Paolo Beck-Peccoz

Non-autoimmune hyperthyrotropinemia has been previously reported among children born prematurely. The aim of this study was to follow up their thyroid function, volume, and structure and to investigate the relationship with growth, IGF-I, lipid profile, and insulin sensitivity. Seventy-two children born prematurely (33.2±2.2 weeks), 26 appropriate (AGA) and 46 small for gestational age (SGA), were evaluated at the age of 7.6±2.3 yr (time 1) and at the age of 11.4±2.3 yr (time 2). We also measured TSH, free T(3) (fT(3)), free T(4) (fT(4)), thyroperoxidase antibodies (TPO-Ab), thyroglobulin antibodies (TG-Ab), thyroid ultrasound, auxological parameters, lipid profile, glucose, and insulin level. In the AGA group TSH was similar in both times (2.7±1.0 vs 3.0±0.9 mU/l) and above the upper normal limit in 4 (15.4%) subjects at time 1 and in 6 (23.7%) subjects at time 2 (ns). In the SGA group, TSH was similar in both times (2.8±1.2 vs 2.5±1.0 mU/l) and above the upper normal limit in 11 (23.9%) subjects at time 1 and 5 (10.8%) subjects at time 2 (ns). fT(4) and fT(3) were always normal and TPO- and TG-Ab absent. Thyroid volume increased progressively, but significantly only in the AGA group (p=0.0005). The thyroid structure was always normal and there was no influence on the growth and the biochemical profile. Some ex-premature babies show a mild and variable thyroid dysfunction, which does not seem to evolve toward an overt thyroid dysfunction.

Background Occurrence in a familial setting is well established for medullary thyroid carcinoma (MTC) and has been more recently reported for papillary thyroid cancer (PTC). Germline mutations or rearrangements of the RET proto‐oncogene are the genetic background of the majority of hereditary MTCs and of about 25–40% of PTCs. patients A large multigenerational familial medullary thyroid cancer (FMTC) family, comprised of four generations and a total of 60 subjects, has been fully evaluated. Studies on germline RET mutations and polymorphisms, on somatic RET activation and on haplotyping with RET‐linked markers, were performed. results RET mutational analysis revealed a rare missense point mutation in exon 15 of RET (A891S), associated with FMTC. Haplotype analysis showed a co‐segregation between the allelic variant 5 of D10S578 marker (which is tightly linked to the RET locus) and the RET mutation. Two patients, from different branches of the family, did not harbour the point mutation A891S despite histological confirmation of MTC. In these cases, haplotype analysis excluded the involvement of the RET gene itself in the pathogenesis of the MTC. In three patients, the coexistence, in different foci, of medullary and papillary thyroid cancer was documented. The genetic studies did not show ret/PTC rearrangements. The microsatellite analysis excluded co‐segregation of RET locus with the MTC/PTC phenotype. conclusions We report a full clinical and molecular analysis of a large FMTC kindred with an uncommon RET mutation. In two family members, phenotype and genotype were not concordant, representing the first evidence of FMTC phenocopies. Furthermore, the association of familial forms of medullary and papillary thyroid cancers has been found in 30% of patients undergoing thyroidectomy for MTC. In these situations, genetic analyses excluded the possible germline involvement of RET. Though FMTC phenocopies are likely to represent an exceptional finding, such a possibility should be taken into account in the genetic counselling for MEN 2 syndromes.

Thyrotropin-secreting pituitary adenomas (TSH-omas) are rare tumors (0.5% of all pituitary adenomas) showing an invasive behavior and usually sporadic, although a few cases are associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant inherited syndrome. This disorder is linked to loss of heterozygosity (LOH) on 11q13 and inactivating mutations of MEN1 gene, which is located in the same chromosomal region. As other types of anterior pituitary adenomas, TSH-omas are the result of a monoclonal outgrowth where the intrinsic genetic defects involving oncogenes or tumor suppressor genes occur in a progenitor cell. However, so far no activating mutations of particular oncogenes or inactivating mutations of tumor suppressor genes have been identified. Starting from the observation that 3–30% of sporadic pituitary adenomas show LOH on 11q13, and that allelic losses on the long arms of chromosome 11, beside 10 and 13, are significantly associated with the transition from the non-invasive to the invasive phenotype, we decided to investigate LOH on 11q13 and mutations of menin in a large series of TSH-omas. Thirteen tumors were evaluated. DNA was extracted from tumors by standard methods and genomic DNA from peripheral blood leukocytes was used as control. LOH was screened by using 3 polymorphic markers on 11q13: D11S956, PYGM, INT-2. In 3 out of 15 cases we could demonstrate LOH on 11q13, but none of the tumors showed menin mutation after sequence analysis. These data strongly suggest that menin does not play a causative role in the development of TSH-omas, and are in agreement with other studies demonstrating a limited role of menin in pituitary sporadic tumorigenesis.

