A.M. Guedj

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

CONTEXT Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. OBJECTIVE We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. RESULTS Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

PROKR2 Variants in Multiple Hypopituitarism with Pituitary Stalk Interruption

CONTEXT Pituitary stalk interruption represents a frequent feature of congenital hypopituitarism, but only rare cases have been assigned to a known genetic cause. OBJECTIVE Using a candidate gene approach, we tested several genes as potential causes of hypopituitarism with pituitary stalk interruption. We hypothesized that ectopic posterior pituitary may be a consequence of defective neuronal axon projections along the pituitary stalk or defective angiogenesis of hypophyseal portal circulation. Considering the role of the prokineticin 2 pathway in angiogenesis and neuronal migration, we screened PROK2 and PROKR2 genes. DESIGN PROK2 and PROKR2 and all genes previously known to be involved in hypopituitarism with pituitary stalk interruption (LHX4, HESX1, OTX2, and SOX3) were screened in 72 index cases with pituitary stalk interruption syndrome from the GENHYPOPIT database. In vitro studies were performed to assess the functional consequences of allelic variants. RESULTS We identified two heterozygous PROKR2 mutations (p.Leu173Arg and p.Arg85His) previously reported in isolated hypogonadotroph hypogonadism and a novel PROKR2 variant (p.Ala51Thr) that, in contrast with both other mutations, did not impair receptor signaling activity. Three allelic variants of HESX1 were identified: the heterozygous p.Phe156Ser and the homozygous p.Arg109X mutations were functionally deleterious, whereas p.Ser67Thr was found as a rare allelic variant in association with p.Arg85His PROKR2 mutation in the same patient. CONCLUSIONS We report PROKR2 variants in congenital hypopituitarism with pituitary stalk interruption, suggesting a potential role of the prokineticin pathway in pituitary development.

The Use of Preoperative Routine Measurement of Basal Serum Thyrocalcitonin in Candidates for Thyroidectomy due to Nodular Thyroid Disorders: Results from 2733 Consecutive Patients

CONTEXT The preoperative routine measurement of basal serum thyrocalcitonin (CT) in candidates for thyroidectomy due to thyroid nodules is currently a subject of debate. OBJECTIVE The objective of this study was to evaluate the role of systematic basal serum CT measurement in improving the diagnosis and surgical treatment of medullary thyroid carcinoma (MTC) in patients undergoing thyroidectomy for nodular thyroid disorders, regardless of preoperative CT levels. DESIGN We determined basal serum CT levels in 2733 consecutive patients before thyroid surgery and performed a pentagastrin test in patients with hypercalcitoninemia. We correlated basal and stimulated CT levels with intraoperative and definitive histopathological findings, and we analyzed the impact of these results on surgical procedures. RESULTS Twelve MTCs were found among the 43 patients with basal serum CT level of 10 pg/ml or greater. Two MTCs were present among the 2690 patients with normal CT levels. MTC was always present in patients with a basal CT of 60 pg/ml or greater. For CT levels ranging from 10 to 59 pg/ml, MTC was diagnosed in 11% of patients. When preoperative hypercalcitoninemia was present, total thyroidectomy associated with comprehensive intraoperative histopathological analysis allowed the intraoperative diagnosis of five latent, subclinical MTCs. The pentagastrin test gave no additional diagnostic information for the management of patients with elevated preoperative basal serum CT level. CONCLUSION Routine measurement of CT in the preoperative work-up of nodular thyroid disorders is useful. This procedure improves intraoperative diagnosis of MTC and enables adapted initial surgery, the most determinant factor of treatment success.

Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations.

OBJECTIVE To confirm the clinical diagnosis of complete androgen insensitivity syndrome (CAIS) by molecular genetic analysis and to determine the prevalence of exon 1 mutations in the androgen receptor (AR) transactivation defects of a large series of CAIS patients. DESIGN International retrospective study. SETTING University Hospital of Montpellier, Department of Hormonology. PATIENT(S) 105 patients with normal female external genitalia, bilateral intra-abdominal or inguinal testis, normal breast development, absent or sparse pubic hair, normal or high endogenous testosterone production, hypoplastic or absent wolffian structures, and 46,XY karyotype. INTERVENTION(S) Sequencing of the AR gene. MAIN OUTCOME MEASURE(S) Prevalence of AR exon 1 mutations. RESULT(S) Over a 10-year period (1997 to 2007), we identified 78 AR gene mutations in 105 patients with CAIS; 21 of them were located in exon 1, and 13 of these were new mutations. We report 13 new mutations in the AR gene. All but one were stop codons, and the last was a splicing abnormality. CONCLUSION(S) The finding that 27% of the mutations in our cohort were localized in exon 1 versus 15% in previous works justifies the sequencing of this exon in patients with CAIS.