Genotype, Mortality, Morbidity, and Outcomes of 3ß-Hydroxysteroid Dehydrogenase Deficiency in Algeria.

Background: 3ß-hydroxysteroid dehydrogenase 2 (3ßHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature and few data on outcomes. Patients and Methods: We report a mixed longitudinal and cross-sectional study from a single Algerian center between 2007 and 2021. Virilization and under-masculinization were assessed using Prader staging and the external masculinization score (EMS), pubertal development staged according to the system of Tanner. Adrenal steroids were measured using mass spectrophotometry (LC-MS/MS). A genetic analysis of HSD3B2 was performed using Sanger sequencing. Results: A 3ßHSD2 defect was confirmed in 6 males and 8 females from 10 families (8 consanguineous), with p.Pro222Gln mutation in all but two siblings with a novel deletion: c.453_464del or p.(Thr152_Pro155del). Probable 3ßHSD2 deficiency was diagnosed retrospectively in a further 6 siblings who died, and in two patients from two other centers. In the genetically confirmed patients, the median (range) age at presentation was 20 (0-390) days, with salt-wasting (n = 14) and genital anomaly (n = 10). The Prader stage for female patients was 2 (1-2) with no posterior fusion of the labia. The EMS for males was 6 (3-9). Median (range) values at diagnosis for 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxypregnenolone (17OHPreg) were elevated: 73.7 (0.37-164.3) nmol/L; 501.2(9.4-5441.3) nmol/L, and 139.7 (10.9-1500) nmol/l (NB >90 nmol/L diagnostic of 3ßHSD2 defect). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5-13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11-14.5) years, with three developing adrenal masses (surgically excised in two) and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43-105), >100 in only two patients and <70 in three. Conclusions: The prevalence of 3ßHSD2 deficiency in Algeria appears high, with p.Pro222Gln being the most frequent mutation. Mortality is also high, with significant morbidity from adrenal tumors and PCOS in adolescence and an increased risk of learning disability. The finding of adrenal tumors in older patients with 3ßHSD2 indicates under-replacement, requiring effective hydrocortisone and fludrocortisone treatment rather than surgical removal.

Preoperative Topical Estrogen Treatment vs Placebo in 244 Children With Midshaft and Posterior Hypospadias.

PURPOSE: Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered. METHODS: We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed. RESULTS: Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86. CONCLUSIONS AND RELEVANCE: Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations.

BACKGROUND: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. METHODS: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation. RESULTS: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. CONCLUSION: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

Disorder of sex development with germ cell tumors: Which is uncovered first?

BACKGROUND: Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery. DESIGN/METHODS: All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed. RESULTS: Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age. CONCLUSION: DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.

Reversion SAMD9 Mutations Modifying Phenotypic Expression of MIRAGE Syndrome and Allowing Inheritance in a Usually de novo Disorder.

Context: MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) syndrome is a severe multisystem disorder with high mortality. It is caused by a heterozygous gain of function mutation in the growth repressor gene SAMD9. The increasing number of reported cases displays a spectrum of phenotypes that may be explained by an adaptation mechanism, with appearance of a somatic second hit mutation with revertant effects. Objective: To determine the genetic basis of the MIRAGE syndrome rapidly corrected in a living and healthy 46,XY patient. Subjects and Methods: A 46,XY patient born with growth restriction and disorders of sex development had thrombocytopenia and necrotizing enterocolitis during the neonatal period suggestive of the syndrome. Faced with the rapid improvement of the patient's phenotype, an adaptation mechanism was sought by repeating genetic analysis at different ages; her parents also underwent genetic analysis. Results: The previously described p.(Thr778Ile) mutation was identified and surprisingly transmitted by the asymptomatic mother in this usually de novo syndrome. To explain the rapid improvement of the patient's phenotype and absence of symptoms in the mother, an adaptation mechanism was sought. For the mother, a non-sense mutation was found (p.(Arg221*)) in cis, and most likely appeared in utero. It was not transmitted to her child. The child harbored a different non-sense mutation (p.(Arg285*)) that most likely appeared near day 20. Conclusions: We show that pathogenic variants can be inherited from a healthy parent as the adaptation mechanism may arise early in life and mask symptoms. Presence of revertant mosaicism mutations could explain "incomplete penetrance" in other disease. For a better management and outcomes in patients, appearance of this natural gene therapy should be sought by repeating genetic analysis.

