Donor splice-site mutations in WT1 are responsible for Frasier syndrome.

Frasier syndrome (FS) is a rare disease defined by male pseudo-hermaphroditism and progressive glomerulopathy. Patients present with normal female external genitalia, streak gonads and XY karyotype and frequently develop gonadoblastoma. Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by unspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. No case of Wilms' tumour has been reported, even in patients with extended follow-up. In contrast with FS patients, most individuals with Denys-Drash syndrome (DDS; refs 6,7) have ambiguous genitalia or a female phenotype, an XY karyotype and dysgenetic gonads. Renal symptoms are characterized by diffuse mesangial sclerosis, usually before the age of one year, and patients frequently develop Wilms' tumour. Mutations of the Wilms'-tumour gene, WT1, cause different pathologies of the urogenital system, including DDS. WT1 is composed of ten exons and encodes a protein with four zinc-finger motifs and transcriptional and tumour-suppressor activities. Alternative splicing generates four isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of three amino acids (KTS) between the third and fourth zinc fingers of WT1 (ref. 17). Here we demonstrate that FS is caused by mutations in the donor splice site in intron 9 of WT1, with the predicted loss of the +KTS isoform. Examination of WT1 transcripts indeed showed a diminution of the +KTS/-KTS isoform ratio in patients with FS.

People Who Chose the Preventive Natural Bioenergetics (NB) COVID-19 Treatment Safely Experienced a Significant Reduction of COVID-19 Symptoms Compared to the General Population.

BACKGROUND AND AIM: The aim of this study is to assess if people who chose to receive the preventive Natural Bioenergetics (NB) COVID-19 treatment would experience safely a strong reduction in frequency and severity of COVID-19 major symptoms (fever, cough, and shortness of breath) compared to the general population. Experimental procedure: The preventive NB COVID-19 treatment is a double acupuncture meridian-based procedure that primes the immune system using acupuncture points and specific substances and sounds on precise body locations. Four hundred and thirty-nine people from seven countries (Canada, USA, Mexico, UK, France, Israel, and Belgium) voluntarily received the non-invasive preventive NB treatment. Data used for this study have been gathered between April 2020 and December 2020. The severity of cases experienced by the general population was statistically compared with those of the 42 infected people of this study. RESULTS AND CONCLUSION: Our analysis suggests the population who chose to receive the preventive NB COVID-19 treatment experienced a strong reduction in frequency and severity of the three major symptoms of COVID-19 (p<0.01) compared to the general population. Nobody in that population needed hospitalization, including the elderly, which can be interpreted as a very significant clinical improvement. Most people did not report any side effects. Only small side effects were reported.

Assessment of physicians' resilience level during the COVID-19 pandemic.

We aim to assess physicians' level of resilience and define factors that improve or decrease the resilience level during the COVID-19 pandemic. Physicians from hospitals located in areas with different COVID-19 caseload levels, were invited to participate in a national e-survey between April and May 2020. Study participants were mainly emergency physicians, and anaesthesiologists, infectious disease consultants, and intensive care. The survey assessed participant's characteristics, factors potentially associated with resilience, and resilience using the Connor-Davidson Resilience Scale (RISC-25), with higher scores indicative of greater resilience. Factors associated with the resilience score were assessed using a multivariable linear regression. Of 451 responding physicians involved in the care of COVID-19 patients, 442 were included (98%). Age was 36.1 ± 10.3 years and 51.8% were male; 63% worked in the emergency department (n = 282), 10.4% in anesthesiology (n = 46), 9.9% in infectious disease department (n = 44), 4.8% in intensive care unit (n = 21) or other specialties (n = 49). The median RISC-25 score was at 69 (IQR 62-75). Factors associated with higher RISC scores were anesthesia as a specialty, parenthood, no previous history of anxiety or depression and nor increased anxiety. To conclude, this study is the first to characterize levels of resilience among physicians involved in COVID-19 unit. Our data points to certain protective characteristics and some detrimental factors, such as anxiety or depression, that could be amenable to remediating or preventing strategies to promote resilience and support caregivers in a pandemic.

[Juvenile granulosa-cell tumor: clinical and molecular expression]. / Tumeurs juvéniles de la granulosa: expression clinique et moléculaire.

