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Objectif Decrire la reponse du cortisol lors d’un test au Synacthen ® des patients avec hyperplasie congenitale des surrenales de forme non classique (NCCAH). Methodes Etude retrospective, comparant le pic de cortisol sous Synacthen ® (250 μg) des patients NCCAH (confirmee par genotypage) a celui d’un groupe temoin (GT) avec pilosite pubienne precoce et reponse de 17OHP. Resultats Au total, 35 patients NCCAH ont ete inclus (26 filles, 9 garcons). Âge moyen : 7,0 ans (0,8–15,6). Le GT etait constitue par 47 enfants (39 filles, 8 garcons), âge moyen : 7,2 ans (0,5–9,9). Cortisol de base des NCCAH : 12,9 μg/dl (4,3–22,2) versus 9,7 (4,2–16,2) dans le GT ( p = 0,0006). Pic de cortisol des NCCAH : 18,2 μg/dl (6,3–40) versus 24,9 (12–30,3) dans le GT ( p Conclusion Une reponse insuffisante du cortisol etait presente chez 60 % des NCCAH. Nous proposons d’instaurer un traitement par hydrocortisone en cas de stress, chirurgie, maladie aigue ou fatigue chez les patients NCCAH non traites qui ont un pic insuffisant de cortisol apres Synacthen ® . La fatigue doit etre documentee objectivement, et reevaluee apres introduction du traitement par hydrocortisone.

Contexte Des issues defavorables, telles l’obesite, l’osteoporose, l’infertilite ont ete decrites chez les patients presentant une HCS revelee dans l’enfance. Objectif Identification des facteurs de risque (FR) impliques dans la survenue de ces complications. Patients et methodes Les criteres etudies etaient ete : IMC, osteodensitometrie, TDM surrenalien, cycles et hirsutisme chez les femmes, et inclusions testiculaires chez les hommes. Pour chaque critere, une analyse univariee a ete realisee a partir des caracteristiques cliniques, genetiques, des parametres hormonaux et de la dose cumulee de traitement recus depuis le diagnostic. Resultats Cent quatre patients (71 femmes, 33 hommes, 69 formes classiques et 35 formes non classiques revelees dans l’enfance) ont ete analyses. Les FR pour un IMC > 25 kg/m 2 , la presence d’une hyperplasie ou de nodules surrenaliens au TDM, d’hirsutisme ou de cycles menstruels irreguliers, etaient lies au controle hormonal de la maladie : 17OHprogesterone, Δ4-androstenedione ou ACTH ( p p p = 0,002) et la dose cumulee de glucocorticoides ( p p = 0,01). La dose cumulee de fludrocortisone etait un FR de presence d’inclusions ( p = 0,03). Discussion Cette etude confirme la forte prevalence des complications a l’âge adulte des patients presentant une HCS diagnostiquee dans l’enfance, et le role cle du traitement et d’equilibre hormonal. Il est donc primordial d’agir le plus precocement possible sur ces differents leviers afin d’optimiser le controle de la maladie.

Introduction L’insuffisance ovarienne primaire est un des signes cardinaux du syndrome de Turner (ST). Les patientes peuvent beneficier d’une prise en charge en assistance medicale a la procreation (AMP). Cependant, peu d’etudes ont rapporte la fertilite spontanee des patientes avec ST. Objectifs Evaluer la frequence de survenue des grossesses spontanees (GS), les facteurs pronostiques de fertilite et le deroulement des grossesses dans une cohorte de patientes avec ST. Patientes et methodes Au total, 321 patientes ont ete recrutees au sein du Centre de Maladies Rares (CRMERC). Les donnees ont ete extraites de la base informatique CEMARA puis les patientes ont ete contactees par telephone. La population controle est la population francaise dont les donnees de fertilite ont ete obtenues a la Direction Generale de la Sante. Resultats Dix-sept patientes ont eu un total de 32 grossesses. Le delai median de conception est de 6 mois. Onze patientes (3,4 %) ont eu au moins 1 GS a terme. Les facteurs predictifs de GS sont la menarche spontanee (16/17) et le caryotype mosaique (12/17). Le taux de fausse-couche chez les patientes est statistiquement superieur (34 % versus 21 %, p Conclusion Cette etude montre que la survenue d’une GS menee a terme chez les patientes avec ST est un evenement rare mais non exceptionnel. Ces donnees sont utiles pour ameliorer les conseils donnes aux patientes sur les possibilites de fertilite en dehors de l’AMP.

