Detailed clinical and radiological features of the first patient with Elsahy-Waters syndrome in East Asia.

Elsahy-Waters syndrome (EWS; OMIM#211380) is a rare autosomal recessive disorder that is caused by loss-of-function variants in CDH11, which encodes cadherin 11. EWS is characterized by brachycephaly, midface hypoplasia, characteristic craniofacial morphology, cervical fusion, cutaneous syndactyly in 2-3 digits, genitourinary anomalies, and intellectual disability. To the best of our knowledge, there have been only six patients of molecularly confirmed EWS. We report the first patient of EWS in East Asia in a Japanese man with a novel splice site homozygous variant of CDH11. We reviewed the clinical and molecular findings in previously reported individuals and the present patient. In addition to the previously reported clinical features of EWS, the present patient had unreported findings of atlantoaxial instability due to posterior displacement of dens, thoracic fusion, thoracic butterfly vertebra, sacralization of the lumbar vertebra (L5), and multiple perineural cysts. The spinal findings in this patient could represent a new spectrum of skeletal phenotypes of EWS. It remains to be clarified whether the multiple perineural cysts in the patient were associated with EWS or coincidental. The current observation might contribute to an expanded understanding of the clinical consequences of loss-of-function of cadherin 11.

Reproductive aging and telomeres: Are women and men equally affected?

Successful reproduction is very important for individuals and for society. Currently, the human health span and lifespan are the object of intense and productive investigation with great achievements, compared to the last century. However, reproduction span does not progress concomitantly with lifespan. Reproductive organs age, decreasing the levels of sexual hormones, which are protectors of health through their action on several organs of the body. Thus, this is the starting point of the organismal decay and infertility. This starting point is easily detected in women. In men, it goes under the surface, undetected, but it goes, nevertheless. Regarding fertility, aging alters the hormonal equilibrium, decreases the potential of reproductive organs, diminishes the quality of the gametes and worsen the reproductive outcomes. All these events happen at a different pace and affecting different organs in women and men. The question is what molecular pathways are involved in reproductive aging and if there is a possible halting or even reversion of the aging events. Answers to all these points will be explained in the present review.

Photo-pollution disrupts reproductive homeostasis in female rats: The duration-dependent role of selenium administrations.

Although selenium is known to be essential for reproductive function, studies have indicated the adverse effect with its prolonged use. The present study investigated the duration-related effect of selenium administrations on reproductive hormones and estrous cycle indices in adult female Wistar rats exposed to a model of light pollution using altered photoperiod (AP). Ninety-six cyclic female Wistar rats displaying 4-5 days' estrous cycle length (ECL) and weighing 148-152 g were randomly divided into short and long experimental cohorts consisting of six groups each and spanning for 1 and 8 weeks, respectively. Each consisted of control, high selenium dose (HSE), low selenium dose (LSE), AP, AP + HSE, and AP + LSE. The rats were orally administered high dose (150 µg/kg) and low dose (100 µg/kg) of sodium selenite once per day. The estrous cycle indices were monitored. Plasma levels of follicle-stimulating hormone, luteinizing hormone (LH), estradiol (E), progesterone (P), prolactin, E/P ratio, and histology of ovary and uterine horn were evaluated. The statistical analysis was performed using Statistical Package for the Social Sciences. In AP rats, HSE and LSE caused no significant effect on LH, E, P, and E/P ratio, ECL, estrus interval (EI), and estrous cycle ratio (ECR). The effect of HSE and LSE on LH, E, P, E/P ratio, and ECL showed no duration-dependent increase, but there was a duration-dependent increase in EI and ECR at low dose. The study indicated that administration of HSE of selenium improved reproductive function in photo-pollution-exposed rats irrespective of the duration of treatment.

Chronic exposure to paroxetine or bupropion modulates the pubertal maturation and the reproductive system in female rats.

