Dinane Samara-Boustani

Insulin cell mass is altered in Csf1op/Csf1op macrophage‐deficient mice

Macrophages play an important role in organ development, tissue homeostasis, and remodeling. Thus, we monitored the presence of F4/80‐positive macrophages in the pancreas of wild‐type mice, and some developmental features of this complex tissue were compared throughout life in wild‐type and macrophage‐deficient Csf1op/Csf1op (op/op) mice. The combined use of immunohistochemistry, morphometry, and cell quantification allows us to evaluate insulin and glucagon cell mass, total and insulin cell proliferation, and apoptosis in fetuses (E18.5), weanings (postnatal day 21), nonpregnant adults, and adults in late pregnancy (18.5 days). F4/80‐positive macrophages were found in pancreases recovered from Csf1op/Csf1+ (op/+) mice but were extremely scarce or absent in pancreas recovered from op/op ones at all studied time‐points. The macrophage‐deficient op/op phenotype was clearly associated with a major insulin mass deficit in fetuses and adults, abnormal postnatal islet morphogenesis, and impaired pancreatic cell proliferation at weaning and late pregnancy. We also obtained indirect evidence of increased neogenesis in this model at time‐points when pancreatic remodeling does occur. The demonstration of the colony‐stimulating factor 1‐dependent macrophage involvement in life‐time pancreas development/remodeling allows us to pinpoint the tissue‐modeling and remodeling functions of this leukocyte lineage.

Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency

OBJECTIVE It remains controversial whether long-term glucocorticoids are charged of bone demineralization in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The aim of this study was to know whether cumulative glucocorticoid dose from the diagnosis in childhood to adulthood in patients with CAH had a negative impact on bone mineral density (BMD). DESIGN This was a retrospective study. METHODS Thirty-eight adult patients with classical and non-classical CAH were included. BMD was measured in the lumbar spine and femoral neck. Total cumulative glucocorticoid (TCG) and total average glucocorticoid (TAG) doses were calculated from pediatric and adult files. RESULTS We showed a difference between final and target heights (-0.82+/-0.92 s.d. for women and -1.31+/-0.84 s.d. for men; P<0.001). Seventeen patients (44.7%) had bone demineralization (35.7% of women and 70% of men). The 28 women had higher BMD than the 10 men for lumbar (-0.26+/-1.20 vs -1.25+/-1.33 s.d.; P=0.02) and femoral T-scores (0.21+/-1.30 s.d. versus -1.08+/-1.10 s.d.; P=0.007). In the salt-wasting group, women were almost significantly endowed with a better BMD than men (P=0.053). We found negative effects of TCG, TAG on lumbar (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), predominantly during puberty. BMI was protective on BMD (P=0.006). CONCLUSION The TCG is an important factor especially during puberty for a bone demineralization in patients with 21-hydroxylase deficiency. The glucocorticoid treatment should be adapted particularly at this life period and preventive measures should be discussed in order to limit this effect.

Cardiovascular findings and management in Turner syndrome: insights from a French cohort

OBJECTIVE Congenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults. DESIGN/METHODS We recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300). RESULTS Informative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0-60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th-75th percentiles: 15-30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7-30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m(2) in 39% of the cohort. CONCLUSION Our study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.

Transient hyper-17-hydroxyprogesteronemia: a clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia

OBJECTIVE Neonatal screening for congenital adrenal hyperplasia (CAH) is characterized by a high false-positive rate, mainly among preterm and low birth weight infants. The aims of this study were to describe a subgroup of infants with transient serum hyper-17-hydroxyprogesteronemia (hyper-17-OHPemia) and to compare them with false positive and affected by 21-hydroxylase deficiency newborns. METHODS We retrospectively analyzed the clinical data of all newborns positive at CAH neonatal screening, who were referred to our hospital to confirm the diagnosis from 2002 to 2006. They were submitted to clinical investigations and blood tests to evaluate 17-hydroxyprogesterone (17-OHP), renin, and electrolyte levels. CAH-unaffected newborns with increased serum 17-OHP were submitted to strict follow-up monitoring, which included an ACTH-stimulating test and genetic analysis of the 21-hydroxylase gene, until serum 17-OHP decreased. RESULTS Thirty-seven newborns with gestational ages ranging from 33 to 40 weeks were studied. Eight infants (three male and five female) were affected by CAH (serum 17-OHP: 277.5 (210-921) nmol/l), 14 (ten male and four female) were false positives (17-OHP: 3.75 (0.3-8.4) nmol/l), and 15 (ten male and five female) showed a serum hyper-17-OHPemia (17-OHP: 15.9 (9.9-33) nmol/l). No mutations of the 21-hydroxylase gene were found in infants with hyper-17-OHPemia and their serum 17-OHP levels were normalized by the third month of life. CONCLUSION We identified a population of infants with transient serum hyper-17-OHPemia, and no clinical signs of disease or 21-hydroxylase gene mutations. No further investigations are necessary after birth in these newborns if 17-OHP levels decrease, other confirmatory tests such as ACTH-stimulation test or genotyping analysis are necessary only if symptoms appear.

High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles

OBJECTIVES To compare the pubertal development, the hormonal profiles and the prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus (T1DM). METHODS Data were collected from 96 obese adolescent girls and 78 adolescent girls with T1DM at Tanner stage IV or V, whose ages ranged between 11.9 and 17.9 years. RESULTS High prevalence of hirsutism and menstrual disorder was found in the obese adolescent girls (36.5 and 42% respectively) and the adolescent girls with T1DM (21 and 44% respectively). The obese girls were significantly younger at pubarche, thelarche and menarche than the girls with T1DM. Hirsutism in the obese girls and those with T1DM was associated with hyperandrogenaemia and a raised free androgen index (FAI). When the cause of the raised FAI was investigated in both the groups of girls with hirsutism, the raised FAI in the obese girls was due to low serum sex hormone-binding globulin (SHBG) levels. In contrast, the raised FAI of the girls with T1DM and hirsutism was due to hyperandrogenaemia. Menstrual disorders in the T1DM girls were associated also with hyperandrogenaemia unlike obese girls. CONCLUSIONS Hirsutism and menstrual disorders are common in obese adolescent girls and adolescent girls with T1DM. Although hyperandrogenaemia is present in both groups of girls, the androgenic profiles of the two groups differ. The hyperandrogenaemia in the obese girls is primarily due to their decreased serum SHBG levels, whereas the hyperandrogenaemia in the girls with T1DM is due to their increased androgen production.

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

OBJECTIVE Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages. METHODS Sanger or massive parallel sequencing of NNT and patient monitoring. RESULTS Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed. CONCLUSIONS NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.

Efficacy and Safety of Growth Hormone Treatment in Children with Hypochondroplasia: Comparison with an Historical Cohort

Background/Aims: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. Methods: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤-2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). Results: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse events were reported. Conclusions: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy.

Inadequate Cortisol Response to the Tetracosactide (Synacthen®) Test in Non-Classic Congenital Adrenal Hyperplasia: An Exception to the Rule?