Objectifs L’HNL est une maladie infiltrative multisystemique rare dans laquelle les atteintes endocriniennes sont mal connues. Nous avons evalue leur prevalence et leur evolution dans une large serie. Patients et methodes Etude observationnelle monocentrique incluant les patients consecutifs avec HNL entre 10/2007 et 05/2013. Evaluation en hospitalisation des fonctions hypophysaire, gonadique, surrenalienne et thyroidienne, ainsi que des metabolismes glucidique, lipidique et osseux. Resultats Sur 64 patients (50 hommes), l’insuffisance somatotrope est le deficit antehypophysaire (DAH) le plus frequent (78,6 %), puis viennent : hyperprolactinemie 44,1 %, insuffisance gonadotrope 22,2 %, insuffisance thyreotrope 9,5 %, insuffisance corticotrope 3,1 %. Il existe ≥ 1 DAH chez 61 % des patients et ≥ 2 chez 30 %. Le diabete insipide, inaugural dans 65 % des cas, est retrouve chez 33,3 % des patients. Les atteintes morphologiques hypophysaires a l’IRM sont rares ( 25 et HTA chez > 50 % des patients et diabete de type 2 chez 1/3 (non correle a la corticotherapie). Les deficits peuvent apparaitre progressivement et sont generalement definitifs. Conclusions Premiere evaluation systematique des atteintes endocriniennes dans une grande serie de patients avec HNL. Elles sont extremement frequentes et doivent faire l’objet d’un depistage systematique au diagnostic ainsi que d’un suivi specialise au long cours.

Contexte L’insuffisance ovarienne prematuree (IOP) est cause d’infertilite, mais une reprise de la fonction ovarienne et une grossesse spontanee peuvent survenir. Objectif Evaluation de l’incidence d’une reprise ovarienne chez des patientes avec IOP, de ses facteurs predictifs et ceux associes a son maintien. Patients et methodes Il s’agit d’une etude portant sur 542 patientes avec une IOP. Nous disposons pour 507 d’entre elles des donnees sur le devenir du fonctionnement ovarien. La reprise ovarienne se definissait par survenue d’une grossesse spontanee et/ou de cycles et/ou un taux de FSH Resultats Au total, 122 femmes (24 % des patientes), âgees de 30,12 ± 6,44 ans, ont eu une reprise d’activite ovarienne au cours d’un suivi moyen depuis le diagnostic d’IOP de 4,12 ± 3,71 ans. Pour 77 % d’entre elles, la reprise a eu lieu dans l’annee suivant le diagnostic. Vingt-quatre grossesses spontanees sont survenues chez 18 femmes (14,7 %). Les criteres predictifs de reprise ovarienne etaient : l’amenorrhee secondaire, les taux de FSH et d’œstradiol non effondres. La duree mediane de reprise etait de 3 ans et 6 mois. Le delai court entre le diagnostic et la reprise (RR a 1,74 ± 0,29) ainsi que les taux bas de FSH au bilan (RR a 1,006 ± 0,002) sont predictifs d’une longue duree de reprise. Discussion La reprise d’une fonction ovarienne des patientes en IOP n’est pas un phenomene rare. Notre etude a identifie les facteurs predictifs de cette reprise ainsi que de sa duree, ce qui devrait permettre d’ameliorer l’information et la prise en charge des patientes.

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.

Prolactin (PRL), a polypeptide hormone secreted mainly by the pituitary and, to a lesser extent, by peripheral tissues, affects more physiological processes than all other pituitary hormones combined since it is involved in > 300 separate functions in vertebrates. Its main actions are related to lactation and reproduction. The initial step of PRL action is the binding to a specific membrane receptor, the PRLR, which belongs to the class 1 cytokine receptor superfamily. PRL-binding sites have been identified in a number of tissues and cell types in adult animals. Signal transduction by this receptor is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases and signal transducers and activators of transcription (STATs). Disruption of the PRLR gene has provided a new mouse model with which to identify actions directly associated with PRL or any other PRLR ligands, such as placental lactogens. To date, several different phenotypes have been analyzed and are briefly described in this review. Coupled with the SAGE technique, this PRLR knockout model is being used to qualitatively and quantitatively evaluate the expression pattern of hepatic genes in two physiological situations: transcriptomes corresponding to livers from both wild type and PRLR KO mice are being compared, and following statistical analyses, candidate genes presenting a differential profile will be further characterized. Such a new approach will undoubtedly open future avenues of research for PRL targets. To date, no pathology linked to any mutation in the genes encoding PRL or its receptor have been identified. The development of genetic models provides new opportunities to understand how PRL can participate to the development of pathologies throughout life, as for example the initiation and progression of breast cancer.

Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12 ± 3% residual activity, whereas in patient 1 a 24 ± 4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.

Although prolactin (PRL) has been long suspected to be involved in the progression of human breast cancer, the failure of clinical improvement by treatment with dopamine agonists, which lower circulating levels of PRL, rapidly reduced the interest of oncologists concerning a potential role of this pituitary hormone in the development of breast cancer. Within the last few years, however, several studies reported first, that PRL is also synthesized in the mammary gland, and second that it exerts its proliferative action in an autocrine/paracrine manner. These observations have led to a reconsideration of the role of PRL as an active participant in breast cancer and are an impetus to search for alternative strategies aimed at inhibiting the proliferative effects of PRL on tumor mammary cells. In this report, we discuss the three possible levels that can be targeted for this purpose: the mammary synthesis of PRL, the interaction of the hormone with its receptor at the surface of mammary cells, and the intracellular signaling cascades triggered by the activated receptor. For each of these steps, we discuss the molecular event(s) that can be targeted, our understanding of the mechanisms involving these putative targets as well as the tools currently available for their inhibition. Besides its proliferative effect, PRL is also involved in the control of angiogenesis through one of its cleaved fragments, named PRL 16K, which has been shown to inhibit the angiogenic process. In view of this biological activity, we discuss first the cleavage of PRL with respect to the human mammary gland and, second, the hypothesis speculating that a balance between the proliferative effect of intact PRL and the anti-angiogenic activity of its 16K-like fragments might be physiologically relevant in the evolution of mammary tumors. If true, our hypothesis would suggest that the enzymatic cleavage of PRL could represent a new molecular target in the search for alternative strategies in the treatment of breast cancer.

Breast cancer in developed countries represents the major cause of cancer mortality in women (1), and the lifetime risk in the early 1990s is estimated to be 1:8 women (2). Despite considerable therapeutic and screening efforts, no decrease in mortality has been observed over the last 10 years.

A single natural loss of function mutation of the follicle stimulating hormone receptor (FSHR) has been described to date. Present in the Finnish population it markedly impairs receptor function, blocking follicle development at the primary stage and presenting as primary amenorrhea with atrophic ovaries. When Western European women with this phenotype were examined for FSHR mutations the result was negative, suggesting that other etiologies corresponding to this clinical pattern are markedly more frequent. We now describe a novel phenotype related to mutations provoking a partial loss of function of the FSHR. A woman with secondary amenorrhea had very high plasma gonadotropin concentrations (especially FSH), contrasting with normal sized ovaries and antral follicles up to 5 mm at ultrasonography. Histological and immunohistochemical examination of the ovaries showed normal follicular development up to the small antral stage and a disruption at further stages. The patient was found to carry compound heterozygotic mutations of the FSHR gene: Ile160Thr and Arg573Cys substitutions located, respectively, in the extracellular domain and in the third intracellular loop of the receptor. The mutated receptors, when expressed in COS-7 cells, showed partial functional impairment, consistent with the clinical and histological observations: the first mutation impaired cell surface expression and the second altered signal transduction of the receptor. This observation suggests that a limited FSH effect is sufficient to promote follicular growth up to the small antral stage. Further development necessitates strong FSH stimulation. The contrast between very high FSH levels and normal sized ovaries with antral follicles may thus be characteristic of such patients.

Prolactin (PRL), secreted by the pituitary, decidua, and lymphoid cells, has been shown to have a regulatory role in reproduction, immune function, and cell growth in mammals. The effects of PRL are mediated by a membrane-bound receptor that is a member of the superfamily of cytokine receptors. Formation of a trimer, consisting of one molecule of ligand and two molecules of receptor, appears to be a necessary prerequisite for biological activity. The function of these receptors is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases (JAKs) and signal transducers and activators of transcription (STATs). To study these receptors, we have used two approaches: mutational analysis of their cytoplasmic domains coupled with functional tests and inactivation (knockout) of the receptor gene by homologous recombination in mice. We have produced mice by gene targeting in embryonic stem cells carrying a germline null mutation of the prolactin receptor gene. Heterozygous (+/-) females show almost complete failure to lactate, following their first, but not subsequent pregnancies. Homozygous (-/-) females are infertile as a result of multiple reproductive abnormalities, including ovulation of premiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Half of the homozygous males are infertile or show reduced fertility. In view of the wide-spread distribution of PRL receptors, other phenotypes including those on the immune system, are currently being evaluated in -/- animals. This study establishes the prolactin receptor as a key regulator of mammalian reproduction and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.