Antidepressant drugs are globally used to treat several psychiatric disorders in pediatric patients and their prescription has continued to increase in recent years, especially among girls. In addition to its well-known metabolic and gastrointestinal side effects, antidepressants can cause sexual dysfunction in adults. However, the effects of the antidepressants on puberty onset and reproductive system remain unclear in children and adolescents. Therefore, the goal of this study is to examine the effects of chronic postnatal antidepressant drugs, paroxetine or bupropion, treatments on puberty onset and reproductive system components in female rats weaned at postnatal day (PND) 21. Female rats (n = 10 for each group) were exposed to vehicle (0.2 mL of saline), paroxetine (3.6 mg/kg in 0.2 mL of saline) or bupropion (17 mg/kg in 0.2 mL of saline) daily by oral gavage from the PND 21 to PND 90-93. Chronic paroxetine or bupropion treatments advanced the puberty onset, but the difference was statistically significant in only the paroxetine group. The exposure to bupropion significantly decreased the serum anti-Müllerian hormone (AMH) levels and luteinizing hormone (LH) levels. There were increases in serum estradiol levels by both antidepressant treatments and the significance was found in only the paroxetine group. Consistent with these results, histopathologic changes were observed in the ovary and uterus tissues taken from both antidepressant-treated rats. The obtained results of chronic postnatal exposure to paroxetine or bupropion may change the timing of puberty onset and lead to disruption of reproductive functions in females.

Maternal Testosterone Excess Contributes to Reproductive System Dysfunction of Female Offspring Mice.

Hyperandrogenism is considered 1 of the most important characteristics of polycystic ovary syndrome, which affects more than 10% of females of reproductive age and is a common cause of infertility. In addition to the effects on patients themselves, maternal androgen excess has also been reported to impair the growth and development of offspring. In our current study, we found that maternal testosterone (T) treatment during different gestational stages increased the percentage of atretic follicle and decreased corpus luteum formation in female offspring. In addition, decreased serum estradiol and increased T levels were also observed in female offspring of T-treated mice during late gestational stage. Further studies revealed that Forkhead box protein L2 (FOXL2) and Cytochrome P450 family 19 subfamily a member 1 (CYP19A1) expression in granulosa cells of these female offspring mice were decreased. By using mouse primary granulosa cells and the KGN cell line, we demonstrated that decreasing FOXL2 and CYP19A1 levels in ovarian granulosa cells partially may contribute to disturbed sex hormone synthesis in female offspring of T-treated mice during the late gestational stage. Findings from our current study highlight a critical role of excess maternal T exposure, especially during the late gestational stage, which could further lead to aberrant ovary development and sex hormone synthesis in female offspring.

Hypogonadism in Pediatric Health: Adult Medicine Concepts Fail.

The classical definition of hypogonadism, used in adult medicine, as gonadal failure resulting in deficient steroid and gamete production, and its classification into hypergonadotropic and hypogonadotropic refer to primary gonadal and hypothalamic-pituitary disorders respectively and may lead to under- or misdiagnosis in pediatrics. Indeed, in children with primary gonadal failure, gonadotropin levels may be within the reference range for age. Conversely, since gonadotropins and steroids are normally low during childhood, it may prove impossible to show the existence of a hypogonadotropic state before pubertal age. Anti-Müllerian hormone (AMH) and inhibin B arise as more adequate biomarkers to assess gonadal function and increase the possibility of making an earlier diagnosis of hypogonadism in children, which may positively impact on timely management.

Síndrome de ovarios poliquísticos. Entidad que demanda diagnóstico temprano / Polycystic ovary syndrome, an entity demanding an early diagnosis

RESUMEN El síndrome de ovario poliquístico se ha convertido en un problema de salud pública, siendo el más común de los desórdenes endocrinos en mujeres en edad reproductiva con estudios que reportan una prevalencia de hasta un 21%. El diagnóstico de esta entidad es importante debido a que representa riesgos metabólicos, cardiovasculares y afecta la capacidad reproductiva de estas pacientes. Se realizó una revisión bibliográfica de los principales artículos relacionados sobre el tema, resumiendo los aspectos fundamentales de este problema de salud.

