Familial occurrence of malformations possibly attributable to vascular abnormalities

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The Journal of Pediatrics January 1986

Familial occurrence of malformations possibly attributable to vascular abnormalities Hubert C. Soltan, M.D., and Lewis B. Holmes, M.D. From the University of Western Ontario Regional Medical Genetics Center, London, Ontario, C a n a d a , and the Embryology-Teratology Unit of Massachusetts General Hospital and Harvard Medical School, Boston

The Poland a n o m a l y / t e r m i n a l transverse forearm amputations, 2 and hemifacial microsomia 3 have been attributed to underlying vascular abnormalities, although the Poland anomaly 4 and limb amputations 5-6amay occur among close relatives. We report a family in which the Poland anomaly (absence of the pectoralis major only), omphalocele, microtia, and unilateral terminal transverse hemimelia occurred in different members of two sets of siblings who are first cousins. A first cousin once removed also had unilateral terminal transverse hemimelia. These findings suggests a familial clustering of a common factor, such as a vascular abnormality, that may have resulted in the occurrence of these different malformations in relatives. CASE REPORTS Patient 1 (IV-16). The patient, the proband (Fig. 1), was referred because several close relatives had severe congenital malformations. She had a left amastia with absence of the areolar region, nipple, and sternal head of the left pectoralis major muscle (Fig. 2, A) but no abnormalities of her left hand. Patient 2 (IV-17). The proband's brother had a ruptured omphalocele that was repaired surgically; he died of postoperative complications. Patient 3 (IV- 15). This maternal first cousin of the proband had a congenital microtia with a preauricular appendage of the right ear and absent right external auditory canal (Fig. 2, B). There were two small auricular appendages on the tragus and helix of the left ear, but the external auditory canal was patent. He did not have macrostomia, coloboma, strabismus, epibulbar dermoid, or hypoplasia of the maxilla or mandible. Patient 4 (IV- 14). This maternal first cousin of the proband and sister of IV-15 had a terminal transverse hemimelia below the right elbow at the end of which were five very small soft tissue knobs (Fig. 2, C). On the right there was no osseous tissue distal to the thickened and shortened radius and ulna. The radial head was displaced laterally, and the olecranon fossa was shallow, with the olecranon markedly thickened. The pectoralis muscle was normal in appearance. Submitted for publication April 26, 1985; accepted July 1, 1985. Reprint requests: H. C. Soltan, M.D., Children's Hospital of Western Ontario, London, Ontario, Canada N6B 1138.

Patient 5 (11I-3). This maternal first cousin of the proband's mother had a terminal transverse hemimelia of the left wrist at the end of which were five tiny soft tissue knobs with nails (Fig. 2, D). Radiographs showed absence of the metacarpals but normal carpal bones. DISCUSSION The etiologic connection among these affected relatives, esPecially the two cousins with unilateral upper limb anomalies, remains unproved. However, a hypothesis of an inherited liability to a common predisposing event, such as a compromised embryonic vascular supply in the region of the affected areas, seems more likely to us than chance association. Different types of vascular abnormalities have been either observed or postulated in relation to some of these malformations, specifically Poland anomaly, hemifacial microsomia (which includes microtia), and terminal transverse hemimelia. Bouvet et al, 1 described a child with left Poland anomaly who had dextrocardia and stenosis of the left subclavian artery and absence of the left internal thoracic artery. They postulated that the malformations were caused by congenital arterial hypoplasia with involvement of the ulnar branch of the brachial artery, leading to abnormalities of fingers 3, 4, and 5, and involvement of the internal thoracic artery branch of the subclavian, causing absence of the sternal head of the pectoralis major. Poswill@ postulated that the unilateral ear deformity and hypoplasia of the same side of the face, as occurs in hemifacial microsomia, could be caused by hemorrhage in this region at the time when the blood supply switches from the stapedial artery to the external carotid artery. An infant with unilateral facial dysplasia and microtia was shown to have persistence of the stapedial artery and absence of some branches of the external carotid artery on that side. 7 Two types of vascular abnormalities have been observed in individuals with terminal transverse hemimelia. Robinow et al. 8 reported a child with a left midforearm amputation in association with coarctation of the aorta, aortic aneurysms, and a dysplastic and aneurysmally dilated left subclavian artery. They postulated that the

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+3 ~14 ~15! Q PolandAnomaly 9 9 Termi alTransverse Hemimnel ia ] Unilateral Microtia

' 21 [ ] Omphalocele ~ Four membersofkindred of unspecified sex

Fig. t. Kindred of proband with Poland anomaly depicting relatives with major malformations.

