Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic NR5A1 (SF-1) frameshift variant: p.(Phe70Serfs*5).

Background: Steroidogenic factor 1 (SF-1), encoded by the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, is a transcriptional factor crucial for adrenal and gonadal organogenesis. Pathogenic variants of NR5A1 are responsible for a wide spectrum of phenotypes with autosomal dominant inheritance including disorders of sex development and oligospermia-azoospermia in 46,XY adults. Preservation of fertility remains challenging in these patients. Objective: The aim was to offer fertility preservation at the end of puberty in an NR5A1 mutated patient. Case report: The patient was born of non-consanguineous parents, with a disorder of sex development, a small genital bud, perineal hypospadias, and gonads in the left labioscrotal fold and the right inguinal region. Neither uterus nor vagina was detected. The karyotype was 46,XY. Anti-Müllerian hormone (AMH) and testosterone levels were low, indicating testicular dysgenesis. The child was raised as a boy. At 9 years old, he presented with precocious puberty treated by triptorelin. At puberty, follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone levels increased, whereas AMH, inhibin B, and testicular volume were low, suggesting an impaired Sertoli cell function and a partially preserved Leydig cell function. A genetic study performed at almost 15 years old identified the new frameshift variant NM_004959.5: c.207del p.(Phe70Serfs*5) at a heterozygous state. He was thus addressed for fertility preservation. No sperm cells could be retrieved from three semen collections between the ages of 16 years 4 months and 16 years 10 months. A conventional bilateral testicular biopsy and testicular sperm extraction were performed at 17 years 10 months of age, but no sperm cells were found. Histological analysis revealed an aspect of mosaicism with seminiferous tubules that were either atrophic, with Sertoli cells only, or presenting an arrest of spermatogenesis at the spermatocyte stage. Conclusion: We report a case with a new NR5A1 variant. The fertility preservation protocol proposed at the end of puberty did not allow any sperm retrieval for future parenthood.

Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-ß and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.

Drug-Induced sleep endoscopy in children: NAVOTEL scoring system development.

OBJECTIVES: Pediatric drug-induced sleep endoscopy (DISE) lacks a universal and easy-to-use scoring system. The velum, oropharynx, tongue, epiglottis (VOTE) scoring system is widely used but needs to be completed in pediatrics. The main objective of this study was to investigate the distribution of obstructive sites in DISE and to propose an appropriate pediatric scoring system. The secondary objective was to evaluate the changes in surgical management induced by the proposed scoring system. METHODS: A single-center prospective 5-year study was conducted from March 2016 to December 2021, including 99 children with a mean age of 7.2 years (±3.7), with pathological preoperative sleep recordings and undergoing DISE. The distribution of all upper airway obstructive sites was studied. RESULTS: Adenoids (A) were the most frequent obstructive site (63% of patients), and the nasal cavities (N) and the larynx (L) were other frequent obstructive sites. These sites are not explored by the VOTE scoring system, leading to the creation of the nose, adenoids, velum, oropharynx, tongue, epiglottis, larynx (NAVOTEL) scoring system. NAVOTEL was significantly correlated with the severity of obstructive sleep apnea-hypopnea syndrome (OSAS) (ρ = 0.2; p = 0.04) and highlighted obstructive sites in 6/9 patients with VOTE = 0. Of these patients, 4 had a complete obstructive site, and 3 had a multisite obstruction. VOTE indicated 8 additional surgical actions; NAVOTEL indicated 50 other actions compared to clinical examination. The NAVOTEL scoring system was exhaustive regarding surgical indications for OSAS. CONCLUSIONS: The NAVOTEL scoring system is exhaustive in pediatric DISE and correlated to OSAS severity. It should be preferred in pediatric DISE.

Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

IgA vasculitis in patients with inflammatory bowel disease: new insights into the role of TNF-α blockers.