ABSTRACT Polycystic ovary syndrome has become a public health problem, being the most common of the endocrine disorders in reproductive-age women, with studies reporting prevalence by 21 %. The diagnosis of this entity is important because it represents metabolic and cardiovascular risk, and affects the reproductive capacity of these patients. The authors carried out bibliographic review of the main articles related with the theme, summarizing the basic aspects of this health problem.

Síndrome de ovarios poliquísticos. Entidad que demanda diagnóstico temprano / Polycystic ovary syndrome, an entity demanding an early diagnosis

RESUMEN El síndrome de ovario poliquístico se ha convertido en un problema de salud pública, siendo el más común de los desórdenes endocrinos en mujeres en edad reproductiva con estudios que reportan una prevalencia de hasta un 21%. El diagnóstico de esta entidad es importante debido a que representa riesgos metabólicos, cardiovasculares y afecta la capacidad reproductiva de estas pacientes. Se realizó una revisión bibliográfica de los principales artículos relacionados sobre el tema, resumiendo los aspectos fundamentales de este problema de salud (AU).

ABSTRACT Polycystic ovary syndrome has become a public health problem, being the most common of the endocrine disorders in reproductive-age women, with studies reporting prevalence by 21 %. The diagnosis of this entity is important because it represents metabolic and cardiovascular risk, and affects the reproductive capacity of these patients. The authors carried out bibliographic review of the main articles related with the theme, summarizing the basic aspects of this health problem (AU).

Prepubertal Genital Bleeding: Examination and Differential Diagnosis in Pediatric Female Patients.

BACKGROUND: Prepubertal genital bleeding can be caused by a variety of etiologies including trauma, infection, structural, hematologic disorders, precocious puberty, and malignancy. Urethral prolapse can be seen in prepubescent girls due to a relative estrogen deficiency. Urethral prolapse classically presents with urethral mass and vaginal bleeding, often associated with constipation. CASE REPORT: A healthy 6-year-old White girl presented to the Pediatric Emergency Department (ED) with vaginal bleeding for 1 day preceded by a few months of constipation. In the ED the patient's physical examination was remarkable for a tender, nonmobile mass at the vaginal introitus. Transabdominal pelvic and renal ultrasounds were unremarkable. The emergency physician's working diagnosis was a vaginal mass concerning for sarcoma botryoides. Pediatric and Adolescent Gynecology (PAG) was consulted. They performed an examination under anesthesia (EUA) with cystoscopy and vaginoscopy. The EUA confirmed a urethral prolapse approximately 2 cm in diameter. The patient was treated with conjugated estrogen vaginal cream. At her 1-month follow-up, the urethral prolapse had resolved. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Performing a proper pelvic examination of a prepubescent girl presenting with vulvovaginal bleeding is crucial to form an accurate diagnosis in the ED setting. By placing the young girl in the frog-leg or knee-chest position and using both lateral and downward traction of the vulva, one can adequately visualize the external genitalia and outer 1/3 of the vagina. This can help streamline diagnosis and avoid unnecessary examinations and anxiety.

[Pathophysiological aspects of neuro-endocrine regulation system in patients with obstructive sleep apnea syndrome]. / Patofiziologicheskie aspekty funktsionirovaniia sistemy neiroéndokrinnoi reguliatsii pri sindrome obstruktivnogo apnoé sna.

