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Nathalie Lévy Bohbot, Jacques Young, Jacques Orgiazzi, Catherine Buffet, Maud François, Brigitte Bernard-Chabert, Céline Lukas-Croisier and Brigitte Delemer

Autoimmune thyroid disease is a common side-effect of interferon-α (IFN-α) treatment of viral hepatitis C. We have described three patients with hepatitis C for whom IFN-α and ribavirin were prescribed and who developed two successive phases of silent thyroiditis followed by hyperthryroidism relapse due to Graves’ disease. These three men had no known history of familial or personal thyroid disease. Destructive thyrotoxicosis appeared 4–6 months after starting IFN-α, followed by Graves’ hyperthyroidism within 8 to11 months. The thyrotropin (TSH) level was normal before IFN-α was started. The diagnosis of destructive thyroiditis was confirmed by anti-TSH receptor antibody (TSHRAb) negativity and the absence of radionuclide (123I or 99Tc) uptake on thyroid scintiscans. Eight to eleven months after starting treatment, TSHRAb positivity and intense scintigraphic uptake confirmed the appearance of Graves’ disease. IFN-α was continued in only one patient. Hence, hyperthyroidism induced by IFN-α could correspond to the first phase of silent thyroiditis, to Graves’ disease or to the succession of both. Rigorous diagnostic procedures with repeated scintiscans and TSHRAb titering are necessary to avoid a false diagnosis and inappropriate therapy.

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Luigi Maione, Andrew A Dwyer, Bruno Francou, Anne Guiochon-Mantel, Nadine Binart, Jérôme Bouligand and Jacques Young

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women. However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation. These are genetic diseases that can be transmitted to patients’ offspring. Importantly, patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex; oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing and is increasingly being used in medical practice. Thus, it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling.

Free access

Jean-Benoît Corcuff, Jacques Young, Pauline Masquefa-Giraud, Philippe Chanson, Eric Baudin and Antoine Tabarin

Context

Severe Cushing's syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described.

Objective

To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism.

Design

Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN).

Patients and settings

A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals.

Intervention

Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities).

Main outcome

Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition.

Results

After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments.

Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal.

Conclusion

Metyrapone–ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism.

Free access

Sophie Brochier, Françoise Galland, Michèle Kujas, Fabrice Parker, Stephan Gaillard, Christian Raftopoulos, Jacques Young, Orsalia Alexopoulou, Dominique Maiter and Philippe Chanson

Context

Adequate postoperative management of nonfunctioning pituitary macroadenomas (NFMAs) remains a challenge for the clinician.

Objective

To identify predictive factors of NFMA relapse after initial surgery.

Patients and methods

This retrospective study included 142 patients operated for an NFMA in two academic centers (CHU Bicêtre in France and UCL St Luc in Belgium). The rate of tumor relapse, defined as recurrence after total surgical resection or regrowth of a surgical remnant, as well as predictive factors was analyzed.

Results

During a mean follow-up of 6.9 years, 10 out of 42 patients (24%) who had complete macroscopic resection of their tumor had recurrence, and 47 out of 100 patients (47%) with a surgical remnant experienced regrowth. The overall relapse rates were 25, 43, and 61% at 5, 10, and 15 years respectively. Invasion of the cavernous sinus, absence of immediate radiotherapy after the first neurosurgery, and immunohistochemical features of the tumor (mainly positive immunostaining for several hormones or for hormones other than gonadotropins) were independent risk factors for tumor relapse. Incomplete excision was only associated with relapse when invasion was withdrawn from the analysis, suggesting that these two factors are closely linked.

Conclusion

NFMAs frequently recur/regrow after initial surgery, particularly when tumor is invasive, precluding complete removal. Immunohistochemical features such as positive immunostaining for several hormones or for hormones other than gonadotropins could help to predict undesirable outcomes.

Free access

Marie-Laure Raffin-Sanson, Bérénice Oudet, Sylvie Salenave, Sylvie Brailly-Tabard, Martine Pehuet, Sophie Christin-Maitre, Yves Morel and Jacques Young

Objective

DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia.

Case report

The proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic–pituitary–gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia.

Conclusion

Long-term preservation of normal hypothalamic–pituitary–gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.

Free access

Sophie Mauclère-Denost, Sophie Leboulleux, Isabelle Borget, Angelo Paci, Jacques Young, Abir Al Ghuzlan, Desiree Deandreis, Laurence Drouard, Antoine Tabarin, Philippe Chanson, Martin Schlumberger and Eric Baudin

Background

The benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown.

