Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of approximately 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development.

No abstract

To investigate the effect of nutrition on tissue carnitine concentrations in infants of different gestational ages, specimens of muscle, heart, liver and kidney obtained at autopsy from 62 infants were analyzed for total acid-soluble carnitine content. Immature infants had smaller carnitine tissue reserves than term infants. Parenterally alimented premature infants (> 10 days old) had lower carnitine levels in heart, liver and kidney than those dying within 24 h after birth. Infants who received oral or intravenous carnitine had larger carnitine tissue reserves than those who did not. These data suggest that both gestational age and exogenous carnitine supply affect tissue carnitine reserves.

Thirteen newborns with lethal short rib-polydactyly (SRP) have been reviewed, 11 with SRP type III (Verma-Naumoff) and 2 with SRP type II (Majewski). In the former group there were three sets of siblings. The excess of males with SRP type III (Verma-Naumoff) is confirmed in this present study. A high frequency of phenotypic females including sex-reversed constitutional males with SRP type I (Saldino-Noonan) is in marked contrast to these findings in SRP type III. Possible hypotheses include variable expressivity in non-Majewski short rib-polydactyly syndromes with sex-reversed and constitutional female cases tending to show more severe phenotypic expression both in terms of major anomalies and skeletal dysplastic effects.

o Deletions if the distal short arm if chromosome 9 have been reported in association with gonadal dysgenesis and xr sex reversal. These findings suggest that this region harbors at least one gene that might be involved in sexual development. Recentstudiesnarrowed the deletion interval to the subtelomeric region 9p24.3. This region contains three genes DMRTI, DMRT3, and DMRT2 characterized by a DM-domain that seems essential for sexual development in Nematoda and Arthropoda. We have investigated the possible role if this gene cluster in a fetus with ring chromosome 9 and male-to-female sex reversal. We could demonstrate by FISH analysis a very small deletion of the terminal short arm if chromosome 9 including the DM-domain gene cluster. This finding gives further evidence that hemiz;ygosi!J if this region can be the cause for male-to-female sex reversal.