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P Caron

Publications and source records attributed to P Caron.

At least 19 recordsLinked to original sources
PubMed2002

Lingual thyroid and hyperthyroidism: a new case and review of the literature.

Lingual thyroid is the result of a defective migration of the thyroid anlage occurring between the 3rd and 7th week of gestation. Whereas mutations in the transcription factor-2 (TTF-2) and PAX8 and in the TSH receptor genes (TSH-R) have been reported in a minority of patients with thyroid dysgenesis, the etiopathogeny of the majority of cases, and in particular of thyroid ectopy, remains unclear. The majority of patients with thyroid ectopy are asymptomatic, but obstructive symptoms as well as hypothyroidism have been observed. Hyperthyroidism is an exceptionally rare finding. To our knowledge, only 2 cases have been reported in the literature to date. Herein, we describe an unusual case of thyrotoxicosis related to a nodular lesion in a lingual thyroid. Treatment consisted in restoration of a euthyroid state with thionamide followed by surgical removal of the ectopic gland. The underlying molecular cause of the ectopic lingual thyroid and the toxic adenoma in this case could not be identified. We speculate that abnormally early differentiation of the thyroid gland could interfere with the migration process, a hypothesis yet to be confirmed.

Adult↗
PubMed2002

Intraoperative testosterone assay for virilizing ovarian tumor topographic assessment: report of a Leydig cell tumor of the ovary in a premenopausal woman with an adrenal incidentaloma.

Ovarian virilizing tumors are rare and can lead to assessment difficulties because of their small size. A 41-yr-old female was referred for evaluation of hirsutism that had increased within the previous 3 yr. Menstrual cycle length was normal. Plasma testosterone was 3.9 ng/ml (normal range, 0.2-0.8 ng/ml), was not suppressible by 2 mg dexamethasone (4.3 ng/ml), and was increased (6.3 ng/ml) after three daily injections of hCG (5000 IU). Abdominal computed tomography scan showed an adrenal nodule (13 x 6 mm) that remained unchanged after 3 months. Ultrasound examination of the pelvis was normal. Ovarian and adrenal venous catheterization did not yield additional information. Topographic assessment was made by intraoperative measurement of testosterone in the samples taken from each ovarian vein (competitive chemiluminescent immunoassay ADVIA Centaur; right ovarian vein, 105 ng/ml; left ovarian vein, 5 ng/ml; peripheral blood, 7 ng/ml). Right annexectomy resulted in normalization of testosterone levels (0.22 ng/ml). Histopathological examination found a Leydig cell tumor of hilar type (1.5 cm). This observation illustrates the usefulness of intraoperative measurement of testosterone by a rapid automated technique for topographic assessment of ovarian virilizing tumor in premenopausal women.

Adult↗
PubMed2002

[Somatuline(R) Autogel(R), a new formulation of lanreotide for the treatment of acromegalic patients].

Lanreotide Autogel((R)) is a new long-acting aqueous preparation of lanreotide for the treatment of acromegaly, and is administered by deep sc injection from small-volume pre-filled syringes. The aim of this study was to evaluate the efficacy and safety of this new long-acting formulation in a large population of acromegalic patients previously responsive to im lanreotide 30mg (sustained release microparticle formulation). Lanreotide Autogel((R)) was administered by deep sc injection every 28 days to 107 patients (54 males, 53 females; mean age 54+/-1.2 years). All patients had been treated with lanreotide 30mg for at least 3 months before study entry, and had a mean GH level<10 ng/mL after at least four subsequent im injections every 14 days (48%), 10 days (32%) or 7 days (20%). Treatment was switched from lanreotide 30mg injected every 14, 10 or 7 days to lanreotide Autogel((R)) 60, 90 or 120mg, respectively, every 28 days. After three fixed-dose injections of lanreotide Autogel((R)), mean lanreotide levels were similar to those obtained at steady state with lanreotide 30mg. During lanreotide Autogel((R)) treatment, the control of acromegalic symptoms was comparable with that previously achieved during lanreotide 30mg treatment. After three injections of lanreotide Autogel((R)), mean values for GH (2.87+/-0.22ng/mL) and IGF-1 (317+/-15ng/mL) were comparable with those recorded at the end of lanreotide 30mg treatment (GH: 2.82 +/- 0.19ng/mL; IGF-1: 323+/-16ng/mL). GH<2.5ng/mL and age-sex-normalised IGF-1 was achieved in 33% and 39% of patients during lanreotide 30mg and lanreotide Autogel((R)) treatment, respectively. Diarrhoea, abdominal pain and nausea were reported by 38, 22 and 18% of patients during lanreotide 30mg treatment, and by 29, 17 and 9% of patients, respectively, during lanreotide Autogel((R)) treatment. In conclusion, this clinical study shows that lanreotide Autogel((R)) is at least as efficacious and well tolerated as lanreotide 30mg. This new long-acting lanreotide formulation, lanreotide Autogel((R)), which is administered from small-volume pre-filled syringes by deep sc injection, is therefore likely to improve the acceptability of medical treatment for patients requiring long-term somatostatin analogue therapy.