Methods

To evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC.

Results

Twenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of >14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3–4 neurological or hematological toxicities were observed in three patients (13.6%).

Conclusion

Employing a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.

Free access

Marie-Laure Kottler, Yen-Yin Chou, Olivier Chabre, Nicolas Richard, Camille Polge, Sylvie Brailly-Tabard, Philippe Chanson, Anne Guiochon-Mantel, Ilpo Huhtaniemi and Jacques Young

Context

Mutations of the FSH β gene, causing in women isolated FSH deficiency and hypogonadism, are very rare and only a few have been described.

Objective

To describe the phenotype and response to recombinant human (rh) FSH of a female patient with a novel homozygous loss-of-function mutation of FSH β, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation.

Patient

A 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency.

Methods and results

Sequencing of the FSH β gene revealed a homozygous 1 bp (G) deletion at codon 79 (c.289delG) of exon 3 which produced a frameshift at codon 79 (A79fs108X) and a premature stop codon at codon 109. The wild-type and mutant FSH β cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the α -subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHβ protein could not be detected in western blot.

In response to a 15-day treatment with rhFSH, sonography revealed multifollicular development in the ovaries. Circulating levels of estradiol and inhibin B were dramatically increased, whereas anti-Mullerian hormone decreased. Serum LH first decreased and then increased, inducing multiovulation associated with supraphysiologic progesterone and inhibin A levels.

Conclusion

A novel FSH β mutation was detected in a hypogonadal woman. rhFSH was effective in ovulation induction in the patient but with signs of ovarian hyperstimulation. The high pretreatment LH levels could contribute to this excessive ovarian response to rhFSH.

Free access

Frédéric Brioude, Jérôme Bouligand, Séverine Trabado, Bruno Francou, Sylvie Salenave, Peter Kamenicky, Sylvie Brailly-Tabard, Philippe Chanson, Anne Guiochon-Mantel and Jacques Young

Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.

In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a non-endocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.

Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.

This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype–phenotype relationships.

Free access

Anne-Lise Lecoq, Jérôme Bouligand, Mirella Hage, Laure Cazabat, Sylvie Salenave, Agnès Linglart, Jacques Young, Anne Guiochon-Mantel, Philippe Chanson and Peter Kamenický

Context

Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma.

Objective

We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers.

Design

An observational cohort study performed between 2007 and 2014 in a single referral center.

Participants

This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes.

Methods

Entire GPR101 and AIP coding sequence were screened for germline mutations.

Results

Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes.

Conclusion

Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis.

Open access

Emmanuelle Kuhn, Luigi Maione, Amir Bouchachi, Myriam Rozière, Sylvie Salenave, Sylvie Brailly-Tabard, Jacques Young, Peter Kamenicky, Patrick Assayag and Philippe Chanson

Context

The effect of pegvisomant on IGF1 levels in patients with acromegaly is well documented, but little is known of its long-term impact on comorbidity.

Aim

The aim of this retrospective study was to evaluate the effects of long-term pegvisomant therapy on cardiorespiratory and metabolic comorbidity in patients with acromegaly.

Patients and methods

We analyzed the long-term (up to 10 years) effect of pegvisomant therapy given alone (n=19, 45%) or in addition to somatostatin analogues and/or cabergoline (n=23, 55%) on echocardiographic, polysomnographic and metabolic parameters in respectively 42, 12 and 26 patients with acromegaly followed in Bicêtre hospital.

Results

At the first cardiac evaluation, 20±16 months after pegvisomant introduction, IGF1 levels normalized in 29 (69%) of the 42 patients. The left ventricular ejection fraction (LVEF) improved significantly in patients whose basal LVEF was ≤60% and decreased in those whose LVEF was >70%. The left ventricular mass index (LVMi) decreased from 123±25 to 101±21 g/m2 (P<0.05) in the 17 patients with a basal LVMi higher than the median (91 g/m2), while it remained stable in the other patients. Pegvisomant reduced the apnoea–hypopnea index and cured obstructive sleep apnea (OSA) in four of the eight patients concerned. Long-term follow-up of 22 patients showed continuing improvements in cardiac parameters. The BMI and LDL cholesterol level increased minimally during pegvisomant therapy, and other lipid parameters were not modified.

Conclusions

Long-term pegvisomant therapy not only normalizes IGF1 in a large proportion of patients but also improves cardiac and respiratory comorbidity.