Ovarian sex cord-stromal tumors are rare tumors that originate from the nongerminal cells of ovary. Two decades ago, the identification of juvenile granulosa-cell tumors (GCT), as a specific entity inside this group, allowed a better treatment of these tumors in children. However, little data have been reported on the natural course of the disease and reliable prognostic factors have not been yet defined. We here review the clinical and genetics aspects of granulosa tumors, based on a series of 40 children. This national collaborative study involved the French Society of Children Cancer and eight clinical departments of pediatric endocrinology. We found that early diagnosis of a tumor, revealed by clinical signs of hyperoestrogeny, is an important prognostic factor. The pathophysiology of these tumors is still debatable and several cellular- and molecular-abnormal signals could be implicated in their development. The role of growth factors and oncogenes through the signaling pathway of MAP kinase is still discussed. According to our data, FSH signaling-transduction pathway, such as a constitutionally activated Galphas, could also be implicated in the induction of granulosa cell proliferation and seems to modulate the invasiveness of the tumor. Last, we have described a low-expression pattern or an extinction of an ovarian-determination gene, FOXL2, which is related to a worse prognosis of this tumor.

Analysis of delays in the prescription of oseltamivir in hospitals and potential for improvement.

OBJECTIVES: Patients hospitalized for influenza should receive early treatment with a neuraminidase inhibitor. PATIENTS AND METHODS: We conducted a retrospective study of the prescription of oseltamivir during the 2016-2017 influenza epidemic among patients hospitalized for influenza confirmed by RT-PCR in the infectious disease department. RESULTS: Treatment with oseltamivir was initiated as recommended in 96% of hospitalized patients presenting with influenza. However, a delay in prescription was observed with only 18% of prescriptions made on the first day. The prescriptions were exclusively initiated in the infectious disease department. CONCLUSION: To improve the early prescription of oseltamivir during the influenza season, two recommendations are essential: oseltamivir availability in the emergency department pharmacy, awareness of physicians of the need to prescribe to any patient hospitalized for a lower respiratory tract infection treatment with a neuraminidase inhibitor upon admission to the emergency department.

Impaired sexual and reproductive outcomes in women with classical forms of congenital adrenal hyperplasia.

OBJECTIVES: The objectives of the study were 2-fold: 1) a detailed description of sexual and reproductive outcomes in adult women with congenital adrenal hyperplasia (CAH) of different phenotypic severity at birth; and 2) comparisons of these outcomes among CAH subtypes and between CAH women and non-CAH control women. DESIGN: This was a cross-sectional study using a face-to-face interview, a written questionnaire, the Female Sexual Function Index, and a gynecological examination. PATIENTS: Patients included 35 women with CAH, representing Prader stages I-V at birth, aged 18-43 yr, who had been treated from birth to adolescence in the same pediatric endocrine clinics. Sixty-nine non-CAH healthy control women were selected from hospital-staff families. RESULTS: None of the CAH women expressed doubts about their gender assignment. Twenty percent (seven of 35) had homosexual inclinations; 23% (eight of 35) were married; three reported a complete lack of sexual activity; and 37% (13 of 35) said they never had heterosexual intercourse with vaginal penetration. Sexual functioning as assessed by the Female Sexual Function Index was much lower in CAH women than controls and lowest in CAH women with high Prader stages. Eighty-one percent (18 of 22) experienced pain during vaginal penetration. Only eight women became pregnant, and 17% (six of 35) had children. CONCLUSIONS: Despite expert medical and surgical care by physicians dedicated to this rare disease, women with CAH still suffer major limitations in their sexual function and reproductive life.

Case-Finding for Persistent Airway Obstruction in Farmers: A Questionnaire With Optimal Diagnosis Criteria.

INTRODUCTION: Appropriate identification of subjects who are candidates for spirometry through case-finding questionnaires may help solve the problem of chronic obstructive pulmonary disease misdiagnosis. The performance of case-finding questionnaires depends at least partially on the characteristics of the population used for their development. The use of an accurate threshold for the forced expiratory volume in 1 second / forced vital capacity ratio to define persistent airway obstruction is also vital in ascertaining chronic obstructive pulmonary disease. METHODS: Using a population examined between October 2012 and May 2013 that included a large subset of agricultural workers both exposed and unexposed to tobacco smoking, the authors aimed to select a combination of items that would identify persons most likely to have persistent airway obstruction defined as forced expiratory volume in 1 second / forced vital capacity less than the lower limit of normal according to the Global Lung Initiative-2012 equations. Two thirds of the population (n=3,397) were randomly selected to develop a questionnaire, and one third (n=1,698) was reserved for questionnaire validation. Statistical analysis was performed in 2016. RESULTS: The selected items were sex, dyspnea, BMI, tobacco smoking habits, age, history of respiratory diseases, and history of occupation at risk. The C-index of the model was 0.84 (95% CI=0.80, 0.88) for the development population and 0.76 (95% CI=0.66, 0.86) for the validation population. Using the selected items in combination, the sensitivity and specificity in identifying persistent airway obstruction were 76% and 77%, respectively, in the development population (and 68% and 73%, respectively, in the validation population) for a threshold value of 2.50%. CONCLUSIONS: This seven-item questionnaire is the first developed from a population comprising a large subset of agricultural workers and using the Global Lung Initiative-2012 equations.