A novel disorder of sex development, characterized by progressive regression of testicular function and cystic leukoencephalopathy.

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc.

A novel morphological approach to gonads in disorders of sex development.

Disorders of sex development are defined as congenital conditions with discordance between the phenotype, the genotype, the karyotype, and the hormonal profile. The disorders of sex development consensus classification established in 2005 are mainly based on chromosomal and biological data. However, histological anomalies are not considered. The aims of this study were to define the specific pathological features of gonads in various groups of disorders of sex development in order to clarify the nosology of histological findings and to evaluate the tumor risk in case of a conservative approach. One hundred and seventy-five samples from 86 patients with disorders of sex development were analyzed following a strict histological reading protocol. The term 'gonadal dysgenesis' for the histological analysis was found confusing and therefore excluded. The concept of 'dysplasia' was subsequently introduced in order to describe the architectural disorganization of the gonad (various degrees of irregular seminiferous tubules, thin albuginea, fibrous interstitium). Five histological types were identified: normal gonad, hypoplastic testis, dysplastic testis, streak gonad, and ovotestis. The analysis showed an association between undifferentiated gonadal tissue, a potential precursor of gonadoblastoma, and dysplasia. Dysplasia and undifferentiated gonadal tissue were only encountered in cases of genetic or chromosomal abnormality ('dysgenesis' groups in the disorders of sex development consensus classification). 'Dysgenetic testes', related to an embryonic malformation of the gonad, have variable histological presentations, from normal to streak. Conversely, gonads associated with hormonal deficiencies always display a normal architecture. A loss of expression of AMH and α-inhibin was identified in dysplastic areas. Foci of abnormal expression of the CD117 and OCT4 immature germ cells markers in dysplasia and undifferentiated gonadal tissue were associated with an increased risk of neoplasia. This morphological analysis aims at clarifying the histological classification and gives an indication of tumor risk of gonads in disorders of sex development.

Evolution of steroids during pregnancy: Maternal, placental and fetal synthesis.

Progesterone, estrogens, androgens and glucocorticoids are involved in pregnancy from implantation to parturition. Their biosynthesis and their metabolism result from complex pathways involving the fetus, the placenta and the mother. The absence of expression of some steroïdogenic enzymes as CYP17 in placenta and in adrenal fetal zone and the better determination of the onset and variation of others especially HSD3B2 during the pregnancy explain the production of the steroid hormones. Moreover the consequences of some disorders of steroidogenesis (especially aromatase, POR, CYP11A1 and 21-hydroxylase deficiencies) in fetus and mother during the pregnancy have permit to elucidate these complex pathways. This better knowledge of steroid hormones production associated with their dosages in maternal plasma/urine or amniotic fluid using new specific assays as LC-MS MS could facilitate the follow-up of normal and pathological pregnancies. Moreover, these advances should be a basis to evaluate the impact of multiple pathologies of the pregnancy and pharmacologic and xenobiotic consequences on their metabolism.

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.

Laparoscopic-assisted vaginal pull-through: A new approach for congenital adrenal hyperplasia patients with high urogenital sinus.

BACKGROUND: To open vaginal cavity to the pelvic floor is part of surgical treatment for urogenital sinus (UGS) in girls with congenital adrenal hyperplasia (CAH). For high UGS, this operative procedure can be challenging and may jeopardise urinary continence. Combined perineal and laparoscopic approaches could be useful to minimise perineal dissection and to facilitate the vaginal lowering. PATIENTS AND METHODS: We report the procedure of a laparoscopic-assisted vaginal pull-through for supra-sphincteric UGS in a 5-year-old girl with CAH. Laparoscopic dissection of the vagina from the posterior wall of the bladder and urethra, division of the confluence and vaginal pull-through to the perineum are described. DISCUSSION: The technique is derived from laparoscopic-assisted treatment for high ano-rectal malformations. Compared with current procedures for treatment for high UGS, laparoscopic-assisted approach allows mobilising vagina with minimal dissection of perineum and complete preservation of urethra. Another major advantage is to provide a direct vision for dissection of the space between rectum and urethra prior to vaginal pull-through. CONCLUSION: Laparoscopic-assisted vaginal pull-through appears to be an interesting approach for high UGS in CAH patients, reducing dissection and risk of urinary incontinence. This new approach needs to be strengthened by other cases.