AIM: To reveal the changes in the pituitary-thyroid, pituitary-gonadal, adrenal components and in the prolactinergic system of neuroendocrine regulation in patients with severe obstructive sleep apnea syndrome (OSAS). MATERIAL AND METHODS: The study involved 51 men aged 46-55 years. The main group (BG) included 37 patients with severe OSAS. The duration of clinical manifestations of OSAS was 10.5±1.5 years. OSAS was verified on the basis of clinical and functional studies and polysomnographic monitoring in accordance with the AASM criteria (2014). The control group (CG) consisted of 14 age-matched men without sleep-disordered breathing. The body mass index in BG was 34.2±1.8 compared to 28.2±2.1 kg/m2 in CG. Serum concentrations of thyroid-stimulating hormone (TTG), free thyroxine (T4), triiodothyronine (T3), cortisol, prolactin, testosterone, luteonizing (LH) and follicle-stimulating (FSH) hormones were determined by the immunoradiological method using the standard DIA test system (Russia) and the analyzer 'Immunotest-800'. RESULTS: Patients with severe OSAS had decreased concentration of free thyroxine (T4) and decreased activity of thyroid stimulating hormone (TSH) (р<0.001), increased concentration of prolactin and cortisol (р<0.001), decreased concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone compared to the controls (р<0.001). CONCLUSION: The changes in the hypothalamic-pituitary-gonadal system are a manifestation of disturbances of the mechanisms of self-regulation and compensation that indicates the presence of maladaptive reactions of the neuroendocrine system.

[Prevalence of reproductive system diseases among female workers in a city and related occupational influencing factors: an analysis of 9944 cases].

Objective: To investigate the prevalence of reproductive system diseases among female workers in a city and related occupational influencing factors. Methods: From June to September, 2016, a cross-sectional survey was used to select 9 944 female workers from six districts of Beijing and then a face-to-face questionnaire survey was performed. Univariate analysis using chi-square test and multivariate logistic regression analysis were used to investigate the risk factors for reproductive system diseases. Results: The age of 9944 female workers ranged from 18 to 65 years (mean 35.53±9.52 years) , and among them, 7 351 (73.92%) were married. The overall prevalence rate of reproductive system diseases among these 9944 female workers during the past three months was 28.29%, and the prevalence rates of hyperplasia of mammary glands, vaginitis, and hysteromyoma were 15.54%, 11.25%, and 6.77%, respectively. After adjustment for age, marital status, education level, and annual family income, the multivariate logistic regression analysis showed that frequent overtime work (odds ratio[OR]=1.119, 95% confidence interval[CI]: 1.070-1.343) , frequent night shifts (OR=1.198, 95%CI: 1.054-1.361) , standing for a long time (OR=1.197, 95%CI: 1.063-1.347) , sitting for a long time (OR=1.327, 95%CI: 1.191-1.479) , heavy workload (OR=1.429, 95%CI: 1.262-1.615) , exposure to lead (OR=1.696, 95%CI: 1.307-2.201) , exposure to mercury (OR=1.452, 95%CI: 1.086-1.940) , and exposure to ionizing radiation (OR=1.679, 95%CI: 1.424-1.980) were associated with reproductive system diseases. Conclusion: The prevalence of reproductive system diseases among female workers in Beijing is not optimistic. Reproductive system diseases are associated with frequent overtime work, frequent night shifts, standing for a long time, sitting for a long time, heavy workload, and exposure to lead, mercury, and ionizing radiation.

Genital ulcers as diagnostic clue for acute myeloid leukaemia.

Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions.

Genital automatisms: Reappraisal of a remarkable but ignored symptom of focal seizures.

OBJECTIVES: Genital automatisms (GAs) are uncommon clinical phenomena of focal seizures. They are defined as repeated fondling, grabbing, or scratching of the genitals. The aim of this study was to determine the lateralizing and localizing value and associated clinical characteristics of GAs. METHODS: Three hundred thirteen consecutive patients with drug-resistant seizures who were referred to our tertiary center for presurgical evaluation between 2009 and 2016 were investigated. The incidence of specific kinds of behavior, clinical semiology, associated symptoms/signs with corresponding ictal electroencephalography (EEG) findings, and their potential role in seizure localization and lateralization were evaluated. RESULTS: Fifteen (4.8%) of 313 patients had GAs. Genital automatisms were identified in 19 (16.4%) of a total 116 seizures. Genital automatisms were observed to occur more often in men than in women (M/F: 10/5). Nine of fifteen patients (60%) had temporal lobe epilepsy (right/left: 4/5) and three (20%) had frontal lobe epilepsy (right/left: 1/2), whereas the remaining two patients could not be classified. One patient was diagnosed as having Rasmussen encephalitis. Genital automatisms were ipsilateral to epileptic focus in 12 patients and contralateral in only one patient according to ictal-interictal EEG and neuroimaging findings. Epileptic focus could not be lateralized in the last 2 patients. Genital automatisms were associated with unilateral hand automatisms such as postictal nose wiping or manual automatisms in 13 (86.7%) of 15 and contralateral dystonia was seen in 6 patients. All patients had amnesia of the performance of GAs. CONCLUSION: Genital automatisms are more frequent in seizures originating from the temporal lobe, and they can also be seen in frontal lobe seizures. Genital automatisms seem to have a high lateralizing value to the ipsilateral hemisphere and are mostly concordant with other unilateral hand automatisms. Men exhibit GAs more often than women.

