The genetic spectrum of a Chinese series of patients with 46, XY disorders of the sex development.

PURPOSE: The etiology of 46, XY disorders of sex development (46, XY DSD) is complex, and studies have shown that different series of patients with 46, XY DSD has different genetic spectrum. In this study, we aimed to investigate the underlying genetic etiology in a Chinese series of patients with 46, XY DSD by whole exome sequencing (WES). METHODS: Seventy patients with 46, XY DSD were enrolled from the Peking Union Medical College Hospital (Beijing, China). The detailed clinical characteristics were evaluated, and peripheral blood was collected for WES to find the patients' rare variants (RVs) of genes related to 46, XY DSD. The clinical significance of the RVs was annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: A total of 57 RVs from nine genes were identified in 56 patients with 46, XY DSD, which include 21 novel RVs and 36 recurrent RVs. Based on the American ACMG guidelines, 43 variants were classified as pathogenic(P) or likely pathogenic (LP) variants and 14 variants were defined as variants of uncertain significance (VUS). P or LP variants were identified in 64.3% (45/70) patients of the series. Thirty-nine, 14, and 4 RVs were involved in the process of androgen synthesis and action, testicular determination and developmental process, and syndromic 46, XY DSD, respectively. The top three genes most frequently affected to cause 46, XY DSD were AR, SRD5A2, and NR5A1. Seven patients were found harboring RVs of the 46, XY DSD pathogenic genes identified in recent years, namely DHX37 in four patients, MYRF in two patients, and PPP2R3C in one patient. CONCLUSION: We identified 21 novel RVs of nine genes, which extended the genetic spectrum of 46, XY DSD pathogenic variants. Our study showed that 60% of the patients were caused by AR, SRD5A2 or NR5A1 P/LP variants. Therefore, polymerase chain reaction (PCR) amplification and Sanger sequencing of these three genes could be performed first to identify the pathogeny of the patients. For those patients whose pathogenic variants had not been found, whole-exome sequencing could be helpful in determining the etiology.

Pregnancy and Progression of Differentiated Thyroid Cancer: A Propensity Score-Matched Retrospective Cohort Study.

CONTEXT AND OBJECTIVE: Differentiated thyroid cancer (DTC) is very common in women of reproductive age. However, it remains unclear whether pregnancy is associated with DTC progression before surgical treatment. METHODS: This retrospective cohort study, conducted at the Peking University Third Hospital in Beijing, China between January 2012 and December 2022, included 311 eligible women aged 20 to 45 years. To control for potential confounders, we first used propensity score matching (PSM) to match the pregnant group (n = 48) with the nonpregnant group (n = 154) on age, tumor size, tumor type, and Hashimoto's thyroiditis status at baseline, and then used Cox proportional risk models stratified by the matched pairs to estimate the association of pregnancy with DTC progression. RESULTS: After PSM, the pregnant and nonpregnant groups were well comparable at baseline (standardized difference < 10% and P > .05). Over an average observation period of 2.5 years, we observed no difference between the pregnant group and the matched nonpregnant group in DTC progression-free survival (hazard ratio [HR] = 0.96; 95% CI, 0.56 to 1.65; P = .895), tumor enlargement-free survival (HR = 0.99; 95% CI, 0.56 to 1.76; P = .969) or lymph node metastasis-free survival (LNM) (HR = 0.67; 95% CI, 0.21 to 2.13; P = .498). The postoperative pathological characteristics also showed no significant difference between the pregnant and nonpregnant groups (P > .05). CONCLUSION: Pregnancy seemed to be irrelevant to DTC progression-free survival before surgical treatment. Further prospective cohort studies are needed to translate this finding into clinical practice.

Mixed hypogonadism: a neglected combined form of hypogonadism.

PURPOSE: Kallmann syndrome is a rare disease characterized by delayed puberty, infertility and anosmia. We report the clinical and genetic characteristics of three patients with Kallmann syndrome who presented with Klinefelter syndrome and defined this neglected combined form of hypogonadism as mixed hypogonadism. METHODS: Clinical data and examinations were obtained, including laboratory examination and magnetic resonance imagination (MRI) of the olfactory structures. Congenital hypogonadotropic hypogonadism (CHH) related genes were screened by next generation sequencing (NGS). RESULTS: Three patients with Kallmann syndrome were included. They had co-existence with Klinefelter syndrome and showed hypogonadotropic hypogonadism. Patient 1 was complicated with germinoma. CONCLUSION: Mixed hypogonadism was defined as hypogonadotropic hypogonadism in Klinefelter syndrome or primary testicular disease. Clinicians should be alert to mixed hypogonadism when spermatogenesis induction failed in patients with CHH or gonadotropin levels decrease in patients with Klinefelter syndrome.

Pulsatile Gonadotropin-Releasing Hormone Therapy Is Associated With Better Spermatogenic Outcomes than Gonadotropin Therapy in Patients With Pituitary Stalk Interruption Syndrome.

