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ContextEndocrine complications are common in pediatric brain tumor patients.ObjectiveTo describe hypothalamic–pituitary–gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment.MethodsWe retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded.ResultsAmong patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency.ConclusionTumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy.

ContextCraniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma.ObjectiveTo evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence).MethodsRetrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (12-month group and in the ResultsIn the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment.ConclusionsNo association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.

Context Endocrine complications are common in pediatric brain tumor patients. Objective We aimed to describe the endocrine follow-up of patients with primary brain tumors. Methods This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. Results Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (−0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (−1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). Conclusion We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Objectives To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

OBJECTIVE Short stature in children and adolescents may lead to social and emotional stress, with negative effects on quality of life (QoL). GH treatment may improve QoL through height normalization. Our objective here was to evaluate general and height-specific QoL after 1 year of GH treatment. DESIGN Prospective, single-center, observational cohort study. METHODS Children ≥ 4 years of age starting GH at our center from 2012 to 2015 to treat short stature were studied. Patients with serious diseases, syndromic short stature, or developmental delay were excluded. At treatment initiation and 1 year later, patients and their parents completed the general PedsQL 4.0 and height-specific Quality of Life in Short Stature Youth (QoLiSSY) questionnaires. Correlations between self-report and parent-report scores and between height gain and QoL improvements were assessed based on Pearson correlation coefficients. RESULTS Seventy-four children (42 boys, 32 girls), median age (± SD), 10.2 ± 3.0 years (range, 4.1 to 16.6 years), were included. The self-report PedsQL indicated significant improvements in emotional (P = 0.02) and social (P = 0.03) QoL. As assessed by the QoLiSSY, children reported improvement of social QoL (+0.2 SD; P = 0.04), and parents reported improvement of children's physical (+0.1 SD; P < 0.0001), emotional (+0.3 SD; P < 0.0001), and social (+0.3 SD; P < 0.0001) QoL. Height SD score (SDS) gains showed moderate positive correlations with QoLISSY self-report score gains (R = 0.53, R2 = 0.28; P < 0.001) and QoLISSY parent-report gains (R = 0.60, R2 = 0.41; P < 0.00001). CONCLUSIONS After 1 year of GH treatment, children had significant gains in emotional and social QoL, as assessed by a general self-report questionnaire and height-specific parent-report questionnaire.

International audience; Objective: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported.Design: Retrospective description of sixteen 46,XX T/OTDSD patients.Results: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient.Conclusions: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls.

Background: Polycystic ovary syndrome (PCOS) is more frequently observed in type 1 diabetes mellitus (T1DM) adult women than in nondiabetic women. No such prevalence has yet been studied in adolescent girls with T1DM. Aim: The aim of this study was to evaluate the prevalence of PCOS in adolescent girls with T1DM and to determine the clinical and hormonal features associated with the disorder. Methods: A cross-sectional study of 53 adolescent girls (gynecological age >2 years) referred for routine evaluation for T1DM was conducted. We diagnosed PCOS using the National Institutes of Health (NIH) and Rotterdam criteria. Results: 26.4 and 47.9% of adolescents had PCOS according to NIH (NIH-PCOS) and Rotterdam (Rotterdam-PCOS) criteria. 66.7% of NIH-PCOS adolescents had a complete phenotype associated with hyperandrogenism, oligomenorrhea, and polycystic ovarian morphology, unlike only 33.3% of the Rotterdam-PCOS adolescents. A family history of type 2 diabetes mellitus (T2DM) was more frequent in PCOS than in non-PCOS girls, whichever criteria were used. Late pubertal development and a T1DM diagnosis close to puberty were factors associated with NIH-PCOS. Conclusion: Adolescents with T1DM had a high prevalence of PCOS. More differences between PCOS and non-PCOS patients were found using the NIH criteria, suggesting that clinical characteristics might be more accurate for diagnosing PCOS in girls with T1DM. A family history of T2DM is associated with a high risk of PCOS.

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.