[Vulvar lichen planus in children]. / Lichen plan vulvaire chez l'enfant.

BACKGROUND: Lichen planus is less common in children about in adults and mostly affects the skin. CASE REPORT: A 9-year-old girl was referred for a purplish blue and violaceous, unilateral and asymptomatic vulvar lesion noted 4 months earlier and stable. Histopathologic examination showed typical features of lichen planus. She responded well and rapidly with topical steroids. DISCUSSION: We report the first case of vulvar lichen planus in a little girl. Mucosal involvement is uncommon in children with lichen planus and genital localisation is extremely rare. Vulvar lichen sclerosis is the principal differential diagnosis. The risk of vulvar synechia and development of vulvar carcinomas warrants regular long-term follow-up.

Effect of hypothalamic and pituitary irradiation on pubertal development in children with cranial tumors.

The purpose of the present study was to report on gonadotropin function and puberty of a large group of children treated by cranial irradiation for cranial and neck tumors and medulloblastoma. Forty-five children of pubertal age were investigated. The mean interval time since radiation was 5 2/12 yr. Gonadotropin and gonadal function were evaluated by clinical criteria, plasma sex steroids, and plasma LH and FSH responses to LRH. Puberty was complete or progressing normally in 31 cases and was abnormal in 14 cases. Severe gonadotropin deficiency, with lack of or slow progression of puberty and decreased LH and FSH responsiveness to LRH, was observed in 5 cases; 2 of these had moderately elevated plasma PRL levels. Secondary amenorrhea or lack of pubertal progression was found in 5 other cases. GH deficiency was associated with gonadotropin deficiency in 9 of these 10 cases. Adrenal function, estimated by basal dehydroisoepiandrosterone, dehydroisoepiandrosterone sulfate, and estrone, was normal according to pubic hair stages. In conclusion, complete or partial gonadotropin deficiency can be the consequence of cranial irradiation in children receiving 6000 rads or less. It is usually associated with GH deficiency. The site of the damage on the pituitary gland or the hypothalamus remains to be demonstrated.

Ovarian function after bone marrow transplantation during childhood.

Ovarian failure is often brought about by the conditioning protocol used for bone marrow transplantation (BMT). We monitored ovarian function in 31 girls conditioned for BMT at 10.3 +/- 0.6 (s.e., 3.2-17.5) years by chemotherapy alone (group 1, n = 8) or chemotherapy plus body irradiation (12 Gy, fractionated in group 2, n = 9, or 10 Gy single total body in group 3, n = 7, and 5 or 6 Gy single thoraco-abdominal in group 4, n = 7, irradiation) at 13.4 +/- 0.4 (11.7-18.6) years. Breast development was normal (n = 11), did not occur (n = 14), or did not progress spontaneously (n = 2) after BMT. The other four girls who menstruated before BMT had permanent amenorrhea. Basal plasma gonadotropin concentrations were measured in 29; follicle-stimulating hormone was increased in them all and luteinizing hormone in 23. At the last clinical evaluation at 16.3 +/- 0.4 (12.1-21.6) years, 23 girls had complete ovarian failure, two had partial ovarian failure, and six had normal ovarian function. Three of these were the youngest group 1 patients and those who had not received busulfan. We conclude that conditioning for BMT given during childhood frequently prevents normal estrogen secretion at puberty. Adequate substitutive treatment may be necessary to induce growth acceleration and sexual development.

Factors affecting gonadal function after bone marrow transplantation during childhood.