The effect of patient, provider and financing regulations on the intensity of ambulatory physical therapy episodes: a multilevel analysis based on routinely available data.

BACKGROUND: Many studies have found considerable variations in the resource intensity of physical therapy episodes. Although they have identified several patient- and provider-related factors, few studies have examined their relative explanatory power. We sought to quantify the contribution of patients and providers to these differences and examine how effective Swiss regulations are (nine-session ceiling per prescription and bonus for first treatments). METHODS: Our sample consisted of 87,866 first physical therapy episodes performed by 3,365 physiotherapists based on referrals by 6,131 physicians. We modeled the number of visits per episode using a multilevel log linear regression with crossed random effects for physiotherapists and physicians and with fixed effects for cantons. The three-level explanatory variables were patient, physiotherapist and physician characteristics. RESULTS: The median number of sessions was nine (interquartile range 6-13). Physical therapy use increased with age, women, higher health care costs, lower deductibles, surgery and specific conditions. Use rose with the share of nine-session episodes among physiotherapists or physicians, but fell with the share of new treatments. Geographical area had no influence. Most of the variance was explained at the patient level, but the available factors explained only 4% thereof. Physiotherapists and physicians explained only 6% and 5% respectively of the variance, although the available factors explained most of this variance. Regulations were the most powerful factors. CONCLUSION: Against the backdrop of abundant physical therapy supply, Swiss financial regulations did not restrict utilization. Given that patient-related factors explained most of the variance, this group should be subject to closer scrutiny. Moreover, further research is needed on the determinants of patient demand.

Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey.

CONTEXT: Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men. OBJECTIVE: The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility. METHODS: From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men. RESULTS: Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. CONCLUSION: We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.

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.

A late 17α-hydroxylase deficiency diagnosis that leads to the discovery of a new CYP17 gene mutation.

17α-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia. It leads to a reduced production of cortisol and sex steroids and thus an increase in adrenocorticotrophic hormone and gonadotrophins levels. High adrenocorticotrophic hormone levels result in an accumulation of 17-deoxysteroids, such as deoxycorticosterone and corticosterone. Deoxycorticosterone and corticosterone have an important mineralocorticoid activity. We report the case of a 66-year-old woman who presented with hypertension and symptomatic hypokalaemia. Primary hyperaldosteronism was suspected and a right adrenal mass was removed. After surgery, the patient was referred to the endocrinology department for persistant hypokalaemia. Actually, she presented some signs of hypogonadism (impuberism, primary amenorrhea, infertility). Cortisol and 17OH-progesterone serum levels were low. Deoxycorticosterone and corticosterone were markedly elevated. The hypothesis of 17α-hydroxylase deficiency was considered and confirmed by genetic exploration. A non-sense mutation c.938G>A (p.Trp313X) in exon 5 of the CYP17 gene was found that had never been reported so far to our knowledge. Moreover, the patient's karyotype found a mosaic Turner syndrome. This case is particularly interesting because of the delay of diagnosis. The 17α-hydroxylase deficiency diagnosis is to be considered when hypertension is associated with hypokalaemia and hypogonadism, even in adult patients.

Late prenatal dexamethasone and phenotype variations in 46,XX CAH: concerns about current protocols and benefits for surgical procedures.

OBJECTIVE: To describe the action of prenatal dexamethasone (PreDex) on the anatomy of female congenital adrenal hyperplasia (CAH) genitalia when started at later stages of gestation. MATERIALS AND METHODS: Our group follows a large cohort of French CAH patients who underwent PreDex therapy, of whom 258 were recently reported. Four 46,XX patients with a delayed PreDex treatment presented with a virilized genitalia and required surgical reconstruction. This is a retrospective report on genital phenotyping at the time of surgery of these four patients who began PreDex therapy at 8, 12, 20, and 28 weeks of gestation. RESULTS: Although this series is limited in number, the anatomical description of the length of the genital tubercle, the height of the urethra-vaginal confluence, and the degree of fusion of the genital folds seems to be dependent upon the starting date of PreDex. Most PreDex treatments prescribed up to now have covered the full duration of gestation. CONCLUSIONS: Our findings suggest that PreDex therapy could be limited to the period of the partitioning window. It is hoped that further prospective multicentric clinical studies will obtain ethical approval in order to elucidate the place and protocols of PreDex therapy in the management of CAH.

