulation of fibrillar material. Many intravillous trophoblastic invaginations were encountered.

The next two pregnancies ended in spontaneous abortion during the first trimes- ter of gestation, but the products of conception were not examined.

The fourth pregnancy ended in a spontaneous abortion at 15-16 weeks post- LMP. The patient was first seen at this time. No pterygium were noted on the specimen. No autopsy was performed. Length measurement of 2 cm corresponded to

Fig. I . Case 1 : postmortem picture

Lethal Multiple Pterygium Syndrome 829

Fig. 2 .

Fig. 3.

Case I : skeletal roentgenogram, spatulate ribs, and multiple bilateral fracture5

Case I: skeletal roentgenogram, lateral view.

Fig. 4. Case 1: roentgenogram of the arms: short 1st and 5th metacarpals, pterygia of the elbow

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an embryonic age of 7 weeks. The placental histology showed some very hypoplastic chorial villi type 111 with clusters of cytotrophoblast and compact decidua presenting areas of necrotic and vascular thrombosis.

Fetus 2

The mother was first seen at 14 weeks post-LMP when fetal death was discov- ered at ultrasonography. The pregnancy was terminated. The fetus had popliteal and axillary pterygia (Fig. 5 ) and redundant skin at the back of the neck, which may have been a cystic mass or an artifact secondary to maceration of the fetus. Fetal measure- ments (length of 6 cm) corresponded to those of 9.5 weeks postconception; no cleft of lip or palate was observed, but there were severe deviations of hands and feet resulting from abnormal flexion of the forearms and legs.

As revealed by the structural appearance of the fused skeletal pieces, the observed defects were most probably the result of a secondary coalescence between primarily separated cartilaginous primordia. The heart showed an atretic ductus arteriosus (uncommon at this age) and a membranous ventricular septa1 defect. After evisceration and alizarin staining, the fetus was cleared in glycerin and examined for skeletal anomalies. Multiple fusions were found between adjacent cartilaginous skel- etal primordia in all four limbs. In the forelimbs symmetrical fusions were present between scapula and humerus (Fig. 6), humerus and ulna, naviculare and multan- gulum majus, and lunatum and triquetrum (Fig. 7). Only the foot skeleton was found

Fig. 5 . Case 2: postmortem picture

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Fig. 6. Alizarin stain.

Case 2: front view of the right shoulder; cartilaginous fusion between humerus and scapula.

Fig. 7. Case 2: palmar view of the right wrist and hand skeleton. Cartilaginous fusion between naviculare and multangulum majus and between lunatum and triquetrum. Alizarin stain.

Fig. 8. cuneiform I . Alizarin stain.

Case 2: dorsal view of the right foot skeleton; cartilaginous fusion between naviculare and

affected in the lower limbs, with multiple fusions between the cartilaginous rudiments of the calcaneus, talus, naviculare, and cuneiform I on the right side (Fig. S), and between naviculare and cuneiform I on the left side. In both limbs, the cartilaginous inetaphyseal portion of most long bones exhibited at autopsy abnormal softness, which was responsible for the deviations observed at external examination (Fig. 7); however, it was difficult to decide whether this latter modification occurred before or after fetal death.

Both cranial and axial skeletons appeared normal. Placental histology showed large avascular chorial villi with scalloped borders and numerous trophoblastic invag- inations. The trophoblastic villous coating was hypotrophic (Fig. 9). No numerical or structural chromosomal abnormality could be identified in either parent. No cytoge- netic studies were obtained.

DISCUSSION

Several syndromes associated with limb pterygia have been described (popliteal pterygium syndrome, antecubital pterygium syndrome, multiple pterygium syndrome. lethal multiple pterygium syndrome, popliteal pterygium with ectodermal dysplasia, and several other syndromes occasionally associated with limb pterygia) . Recently these syndromes were reviewed by Hall et al [ 19821.

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Fig. 9. Case 2: placenta: scalloped villous border, trophoblastic invaginations.

Because of the presence of multiple pterygia, intrauterine death, and parental consanguinity, our cases would most closely correspond to the lethal multiple ptery- gium syndrome [Hall et al, 19821.

At least three different lethal multiple pterygium conditions are now recognized, all of which appear to be autosomal recessive traits [Hall, 1982; Chen et al, 19831. The first concerns two sibships of three children presenting multiple pterygia, hypo- plastic lungs, and facial anomalies [Hall et al, 1982; Gillin and Pryse-Davis, 19761. The second consists of three isolated cases presenting with multiple pterygia, fetal hydrops, pulmonary and cardiac hypoplasia, facial anomalies, cleft palate, and short neck with a cystic mass at the back of the head and neck. All three cases had spinal cord involvement. Histologic studies of the skeleton showed cartilaginous and bony fusion of the spinous processes, and fusion of epiphyseal cartilages of distal humerus and proximal ulna [Chen et al, 19821. In the third condition, multiple pterygia were associated with absolute absence of muscles in the lower limbs [Hall 19821.