International audience; The French endocrinology society (SFE) and the French pediatric endocrinology society (DFSDP) have drawn up recommendations for the management of primary and secondary adrenal insufficiency in the adult and child, based on an analysis of the literature by 19 experts in 6 work-groups. A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms except hyperpigmentation which is observed in primary adrenal insufficiency. Diagnosis rely on plasma cortisol and ACTH measurement at 8am and/or the cortisol increase after synacthen administration. When there is a persistant doubt of secondary adrenal insufficiency, insulin hypoglycemia test should be carried out in adults, adolescents and children older than 2 years. For determining the cause of primary adrenal insufficiency, measurement of anti-21-hydroxylase antibodies is the initial testing. An adrenal CT scan should be performed if auto-antibody tests are negative, then assay for very long (Y. Reznik). chain fatty acids is recommended in young males. In children, a genetic anomaly is generally found, most often congenital adrenal hyperplasia. In the case of isolated corticotropin (ACTH) insufficiency, it is recommended to first eliminate corticosteroid-induced adrenal insufficiency, then perform an hypothalamic-pituitary MRI. Acute adrenal insufficiency is a serious condition, a gastrointestinal infection being the most frequently reported initiating factor. After blood sampling for cortisol and ACTH assay, treatment should be commenced by parenteral hydrocortisone hemisuccinate together with the correction of hypoglycemia and hypovolemia. Prevention of acute adrenal crisis requires an education of the patient and/or parent in the case of pediatric patients and the development of educational programs. Treatment of adrenal insufficiency is based on the use of hydrocortisone given at the lowest possible dose, administered several times per day. Mineralocorticoid replacement is often necessary for primary adrenal insufficiency but not for corticotroph deficiency. Androgen replacement by DHEA may be offered in certain conditions. Monitoring is based on the detection of signs of under-and over-dosage and on the diagnosis of associated auto-immune disorders.; La Société française d'endocrinologie (SFE) et la Société française d'endocrinologie pédiatrique (SFEDP) ont élaboré des recommandations sur la prise en charge de l'insuffisance surrénale primaire et secondaire de l'adulte et de l'enfant, à partir d'une analyse de la littérature réalisée par 19 experts répartis en 6 groupes de travail. Le diagnostic d'insuffisance surrénale doit être évoqué devant l'association de signes cliniques et biologiques non spé-cifiques, en dehors de la mélanodermie observée dans l'insuffisance surrénale primaire. Le diagnostic repose sur les dosages du cortisol et de l'ACTH le matin et/ou le dosage du cortisol après stimulation par l'ACTH synthétique (synacthène). En cas de doute, le test d'hypoglycémie insulinique est le test de référence chez l'adulte l'adolescent et l'enfant de plus de 2 ans. La recherche étiologique est basée sur le dosage en 1 re intention des anticorps anti 21-hydroxylase. En cas de négativité, un scanner surrénalien sera réalisé, puis le dosage des acides gras à chaînes longues sera effectué chez le garçon. Chez l'enfant, une cause génétique sera recherchée, principalement l'hyperplasie congénitale des surrénales. Devant un déficit corticotrope, après la recherche d'une prise prolongée de glucocorticoïdes sera effectuée une imagerie hypothalamo-hypophysaire. L'insuffisance surrénale aiguë est une complication grave souvent déclenchée par une infection gastro-intestinale. Elle nécessite après prélèvement pour dosage du cortisol et ACTH l'administration parentérale d'hémisuccinate d'hydrocortisone et la correction de l'hypovolémie et/ou de l'hypoglycémie. Sa prévention repose sur l'éducation thérapeutique du patient pour laquelle des programmes seront développés. Le traitement de l'insuffisance surrénale s'appuie sur la prise pluriquotidienne d'hydrocortisone à la dose la plus faible possible. La substitution minéralocorticoïde est réalisée en cas d'insuffisance surrénale primaire mais n'est pas nécessaire en cas d'insuffisance surrénale secondaire. La substitution androgénique par la DHEA peut être proposée dans cer-taines indications précises. La monitoring comportera la recherche de signes cliniques et biologiques de sous/surdosage et de maladies auto-immunes associées.