Acromegaly↗
PubMed2001

[Primary fibromatosis of the breast].

Primary fibromatosis of the breast is a very rare pathology which looks like a malignant tumor, clinically and radiologically. Fibromatosis of the breast is characterised by a local invasion and a risk of recurrence. Positive diagnosis is provided by histology and its treatment is surgical. The aim of this study was to report one case and to emphasize the difficulties encountered in the diagnosis and the treatment.

Adult↗
PubMed2001

Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas.

Although both somatostatin receptor subtype 2 (SSTR2) and SSTR5 messenger ribonucleic acid (mRNA) are consistently expressed in GH-secreting adenomas, SSTR2 has been believed to be the key modulator of somatostatin-mediated inhibition of GH release. The somatostatin agonists currently in clinical use, octreotide and lanreotide, are directed mainly to SSTR2 (IC(50) 12- to 18-fold higher than for SSTR5). Recently, however, it was demonstrated that an SSTR5 preferential agonist, BIM-23268, not only suppressed PRL release from prolactinomas and mixed GH-PRL adenomas, but also inhibited GH release in about half of GH adenomas. In addition, the SSTR5-preferring analog showed a slight additive effect when used in combination with SSTR2 preferential drugs at submaximal concentrations in octreotide partially sensitive adenomas. In the present study we quantified SSTR2 and SSTR5 mRNA expression and the GH-suppressive effects of somatostatin-14; octreotide; a SSTR2-preferential compound, BIM-23197; a SSTR5-preferential compound, BIM-23268; and a new SSTR2- and SSTR5-bispecific compound, BIM-23244, in GH-secreting tumors classified as either full responders to octreotide (n = 5) or partially sensitive to octreotide (n = 5). The octreotide-sensitive GH secretory adenomas presented with a high level of both SSTR2 and SSTR5 mRNA expression [222 +/- 61 and 327 +/- 136 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively]. In these tumors the suppression of GH release was similarly achieved at picomolar ranges by octreotide, BIM-23197, and BIM-23244 (EC(50) = 25 +/- 15, 3 +/- 2, and 3 +/- 3 pmol/L, respectively). The compounds preferential for only SSTR5 were unable to inhibit GH release in such tumors. Among the octreotide partially responsive tumors, SSTR2 mRNA expression was 9-fold lower than in the octreotide-sensitive tumors (25 +/- 12 vs. 222 +/- 61 pg/pg GAPDH; P < 0.015), whereas SSTR5 mRNA expression was approximately 7-fold higher than in the octreotide-sensitive tumors (2271 +/- 1197 pg/pg GAPDH). In these octreotide partially responsive tumors, the SSTR5-preferential compound, BIM-23268, and the SSTR2- and SSTR5-bispecific compound, BIM-23244, were quite effective in suppressing GH secretion (EC(50) = 25 +/- 13 and 50 +/- 31 pmol/L, respectively). Similarly, BIM-23244, was able to suppress by 51 +/- 5% PRL release from five mixed GH- and PRL-secreting adenomas. These data indicate that due to heterogeneous expression of SSTR2 and SSTR5 receptor subtypes, in GH-secreting tumors, a bispecific analog, such as BIM-23244, that can activate both receptors could achieve better control of GH hypersecretion in a larger number of acromegalic patients.