OBJECTIVE: To compare the effects of combined gonadotropin and pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis in patients with pituitary stalk interruption syndrome (PSIS). METHODS: Male patients with PSIS (N = 119) were retrospectively studied. Patients received pulsatile GnRH therapy (N = 59) were divided into response and poor-response groups based on luteinizing hormone (LH) levels after 1-month treatment with a cutoff value of 1 or 2 IU/L. Participants with gonadotropin therapy were divided into human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) group (N = 60), and patients with pulsatile GnRH therapy were classified into GnRH group (N = 28) with treatment duration ≥6 months. RESULTS: The overall success rates of spermatogenesis for hMG/hCG and GnRH therapy were 51.67% (31/60) vs 33.90% (20/59), respectively. GnRH group required a shorter period to induce spermatogenesis (8 vs 15 months, P = .019). hMG/hCG group had higher median total testosterone than GnRH group [2.16, interquartile range(IQR) 1.06-4.89 vs 1.31, IQR 0.21-2.26 ng/mL, P = .004]. GnRH therapy had a beneficial effect on spermatogenesis compared to hMG/hCG therapy (hazard ratio 1.97, 95% confidence interval 1.08-3.57, P = .026). In patients with pulsatile GnRH therapy, compared with the poor-response group, the response group had a higher successful spermatogenesis rate (5.00% vs 48.72%, P = .002) and higher median basal total testosterone (0.00, IQR 0.00-0.03 vs 0.04, IQR 0.00-0.16 ng/mL, P = .026) with LH = 1 IU/L as the cutoff value after 1-month pulsatile GnRH therapy. CONCLUSIONS: Pulsatile GnRH therapy was superior to hMG/hCG therapy for spermatogenesis in patients with PSIS. Earlier spermatogenesis and higher concentrations of sperm could be obtained in the GnRH group if patients received therapy over 6 months.

In vitro functional study of fifteen SRD5A2 variants found in Chinese patients and the relation between the SRD5A2 genotypes and phenotypes.

The 5α-reductase type 2 (5α-RD2) deficiency is one of the most common etiology of 46, XY disorders of sex development and is caused by pathogenic variants in SRD5A2. Massively parallel sequencing contributes to identification of numerous novel SRD5A2 variants, in vitro functional study could help to determine their pathogenicity. In this study, we aim to present the functional study of fifteen SRD5A2 variants found in Chinese patients and explore the genotype-phenotype association. We collected the clinical manifestation and genotype of 38 patients with 5α-RD2 deficiency who visited our center between 2009 and 2021. The pathogenicity of seven missense SRD5A2 variants, were predicted by in-silico tools. Furthermore, fifteen SRD5A2 variants without reported functional assay were studied in vitro to analyze the role of these variants in enzymatic activity. Twenty-four SRD5A2 rare variants were identified in 38 patients with 5α-RD2 deficiency. Fifteen variants without reported functional assay decreased the conversation of testosterone (T) to dihydrotestosterone(DHT) and caused the almost complete loss of enzyme activity (<8 %) in our in-vitro functional study. Thirty-eight patients with three different external genital phenotypes (complete female, clitoromegaly and hypospadias) were found to have same variants. Patients with different testicular position (scrotum/clitoris and cryptorchidism) were found to have same variants. Our study showed 15 SRD5A2 variants caused complete loss of 5α-RD2 enzyme activity by functional study. Patients with different clinical phenotypes can have the same genotypes and no obvious genotype-phenotype association exist in our series patients.

The Association of Pregnancy with Disease Progression in Patients Previously Treated for Differentiated Thyroid Cancer: A Propensity Score-Matched Retrospective Cohort Study.

Background: Differentiated thyroid cancer (DTC) is increasingly common in women of reproductive age. However, whether pregnancy increases the risk of DTC progression/recurrence after treatment remains controversial. The study aimed to assess the association of pregnancy with risk of progression in patients previously treated for DTC. Methods: This was a retrospective cohort study following 123 pregnant women and 1376 nonpregnant women at Peking University Third Hospital after initial treatment for DTC between January 2012 and December 2022. To control the effect of confounding, we carefully matched pregnancy (n = 107) and nonpregnancy groups (n = 298) in terms of baseline characteristics by using propensity score matching (PSM). Results: At baseline, the pregnancy and nonpregnancy groups were balanced in all matched variables. At follow-up, the percentage of DTC progression in the two groups was 12 (11.8%) and 47 (15.8%), respectively. Regression models showed no evidence of association of pregnancy with the risk of progression (odds ratio: 0.74 and 95% confidence interval: 0.37-1.50; p = 0.404), and remained consistent across long/short follow-up and other subgroup variables. We found that the shorter the time interval between treatment and pregnancy, the higher the risk of DTC progression (ptrend = 0.019). Conclusions: The risk of DTC progression in pregnant women was not higher than that in the well-matched, nonpregnant women. For young women previously treated for DTC, disease progression might not be a concern for their future pregnancy plan, but it seems safer to wait at least 1 year before pregnancy compared with immediate pregnancy.