Elsahy-Waters syndrome is caused by biallelic mutations in CDH11.

Elsahy-Waters syndrome (EWS), also known as branchial-skeletal-genital syndrome, is a distinct dysmorphology syndrome characterized by facial asymmetry, broad forehead, marked hypertelorism with proptosis, short and broad nose, midface hypoplasia, intellectual disability, and hypospadias. We have recently published a homozygous potential loss of function variant in CDH11 in a boy with a striking resemblance to EWS. More recently, another homozygous truncating variant in CDH11 was reported in two siblings with suspected EWS. Here, we describe in detail the clinical phenotype of the original CDH11-related patient with EWS as well as a previously unreported EWS-affected girl who was also found to have a novel homozygous truncating variant in CDH11, which confirms that EWS is caused by biallelic CDH11 loss of function mutations. Clinical features in the four CDH11 mutation-positive individuals confirm the established core phenotype of EWS. Additionally, we identify upper eyelid coloboma as a new, though infrequent clinical feature. The pathomechanism underlying EWS remains unclear, although the limited phenotypic data on the Cdh11-/- mouse suggest that this is a potentially helpful model to explore the craniofacial and brain development in EWS-affected individuals.

Reproductive endocrine phenotypes relating to CHD7 mutations in humans.

Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ∼60-80% of cases) and represent the letter "G" in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH-synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is one of the constituent phenotypes within CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion.

Indocyanine Green Lymphographic and Lymphoscintigraphic Findings in Genital Lymphedema-Genital Pathway Score.

BACKGROUND: Although genital lymphedema is a challenging disease, its mechanism is unclear. The aim of this study was to identify the lymphatic flow in genital lymphedema and establish a suitable examination for genital lymphedema. METHODS: We injected phytic acid or albumin labeled with 99mTc at the bilateral first web spaces of the feet of 47 patients for lymphoscintigraphy. For indocyanine green (ICG) lymphography, we injected ICG into the first web spaces of both feet and other points if necessary. We established a genital pathway score (GPS). In GPS 0, there was no dermal backflow in genitalia. In GPS 1, dermal backflow was observed in the genitalia, but not in the groin. In GPS 2 and 3, splash pattern and stardust pattern were in the genitalia, respectively, with dermal backflow in the groin. RESULTS: Twenty-eight patients (59.6%) reported subjective symptoms of genital lymphedema. Accumulation of isotope in the genital region was observed on 32 sides (34.0%) in lymphoscintigraphy. On ICG lymphography, 37 sides were classified as GPS 0. Nine sides were GPS 1, which indicated that the lymphatic accumulation in the genitalia seemed to flow from the contralateral side. Twelve sides were GPS 2, and 36 were GPS 3. Dermal backflow was observed in 60.6% of patients. Chi-square tests showed a significant relationship between prior radiotherapy and the presence of genital lymphedema (p = 0.046). CONCLUSIONS: A pathway from the inguinal lymph nodes to the genital region was observed on lymphoscintigraphy in genital lymphedema. The sensitivity was greater with ICG lymphography than lymphoscintigraphy.