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We report on two patients with an unusual combination of multiple congenital anomalies including holoprosencephaly, encephalocele, and additional defects commonly observed in the VACTERL and schisis "associations." One of the infants had a chromosome abnormality characterized by partial duplication and deletion of chromosome 18. VACTERL association was characterized recently as a primary developmental field defect (DFD) [Martínez-Frías et al., 1998: Am J Med Genet 76:291-296]. In some cases, sequences may also represent uncomplicated DFDs. We suggest that findings in both of these cases represent abnormalities of blastogenesis involving the primary field resulting in holoprosencephaly and VACTERL and schisis anomalies, and show that similar primary DFDs are causally heterogeneous., (Copyright 2002 Wiley-Liss, Inc.)

Schinzel phocomelia syndrome is characterized by limb/pelvis hypoplasia/aplasia: specifically, intercalary limb deficiencies and absent or hypoplastic pelvic bones. The phenotype is similar to that described in a related multiple malformation syndrome known as Al-Awadi/Raas-Rothschild syndrome. The additional important feature of large parietooccipital skull defects without meningocele, encephalocele, or other brain malformation has thus far been reported only in children with Schinzel phocomelia syndrome. We recently evaluated a boy affected with Schinzel phocomelia born to nonconsanguineous healthy parents of Mexican origin. A third-trimester fetal ultrasound scan showed severe limb deficiencies and an absent pelvis. The infant died shortly after birth. Dysmorphology examination, radiographs, and autopsy revealed quadrilateral intercalary limb deficiencies with preaxial toe polydactyly; an absent pelvis and a 7 x 3-cm skull defect; and extraskeletal anomalies including microtia, telecanthus, micropenis with cryptorchidism, renal cysts, stenosis of the colon, and a cleft alveolar ridge. A normal 46,XY karyotype was demonstrated, and autosomal recessive inheritance was presumed on the basis of previously reported families. This case report emphasizes the importance of recognizing severe pelvic and skull deficiencies (either post- or prenatally) in differentiating infants with Schinzel phocomelia from other multiple malformation syndromes that feature intercalary limb defects, including thalidomide embryopathy and Roberts-SC phocomelia., (Copyright 2001 Wiley-Liss, Inc.)

We discuss an unlabelled specimen of tetraphocomelia and bilaterally cleft lip from the former Virchow Museum of our Medical School. Identity of the subject with a case of what was later termed "Roberts syndrome" published by Rudolf Virchow in 1898 is demonstrated. Rediscovery of this important historical case is gratifying, since almost 95% of the specimens of Virchow's collection were lost during World War II. We have restudied Virchow's case. Recent CT scan images of the fetus are presented. We review data from the literature and present new clinical details. The fate of the original clinical data after passing through three reviews is documented briefly. We also reconstruct Virchow's view on phocomelia and its consequences for later research.

We present a 46,XX stillborn fetus with tetraphocomelia, absence of ears, severe hypoplasia of nose, cleft palate, pulmonary hypoplasia, imperforate anus and vagina, and phallus-like structure on an otherwise undefined perineum. The pattern of abnormalities resembles the tetraphocomelic condition described by Zimmer et al. in 1985. Tetraphocomelia, ear/nose hypoplasia with facial clefts, pulmonary hypoplasia, and defects of the caudal end including imperforate anus, and abnormal genitalia constitute a distinct pattern of malformation termed Zimmer phocomelia. Principal coordinate analysis with Gower's similarity index supported the clinical impression that cases reported by Zimmer and the present case are distinct from other phocomelic conditions. Although Zimmer phocomelia is currently referred to as "X-linked amelia," documentation of a female case with a penis-like structure in this report as well as consanguinity in the original family in Zimmer's report indicates that this condition is likely inherited in an autosomal recessive fashion. Zimmer phocomelia may be a more appropriate name than X-linked amelia.

Amelia is a rare, usually sporadic malformation. We report on a family in which three fetuses had amelia of the upper limbs and variable deficiency of the lower limbs. The fetuses also had minor facial anomalies. Recurrence of the condition in sibs of both sexes suggests autosomal recessive inheritance. Recurrent amelia has been documented in only a few families most often associated with a different set of malformations. Possibly, mutations in more than one gene with different modes of transmission can lead to this severe limb deficiency. We speculate that the mutation found in our cases interferes with formation of the apical ectodermal ridge in the upper limbs and results in its premature degeneration in the lower limbs.

