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Rong Huang, Yu Dong, Anne Monique Nuyt, Emile Levy, Shu-Qin Wei, Pierre Julien, William D Fraser, and Zhong-Cheng Luo

Objective: Large birth size programs an elevated risk of type 2 diabetes in adulthood, but data are absent concerning glucose metabolic health impact in infancy. We sought to determine whether large birth size is associated with insulin resistance and β-cell function in infancy, and evaluate the determinants.

Design and Participants: In the Canadian 3D birth cohort, we conducted a nested matched (1:2) study of 70 large-for-gestational-age (LGA, birth weight >90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) control infants. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) at age 2-years.

Results: HOMA-IR and HOMA-β were similar in LGA and OGA infants. Adjusting for maternal and infant characteristics, decelerated growth in length during early infancy (0-3 months) was associated a 25.8% decrease (95% confidence intervals 6.7-41.0%) in HOMA-β. During mid-infancy (3-12 months), accelerated growth in weight was associated with a 25.5% (0.35-56.9%) increase in HOMA-IR, in length with a 69.3% increase (31.4-118.0%) in HOMA-IR and a 24.5% (0.52-54.3%) increase in HOMA-β. Decelerated growth in length during late infancy (1-2 years) was associated with a 28.4% (9.5-43.4%) decrease in HOMA-IR and a 21.2% (3.9-35.4%) decrease in HOMA-β. Female sex was associated with higher HOMA-β, Caucasian ethnicity with lower HOMA-IR, and maternal smoking with lower HOMA-β.

Conclusions: The study is the first to demonstrate that large birth size is not associated with insulin resistance and β-cell function in infancy, but infancy growth pattern matters. Decelerated infancy growth may be detrimental to beta-cell function.

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Nelly Burnichon, Charlotte Lepoutre-Lussey, Julien Laffaire, Noémie Gadessaud, Vincent Molinié, Anne Hernigou, Pierre-François Plouin, Xavier Jeunemaitre, Judith Favier, and Anne-Paule Gimenez-Roqueplo

Objective

In this report, we describe a new patient with unexplained familial bilateral pheochromocytoma. Following the recent description of TMEM127 as a new pheochromocytoma susceptibility gene, the aim of this study was to test the hypothesis of a causative TMEM127 gene mutation in this patient.

Design

Pheochromocytoma susceptibility genes were analyzed in germline DNA and losses of heterozygosity (LOH) assessed by BAC array comparative genomic hybridization in tumor DNA. SDHB expression and S6 kinase (S6K) phosphorylation were analyzed by immunohistochemistry. Genome-wide expression microarray studies were performed, and vascular density was quantified after CD34 immunohistochemistry.

Results

A first germline variant was identified in the SDHB gene (c.158G>A; p.Gly53Glu). However, a positive SDHB immunostaining in the tumor indicated that this SDHB variant was a non-functional polymorphism. A novel TMEM127 germline mutation (c.140C>A, p.Ala47Asp) associated with a 2q11 LOH was found. Transcriptome and immunohistochemical analyses showed that TMEM127-related pheochromocytoma clusterized with NF1-related and RET-related tumors in a large series of pheochromocytomas and paragangliomas, exhibited a reduced TMEM127 mRNA expression and displayed a low vascularization. The phosphorylation of S6K observed in this tumor was suggestive of an activation of the MTOR pathway.

Conclusions

Pathological and genomic data demonstrated that a TMEM127 gene mutation not previously described was causative of a new case of familial bilateral pheochromocytoma. This report highlights the importance of supplementary analyses on tumor tissue to provide an accurate pheochromocytoma/paraganglioma genetic testing result to affected patients.