Objective Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. Methods Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. Results Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. −2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). Conclusion This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms (fatigue, anorexia, weight loss, hypotension, hyponatremia and hyperkalemia amongst adrenal causes of insufficiency). The diagnosis should be considered in case of pituitary disease or a state of shock. Treatment should be commenced immediately without waiting for confirmation from biochemical tests, which rely on cortisol level at 8am (expected to be low) and on ACTH level (expected to be high in the case of primary adrenal insufficiency). If these tests are inconclusive, a Synacthen test should be carried out. The threshold limits are provided as a guide. Low plasma cortisol and normal to low plasma ACTH indicates a pituitary origin for the deficiency. In this situation, the Synacthen test can give a false normal result, and if this adrenal insufficiency is strongly suspected, an insulin hypoglycemia test or metyrapone (Metopirone®) test should be carried out. In children younger than 2yr, hypoglycemia, dehydration and convulsions are frequently observed and in young girls, virilization is suspect of congenital adrenal hyperplasia . The circadian rhythm of cortisol is not present until after 4months of age and the Synacthen test is the only one that is feasible. In children older than 2yrs, the signs and diagnostic methods are the same as in the adult. Cessation of corticosteroid treatment is a frequent circumstance however there is little published data and no evidence for definitive guidelines. After ceasing a short period of corticosteroid treatment, patient education is all that is required. After longer treatment, consensus leaves the choice up to the physician, between educating the patient and prescribing hydrocortisone in case of stress, or prescribing low daily dose hydrocortisone and evaluating the ACTH axis over time until normal function is recovered.

Annales d'Endocrinologie - In Press.Proof corrected by the author Available online since samedi 25 novembre 2017

International audience; no abstract.

ObjectiveThe prevalence of severe primary IGF1 deficiency (IGFD) is unclear. IGFD must be identified promptly as treatment with recombinant human IGF1 (rhIGF1) is now available. Our objective was to characterize and assess the prevalence of severe primary IGFD in a large cohort of patients evaluated for short stature at a pediatric endocrinology unit in France.DesignObservational study in a prospective cohort.MethodsConsecutive patients referred to our unit between 2004 and 2009 for suspected slow statural growth were included. Patients were classified into eight etiological categories. IGFD was defined by height ≤−3 SDS, serum IGF1 levels ResultsOut of 2546 patients included, 337 (13.5%) were born small for gestational age and 424 (16.9%) had idiopathic short stature. In these two categories, we identified 30 patients who met our criterion for IGFD (30/2546, 1.2%). In these 30 patients, we assessed the response to IGF1 generation test, time course of IGF1 levels, and efficiency of GH replacement therapy. The results indicated that only four of the 30 children were definite or possible candidates for rhIGF1 replacement therapy.ConclusionThe prevalence of severe primary IGFD defined using the standard criterion for rhIGF1 treatment was 1.2%, and only 0.2% of patients were eligible for rhIGF1 therapy.

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.

Objectif Les patients porteurs d’une mosaique 45,X/46,XY peuvent presenter une large variete de phenotypes. Peu d’etudes se sont interessees aux patients avec phenotype masculin normal a la naissance, bien qu’ils representent 90 % de ces patients. L’objectif de cette etude est de decrire la croissance, l’evolution pubertaire et l’existence de pathologies associees dans une cohorte de garcons presentant une mosaique 45,X/46,XY, sans anomalie de la differenciation des organes genitaux externes. Methodes Etude retrospective longitudinale multicentrique sur une cohorte de 35 patients, suivis entre 1982 et 2016. Resultats Vingt patients ont eu un diagnostic en prenatal et 14 patients en postnatal principalement pour petite taille. Ces patients presentent majoritairement un retard de croissance qui s’aggrave a la puberte avec une taille adulte moyenne de 156 cm (± 6 cm) soit a 2,3 DS de leur taille cible (± 0,9 DS). Soixante-dix pour cent des patients avaient des signes turneriens dont 8 patients avec malformations cardiaques ou renales. Quinze patients presentaient une anomalie mineure des organes genitaux dont 9 cryptorchidies unilaterales et un patient a developpe un carcinome embryonnaire testiculaire, temoignant d’un certain degre de dysgenesie gonadique. De plus, le malgre un developpement pubertaire spontane dans 92 % des cas, la fonction testiculaire s’epuise, puisque 56 % des patients avaient des signes biologiques d’insuffisance sertolienne en fin de la puberte. Conclusion Cette etude souligne la necessite de suivre au long cours l’ensemble des patients 45,X/46,XY quel que soit leur mode de diagnostic, avec une attention particuliere sur la croissance, la fonction gonadique, et le depistage de malformations associees.

P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399_E401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399_E401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17α-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399_E401 revealed reduced stability and flexibility of the mutant. In conclusion, P399_E401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399_E401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.