We report on an 8-year-old boy with a pattern of multiple congenital anomalies that strongly suggest DK-phocomelia syndrome. Birth findings included bilateral upper limb amelia, occipital encephalocele, agenesis of the corpus callosum, right auricular tag, scoliosis, small penis, and cryptorchidism. Dental malocclusion was observed in the follow-up. This is the first case with on 8-year follow-up report of DK-phocomelia syndrome.

Sirenomelia, which has been reported for more than 450 years, is the most severe form of caudal dysplasia. This disorder is classically associated with agenesis or severe dysplasia of the urinary tract. A 27-year-old gravida 3 para 0020 presented at 19 weeks' gestation with monoamniotic twins, one normal and one with sirenomelia. The pregnancy miscarried following invasive diagnostic testing. Autopsy confirmed the findings of sirenomelia, meningomyelocele, omphalocele, persistent cloaca, and two normal kidneys. The abnormalities accompanying sirenomelia appear as a spectrum. The pathogenic theories of sirenomelia are reviewed in light of this case with normal kidneys.

We report on a woman with bilateral femoral hypoplasia and Rokitansky sequence, malformations that up to now had not been described together. There are no other cases in the family, and no history of prenatal teratogen exposure. This case may be part of a mesodermal malformation spectrum.

We report on a male infant with Brachmann-de Lange syndrome (BDLS) and ulnar hemimelia and monodactyly but also absence of both tibiae, the right distal femur being bifurcated. One similar observation was published earlier. The question is raised whether these malformations are coincidental or a rare component of BDLS.

We report on a 3-month-old infant whose sirenomelia was diagnosed prenatally. The infant is neurologically normal and has "fusion" of the lower limbs with associated renal dysplasia, imperforate anus, pelvic and sacral "dysplasia," and genital abnormalities. In addition she has a preauricular skin tag and rib fusion. The infant's anomalies are compatible with life and surgical separation of the lower limbs is planned.

We report on a girl born with phocomelia of both lower limbs, with 3-toed feet and partial sacral agenesis. She had normal growth of the upper limbs and trunk, and normal intelligence. Ultrasound study performed during the subsequent pregnancy documented a large skull defect with an intact brain. Fetal autopsy following the termination of that pregnancy was not done. We think this is a further report of the phocomelia syndrome with additional anomalies as reported by Schinzel [Hum Genet 84:539-541, 1990].

The skeleton of a 35- to 40-year-old male (A.D. 1250 to 1300) with distal phocomelia (intercalary transverse) of the right forearm and severe (90-100 degrees) right-sided scoliosis is examined. Congenital malformation of the the right forearm resulted in absence of the radius and ulna, and attachment of the upper arm and hand to the trunk. Lesser abnormalities consist of a-hypoplastic right scapula and misshapened ribs and sternum. This rare deformity reflects the variability and antiquity of congenital malformations of the upper limb.

Limb body-wall complex and sirenomelia sequence are uncommon birth defects and their association is extremely rare. Their overlapping manifestations and their concurrence in our patient suggest that they share a common cause and belong to a group of pathologically closely related conditions. Embryonic vascular disruption may be a common pathogenesis in both anomalies.

A case is presented of twin gestation in which one gestational sac was completely resorbed and the remaining twin was subsequently found to be sirenomelic. First-trimester prenatal ultrasound examination demonstrated a second gestational sac that disappeared 2 weeks later. The sonographic features that led to the diagnosis of sirenomelia in the remaining fetus included severe renal dysgenesis, persistently apposed lower extremities, and absence of fibulae. Postmortem examination, including angiographic studies of the fetus, revealed caudal dysgenesis and a single umbilical artery that arose from the abdominal aorta. Sirenomelia occurs more frequently in twin gestations than in singletons. This case suggests that the association between twinning and sirenomelia may be greater than is currently recognized. Two hypotheses are given to explain this association.

The combination of sirenomelia and anencephaly was observed in a stillborn dizygotic twin. A review of the literature revealed no other patients reported to have both conditions. Various explanations concerning the genesis of sirenomelia, and also the combination with anencephaly, are discussed.