Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. HYPOTHESIS: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. DESIGN: Cross-sectional study. SETTING: University Research Laboratory. SUBJECTS: 158 patients with nHH/KS. METHODS: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. MAIN OUTCOME MEASURES: P/LP variants in nHH/KS genes. RESULTS: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. CONCLUSION: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.

Perplexing findings during laparoscopic evaluation for tubal factor infertility resulting from a gastric leak after bariatric surgery: A case report.

Tubal factor is the primary type of female infertility, accounting for 25-35% of cases. Common causes include inflammation due to pelvic inflammatory disease, septic abortion, tubal surgery, and surgical adhesions. Bariatric surgery is becoming increasingly popular as rates of obesity rise, with over 256,000 surgeries performed in 2019. Half of these procedures were performed on women of reproductive age. This is the first reported case of a patient with tubal factor infertility as a result of a gastric leak from a remote sleeve gastrectomy that led to extensive abdominal and pelvic adhesions.

Genetics of hypogonadotropic Hypogonadism-Human and mouse genes, inheritance, oligogenicity, and genetic counseling.

Hypogonadotropic hypogonadism, which may be normosmic (nHH) or anosmic/hyposmic, known as Kallmann syndrome (KS), is due to gonadotropin-releasing hormone deficiency, which results in absent puberty and infertility. Investigation of the genetic basis of nHH/KS over the past 35 years has yielded a substantial increase in our understanding, as variants in 44 genes in OMIM account for ~50% of cases. The first genes for KS (ANOS1) and nHH (GNRHR) were followed by the discovery that FGFR1 variants may cause either nHH or KS. Associated anomalies include midline facial defects, neurologic deficits, cardiac anomalies, and renal agenesis, among others. Mouse models for all but one gene (ANOS1) generally support findings in humans. About half of the known genes implicated in nHH/KS are inherited as autosomal dominant and half are autosomal recessive, whereas only 7% are X-linked recessive. Digenic and oligogenic inheritance has been reported in 2-20% of patients, most commonly with variants in genes that may result in either nHH or KS inherited in an autosomal dominant fashion. In vitro analyses have only been conducted for both gene variants in eight cases and for one gene variant in 20 cases. Rigorous confirmation that two gene variants in the same individual cause the nHH/KS phenotype is lacking for most. Clinical diagnosis is probably best accomplished by targeted next generation sequencing of the known candidate genes with confirmation by Sanger sequencing. Elucidation of the genetic basis of nHH/KS has resulted in an enhanced understanding of this disorder, as well as normal puberty, which makes genetic diagnosis clinically relevant.

Decreasing use of epidural analgesia with increasing minimally invasive lobectomy: Impact on postoperative morbidity.

OBJECTIVE: The goal of this study is to investigate the use of EA and its impact on the postoperative short-term outcomes of patients with non-small cell lung cancer (NSCLC) who received a lobectomy by either minimally invasive surgery (MIS) or thoracotomy. MATERIALS AND METHODS: We investigated 793 patients who underwent lobectomy for pathological stage I-III NSCLC without induction therapy during two time periods, an early-time period (2009-2010: MIS, n = 204 [53%]; and thoracotomy, n = 182 [47%]) and a late-period (2014-2015: MIS, n = 308 [76%]; and thoracotomy, n = 99 [24%]). Patient characteristics, including pulmonary function tests, comorbidities, and use of EA, as well as short-term outcomes, including length of stay, morbidity, and mortality were assessed and compared between early-and late-time periods. We also compared patients who received EA (n = 150) with patients who did not receive EA (n = 158) following MIS lobectomy in the late-time period. RESULTS: The use of MIS lobectomy increased during the late-time period compared to the early-time period (p < 0.001). In patients who underwent MIS lobectomy, the use of EA significantly decreased in the late-time period compared to the early-time period (2009-2010 vs. 2014-2015, 95% vs. 51%; p < 0.001). There was no difference in postoperative morbidity and mortality between the two time periods in both MIS and thoracotomy. In the late-time period MIS group, the length of stay in the no EA group (n = 150) was shorter than that in the EA group (n = 158) (3 vs. 4 days, p = 0.038). There was no difference in morbidity and mortality between the EA and no EA groups. CONCLUSION: In our study cohort, the observed decrease in the use of EA with the increasing rate of MIS lobectomy did not negatively affect postoperative short-term outcomes.