OBJECTIVE: The association of IgA vasculitis (IgAV) and IBD is rarely described, mainly during anti-TNF-α therapy. We aimed to describe the association of IgAV and IBD. METHODS: We retrospectively analysed the association of IgAV and IBD through the implication of the GETAID and FVSG networks. Characteristics of IBD and IgAV were collected using a standardized case report form. RESULTS: Forty-three cases were included. IBD [mainly Crohn's disease (CD) in 58%] preceded IgAV in 38 (88%), with median interval of 9.2 (IQR 5.4-15.4) years. In these 38 patients, at IgAV diagnosis, five (13%) had active IBD and 28 (74%) were treated with anti-TNF-α for a median duration of 31.5 (IQR 19-56) months. Main IgAV manifestations were purpura all patients (100%), joints in 20/35 (57%), renal in 15/35 (43%) and gastrointestinal in 11/35 (31%) involvement. IgAV was treated with glucocorticoids in 25 (66%), colchicine in six (16%), CYC in six (16%) and anti-TNF-α were discontinued in 15/28 (54%). No IgAV relapse occurred when TNF-α blockers were stopped, vs 23% in patients pursuing it. Conversely, five (33%) had IBD flare or complication after anti-TNF-α cessation vs one (8%) in those continuing biologics. Anti-TNF-α were resumed in six (40%), with subsequent IgAV relapse in four (67%). CONCLUSIONS: This large cohort suggests that TNF-α blockers may promote the onset of IgAV in IBD. Discontinuation of anti-TNF-α was associated with vasculitis remission but increased risk of IBD relapses, whereas continuation of anti-TNF-α was associated with IBD remission but vasculitis relapse.

A Magnetic Resonance Imaging Index to Predict Crohn's Disease Postoperative Recurrence: The MONITOR Index.

BACKGROUND & AIMS: We developed and validated a magnetic resonance imaging-based index to predict Crohn's disease (CD) postoperative recurrence (POR). METHODS: Patients with CD who underwent a postoperative evaluation for recurrence (with colonoscopy and MRI no longer than 105 days apart) were included between 2006 and 2016 in University Hospital of Nancy, France. MRI items with good levels of intra-rater and inter-rater agreement (Gwet's coefficient ≥0.5) were selected. The MRI in Crohn's Disease to Predict Postoperative Recurrence (MONITOR) index's performance was assessed in terms of the area under the receiver operating characteristic curve (AUROC) and accuracy, by considering the Rutgeerts score as the gold standard. The MONITOR index was validated with a bootstrap method and an independent cohort. RESULTS: Seventy-three MRI datasets were interpreted by 2 radiologists. Seven items (bowel wall thickness, contrast enhancement, T2 signal increase, diffusion-weighted signal increase, edema, ulcers, and the length of the diseased segment) had a Gwet's coefficient ≥0.5 and were significantly associated with the Rutgeerts score, leading to their inclusion in the MONITOR index. All the items had a weighting of 1, except the "ulcers" item weighting 2.5, reflecting the higher adjusted odds ratio. The AUROC [95% confidence interval] for the prediction of endoscopic POR (Rutgeerts score >i1) was 0.80 [0.70-0.90]. The optimal threshold was a MONITOR index ≥1, giving a sensitivity of 79%, a specificity of 55%, a predictive positive value of 68%, and a predictive negative value of 68%. The bootstrap validation gave an AUROC of 0.85 [0.73-0.97]. In the validation cohort, a MONITOR index ≥1 gave a sensitivity of 87%, a specificity of 75%, a predictive positive value of 84.6%, and a predictive negative value of 75%. CONCLUSIONS: The MONITOR index is an efficient, reliable, easy-to-apply tool that can be used in clinical practice to predict the POR of CD.

Comparison of short- and long-term effectiveness between ustekinumab and vedolizumab in patients with Crohn's disease refractory to anti-tumour necrosis factor therapy.