Conditioning for bone marrow transplantation (BMT) may alter viability of germ cells and production of gonadal hormones. We analyzed the risk factors for gonadal failure after 12 Gy total body irradiation (TBI) given as six fractions (n = 31, group 1), 10 Gy (one dose) TBI (n = 20, group 2), 6 Gy (one dose) total lymphoid irradiation (TLI, n = 17, group 3) and chemotherapy alone (n = 7, group 4), given at 7.7 +/- 0.4 (0.6-13.6) years. Among the 34 girls, seven (20.6%) had normal ovarian function with regular spontaneous menstruation and normal plasma follicle-stimulating (FSH) and luteinizing (LH) hormones, five (14.7%) had partial ovarian failure with regular menstruation but increased FSH and/or LH, and 22 (64.7%) had complete ovarian failure. The 24 girls with chronological and bone ages >13 years included similar percentages, with increased FSH or LH in all four groups. There was a positive correlation between age at BMT and FSH (r = 0.54, P < 0.01), but not with lh, and between fsh and lh (r = 0.8, P = 0.0003). Plasma FSH concentrations had returned to normal spontaneously in six cases, and those of LH in two cases. Among the 41 boys, 16 (39%) had normal testicular function and 25 (61%) had tubular failure and increased FSH. Of these, 10 also had Leydig cell failure (three complete and seven partial). The 18 boys with chronological and bone ages >15 years included similar percentages with increased FSH or LH in groups 1 to 3, and testicular volume was significantly lower in group 2 than in group 3 (P = 0.008). There was no correlation between age at BMT and FSH, LH or testosterone, but there was a negative correlation between FSH and inhibin B (rho = -0.87, P < 0.003). we conclude that girls are more likely to suffer ovarian failure the older they are at bmt, and that early ovarian recovery is possible. the negative correlation between fsh and inhibin b in boys suggests that this parameter is an additional indicator of tubular function.

Pubertal metrorrhagia.

OBJECTIVE: To determine the clinical characteristics of pubertal metrorrhagia and its treatment, depending on severity; to evaluate the frequency of etiologies and the influence of hemostatic abnormalities; and to describe severe pubertal metrorrhagia. Design, setting and participants. This retrospective study examined all the files (n = 105) of adolescents presenting for pediatric gynecology consultation at a children's hospital between January 1979 and June 1993. RESULTS: The mean age of patients at the first consultation was 13 years. Metrorrhagia began in the year after the first menstrual period in 85% of cases. The causes were functional (83 cases), primary hemostatic disorder (14 cases), hemostatic disorder secondary to renal or hepatic disease (7 cases), or tumor (1 case). The cases were assigned to one of three groups, according to the severity of anemia; group I, mild anemia, hemoglobin Hb > 11 g%, 64 cases; group II, moderate anemia, Hb 8-11 g%, 23 cases; and group III, severe anemia, Hb < 8 g%, 18 cases. Of the 14 patients suffering from primary hemostatic disorders, 7 had been diagnosed before the onset of metrorrhagia; the disorder was revealed by the metrorrhagia in the remaining 7. Only 1 of these patients was severely anemic (known factor X deficiency). Four patients suffering from moderate von Willebrand's disease were discovered after specific tests; they were mildly or moderately anemic. The severe anemias (group III) all occurred during the first three periods. This group had functional disorders in 15 of 18 cases. Treatment continued to be required in 10 of 18 cases followed for more than 3 years. Treatment was progestin for group I and II patients or an estroprogestin, followed by a progestin, for group III. Curettage was never required. CONCLUSIONS: The most common cause of pubertal metrorrhagia is a functional disorder (80% of cases). Hemostatic disorders likely to cause severe menstrual hemorrhage were known before the age of menarche; these disorders must be controlled by hormone treatment begun before or at the time of the first menstrual period. Severe forms that arise during the initial three menstrual cycles are functional in most cases. These should be given a course of treatment lasting several years. There is a high risk of recurrence. Treatment is medical and hormonal in all cases.

[Menstrual cycle disorders in adolescents]. / Les troubles du cycle menstruel de l'adolescente.

Long cycles and excessive uterine bleeding are the most common menstrual disorders in adolescents. Long cycles usually result from a benign transitory functional disorder which spontaneously resolves within two to three years after menarche; however, this diagnosis can only be retained in the absence of hirsutism or galactorrhea as revealing symptoms of functional ovarian hyperandrogenism, polycystic ovary syndrome, late form of congenital adrenal hyperplasia or hyperprolactinemia; ovarian failure will be considered in case of isolated long cycles persisting more than two years after menarche. Excessive uterine bleeding usually occurs early after menarche. Although the main cause is functional, resulting from anovulation and the related absence of progesterone, coagulation disorders must always be excluded. Management of these disorders are described.

[Primary amenorrhea revealing congenital hydrocephalus]. / Aménorrhée primaire révélant une hydrocéphalie congénitale.

UNLABELLED: Among the various endocrine manifestations of chronic hydrocephaly, amenorrhea is not exceptional, whereas late puberty and obesity are the most frequent. The hypothalamic gonadotropic function usually returns to normal within the few months following the ventricular shunt. CASE REPORT: A 16 year-old girl, with a von Recklinghausen's disease, developed amenorrhea 2 years after the onset of puberty. X-rays of her skull showed an enlarged sella turcica and a diagnosis of hydrocephalus due to aqueductal stenosis was finally made. As her head circumference was retrospectively shown at +3 SD as early as the first month of life, the stenosis was certainly congenital, a feature known to occur in 2% of patients with von-Recklinghausen's disease. CONCLUSION: In symptomatic forms of aqueductal stenosis, the preferred surgical procedure is ventriculocisternostomy under endoscopy. Recovery of intellectual functions is often incomplete. Early diagnosis of hydrocephalus is of paramount importance; ultrasonography through anterior fontanel should be proposed to any infant with head circumference reaching +3 SD.