La hiperplasia suprarrenal congenita (HSC) es una enfermedad endocrina genetica de transmision autosomica recesiva, resultado del deficit de una de las enzimas de la esteroidogenesis, responsable de la sintesis de cortisol. Se trata de una entidad patologica compleja que agrupa varias formas clinicas, biologicas y geneticas. En la mayoria de casos, existe un deficit de 21-hidroxilasa. Con menor frecuencia, el deficit es de 11β-hidroxilasa, 3β-hidroxiesteroide deshidrogenasa, 17α-hidroxilasa o, excepcionalmente, de StAR y P450 oxidorreductasa. El tratamiento de la HSC se basa en un tratamiento sustitutivo con hidrocortisona, asociada en mayor o menor medida a fludrocortisona en caso de deficit de mineralcorticoides. Actualmente, existe diagnostico prenatal y cribado neonatal de la HSC por deficit de 21-hidroxilasa, con el objetivo de evitar la virilizacion en las ninas y las complicaciones neonatales, que pueden resultar fatales. Las consecuencias en la edad adulta de estas enfermedades, a menudo mal evaluadas, no deben subestimarse, tanto desde el punto de vista del equilibrio hormonal y de la fecundidad como de las posibles consecuencias a largo plazo del tratamiento con glucocorticoides, lo que exige una transicion adecuada entre el ambito de la endocrinologia pediatrica y la del adulto.

ObjectiveIt 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).DesignThis was a retrospective study.MethodsThirty-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.ResultsWe 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; Ps.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 (PP=0.002) and femoral T-scores (P=0.006, PP=0.006).ConclusionThe 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.

L’obesite commune est une surcharge ponderale par accumulation des graisses de reserve. Elle se definit par un exces de poids de 20% ou plus a partir d’un poids de reference etabli en tenant compte de la taille, du sexe et de l’âge du sujet, et survient soit avant deux ans, soit en periode de latence (6-7 ans) soit en periode pre-pubertaire. S’il semble aujourd’hui legitime d’avancer l’existence d’un faisceau de causalites, de problematiques en cause dans ce symptome, des facteurs psychodynamiques viendraient pre-organiser l’obesite infantile. La specificite du tableau clinique amene a interroger les possibilites du traitement de la perte tant narcissique qu’objectale et la fonction anti-depressive du surpoids a travers une conduite iterative incorporative. A l’adolescence, la reviviscence de la nevrose infantile associee a l’obligation de s’amender des figures parentales peut peser sur le fonctionnement psychique du jeune et generer ou aggraver une obesite (infantile). Dans une etude clinique, inscrite dans une recherche medico-psychologique sur les anomalies du developpement pubertaire dans le diabete de type I et l’obesite, l’hypothese selon laquelle la pregnance d’une problematique depressive (pregenitale ?) chez des jeunes filles en surpoids temoignerait du difficile traitement psychique de la perte, est mise a l’epreuve. Cette etude psychopathologique explore la dynamique psychique d’adolescentes obeses depuis l’enfance. Le cadre methodologique est constitue d’un entretien clinique, de tests projectifs (Rorschach et TAT) et de deux auto-questionnaires de depression (MDI-C) et d’estime de soi (Coopersmith). Les resultats, obtenus sur dix jeunes filles dont l’obesite est reperee des l’enfance, permettent de degager des thematiques transversales dans lesquelles la fragilite narcissique, la depressivite, la problematique separation/individuation associee au non-acces a l’ambivalence et la problematique identificatoire sont centrales.

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.

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 Conclusions: The cortisol response to tetracosactide was inadequate (

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.

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.

ObjectiveTo assess the prevalence of skeletal dysplasias (SDs) in patients with idiopathic short stature (ISS) or small for gestational age (SGA) status.SettingRare Endocrine/Growth Diseases Center in Paris, France.DesignA prospective study on consecutive patients with ISS and SGA enrolled from 2004 to 2009.MethodWe used a standardized workup to classify patients into well-established diagnostic categories. Of 713 patients with ISS (n=417) or SGA status (n=296), 50.9% underwent a skeletal survey. We chose patients labeled normal or with a prepubertal slowdown of growth as a comparison group.ResultsDiagnoses were ISS (16.9%), SGA (13.5%), normal growth (24.5%), transient growth rate slowing (17.3%), endocrine dysfunction (12%), genetic syndrome (8.9%), chronic disease (5.1%), and known SD (1.8%). SD was found in 20.9% of SGA and 21.8% ISS patients and in only 13.2% in our comparison group. SD prevalence was significantly higher in the ISS group than in the comparison group, especially (50%) for patients having at least one parent whose height was ConclusionSD may explain more than 20% of cases of growth retardation ascribed to ISS or SGA, and this proportion is higher when parental height is