Lethal Multiple F’terygium Syndrome 833

In lethal multiple pterygium syndromes, fetal death usually occurs later in gestation, after 30 weeks. Only in the lethal multiple pterygium syndrome described by Chen et al [ 19831 did fetal death occur during the second trimester of gestation in five out of seven cases. All reported cases but one had pulmonary hypoplasia [Hall et al, 1982; Chen et al, 19821. In our cases, major pulmonary hypoplasia can be excluded; however, the lungs were not weighed.

One of our cases had cleft of lip and of palate. In the autosomal recessive multiple pterygium syndrome and in the lethal multiple pterygium syndrome, cleft lip has not yet been reported. However, 35% of the multiple pterygium syndrome patients have cleft palate. Cleft lip is even more frequent (84%) in the autosomal dominant popliteal pterygium syndrome [Hall et al, 19821.

As cartilaginous fusions of bones are often not visible on skeletal X rays, they would not be recognized in lethal multiple pterygium syndromes unless looked for specifically. In our cases they were demonstrated by careful anatomical examination and staining.

Cardiac anomalies usually are not seen in patients with multiple pterygia; in our case 2, fetal death could have been related to the atretic ductus arteriosus with too small a ventricular septa1 defect to compensate.

Placental histology has not been described in any of the published cases of lethal multiple pterygium syndrome. The three miscarriages studied here were all associated with placental anomalies. The two miscarriages with a fetus with multiple pterygia have similar placental anomalies, ie, scalloped villous borders and numerous intrav- illous trophoblastic invaginations. This type of histopathologic change is encountered in 90% of cases with triploidy [Szulman et al, 19811. Although chromosomes of these fetuses were not studied, the diagnosis of triploidy is unlikely, as triploidy is associ- ated with a characteristic clinical picture, which was not seen in our cases [Bocian et al, 19781. The miscarriage with no evident pterygium had placental anomalies fre- quently encountered in trisomies [Philippe, 19741 and could be unrelated to the two other miscarriages. Both parents had normal chromosomes. It is going to be of importance to study placental histomorphology in all cases of lethal multiple ptery- gium syndrome, to determine if the changes observed in these cases are specific to this type of lethal multiple pterygium syndrome.

Two main, though purely conjectural, theories have been proposed to explain the genesis of congenital pterygia [Warkany, 19711. According to the first one, cutaneous folds are the consequence of early embryonic and fetal edema. The edema might result from either lymphangiectatic swellings or from various kinds of hemo- dynamic disturbances. The second hypothesis ascribes a determining role to an absence or important reduction of fetal movements. It proposes that normal limb movement contributes to the harmonious growth of the skin covering the limbs. The skeletal defects observed in case 2 might be considered as indirect evidence in favor of the second hypothesis, since the observed epiphyseal fusions would be expected to result in an absence or reduction of fetal movements [Andersen and Bro-Rasmussen, 1961; Drachman and Sokoloff, 1966; Milaire, 1974; Mitrovic, 19821. The lack of movement was not verified in fetus 2 who died before echography. However, absence of limb and body movements was demonstrated by echography in his sib (fetus 1). The histological findings in the cartilage of one of the cases described by Chen et a1 [I9831 suggest that an epiphyseal anomaly might be the primary defect. Thus a

834 Van Regemorter et al

relationship seems to exist between the observed skeletal anomalies and the apparent absence of fetal movements; however, the link between this latter condition and the genesis of cutaneous folds remains purely conjectural. The idea formulated by Hall et al [I9821 that the mechanical stretching imposed on the embryonic skin might contribute to the harmonious growth of cutaneous tissues is not based on any experi- mental evidence; moreover, it is also evident that the occurrence of pterygia is quite rare among the various conditions characterized by the absence of fetal movements. Furthermore, humeroradial synostosis is not associated with antecubital pterygium. The association of congenital pterygia and epiphyseal fusions might thus be purely coincidental both being the consequence of the detrimental effect of one single gene, the former being presumably attributable to subcutaneous edema related to hemody- namic perturbations.

ACKNOWLEDGMENTS

We thank Dr. J.G. Hall for helpful discussion and encouragement. We are grateful to Drs. Pratola and Jeanty for providing us with the roentgenograms and photographs of case 1 and Drs. Hayez, Vamos, and Perlmutter-Cremer for their encouragement.

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Bocian M, Karp LE, Mohandas T, Sarti D and Lachnxn R, Wisot A (1978): Intrauterine diagnosis of triploidy: The use of radiologic and ultrasonographic techniques in conjunction with amnioccnte- sib. Am J Med Genet 1:323-332.

Chen H. Immken L. Blumberg B, Lachman R, Yang S , Rimoin D, Rightmire D, Bachnian R, Eteson D and Stewart F ( 1982): Lethal form of multiple pterygium syndrome. A prenatally diagnosable entity. Birmingham Birth Defects Meetings.

Chen H. Immken L, Lachnian R, Yang S, Rimoin DL. Rightmire D, Eteson D. Stewart F, Beemcr FA, Opitz J, Gilbert EF, Langcr LO, Shapiro LR, Duncan PA (1984): Syndrom of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies - Delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809-826.

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