BACKGROUND: The best option between vedolizumab and ustekinumab after anti-tumour necrosis factor (TNF) failure remains unclear in Crohn's disease. AIMS: To compare the short- and long-term effectiveness of vedolizumab and ustekinumab in Crohn's disease patients with prior anti-TNF exposure. METHODS: All Crohn's disease patients treated with ustekinumab or vedolizumab after exposure to at least one anti-TNF agent were included from two referral centres. Primary endpoint was corticosteroid-free clinical remission defined as Crohn's disease activity index <150 at week 54. Deep remission (corticosteroid-free clinical remission and faecal calprotectin <100 µg/g) was assessed at week 14. Propensity-matched analyses were applied to make the two groups comparable. RESULTS: Overall, 312 patients (ustekinumab = 224 and vedolizumab = 88) were included. After propensity score analysis, ustekinumab was more effective to achieve corticosteroid-free clinical remission at week 54 (49.3% vs 41.2%, P = 0.04) and deep remission at Week 14 (25.9% vs 3.8%, P = 0.02) than vedolizumab. The rate of primary nonresponders (6.7% vs 14.8%, P = 0.034) and the long-term risk of drug discontinuation due to therapeutic failure (HR = 1.53 [1.04-2.07], P = 0.029) were lower in patients treated with ustekinumab compared with vedolizumab. Predictors of ustekinumab failure were complicated phenotype (odds ratio [OR] = 2.35 [1.31-4.22]; P = 0.004) and anti-TNF primary non-response (OR = 2.55 [1.27-5.12]; P = 0.008). We did not find any predictor of corticosteroid-free clinical remission in patients treated with vedolizumab. Vedolizumab was less effective than ustekinumab in patients >35 years old (OR = 0.41 [0.19-0.87]), with noncomplicated phenotype (OR=0.42 [0.18-0.96]), no prior bowel resection (OR = 0.49 [0.24-0.96]), and no steroids at baseline (OR=0.47 [0.23-0.97]). CONCLUSION: Ustekinumab was more effective to achieve early and long-term effectiveness than vedolizumab in Crohn's disease patients who previously failed response to anti-TNF agents.

Low Levels of Fecal Calprotectin 3 Months After Surgery Predict Subsequent Endoscopic Postoperative Remission in Crohn's Disease.

BACKGROUND/AIMS: In Crohn's disease (CD) few data are available on the usefulness of monitoring fecal calprotectin (FC) in the early postoperative setting. We assessed prospectively the accuracy of FC measured 3 months after surgery to predict the risk of endoscopic postoperative recurrence (POR) within 1 year after resection. METHODS: In 55 consecutive CD patients who had undergone ileocolonic resection samples were collected 3 months after surgery for measuring serum CRP and FC. Endoscopic POR was assessed by ileocolonoscopy within 6-12 months (median 7 months). Receiver operating characteristic (ROC) curves were generated to assess accuracy of the markers, to determine the best threshold and to calculate sensitivity, specificity, positive and negative predictive values. RESULTS: In contrast with median CRP levels, median FC concentrations measured 3 months after surgery were significantly higher in patients who later experienced endoscopic POR (Rutgeerts ≥ i2) compared with those who stayed in endoscopic remission within the following 6-12 months (205 µg/g IQR [106-721] vs. 103 µg/g IQR [60-219], p = 0.008). Area under the ROC curve for FC was 0.71. The best cutoff value of FC to identify patients in subsequent endoscopic remission 3 months after surgery was 65 µg/g (96% sensitivity, 31% specificity, 50% positive and 91% negative predictive values). In multivariate analysis, FC < 65 µg/g at 3 months was the only factor associated with subsequent endoscopic remission. CONCLUSION: FC measured 3 months after surgery below 65 µg/g is an accurate marker to identify CD patients who will later stay in endoscopic remission within 1 year after resection.

Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease.

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-ß, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

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.

Sarcopenia and visceral obesity assessed by computed tomography are associated with adverse outcomes in patients with Crohn's disease.

BACKGROUND: Altered body composition may impact on the clinical course of Crohn's disease (CD) but is not detected by the simple body mass index (BMI) assessment. AIM: To assess the prevalence of sarcopenia and visceral obesity by a single computed tomography (CT) slice, and its association with adverse events in an adult hospitalized CD cohort. METHODS: 88 CD patients who had abdominal CT scans during hospitalization were retrospectively enrolled. The skeletal muscle index (SMI) at the third lumbar vertebra level was used to assess sarcopenia. Sarcopenia was defined as a SMI <38.5 cm2/m2 in women, <52.4 cm2/m2 in men and visceral obesity as a visceral fat area ≥130 cm2. Clinical malnutrition was defined by a BMI <18.5 kg/m2. Univariate analysis was performed, and predictors for surgery in the follow-up were entered in a stepwise logistic regression model for multivariate analysis. RESULTS: The prevalence of sarcopenia was 58%, malnutrition 21.6%, and visceral obesity 19.3%. Among sarcopenic patients, 49% had a normal BMI, 13.7% were overweight, and 1(2%) was obese. Sarcopenic CD patients had significantly more abscesses (51% vs 16.7%, p = 0.001), hospitalizations (61.2% vs 36.1%, p = 0.022) and digestive surgery (63.3% vs 27.8%, p = 0.001) than non-sarcopenic patients during the follow-up, whereas usual malnutrition assessment was not correlated with disease outcomes. In multivariate analysis, both sarcopenia and visceral obesity were associated with further occurrence of digestive surgery. CONCLUSION: Both sarcopenia and visceral obesity were associated with adverse outcomes in severe CD patients whereas usual nutritional assessment was not.