We discuss here the secular early onset of puberty in children, the central mechanisms of puberty as well as the clinical aspects of central precocious puberty in children. How to suspect it, how to explore it and how to treat it are the main topics of this article., Après avoir rappelé les mécanismes centraux de la puberté, nous nous focalisons sur les aspects cliniques de la puberté précoce centrale chez l’enfant. Comment la suspecter, comment l’explorer, comment la traiter : voilà les points qui sont développés dans cet article., Polak Michel, Samara-boustani Dinane, Beltrand Jacques, Flechtner Isabelle, Thalassinos Caroline, Bidet Maud, Pinto Graziella. Le systeme gnrh : implications dans la puberté précoce de l’enfant. In: Bulletin de l'Académie Vétérinaire de France tome 167 n°1, 2014. Janvier-Mars 2014. pp. 79-85.

Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment.We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS).Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010.The patients were treated in a pediatric teaching hospital in Paris, France.Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years).Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate.Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P.05) and higher prevalence of normal BMI (38% vs 17%, P.01). Mean number of surgical procedures was not significantly different in the 2 cohorts.Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

ObjectiveCongenital 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/methodsWe 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).ResultsInformative 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/m2 in 39% of the cohort.ConclusionOur 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.

ObjectivesTo 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).MethodsData 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.ResultsHigh 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.ConclusionsHirsutism 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.

Osteoporosis has been an understandable concern for children and adult patients with congenital adrenal hyperplasia (CAH) who may receive or have received supraphysiological doses of glucocorticoids. Some previous reports on bone mineral density (BMD) in adult CAH patients showed no significant differences in BMD between patients with CAH and controls, but others have found lower BMD in CAH patients. In reports documenting the BMD reduction, this outcome has been attributed to an accumulated effect of prolonged exposure to excess glucocorticoids during infancy and childhood. We recently conducted a trial to establish the role of the total cumulative glucocorticoid dose on BMD. We established for the first time that there was a negative relationship between total cumulative glucocorticoid dose and lumbar and femoral BMD. Women might benefit from the preserving effect of estrogens compared to men. BMI (Body Mass Index) also appeared to protect patients from bone loss. In light of this, physicians should bear in mind the potential consequences of glucocorticoids on bone and therefore adjust the treatment and improve clinical and biological surveillance from infancy. Furthermore, preventive measures against corticosteroid-induced osteoporosis should be discussed right from the beginning of glucocorticoid therapy.

The association between hypothalamic dysfunction and obesity is well documented in both clinical and experimental models. The authors describe 2 children who developed obesity that could not be explained by endocrinological, genetic, or eating disorders. In both cases, cranial MR imaging revealed the typical appearance of a lipoma in the paramedian hypothalamus. In the absence of other etiologies, the authors hypothesized that in these 2 children obesity was caused by their hypothalamic lipomas. To the authors' knowledge, these are the first cases of hypothalamic lipomas likely to be causing obesity that have been described in children. These cases highlight the importance of performing cranial MR imaging in children with otherwise unexplained obesity.

Certaines pathologies auto-immunes sont plus frequemment retrouvees dans le syndrome de Turner : thyroidite auto-immune, maladie cœliaque, maladies inflammatoires digestives, diabete de type 1, atteinte hepatique.

ObjectiveNeonatal 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.MethodsWe 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.ResultsThirty-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.ConclusionWe 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.

Summary Objective The efficacy and safety of height-limiting therapy with high-dose 17 β -oestradiol in girls with constitutionally tall stature (CTS) are controversial. We evaluated the effectiveness of high-dose 17 β -oestradiol in premenarchal girls with CTS treated until their bone age reached 14 years. Design We retrospectively reviewed the medical records of the girls managed between 1989 and 2000 with high-dose 17 β -estradiol for CTS with a predicted final height greater than +3SDs. Patients Tw enty-six girls met our inclusion criteria. At baseline, mean chronological age was 12·06 ± 1·51 years and mean height was 171·1 ± 6·5 cm with a height standard deviation score of 4·5 ± 0·24, and mean predicted final height was 183·0 ± 4·2 cm. Treatment was stopped when bone age reached 14 years; mean treatment duration was 1·62 ± 0·76 years. Measurements The following were obtained at 6-month intervals: height, body weight, Tanner stage, bone age, plasma cholesterol and triglycerides, plasma glucose and side effects. A mailed questionnaire on final height and satisfaction was sent 2 years after treatment discontinuation (response rate, 24/26). Results Final height was significantly ( P < 0·001) reduced, by 2·4 ± 3·2 cm, as compared to predictions. High-dose 17 β -estradiol therapy decreased growth velocity and significantly increased skeletal maturation ( P < 0·001). Linear growth after treatment discontinuation was 3·3 ± 1·9 cm. No serious side effects were recorded. Most of the patients were satisfied with the treatment. Conclusion High-dose 17 β -estradiol was moderately effective in reducing final height and should probably be reserved for selected patients, particularly as knowledge on potential long-term side effects is lacking.