Acromegaly↗
PubMed2001

Efficacy of the long-acting octreotide formulation (octreotide-LAR) in patients with thyrotropin-secreting pituitary adenomas.

The presence of somatostatin receptors on TSH-secreting pituitary adenomas allows treatment of central hyperthyroidism with somatostatin analogs. Six women and 5 men (mean +/- SEM age, 43 +/- 3 yr) presented TSH-secreting pituitary adenomas (micro, n = 2; macro, n = 9). Seven patients had previously been treated with partial surgical removal (n = 6) and/or external radiation (n = 4) of their adenoma at least 1 yr before the study, whereas 4 patients had not been treated before somatostatin analog therapy. TSH, free T(4), and free T(3) levels were in the normal range during treatment with sc injections (n = 9) or continuous infusion (n = 2) of octreotide (280 +/- 25 microg/day). Mean thyroid hormone levels increased (P < 0.01) after the washout period (34 +/- 6 days). The patients received monthly im injections of 20 mg Octreotide-LAR. In patients with an elevated free T(4) level after 3 months (n = 1) the Octreotide-LAR dose was increased to 30 mg. After 3 months of Octreotide-LAR treatment, TSH, free T(4)/T(3), and alpha-subunit levels decreased, and 10 patients were euthyroid with normal free T(4) levels. These results remained at the same level over the next 3 months. There were no statistically significant differences in the TSH and free T(4) responses to sc octreotide or im Octreotide-LAR between previously untreated patients and patients who had undergone surgical resection and/or pituitary radiation before somatostatin analog treatment. During Octreotide-LAR treatment, minor digestive problems or moderate discomfort at the injection site, lasting less than 48 h, were reported in 6 and 5 patients, respectively. Gallbladder echographies did not reveal new gallstones during Octreotide-LAR treatment. In conclusion, this study shows that monthly im Octreotide-LAR is as effective as daily sc octreotide in controlling hyperthyroidism in patients with TSH-secreting pituitary adenomas, in both previously untreated patients and patients treated with surgery and/or pituitary radiotherapy. Octreotide-LAR is well tolerated, except for minor digestive problems or mild pain at the injection site. Therefore, Octreotide-LAR appears to be a useful therapeutic tool to facilitate medical treatment of TSH-secreting pituitary adenomas in patients who need long-term somatostatin analog therapy.

Adenoma↗
PubMed2001

Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study.

OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.

Adolescent↗
PubMed2000

Retroperitoneal laparoscopic adrenalectomy: clinical experience in 52 procedures.

OBJECTIVES: Laparoscopic adrenalectomy has become an effective option for removal of small adrenal tumors. The aim of this prospective study was to evaluate the retroperitoneal approach with regard to intraoperative complications, morbidity, and length of hospital stay. METHODS: Between September 1996 and October 1999, we performed 52 laparoscopic adrenalectomies (31 left, 21 right) for benign lesions by a retroperitoneal approach in 44 patients (27 women, 17 men) with a mean age of 46.9 years (range 17 to 74). The average adrenal tumor size was 32 mm (range 10 to 63). All procedures required four trocars and a mean operative time of 135 minutes (range 75 to 240). RESULTS: There was no mortality, conversion rate to open surgery was 1.9%, and estimated blood loss was 80 mL (range 30 to 200). With a mean follow-up of 16 months, morbidity was 17.2%, which included intraoperative complications (5. 7%) with two vascular injuries, and postoperative complications (11. 5%) with wound infections, deep hematoma, and parietal dehiscence. Average length of hospital stay was 5 days with a mean analgesic consumption of 2 days (range 1 to 5). CONCLUSIONS: The retroperitoneal approach in laparoscopic adrenalectomy appears to be a minimally invasive and safe therapeutic option that may become the standard for unilateral or bilateral adrenal tumors not larger than 7 cm. However, a learning curve in laparoscopy is indispensable before starting this type of procedure.

Adolescent↗
PubMed2000

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Acromegaly↗
PubMed2000

Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a slow release formulation of the somatostatin analog lanreotide.