The role of PRL in human breast tumorigenesis is not well understood. One of the limitations is the difficulty of accurately measuring PRL receptors (PRLR) in human tissues. We established a quantitative PCR method (Q-PCR) in T-47D human breast cancer cells and applied it to 29 patients, 25 of whom presented with either cancer or fibroadenoma. Four patients underwent a mammoplasty, and normal epithelial cells were cultured before Q-PCR. In T-47D cells, 31 x 10(6) messenger RNA molecules were detected per microgram of total RNA. In all patients, expression of the PRLR gene was detected, varying from 1500 to 1 x 10(6) molecules/microgram of RNA in normal tissues and from 4500 to 34.7 x 10(6) molecules/microgram of RNA in tumors. PRLR expression was always greater in tumor than in normal contiguous tissue and similar in cultured mammary epithelial cells and normal breast tissues. Estradiol and progesterone receptor-negative tumors expressed low levels of PRLR transcripts, similar to normal breast tissue from menopausal women. Immunocytochemical analysis of PRLR confirmed stronger staining in almost all tumor samples compared with normal tissues. A messenger RNA encoding locally produced human PRL was also identified by RT-PCR in every sample tested. Our results confirm PRLR gene expression in all tissues studied, and moreover, indicate that this expression is increased in human breast tumors vs. normal contiguous tissues.

Tamoxifen-induced histological changes in the endometrium of postmenopausal breast cancer patients were determined in 40 women who had undergone hysteroscopy examinations. Endometrial samples were obtained from 15 of these women for histological examination. With hysteroscopy, the endometrium showed very specific changes combining diffuse epithelial atrophy and round protuberances due to cystic glands. Histological examination confirmed the atrophy of the luminal and glandular epithelia, coexisting with large, dilated cystic glands. The stroma was dense and rich in collagen fibers associated with edematous areas. Polyps were present in 17 patients. The endometrial thickening observed in ultrasonography has often been interpreted as “endometrial hyperplasia,” whereas the endometrium of postmenopausal patients treated with tamoxifen showed “cystic glandular atrophy.” The cystic glands account for the thickened appearance observed in ultrasonography.

Previous reports demonstrated that prolactin receptors (PRL-R) are widely expressed on cells of the immune system. We analyzed a possible regulation of PRL-R expression on human mononucleated blood cells by prolactin (PRL) itself. PRL-R expression was analyzed by immunofluorescence on T and B lymphocytes and monocytes from peripheral blood mononucleated cells (PBMC) of patients with hyperprolactinemia or acromegaly compared with sex- and age-matched control subjects. The frequency of PRL-R positive cells and the intensity of PRL-R expression was only modified among the CD8+ T cell population of hyperprolactinemic patients with macroadenoma. No correlation was reported between PRL-R expression and circulating PRL levels. The percentage of PRL-R+ cells on B or T lymphocytes and monocytes as well as the capacity of PBMC to proliferate in response to T cell mitogens were not significantly different in bromocriptine-treated compared with untreated patients. These findings suggest that factors other than pituitary PRL play the major role in regulating PRL-R expression on cells of the immune system. Journal of Endocrinology (1995) 147, 353–359

Publisher Summary Prolactin (PRL) is involved in a wide range of cellular and physiological effects in several species of male and female vertebrates. The in vivo studies in rats have shown that hypoprolactinemia induced by hypophysectomy inhibits the development of delayed cutaneous hypersensibility. The in vitro studies have confirmed the stimulatory effect of PRL on immune cells—such as induction of IL-2 receptors and an increase of IL-2 secretion in primary lymphocytes from ovariectomized rats. The PRL may act directly and/or indirectly on lymphocytes by interaction with specific receptors (R) on the cell membrane. This chapter presents an analysis of the distribution of PRLR in both central and peripheral murine lymphoid organs, showing that almost 90% of cells from thymus and bone marrow are labeled by the anti-PRLR mAb, while cells from spleen and lymph nodes are also labeled, but at a lower level. The experiment explained in the chapter underlines the crucial role of the cytoplasmic domain in signal transduction. The data presented in the chapter suggests that under some circumstances, the PRLR could exert its immunomodulatory activity by a direct action, acting as a transport protein, translocating PRL to the nucleus. One of the functions of the short form of PRLR in lymphocytes could be to promote internalization, while the long form would be responsible for other functions. The tissue-specific expression and independent regulation of the different forms of the PRLR suggest that they may have separate but specific biological functions.