Objectif Comparer le developpement pubertaire, la prevalence de l’hirsutisme et des anomalies du cycle menstruel et le profil hormonal d’adolescentes diabetiques de type 1 (DID) et d’adolescentes obeses. Patients et methodes Les donnees cliniques et biologiques ont ete recueillies chez 78 patientes DID et 96 patientes obeses âgees de 11,9 ans a 17,9 ans et ayant un stade pubertaire Tanner 4 ou 5. Resultats On retrouve une augmentation de la prevalence de l’hirsutisme et des troubles de regles chez les patientes DID (21 % et 44 % respectivement) et chez les patientes obeses (36,5 % et 42 % respectivement). L’âge de la pubarche, thelarche et de la menarche est plus tardif chez les patientes DID compare aux patientes obeses. L’hirsutisme chez les patientes DID comme les patientes obeses est lie a une hyperandrogenie biologique avec une augmentation de la fraction libre calculee de la testosterone. Cette augmentation du taux libre de testosterone est liee a une elevation des taux de testosterone totale chez les adolescentes DID, alors qu’elle est due a une diminution du taux de la SHBG (Sex Hormone Binding Globulin) chez les adolescentes obeses. Chez les patientes DID, le taux de testosterone libre est correle positivement au taux d’hbA1c. Les anomalies du cycle menstruel sont associees a une hyperandrogenie biologique uniquement chez les patientes DID Conclusion L’hirsutisme et les troubles des regles sont frequents chez les adolescentes DID et les adolescentes obeses. Malgre une hyperandrogenie presente dans les 2 groupes de patientes, le profil hormonal de chacun differe. En effet l’hyperandrogenie chez les patientes DID est liee a une augmentation de la secretion d’androgenes alors que celle-ci est essentiellement due a une diminution de la SHBG chez les patientes obeses. L’origine de l’insuline, exogene chez les patientes DID, endogene chez les patientes obeses pourrait expliquer cette difference hormonale.

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.

Background P450 aromatase (CYP19A1) is essential for the biosynthesis of estrogens from androgen precursors. Mutations in the coding region of CYP19A1 lead to autosomal recessive aromatase deficiency. To date over 20 subjects have been reported with aromatase deficiency which may manifest during fetal life with maternal virilization and virilization of the external genitalia of a female fetus due to low aromatase activity in the steroid metabolizing fetal–placental unit and thus high androgen levels. During infancy, girls often have ovarian cysts and thereafter fail to enter puberty showing signs of variable degree of androgen excess. Moreover, impact on growth, skeletal maturation and other metabolic parameters is seen in both sexes. Objective and hypothesis We found a novel homozygous CYP19A1 mutation in a 46,XX girl who was born at term to consanguineous parents. Although the mother did not virilize during pregnancy, the baby was found to have a complex genital anomaly at birth (enlarged genital tubercle, fusion of labioscrotal folds) with elevated androgens at birth, normalizing thereafter. Presence of 46,XX karyotype and female internal genital organs (uterus, vagina) together with biochemical findings and follow-up showing regression of clitoral hypertrophy, as well as elevated FSH suggested aromatase deficiency. Interestingly, her older brother presented with mild hypospadias and bilateral cryptorchidism and was found to carry the same homozygous CYP19A1 mutation. To confirm the clinical diagnosis, genetic, functional and computational studies were performed. Methods and results Genetic analysis revealed a homozygous R192H mutation in the CYP19A1 gene. This novel mutation was characterized for its enzymatic activity (Km, Vmax) in a cell model and found to have markedly reduced catalytic activity when compared to wild-type aromatase; thus explaining the phenotype. Computational studies suggest that R192H disrupts the substrate access channel in CYP19A1 that may affect binding of substrates and exit of catalytic products. Conclusion R192H is a novel CYP19A1 mutation which causes a severe phenotype of aromatase deficiency in a 46,XX newborn and maybe hypospadias and cryptorchidism in a 46,XY, but no maternal androgen excess during pregnancy.