Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis.

In a new cohort of 141 unrelated patients affected by Kallmann syndrome we identified FGFR1 sequence variants in 17 patients, all in the heterozygous state. The fifteen novel variants consist of 10 missense (p.N77K, p.C101F, p.R250W, p.G270D, p.P283R, p.S332C, p.H621R, p.S685F, p.I693F, p.R822C), two nonsense (p.E324X, p.R661X), a frameshift (p.S439fs), and two splice site (c.1081G>C and c.1977+1G>A) changes. However, the p.N77K and p.R822C changes were also found in two and one out of 150 healthy control individuals, respectively, and therefore, their pathogenic effect is questionable. Notably, three alterations (p.E324X, p.S332C, c.1081G>C) are located in the alternative exon 8B that codes for the FGFR1c isoform, thus indicating that this isoform plays a crucial role in the development of the olfactory system in man. Moreover, the presence of cleft palate in a patient carrying the p.E324X change shows that FGFR1c is important for palate morphogenesis too.

Risk of second primary cancer following differentiated thyroid cancer.

Concerns remain over the risk of cancer following differentiated thyroid carcinoma and its causes. Iodine-131 ((131)I) and external irradiation are known to have potential carcinogenic effects. Thyroid carcinoma is a polygenic disease which may be associated with other malignancies. We investigated the incidence of second cancer and its aetiology in a cohort of 875 patients (146 men, 729 women) with differentiated thyroid carcinoma originating from Basse-Normandie, France. Cancer incidence was compared with that of the general population of the Département du Calvados matched for age, gender and period. The cumulative proportion of second cancer was estimated using the life-table method. Factors that correlated with the risk of second cancer were studied using the Cox model. After a median follow-up of 8 years, 58 second cancers had been observed. Compared with general population incidence rates, there was an overall increased risk of second cancer in women [standardised incidence ratio (SIR)=1.52; P<0.01], but not in men (SIR=1.27; P>0.20). Increased risk related to cancers of the genitourinary tract (SIR=3.31; P<0.001), and particularly to cancer of the kidney (SIR=7.02; P<0.01). Multivariate analysis showed that age above 40 years (P<0.01) and a history of previous primary cancer (P<0.001) correlated with risk. In contrast, neither cervical irradiation nor cumulative activity of (131)I was related to the risk. These data confirm that women with differentiated thyroid carcinoma are at risk of developing a second cancer of the genitourinary tract and kidney. Only age and medical history of primary cancer before thyroid carcinoma are risk factors for second cancer. Common environmental or genetic factors as well as long-term carcinogenic effects of primary cancer therapy should be considered.

Major hyperestrogenism in a feminizing adrenocortical adenoma despite a moderate overexpression of the aromatase enzyme.

A 30-year-old male was referred for the rapid development of gynecomastia, and dramatic hyperestrogenemia was assessed: plasma estrone, estradiol but also cortisol were not suppressed by high-dose dexamethasone, while gonadotropin pulsatility was completely abolished. A 60-mm right adrenal tumor was evidenced on computed tomography-scan, and the patient underwent adrenalectomy. The tumor was found to express a moderate increase in aromatase activity compared with adjacent non-neoplastic adrenal tissue. Quantitative RT-PCR also showed a weak and non-significant increase in total aromatase mRNA in the tumor compared with normal adrenal tissue. Aromatase transcripts were mainly promoter PII-derived, but different patterns of aromatase minor transcripts were found: promoter I.3- and I.6-derived transcripts were identified in the tumor, while only promoter I.4-derived transcripts were found in normal adrenal. This case report demonstrates that a sharp aromatase overexpression is not a prerequisite for clinical and biochemical hyperestrogenism, and further characterizes the aromatase promoter utilization in this feminizing adrenocortical tumor and in the normal adrenal cortex.

The effect of age, body mass index, and fasting triglyceride level on postprandial lipemia is dependent on apolipoprotein E polymorphism in subjects with non-insulin-dependent diabetes mellitus.

The aim of this study was to evaluate in non-insulin-dependent diabetes mellitus (NIDDM) subjects the respective influence of apolipoprotein (apo) E polymorphism, age, gender, weight, fasting triglyceride (TG) status, and glycemic status on postprandial lipemia. Apo E genotyping was performed in consecutive NIDDM hospitalized patients in order to recruite size-adjusted groups of each apo E genotype. In 57 NIDDM including 22 E3/3 (E3), 18 E2/3 (E2), and 17 E4/3 (E4) subjects, an 8-hour vitamin A-fat loading test was performed and TG and retinyl palmitate (RP) measured. Fasting TG level correlated with the TG area under the incremental curve (AUIC) (r = 0.512, P <.001) but not with RP AUIC. Despite not different fasting and postprandial TG concentrations, E2 and E4 carriers exhibited a 2- to 3-fold higher RP AUIC than E3 carriers (P =.01). Multivariate analysis indicated an age x apo E interaction on postprandial TG (P <.01), since the unfavorable effect of E2 and E4 allele on TG AUIC was unmasked by aging. In addition, a fasting TG x apo E interaction on postprandial TG was shown (P <.01), and the correlation between fasting TG and TG AUIC was actually restricted to E2 or E4 carriers. Finally, the negative correlation between BMI and postprandial TG observed in the experimental group was actually restricted to E4 carriers (r = -0.77, P <.001). Our results indicate interactions between apo E polymorphism and aging, fasting TG level and BMI that may be important for analyzing postprandial TG clearance in NIDDM.