ObjectiveWomen with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility.DesignCase/control study.MethodsSixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28±3 days), were included. LH pulse patterns over 6 h were determined in patients and controls.ResultsNo differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels.ConclusionsLH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

Two different forms of the prolactin receptor, differing in the length of their cytoplasmic domains, have been characterized in many tissues of rodents. To better understand whether short and long forms of PRLR are involved in the immune effects of PRL, we evaluated the distribution of these different forms in the thymus, spleen, lymph nodes and bone marrow from rats and mice. Total RNA was used for cDNA synthesis which was amplified by PCR, using oligonucleotides specific to the different forms of the prolactin receptor. We detected transcripts encoding both forms of prolactin receptor in all lymphoid tissues examined in mouse and rat. Finally we studied the transcript encoding prolactin itself in these rodent tissues; a clear signal was only found in rat thymus. The ubiquitous presence of both forms of receptor transcripts in different lymphoid tissues points to an important role of the PRLR and suggests that such forms of the receptor may be involved in differential functions in lymphocytes.

The secretory polypeptide 7B2 is produced in different endocrine and neuroendocrine cells, where it is presumed to play a role in the hormone secretion mechanism. In this study, we examined a pattern of 7B2 mRNA expression in the mouse and rat pituitary gland. When [35S]-labeled antisense cRNA probes were used for in situ hybridization, 7B2 mRNA transcripts were detected within virtually all endocrine cells of the anterior lobe (gonadotrophs, thyrotrophs, corticotrophs, somatotrophs and lactotrophs) and of the intermediate lobe (melanotrophs). The posterior lobe was negative. By immunocytochemistry, 7B2 accumulation was observed within melanotrophs in the intermediate lobe and within gonadotrophs and thyrotrophs in the anterior lobe. The question of 7B2 production in other pituitary cells, such as corticotrophs, somatotrophs and lactotrophs, was studied under culture conditions. The corticotroph AtT-20 and somatrotroph GH3 cell lines both expressed 7B2 mRNA and contained 7B2 protein detectable by radioimmunoassay. However, this protein could not be visualized by immunocytochemistry. Thus, it is possible that 7B2 is produced in all hormone-synthesizing cells of the pituitary gland, being stored only within some of them and rapidly exported after synthesis from others.

In order to investigate whether a calcium channel blocker could modulate the protein kinase C activity in normal and estradiol pretreated rat pituitary, female Wistar rats were treated or not (controls) with ± PN 200-110 (3 mg · kg−1 · day−1, sc) for 8 days or with estradiol cervical implants for 8 or 15 days, alone or in combination with PN 200-110 the last 8 days. Estradiol treatment induced a significant increase in plasma prolactin levels and pituitary weight. PN 200-110 administered to normal rats did not modify these parameters, whereas it reduced the effects of the 15 days estradiol treatment on prolactin levels (53.1 ± 4.9 vs 95.0 ±9.1 μg/l, p

1. In order to examine the potential role of endogenous atrial natriuretic peptide (ANP) in modulating the increased sodium excretion per nephron in chronic renal failure, we studied healthy subjects with normal renal function (group I) and patients with moderate (group II) or severe chronic renal failure (group III) before, during and after administration of an intravenous sodium load. All subjects had been on a controlled diet containing 120 mmol of sodium per day for 5 days before the study. 2. Under basal conditions, plasma ANP and fractional excretion of sodium (FENa) were highest in group III. Both parameters increased in response to the sodium load in the three groups studied (P < 0.001). Changes with time differed from group to group (P < 0.05), the more marked response for both parameters being observed in group III. After adjustment with respect to plasma ANP (analysis of covariance), FENa was no longer modified in response to the sodium load, whereas adjustment of FENa with respect to mean blood pressure was without consequence on the significance of its change with time. This demonstrates that plasma ANP, but not mean blood pressure, represents the main factor producing variation in FENa during and after the sodium load. 3. These results suggest an important role for plasma ANP in promoting adaptation of short-term sodium excretion in response to an acute sodium load in patients with chronic renal failure who ingest a normal sodium intake.

Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharo-phimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype-phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and III by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.