[Genital bleeding secondary to chemotherapy in adolescent girls]. / Métrorragies de l'adolescente au cours des chimiothérapies responsables de thrombopénies sévères.

UNLABELLED: Severe genital bleeding during adolescence can occur in the event of thrombocytopenia related to chemotherapy. Preventive hormonal treatment to induce therapeutic amenorrhea is recommended by some clinicians. Nevertheless, the adverse effects of oestroprogestative treatment, such as thromboembolic risk or hepatic toxicity, could potentialize the adverse effects of some chemotherapies. AIM OF THE STUDY: To assess retrospectively the risk of genital bleeding associated with thrombocytopenia secondary to chemotherapy in a population of adolescent girls for whom therapeutic amenorrhea was induced or not. PATIENTS AND METHODS: Among 140 girls, 12 to 18 years old, who were subjected to chemotherapy between 1991 and 1998, 24 girls presented at least one thrombocytopenic event (platelet level < 20 x 10(9) l(-1)) and were included. RESULTS: Six out of 24 adolescent girls received hormonal therapy to induce amenorrhea. Only one bleeding event was observed, in a girl who had not received preventive oestroprogestative treatment. Vital prognosis was preserved. Furthermore, spontaneous amenorrhea occurring before chemotherapy was observed in 33% of the patients and permanent secondary ovarian insufficiency in 17% of the patients. CONCLUSION: The risk of genital bleeding among adolescent population at risk of chemotherapy-induced thrombocytopenia is low. The high frequency of amenorrhea, secondary to weight loss or to chemotherapy toxicity, should raise questions as to the usefulness of preventive oestroprogestative treatment.

[Precocious puberty. Comment on the diagnostic conditions and etiological aspects]. / Pubertés précoces. Réflexion sur les conditions de diagnostic et les aspects étiologiques.

The present review is based on the retrospective study of 124 children with precocious puberty, 92 girls and 32 boys. In girls, the analysis of the clinical initial presentation has shown that premature pubarche (n = 18), premature adrenarche (n = 2) or isolated menstruations (n = 3) must be ruled out, as these symptoms can remain isolated for more than a year. However, in most cases the presence of growth acceleration and vaginal estrogenisation was of major diagnostic value. Bone maturation, although generally accelerated, can be normal in recently developed puberty. Precocious puberty may proceed by steps, with complete disappearance of physical signs in the intervals. Organic causes were found in 31% of the girls, and 44% of the boys with some characteristic features as rapid progression, and elevated LH response to LRF stimulation. Main causes were glioma of the optic chiasma (n = 11), 3rd ventricule invasive tumors, hamartoma (n = 8). The latter should be looked for by a non invasive procedure as the CT scan. In girls, precocious puberty with very high circulating estrogen levels was observed as part of a McCune-Albright syndrome. As the effect of precocious puberty on the final adult height is variable, the evaluation of therapeutic results remains uncertain. Medroxyprogesterone as well cyproterone acetate have not been fully efficient in controlling bone maturation. More recently, and still controversial, the treatment with long acting LRF analogues might provide a more satisfactory statural prognosis.

[Study of sex determination gene (SRY) in 46,XY gonadal dysgenesis]. / Etude du gène du déterminisme du sexe (SRY) dans les dysgénésies gonadiques 46,XY.

During mammalian embryogenesis, the presence of the SRY gene determines the bipotential gonad to develop as a testis. 46,XY sex reversal has been described in man. It is associated with an essentially female phenotype and a streak gonad. In a collaborative study, we analysed 36 patients with a 46,XY sex reversal. The testis determining region of the Y chromosome was analysed by Southern blotting and by DGGE analysis of the SRY open reading frame (orf). We found a total of 7 mutations in the testis determining region including the SRY gene. This brings to 19 the total number of mutations in SRY associated with sex reversal. No relationship was found between the SRY status and the presence or absence of gonadoblastoma. However, a correlation was observed between the SRY genotype and the histology of the gonad. A mutant in SRY is associated with a completely dysgenetic gonad. The presence of immature testicular tubules is usually observed when SRY is normal. These latter results suggest the existence of as yet unidentified testis determining genes.