Aims: To describe cortisol response to tetracosactide and to review the literature on adrenal function in non-classic congenital adrenal hyperplasia (NCCAH) patients. Methods: We compared cortisol responses to tetracosactide (250 μg) between NCCAH patients and a comparison group (CG) of patients with premature pubarche and normal tetracosactide test. An adequate cortisol response was defined as a peak ≥18 μg/dl. Results: We included 35 NCCAH patients (26 girls, 9 boys), whose mean age at testing was 7.0 years (0.8-15.6), and 47 patients in the CG (39 girls, 8 boys), whose mean age was 7.2 years (0.5-9.9). Baseline cortisol was significantly higher in the NCCAH group than in the CG [12.9 (4.3-22.2) vs. 9.7 (4.2-16.2) μg/dl, respectively; p = 0.0006]. NCCAH patients had lower cortisol peak response compared to the CG [18.2 (6.3-40) vs. 24.9 (12-30.3) μg/dl, respectively; p < 0.0001]. Peak cortisol was <18 μg/dl in 21/35 (60%) NCCAH patients versus 1/47 (2.1%) in the CG. No NCCAH patients had acute adrenal insufficiency, but 2 reported severe fatigue that improved with hydrocortisone. Conclusions: The cortisol response to tetracosactide was inadequate (<18 μg/dl) in 60% of patients with NCCAH. Hydrocortisone therapy may deserve consideration when major stress (surgery, trauma, childbirth) or objectively documented fatigue occurs in NCCAH patients with inadequate cortisol response.

Water and Electrolyte Disorders at Long-Term Post-Treatment Follow-Up in Paediatric Patients with Suprasellar Tumours Include Unexpected Persistent Cerebral Salt-Wasting Syndrome

Background: Patients with brain tumours have a high risk of water and electrolyte disorders (WED). Postsurgery diabetes insipidus (DI) may be transient or permanent, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) are usually transient. Methods: Retrospective study, including patients with suprasellar tumours, treated at Hôpital Necker, Institut Gustave-Roussy or Institut Curie, in Île-de-France, between 2007 and 2011. WED were noted if they persisted >1 month after surgery. Results: 159 patients were included, 54.1% girls, 43.9% boys. Tumour types were: glioma (43.4%), craniopharyngioma (43.4%), germinoma (11.3%), others (1.9%). Age at diagnosis was 7.1 ± 4.6 years. The median time from end of treatment was 1.9 (0-7.8) years. DI was the most frequent disorder after tumour treatment (50.3%) and was significantly associated with surgery (p < 0.001). Persistent CSWS was present in 3.6%, persistent SIADH in 1.3%. Two cases of hypernatraemia were due to adipsia. Thyrotropin deficiency after treatment was noted in 68.9% of patients tested, adrenocorticotropin deficiency in 66.2%. Conclusions: Patients with suprasellar tumours have a high incidence of long-term WED, mainly DI. Assessment of thyrotroph and corticotroph function, and thirst sensation, is necessary to diagnose and manage these disorders correctly. CSWS may be persistent in few patients and requires special attention to prescribe the appropriate care.

Efficacy and Safety of Continuous Subcutaneous Infusion of Recombinant Human Gonadotropins for Congenital Micropenis during Early Infancy

Background: Early postnatal administration of gonadotropins to infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty, thereby increasing penile growth. We assessed the effects of gonadotropin infusion on stretched penile length (SPL) and hormone levels in infants with congenital micropenis. Methods: Single-center study including 6 males with micropenis in case of isolated CHH (n = 4), panhypopituitarism (n = 1), and partial androgen insensitivity syndrome (PAIS; n = 1). Patients were evaluated at baseline, monthly and at the end of the study through a clinical examination (SPL, testicular position and size), serum hormone assays (testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Müllerian hormone [AMH]), and ultrasound of penis/testes. Results: In CHH, significant increases occurred in serum testosterone (from undetectable level to 3.5 ± 4.06 ng/mL [12.15 ± 14.09 nmol/L]), SPL (from 13.8 ± 4.5 to 42.6 ± 5 mm; p < 0.0001), inhibin B (from 94.8 ± 74.9 to 469.4 ± 282.5 pg/mL, p = 0.04), and AMH (from 49.6 ± 30.6 to 142 ± 76.5 ng/mL, p = 0.03). Micropenis was corrected in all patients, except one. On treatment, in the patient with PAIS, SPL was increased from 13 to 38 mm. Conclusions: Early gonadotropin infusion is a safe, well-tolerated and effective treatment. The effect in PAIS has not been reported previously. Long-term follow-up is needed to assess the impact, if any, on future fertility and reproduction.