New management strategy of pregnancies at risk of congenital adrenal hyperplasia using fetal sex determination in maternal serum: French cohort of 258 cases (2002-2011).

CONTEXT: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions. OBJECTIVE: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test). DESIGN AND SETTING: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice. PATIENTS: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included. INTERVENTION: DEX was offered after informed consent to pregnant women. MAIN OUTCOME MEASURE: The sensitivity of an early SRY test was evaluated after data collection. RESULTS: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero. CONCLUSIONS: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.

Adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients.

OBJECTIVES: Several cases of testicular adrenal rest tumours have been reported in men with congenital adrenal hyperplasia (CAH) due to the classical form of 21-hydroxylase deficiency but the prevalence has not been established. The aims of this report were to evaluate the frequency of testicular adrenal rest tissue in this population in a retrospective multicentre study involving eight endocrinology centres, and to determine whether treatment or genetic background had an impact on the occurrence of adrenal rest tissue. MATERIAL AND METHODS: Testicular adrenal rest tissue (TART) was sought clinically and with ultrasound examination in forty-five males with CAH due to the classical form of 21-hydroxylase deficiency. When the diagnosis of testicular adrenal rest tumours was sought, good observance of treatment was judged on biological concentrations of 17-hydroxyprogesterone (17OHP), delta4-androstenedione, active renin and testosterone. The results of affected and non-affected subjects were compared. RESULTS: TART was detected in none of the 18 subjects aged 1 to 15years but was detected in 14 of the 27 subjects aged more than 15years. Five patients with an abnormal echography result had no clinical signs. Therapeutic control evaluated at diagnosis of TART seemed less effective when diagnosis was made in patients with adrenal rest tissue compared to TART-free subjects. Various genotypes were observed in patients with or without TART. CONCLUSION: Due to the high prevalence of TART in classical CAH and the delayed clinical diagnosis, testicular ultrasonography must be performed before puberty and thereafter regularly during adulthood even if the clinical examination is normal.

Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys.

CONTEXT: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. OBJECTIVE: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. METHODS: This is a multicenter retrospective study. RESULTS: Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment. CONCLUSIONS: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.

BACKGROUND: The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off. RESULTS: Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter. CONCLUSIONS: These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.

Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature.

BACKGROUND: Somatotropinoma, a pituitary adenoma characterised by excessive production of growth hormone (GH), is extremely rare in childhood. A genetic defect is evident in some cases; known genetic changes include: multiple endocrine neoplasia type 1 (MEN1); Carney complex; McCune-Albright syndrome; and, more recently identified, aryl hydrocarbon receptor-interacting protein (AIP). We describe seven children with somatotropinoma with a special focus on the differences between genetic and sporadic forms. METHODS: Seven children who presented in our regional network between 1992 and 2008 were included in this retrospective analysis. First-type therapy was somatostatin (SMS) analogues or transsphenoidal surgery. Control was defined as when insulin-like growth factor-1 (IGF-1) levels were within the normal range for the patient's age at 6 months after therapy, associated with decreasing tumour volume. RESULTS: Patients were aged 5-17 years and the majority (n = 6) were male. Four patients had an identified genetic mutation (McCune-Albright syndrome: n = 1; MEN1: n = 1; AIP: n = 2); the remaining three cases were sporadic. Accelerated growth rate was reported as the first clinical sign in four patients. Five patients presented with macroadenoma; invasion was noted in four of them (sporadic: n = 1; genetic: n = 3). Six patients were treated with SMS analogues; normalisation of IGF-1 occurred in one patient who had a sporadic intrasellar macroadenoma. Multiple types of therapy were necessary in all patients with an identified genetic mutation (4 types: n = 1; 3 types: n = 2; 2 types: n = 1), whereas two of the three patients with sporadic somatotropinoma required only one type of therapy. CONCLUSIONS: This is the first series that analyzes the therapeutic response of somatotropinoma in paediatric patients with identified genetic defects. We found that, in children, genetic somatotropinomas are more invasive than sporadic somatotropinomas. Furthermore, SMS analogues appear to be less effective for treating genetic somatotropinoma than sporadic somatotropinoma.