Somatostatin analogs have been shown to be effective for the treatment of TSH-secreting pituitary adenomas. However, their use in this indication is limited by the fact that available analogs require several daily sc injections. The present study was performed to evaluate the effects of a slow release formulation of the somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size and to assess the tolerance in a series of thyrotropinomas treated for 6 months. Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1 month. Then, according to the free T3 (fT3) plasma level measured, 9 of 18 patients were injected twice monthly, and 7 of 18 patients received SR-L every 10 days for 5 additional months. One patient was dismissed from the study in month 1 of the study for side-effects and another in month 3 for noncompliance to the protocol. Clinical and biological evaluations (plasma TSH, free alpha-subunit, fT4, fT3, and lanreotide levels) were performed before and in months 1, 3, and 6 of treatment. Pituitary magnetic resonance imaging and gallbladder ultrasonography were performed both at entry and at the end of the study. Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable patients. Mean (+/- SEM) plasma lanreotide levels reached 1.11 +/- 0.43 and 1.69 +/- 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then remained stable until the end of the study. During therapy, the plasma TSH level decreased from 2.72 +/- 0.32 to 1.89 +/-0.27 mU/L (P < 0.01), with parallel significant changes in free alpha-subunit. During the same period, plasma fT4 and fT3 levels decreased from 37.9 +/- 2.9 to 19.7 +/- 2.3 pmol/L (P < 0.01) and from 14.6 +/- 1.1 to 8.3 +/- 0.8 pmol/L (P < 0.01), respectively. No statistically significant change in mean adenoma size was observed after 6 months of treatment. Side-effects, including pain at the injection point, abdominal cramps, and diarrhea, were mild and transient and did not lead to interruption of the treatment. No gallstones occurred during the study. SR-L appears to be able to suppress clinical signs of hyperthyroidism in our series of patients with TSH-secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid hormone levels, which were normalized in 13 of 16 cases. The effect was maintained throughout the treatment using 2 or 3 SR-L injections monthly without any problem of tolerance. We conclude that SR-L is a safe and effective treatment of thyrotropinomas and avoids the drawbacks of the modes of administration of other somatostatin analogs, given three times daily.

Adenoma↗
PubMed2000

Variable growth hormone profiles following withdrawal of long-term 30mg slow-release lanreotide treatment in acromegalic patients: clinical implications.

OBJECTIVE: Intramuscular injections of 30mg slow-release (SR) lanreotide (every 10 to 14 days) are an effective treatment in acromegalic patients. Because of an ongoing need to assess the efficacy and the tolerance of a new formulation of a depot preparation of lanreotide, we have evaluated prospectively GH profiles following withdrawal of 30mg slow-release lanreotide in a cohort of acromegalic patients. PATIENTS: Fifty-one acromegalic patients, controlled during long-term 30mg SR lanreotide treatment (GH: 1.44 +/- 0.64 microgram/l, IGF-I: 316 +/- 145ng/ml) (mean +/- s.d.), were studied following the withdrawal of the drug. MEASUREMENTS: Mean GH (half-hour samples, 0800-1200h), IGF-I and lanreotide levels were evaluated 14, 28, and 42 days following the last 30mg SR lanreotide injection. RESULTS: Mean GH levels remained below 2.5 microgram/l in 32 patients (group 1) twenty-eight days following SR lanreotide withdrawal. In these patients, mean GH and IGF-I levels had increased from 1.2 +/- 0.6 to 1.7 +/- 0.5 microgram/l (P < 0001), and from 283 +/- 138 to 359 +/- 168ng/ml (P < 0.001) respectively. In the 19 other patients (group 2), mean GH concentrations had risen above 2.5 microgram/l at 28 days following SR lanreotide withdrawal. Mean GH and IGF-I levels had increased from 1.9 +/- 0.4 to 5.1 +/- 2.8 microgram/l (P < 0.001), and from 371 +/- 143 to 568 +/- 206ng/ml (P < 0.001) respectively. Patients of groups 1 and 2 were comparable with regard to age, sex, tumoral status, mean GH levels before somatostatin analogue treatment, and previous treatments such as radiotherapy and duration of somatostatin analogue therapy, but 75% of group 1 patients underwent surgery compared with 37% of group 2 patients (P < 0.01). Twenty-eight days following SR lanreotide withdrawal, mean lanreotide levels in group 1 and group 2 had decreased from 1.6 +/- 0.7 to 0.6 +/- 0.3ng/ml (P < 0.001), and from 2.7 +/- 2.0 to 0.7 +/- 0.7ng/ml (P < 0.001) respectively. A negative correlation was observed between the lanreotide levels and GH and IGF-I concentrations in the two groups of patients, but the inhibition of GH/IGF-I concentrations by lanreotide levels was higher in group 1 patients than in those of group 2. Six patients of group 1 were treated with 30mg SR lanreotide injected at monthly intervals. During monthly follow-up, mean GH levels increased above 2.5 microgram/l in 2 patients. After 12 months follow-up, mean GH and IGF-I levels from 4 other patients were similar to those obtained with previous therapeutic sequence (i.e. intramuscular injections every 14 days). CONCLUSION: The degree of responsiveness to lanreotide and the duration of somatotroph suppression following lanreotide withdrawal are variable in acromegalic patients controlled during long-term 30mg SR lanreotide treatment. In patients displaying high sensitivity to lanreotide, the interval between i.m. 30mg SR lanreotide injections can be increased to one month, thus reducing the cost of the therapy, without altering its efficacy upon GH/IGF-I control.