Fig. 2. Malformations in four members of kindred. A, Seven-year-old proband (IV-t6) with absent nipple, breast, and sternal head of pectoralis major muscle on left. B, Abnormal right ear in proband's first cousin (IV-15) after surgical repair. C, Unilateral (right) hemimelia in proband's first cousin (1V-14). D, Unilateral (left) hemimelia in proband's mother's first cousin (111-3).

forearm malformation was caused by "fairly sudden occlusion," presumably during early fetal development. H o y m e et al. z reported three infants with unilateral terminal transverse hemimelia, in whose placentas there was evidence of vascular occlusion. The authors suggested that

embolization from placental vascular thrombi occluded the brachial artery in the affected arm, resulting in necrosis and loss of limb tissue distal to the occlusion. They reported a fourth case, a fetus of 80 days gestation, who was born after severe prolonged fetal blood loss. The stump

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Clinical and laboratory observations

of the terminal transverse defect was necrotic; there was a large thrombus occluding the left brachial artery just proximal to the area of limb necrosis. Of the five malformations that occurred in this family, only omphalocele has not been attributed to a vascular abnormality. We considered the possibility that our subject had gastroschisis, an abdominal closure defect attributed to intrauterine interruption of the omphalomesenteric artery? However, the recorded detailed description of the defect indicates that it was indeed an omphalocele. In postulating a familial vascular predisposition to the occurrence of malformations in a family such as the one described here, we must consider the possible pathogenetic mechanisms involved. The vascular abnormalities described or postulated include hemorrhage in a region, occlusion of a vessel, and malformed vessels. Another type of vascular abnormality was observed by Hootnick et al., l~ who found a lack of the normal vessels and an abnormal persistence of embryonic vessels in association with absence or shortening of the fibula in an amputated human limb. Bouwes Bavinck and Weaver It have postulated that several malformations, including the Poland anomaly and terminal transverse defects, could be caused by vascular interruptions during or around the sixth week of embryonic development. N o n e of the five malformations that occurred in this family has been attributed to a single mutant gene. However, an increased incidence among sibs and offspring has been observed for terminal transverse hemimelia, 5 mierotia, ~2and omphalocele. 13As was noted above, there are reports of the familial occurrence of Poland anomaly. 4 W e conclude that the occurrence of several such defects in a family may indicate the possibility of a common underlying vascular abnormality. The importance of court-

The Journal of Pediatrics January 1986

seling about the magnitude of the risk of recurrence is apparent. REFERENCES 1. Bouvet .IP, Leveque D, Bernetieres F, Gros JJ. Vascular origin of Poland syndrome? Eur J Pediatr 1978;128:17. 2. Hoymc HE, Jones KL, Van Allen MI, Saunders BS, Bcnirschke K. Vascular pathogenesis of transverse limb reduction defects. J PEr~IATR 1982;101:839. 3. Poswillo D. The pathogenesis of the first and second branchial arch syndrome. Oral Surg 1978;35:302. 4. Sujansky E, Riccardi VM, Matthew AL. The familial occurrence of Poland syndrome. Birth Defects 1977;3A:117. 5. Birch-Jensen A. Congenital deformities of the upper extremities Copenhagen: Ejnar Munksgaard, 1949:105-12. 6. Hecht JT, Scott CI Jr. Limb deficiency syndrome in half-sibs. Clin Genet 1981;20:432. 6a. Graham JM Jr, Struckmeyer CL, Hallowell C. Dominantly inherited unilateral ectrodactyly. Am J Human Genet 1984;36:535. 7. PascuaI-Castroviejo I: Persistence of the stapedial artery in a first arch anomaly: a case report. Cleft Palate J 1983; 20:146. 8. Robinow M, Schatzman ER, Oberheu K. Peromelia, ipsilateral subclavian atresia, coarctation, and aneurysms of the aorta resulting from intrauterine vascular occlusion. J PEDIATR 1982;101:84. 9. Hoyme HE, Higginbottom MC, Jones KL. The vascular pathogenesis of gastroschisis: intrauterine interruption of the omphalomesenteric artery. J PEDIATR 1981;98:228. 10, Hootnick DR, Levinsohn EM, Randall PA, Packard DS Jr. Vascular dysgenesis associated with skeletal dysplasia of the lower limb. J Bone Joint Surg [Am] 1980;62:1123. 11. Bouwes Bavinck JND, Weaver DD. The subclavian artery supply disruption sequence. Am J Med Genet 1985 (in press). 12. Aase JM, Tegtmeier RE: Microtia in New Mexico: evidence for multifactorial causation. Birth Defects 1977;13(3A): 113, 13. DiLiberti JH: Familial omphalocele: analysis of risk factors and case report. Am J Med Genet 1982;13:263.

Lowered plasma albumin concentration in fetal Turner syndrome Thomas H. Shepard, M.D., Mark H. Wener, M.D., Selma A. Myhre, M.D., and Durlin E. Hickok, M.D. From the Central Laboratory for Human Embryology, Departments of Pediatrics, Laboratory Medicine, and Obstetrics and Gynecology, School of Medicine, University of Washington, and the Department of Perinatology, Swedish Hospital Medical Center, Seattle

Submitted for publication March 6, 1985; accepted July 1, 1985. Reprint requests: Thomas H. Shepard, Central Laboratory for Human Embryology, Department of Pediatrics RD-20, School of Medicine, University of Washington, Seattle, WA 98195

Previous studies in macerated fetuses with 45,X Turner syndrome have reported generalized edema and the presence of nuchal cystic hygromas. W e studied six fetuses in a state fresh enough to allow accurate measurement of plasma protein concentration, to determine whether plas-