Betaine anhydrous in homocystinuria: results from the RoCH registry.

BACKGROUND: The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year. RESULTS: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine ß-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns. CONCLUSIONS: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.

[Atypical genital development and tumor risk]. / Atypie du développement génital et risque tumoral : synthèse de la réunion scientifique du 25 mai 2018 organisée par le « Centre de référence des maladies rares du développement génital du fœtus à l'adulte ¼.

Atypical genital development (AGD), also called disorders of sex development are a set of miscellaneous pathologies who have in common a morphological and/or functional abnormality of the internal and/or external genital organs. The Chicago classification identifies 3 major groups based on karyotype, hormone balance and genetic studies. Some AGD predispose to the occurrence of tumors, mainly malignant germ cell tumors. The tumor risk depends on many factors: the type of AGD, the position of the gonad, the age of the patient, the phenotype, the function of the gonad and the presence of germ cells in the gonad. AGD with the highest tumor risk are those with gonadal dysgenesis, implying an incomplete differentiation of the bipotential gonad (dysplasia). Monitoring of patients with AGD and indication of prophylactic gonadectomies should be individualized according to tumor risk.

Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene.

Exocrine pancreatic insufficiency (EPI) is rare in children, with most if not all cases occurring as part of syndromic conditions such as cystic fibrosis and Shwachman-Diamond syndrome. Here we report two cases, both presenting with severe EPI around 5 months of age. Characterized by diffuse pancreatic lipomatosis, they otherwise exhibited no remarkable deficiencies in other organs. Novel non-identical homozygous variants (a deletion removing the entire SPINK1 gene and an insertion of a full-length inverted Alu element into the 3'-untranslated region of the SPINK1 gene) resulting in the complete functional loss of the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) were identified in each patient. Having correlated our findings with current knowledge of SPINK1's role in exocrine pancreas pathophysiology, we propose that complete and partial functional losses of the SPINK1 gene are associated with quite distinct phenotypes, the former causing a new pediatric disease entity of severe infantile isolated EPI.

Laryngotracheal Stenosis in Children and Infants With Neurological Disorders: Management and Outcome.

INTRODUCTION: The goal of this retrospective study is to compare the management and outcome of surgical treatment of laryngotracheal stenosis in children and infants with and without an associated neurological disorder. PATIENTS AND METHOD: In a series of children operated on for subglottic stenosis (SGS), patients with an associated neurological disorder were identified. The following criteria were compared in children with and without neurological disease: grade of stenosis, age, technique (Crico-Tracheal Resection (CTR), Laryngo-Tracheo-Plasty (LTP) in single and 2 stage, laser), analyzing duration, preoperative tracheostomy, decannulation rate, preoperative gastrostomy, and number of days in intensive care unit and in hospital. RESULTS: Two hundred twenty-three children were operated on for subglottic stenosis, of whom 68 (30.5%) had an associated neurological disorder. Some criteria were found to be statistically different between the 2 populations: mean age of 43 months in neurological population versus 13 months (P < .001). The distribution of the grades of SGS appeared similar in the 2 groups (P = .088), and the mean duration of stay in hospital and in ICU were not statistically different (respectively, P = .186 and P = .056) between the 2 groups; a 2-stage procedure was performed more frequently than 1-stage in the cases with associated neurological disorder-66.6% versus 36.5% (P = .013); the median duration of stenting was 20 days in those with neurological disease versus 12 (P = .021). Preoperative tracheotomy was noted in 75% of neurological patients versus 47.7% of the others (P < .001). The outcome was considered to be good (decannulation and no further treatment) following a single procedure in 82.4% of patients with neurological disorder, as against 86.5% of neurologically unimpaired subjects. The difference in outcome of surgery was not statistically different (P = .392) between the 2 groups. DISCUSSION AND CONCLUSION: It appears that subglottic stenosis in children with associated neurological disorder is not more severe than in neurologically normal patients. In three-quarters of the neurologically impaired cases, a preoperative tracheostomy was needed, but the rates of failure of postoperative decannulation are not statistically significant between the 2 groups. In our experience, 2-stage techniques are more often performed than single stage in this population in order to allow airway safety, for example after feeding. If properly managed, the final results are similar in the 2 populations.