Acromegaly↗
PubMed2000

Markers of tumor invasion are major predictive factors for the long-term outcome of corticotroph microadenomas treated by transsphenoidal adenomectomy.

OBJECTIVE: To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension. DESIGN: Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences). Pre-, per- and postoperative parameters were analyzed as predictors of the long-term outcome. METHODS: Baseline hormone assessments were performed preoperatively, 8 days after surgery and every 6-12 months thereafter. Pituitary magnetic resonance imaging (MRI) allowed analysis of possible tumor extension to adjacent structures. Apparent completeness of the surgical removal was determined, and fragments labeled either 'tumor' or 'surrounding pituitary tissue' were submitted to serial sectioning. RESULTS: Immediate control of hypercortisolism was achieved in 43/53 patients (81%). However, later recurrences were observed in five patients (9%). Preoperative MRI showed tumor extension into adjacent structures with good specificity (91%) for prediction of surgical failure. Evidence of local invasion at surgery was also significantly predictive of the long-term outcome. A corticotroph adenoma was found at histological examination in 96% of the patients, and 26% had irregular limits, a feature significantly correlated with a poor outcome. Immediate postoperative plasma cortisol did not allow discrimination between long-term remissions and recurrences. CONCLUSION: Surgical failure was best predicted by signs of tumor 'invasiveness' at MRI, confirmed by peroperative examination and histology.

Adenoma↗
PubMed1999

Hippocrate: a safe robot arm for medical applications with force feedback.

We have developed a robotic system to assist doctors when they are moving ultrasonic probes on a patient's skin while exerting a given effort. The probes are used to monitor arteries for cardiovascular disease prevention, namely to reconstruct the three-dimensional profile of arteries. A preliminary feasibility study making use of an industrial robot has been made to validate the force control scheme. It has proven the interest of the robotized approach for such medical applications where force control is needed. In order to comply with safety constraints, a dedicated robotic system 'Hippocrate' has been designed. This paper describes the arm and the controller architectures, with emphasis on design strategies selected to meet safety requirements. Preliminary in vivo results are presented as well as a possible new application of Hippocrate as a tool for reconstructive surgery.

Angiography↗
PubMed1999

Combined hypothalamic-pituitary-gonadal defect in a hypogonadic man with a novel mutation in the DAX-1 gene.

