A novel deletion in the thyrotropin Beta-subunit gene identified by array comparative genomic hybridization analysis causes central congenital hypothyroidism in a boy originating from Turkey.

BACKGROUND: Isolated central congenital hypothyroidism (ICCH) is rare but important. Most ICCH patients are diagnosed later, which results in severe growth failure and intellectual disability. OBJECTIVE: We describe a boy with ICCH due to a large homozygous TSHß gene deletion. RESULTS: A 51-day-old male Turkish infant, whose parents were first cousins, was admitted for evaluation of prolonged jaundice. His clinical appearance was compatible with hypothyroidism. Venous thyrotropin (TSH) was undetectably low, with a subsequent low free T4 and a low free T3, suggestive of central hypothyroidism. Using different PCR protocols, we could not amplify both coding exons of the boy's TSHß gene, which suggested a deletion. An array comparative genomic hybridization (aCGH) using specific probes around the TSHß gene locus showed him to be homozygous for a 6-kb deletion spanning all exons and parts of the 5' untranslated region of the gene. CONCLUSIONS: Infants who are clinically suspected of having hypothyroidism should be evaluated thoroughly, even if their TSH-based screening result is normal. In cases with ICCH and undetectably low TSH serum concentrations, a TSHß gene deletion should be considered; aCGH should be performed when gene deletions are suspected. In such cases, PCR-based sequencing techniques give negative results.

Revisiting the recurrence risk of nonsyndromic cleft lip with or without cleft palate.

Sub-epithelial defects (i.e., discontinuities) of the superior orbicularis oris (OO) muscle appear to be a part of the phenotypic spectrum of cleft lip with or without cleft palate (CL ± P). Analysis of the OO phenotype as a clinical tool is hypothesized to improve familial recurrence risk estimates of CL ± P. Study subjects (n = 3,912) were drawn from 835 families. Occurrences of CL ± P were compared in families with and without members with an OO defect. Empiric recurrence risks were calculated for CL ± P and OO defects among first-degree relatives (FDRs). Risks were compared to published data and/or to other outcomes of this study using chi-square or Fisher's exact tests. In our cohort, the occurrence of CL ± P was significantly increased in families with OO defects versus those without (P < 0.01, OR = 1.74). The total FDR recurrence of isolated OO defects in this cohort is 16.4%; the sibling recurrence is 17.2%. The chance for one or more FDRs of a CL ± P proband to have an OO defect is 11.4%; or 14.7% for a sibling. Conversely, the chance for any FDR of an individual with an OO defect to have CL ± P is 7.3%; or for a sibling, 3.3%; similar to published recurrence risk estimates of nonsyndromic (NS) CL ± P. This study supports sub-epithelial OO muscle defects as being part of the CL ± P spectrum and suggests a modification to recurrence risk estimates of CL ± P by utilizing OO defect information.

Whorl patterns on the lower lip are associated with nonsyndromic cleft lip with or without cleft palate.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect due to both genetic and environmental factors. Whorl lip print patterns are circular grooves on the central upper lip and/or the left and right lower lip. To determine if whorls are more common in families with CL/P than in controls, the Pittsburgh Orofacial Cleft Study collected lip prints from over 450 subjects, that is, individuals with CL/P, their relatives, and unrelated controls-from the U.S., Argentina, and Hungary. Using a narrow definition of lower-lip whorl, the frequency of whorls in the U.S. sample was significantly elevated in cleft individuals and their family members, compared to unrelated controls (14.8% and 13.2% vs. 2.3%; P = 0.003 and 0.001, respectively). Whorls were more frequent in CL/P families from Argentina than in CL/P families from the U.S. or Hungary. If these results are confirmed, whorl lip print patterns could be part of an expanded phenotypic spectrum of nonsyndromic CL/P. As such, they may eventually be useful in a clinical setting, allowing recurrence risk calculations to incorporate individual phenotypic information in addition to family history data.

Sudden infant death syndrome (SIDS) in African Americans: polymorphisms in the gene encoding the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP).

AIMS: Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) are prone to sudden death in the second post-natal week, having respiratory and metabolic disturbances reminiscent of the human Sudden Infant Death Syndrome (SIDS). Here we test the hypothesis that the human PACAP gene is a site of genetic variance associated with SIDS in a cohort of 92 victims and 92 matched controls. METHODS: Using polymerase chain reaction and sequencing, we examined the PACAP gene in 92 SIDS cases (46 Caucasians and 46 African Americans) and 92 race- and gender-matched controls. RESULTS: We found no significant associations between PACAP and SIDS in Caucasians. However, in the African Americans, a non-synonymous single nucleotide polymorphism (i.e. an aspartic acid/glycine coding variant, rs2856966) within exon 2 of PACAP was significantly associated with SIDS (p = 0.004), as were haplotypes containing this polymorphism (p < 0.0001). Glycine was three times more likely at this location in the African-American SIDS victims (17 cases) than African-American controls (5 cases). CONCLUSION: These data are the first to suggest an association between a variant within the coding region of the PACAP gene and SIDS. Based on these findings, further investigations are warranted into the functional importance of PACAP signaling in neonatal survival and the role of PACAP-signaling abnormalities in SIDS.