Surgery in disorders of sex development (DSD) with a gender issue: If (why), when, and how?

Ten years after the consensus meeting on disorders of sex development (DSD), genital surgery continues to raise questions and criticisms concerning its indications, its technical aspects, timing and evaluation. This standpoint details each distinct situation and its possible management in 5 main groups of DSD patients with atypical genitalia: the 46,XX DSD group (congenital adrenal hyperplasia); the heterogeneous 46,XY DSD group (gonadal dysgenesis, disorders of steroidogenesis, target tissues impairments …); gonosomic mosaicisms (45,X/46,XY patients); ovo-testicular DSD; and "non-hormonal/non chromosomal" DSD. Questions are summarized for each DSD group with the support of literature and the feed-back of several world experts. Given the complexity and heterogeneity of presentation there is no consensus regarding the indications, the timing, the procedure nor the evaluation of outcome of DSD surgery. There are, however, some issues on which most experts would agree: 1) The need for identifying centres of expertise with a multidisciplinary approach; 2) A conservative management of the gonads in complete androgen insensitivity syndrome at least until puberty although some studies expressed concerns about the heightened tumour risk in this group; 3) To avoid vaginal dilatation in children after surgical reconstruction; 4) To keep asymptomatic mullerian remnants during childhood; 5) To remove confirmed streak gonads when Y material is present; 6) It is likely that 46,XY cloacal exstrophy, aphallia and severe micropenis would do best raised as male although this is based on limited outcome data. There is general acknowledgement among experts that timing, the choice of the individual and irreversibility of surgical procedures are sources of concerns. There is, however, little evidence provided regarding the impact of non-treated DSD during childhood for the individual development, the parents, society and the risk of stigmatization. The low level of evidence should lead to design collaborative prospective studies involving all parties and using consensual protocols of evaluation.

Inaugural cerebral sinovenous thrombosis revealing homocystinuria in a 2-year-old boy.

Cerebral sinovenous thrombosis is unusual during childhood and requires early and accurate management because of its detrimental consequences. We report on the case of a 2-year-old boy with mild psychomotor delay, who presented with nonfebrile acute ataxia. A brain computed tomographic (CT) scan showed complete thrombosis of the superior sagittal sinus, confirmed by magnetic resonance angiography and associated with a right frontal hemorrhagic infarction. Systematic screening for thrombophilia revealed homocystinuria linked to cystathionine ß-synthase deficiency with underlying compound heterozygosity. The evolution was favorable after anticoagulant therapy, specific diet, and vitamin supplementation. This case is of interest because of the unusual clinical presentation as a pediatric cerebral sinovenous thrombosis. Furthermore, homocystinuria is rarely revealed by cerebral sinovenous thrombosis at the onset of the disease and should systematically be ruled out in pediatric stroke.

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.

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.

Does androgen stimulation prior to hypospadias surgery increase the rate of healing complications? - A preliminary report.

OBJECTIVE: Androgens have a positive effect on penile growth in children, but they may also have a repressive effect on the healing process. The aim of this prospective study was to compare the outcomes of onlay urethroplasty with and without preoperative androgen stimulation in patients with severe hypospadias. PATIENTS AND METHOD: Of 300 severe hypospadias cases treated at a single institution, 126 operated on by the same surgeon had complete follow-up data, and 30 of these received preoperative androgen treatment (human chorionic gonadotrophin and/or systemic testosterone) 1-24 months before surgery. RESULTS: Thirty-five patients presented with a complication (27.7%) of whom 26 (20.6%) had a fistula or dehiscence. Among patients on androgen stimulation there was a 30% healing complication rate (9/30) whereas for those without this was 17.7% (17/96). When androgenic treatment was given > 3 months prior to surgery the healing complication rate was 21.7% (5/23), and when < 3 months prior to surgery the rate reached 57% (4/7). Mean follow up was 41 months (10-97). CONCLUSION: Although the numbers were too small in this series to reach statistical significance, the tissular interactions of androgens in the healing process reported by dermatologists should alert the hypospadiologists and lead to a further prospective study to define the optimal protocol for stimulation of the penis in specific cases without affecting outcome.