We report on 6 (3 male, 3 female) Manitoba Indian children with hypertelorism and variable combinations of unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. These children belong to 4 related families. The parents and 7 other sibs are clinically unaffected. The family histories are otherwise unremarkable. The presence of 2 major malformations in sibs and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. The differential diagnosis includes cryptophthalmos syndrome and several other related malformation syndromes. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution make autosomal recessive inheritance more likely.

Maternal biotin deficiency is strongly teratogenic in CD-1 mice. The most common malformations are craniofacial and limb defects such as cleft palate, micrognathia and micromelia. The effect of biotin deficiency on palatal development in mouse embryos on d 12 of gestation was studied by culturing mouse embryonic palates in serum-free medium using a suspension culture system. In control embryos palatal processes developed to the fused stage after 72 h in culture. The fusion of palatal processes was further increased by the addition of biotin (10(-8) mol/L) to the medium. The addition of organic acids such as propionic, beta-methyl crotonic or beta-hydroxy isovaleric acids as well as avidin to the medium did not affect the stage of palatal formation. Cycloheximide completely blocked the fusion of palatal shelves. In embryos from biotin-deficient mice, the incidence of fusion between the palatal shelves was < 7% and increased to > 30% when biotin (10(-8)-10(-6) mol/L) was added to the medium. The addition of fatty acids to the organ culture medium did not have any effect on the fusion of palatal processes. The incorporation of 35S-methionine into protein from biotin-deficient embryo explants was 88% of that in controls. The results indicate that biotin deficiency may interfere directly with synthesis of specific proteins and the formation of palatal processes.

The morphogenesis of developmental defects induced by amniotic sac puncture was studied at the gross and microscopic levels. In fetuses recovered from 15 min to 48 h after amniocentesis, a pattern of hemorrhagic lesions, excessive accumulation of interstitial fluid, followed by tissue necrosis and leading ultimately to the reduction or amputation of distal limb segments and morphological changes in the head, was observed. These changes were indicative of venous stasis, hypervolemia and embryonic oxygen deficiency. Γntrauterine compression of the fetus and the obstruction of the fetomaternal circulation were considered to be the primary etiological factors in amniocentesis-induced anomalies which included hemorrhagic lesions, limb reductions and amputations, deformities of the head and abdominal regions, generalized edema and postural moulding.

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