Central hypothyroidism (CH) is a rare cause of hypothyroidism, generally due to either pituitary or hypothalamic defects. On the basis of its etiology, it is possible to distinguish acquired and hereditary forms. Hereditary CH can be isolated or associated with combined pituitary hormone deficiency (CPHD). In the former case, alterations of only two genes, TSHbeta and the TRH receptor, have so far been described as responsible for the disorder. In hereditary CH associated with CPHD, inactivating mutations of different pituitary transcription factors (HESX1, PROP-1, POU1F1) have been found involved in the pathogenesis of the disease. Finally, an association between CH and severe obesity has been described in patients with leptin receptor (Leptin-R) mutations. The clinical consequences of CH in adult life vary greatly depending on the etiology, the severity of the thyroid impairment, the extent of the associated hormone deficiencies, and the age of the patient at the time of the onset of the disease. In general, acquired CH is less severe than the congenital form because of the constitutive activity of the wild-type TSH-receptor. Symptoms and signs of thyroid insufficiency are usually milder than those of primary hypothyroidism, and goiter is always absent. In CPHD, most patients have other endocrine manifestations of the disease (growth failure, delayed puberty, adrenal insufficiency, diabetes insipidus) that lead them to seek medical attention before the hypothyroidism becomes severe. Early diagnosis of the congenital form by neonatal screening for hypothyroidism is strongly recommended in order to avoid cretinism. Replacement therapy with L-thyroxine administration has to be established as soon as possible.

Gonadotropins control male and female gonadal function by acting through specific recptors. The recent description of several mutations in LH and FSH receptors has significantly improved our understanding of the pathophisiology of several sexual disorder. Both gain- and loss-of-function germline mutations leading to constitutive receptor activation or to hormone resistance have been described. The clinical impact of these mutant receptors can be markedly different, depending upon the sex of the affected patient and the degree of functional alteration. Numerous mutations were described in LH receptor gene. Constitutive activation of this receptor leads to male-limited precocious pseudopuberty, whereas hypergonadotropic hypogonadism is the clinical phenotype of LH resistance. On the other hand, few mutations of FSH receptor were described so far. Inactivating mutations of FSH receptor are involved in some cases of hypergonadotropic hypogonadism with a more severe impairment of fertility in female patients. Only one gain-of-function mutation of FSH receptor was reported to maintain fertility in one hypophysectomized man. This review is focused on the known genetic alterations of gonadotropic receptors in humans and their impact on male sexual differentiation and fertility.

BACKGROUND: One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. OBJECTIVE: To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. PATIENTS: Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. METHODS: GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. RESULTS: Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. CONCLUSION: In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.

We report the intra-uterine and postnatal thyroid status of a newborn, whose mother, affected with Hashimoto's thyroiditis superimposed on a previous Graves' disease, again became hyperthyroid during the third trimester of pregnancy. The mother had very high levels of anti-thyroid auto-antibodies, including TSH receptor auto-antibodies (TRAb) measured as TSH-binding inhibiting auto-antibodies (TBIAb). In order to exclude fetal thyroid dysfunction due to passive transplacental transfer of TRAb, fetal blood samples were obtained by cordocentesis at 21, 27 and 32 weeks of gestation. A transplacental transfer of TRAb was already seen at 21 weeks, but no alteration of fetal thyroid function was present at that time. In the following weeks, a rise in TRAb and circulating thyroid hormones was observed both in the fetus and mother, accompanied by overt hyperthyroidism in the mother and by growth retardation in the fetus. At birth, TRAb were shown to have stimulating activity both in the newborn and mother. This report documents the early transplacental passage of thyroid auto-antibodies and underlines the importance of close follow-up of pregnant women with auto-immune thyroid disorders.