We have studied a 20-yr-old male patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism (HH) due to a C to A transversion at nucleotide 825 in the DAX-1 gene, resulting in a stop codon at position 197. The same mutation was detected in his affected first cousin (adrenal hypoplasia congenita and HH) and in a heterozygous state in their carrier mothers. The patient had had acute adrenal insufficiency at the age of 2 yr and 6 months, bilateral cryptorchidism corrected surgically at the age of 12 yr, and failure of spontaneous puberty. Plasma testostereone (T) was undetectable (<0.30 nmol/L), gonadotropin levels were low (LH, <0.4 IU/L; FSH, 1.5 IU/L) and not stimulated after i.v. injection of 100 microg GnRH. The endogenous LH secretory pattern was apulsatile, whereas free alpha-subunit (FAS) levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalamic GnRH secretion. During i.v. pulsatile GnRH administration (10 microg/pulse every 90 min for 40 h), each GnRH pulse induced a LH response of low amplitude (0.54 +/- 0.05 UI/L), whereas mean LH (0.45 +/- 0.01 IU/L) and FAS (63 +/- 8 mU/L) levels remained low. Amplitude of LH peaks (0.83 +/- 0.09 IU/L), mean LH (0.53 +/- 0.02 IU/L), and FAS (161 +/- 18 mU/L) levels increased (P < 0.01), whereas the T concentration remained low (0.75 nmol/L) when the pulsatile GnRH regimen was raised to 20 microg/pulse for a 40-h period, suggesting a partial pituitary resistance to GnRH. Thereafter, plasma T levels remained in prepubertal value after three daily im injections of 5000 IU hCG (3.6 nmol/L) and after 1-yr treatment with weekly i.m. injections of 1500 IU hCG (1.2 nmol/L), implying Leydig cell resistance to hCG. The patient had a growth spurt, bone maturation, progression of genital and pubic hair stages, and normalization of plasma T level (15.8 nmol/L) after a 12-month treatment with twice weekly injections of hCG and human menopausal gonadotropin (75 IU International Reference Preparation 2) preparations, suggesting that, in presence of FSH, a Sertoli cell-secreted factor stimulated Leydig cell production of T. In conclusion, we report a novel mutation in the DAX-1 gene in patients with AHC and HH. Our results suggest that the hypogonadism is due to a combined hypothalamic-pituitary-gonadal defect and imply that the DAX-1 gene may play a critical role in human testicular function.

Base Sequence↗
PubMed1999

Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration.

We have studied a kindred with three siblings with isolated hypogonadotropic hypogonadism caused by compound heterozygote mutations in the GnRH receptor gene. The disorder was transmitted as an autosomal recessive trait. The R262Q mutation in intracellular loop 3 of the receptor was associated with a mutation in the third transmembrane domain of the receptor, A129D, that has never been described before. This A129D mutation results in a complete loss of function, indicated by the lack of inositol triphosphate (TP3) 3 production by transfected Chinese hamster ovary (CHO) cells after GnRH stimulation. The two brothers had microphallus and bilateral cryptorchidism and were referred for lack of puberty, whereas their sister had primary amenorrhea and a complete lack of puberty. Their basal gonadotropin concentrations were below the reference range, and their endogenous LH secretory patterns were abnormal, with a low-normal frequency of small pulses or no apparent LH pulse. Pulsatile GnRH administration (10 microg/pulse every 90 min for 40 h) resulted in increased mean LH without any significant changes in testosterone levels in the two brothers, whereas the LH secretory profile of their sister remained apulsatile. Larger pulses of exogenous GnRH (20 microg every 90 min for 24 h) caused the sister to produce recognizable low amplitude LH pulses. The concentrations of free alpha-subunit significantly increased in all patients during the pulsatile GnRH administration. Thus, these hypogonadal patients are partially resistant to pulsatile GnRH administration, suggesting that they should be treated with gonadotropins to induce spermatogenesis or ovulation rather than with pulsatile GnRH.

Adolescent↗
PubMed1999

A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma.

Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A syndromes are dominantly inherited diseases caused by activating germline mutations of the RET protooncogene. The majority of these patients carry a germline point mutation affecting one of five cysteine residues encoded by exon 10 (codon 609, 611, 618, or 620) or 11 (codon 634). In a few FMTC families, point mutations involving noncysteine codons in exon 13 (codons 768, 790, and 791), 14 (codon 804), or 15 (codon 891) have been reported. Hirschsprung's disease is a nonneoplastic disorder associated with RET mutations leading to a loss of function effect. Mutations are identified in 50% of the familial cases and are scattered along the gene. We now report the study of a FMTC family with four affected members and a history of fatal neonatal intestinal obstruction in the sister of the proband. Genetic analysis demonstrated the absence of an usual FMTC mutation and the presence of a germline 9-bp duplication in RET exon 8 in the heterozygous state in all patients with MTC. This new mutation creates an additional cysteine residue in the extracellular cysteine-rich domain of RET. Further studies are warranted to confirm whether this new mutation is causing MTC only or could be associated with Hirschsprung's disease.

Adult↗