Molecular analysis of 12 Chinese patients with 11ß-hydroxylase deficiency and in vitro functional study of 20 CYP11B1 missense variants.

Steroid 11ß-hydroxylase deficiency (11ß-OHD) is a rare autosomal recessive disorder caused by pathogenic variants of CYP11B1 gene. This study aimed to perform molecular analysis of a Chinese 11ß-OHD series and in vitro functional study of twenty CYP11B1 missense variants. Twelve Chinese patients with clinical diagnosis of 11ß-OHD were included in the study to analyze their molecular etiology. Genomic DNA of patients was extracted to be sequenced all coding exons and intronic flanking sequences of CYP11B1. Fourteen missense variants found in 12 patients mentioned above along with 6 missense variants previously reported by our team were evaluated functionally. Amino acid substitutions were analyzed with computational program to determine their effects on the three-dimensional structure of CYP11B1 protein. Clinical characteristics and hormone levels at baseline of the 18 patients carrying 18 missense variants aforementioned were recorded to perform genotype-phenotype correlation. A total of 21 rare variants including 9 novel and 12 recurrent ones were identified in 12 patients, out of which 17 were missense, 2 were nonsense, 1 was a splice site variant, and 1 was a deletion-insertion variant. Results of in vitro functional study revealed that 3 out of 20 missense mutants (p.Leu3Pro, p.Gly267Ser, and p.Ala367Ser) had partial enzyme activity and the other 17 had little enzymatic activity. The impairment degree of enzymatic activity in vitro functional study was also reflected in the severity degree of interaction change between the wild-type/mutant-type amino acid and its adjacent amino acids in three-dimensional model. In conclusion, the addition of 9 novel variants expands the spectrum of CYP11B1 pathogenic variants. Our results demonstrate that twenty CYP11B1 variants lead to impaired 11ß-hydroxylase activity in vitro. Visualizing these variants in the three-dimensional model structure of CYP11B1 protein can provide a plausible explanation for the results measured in vitro.

The diagnostic value of the olfactory evaluation for congenital hypogonadotropic hypogonadism.

Objective: The aim of this study was to evaluate the diagnostic accuracy of different olfactory evaluation tools in congenital hypogonadotropic hypogonadism (CHH) patients. Methods: Seventy-one CHH patients were prospectively recruited at Peking Union Medical College Hospital between November 2020 and July 2021. The Chinese Olfactory Function Test (COFT) and Self-reported Olfactory Scale (SROS) were adapted as the subjective tools for the evaluation of olfactory function, and magnetic resonance imaging of olfactory apparatus (MRI-OA) was the objective tool. The olfactory bulb volume (OBV) and the olfactory sulcus depth (OSD) were quantified. Results: Based on the COFT, 36 patients were categorized as having normosmic CHH (nCHH), and the other 35 patients were categorized as having Kallmann syndrome (KS). Among nCHH patients, 35 patients were classified as having normal olfaction and 1 patient had abnormal olfaction by SROS. For KS patients, there were 30 patients grouped into abnormal olfaction, while 5 patients had normal olfaction by SROS. For MRI-OA, 67% (18/27) of nCHH patients showed normal olfactory apparatus, and 33% (9/27) showed bilateral or unilateral olfactory bulb aplasia or hypoplasia. Among KS patients, 96% (27/28) of patients showed bilateral olfactory bulb hypoplasia or aplasia, and 4% (1/28) of patients showed normal olfactory apparatus. All six patients with unilateral olfactory bulb aplasia and three patients with bilateral olfactory bulb aplasia showed normal olfactory function. The accuracy of the SROS in the diagnosis of nCHH and KS was 91.5%, with a sensitivity of 0.857 and a specificity of 0.972, while the accuracy of MRI-OA is 92.7%, with a sensitivity of 0.964 and a specificity of 0.889. Conclusion: SROS and MRI-OA both showed high accuracy to distinguish between KS and nCHH. The abnormal structure of the olfactory apparatus was relatively common in nCHH patients. CHH patients with unilateral olfactory bulb aplasia dysplasia usually had normal olfaction. Normal olfaction without apparent olfactory bulbs is rare but occurred in male CHH patients.

Bone Mineral Density in Pituitary Stalk Interruption Syndrome: The Role of Insulin-Like Growth Factor-1 and Testosterone at Different Skeletal Sites.

OBJECTIVE: This study aimed to determine the clinical indicators influencing bone mineral density (BMD) of the lumbar spine and femoral neck in patients with pituitary stalk interruption syndrome (PSIS) who underwent multiple hormone replacement therapy (MHRT). METHODS: Male patients with PSIS (n = 51) who underwent MHRT for at least 1 year were enrolled in this study. Their BMD parameters were recorded and compared with age-, weight-, and height-matched control adults. In addition, we performed multiple linear regression analysis to correlate clinical parameters with BMD parameters at 2 different sites. RESULTS: Fifty-one patients with PSIS had a mean age of 30.39 ± 5.50 years. After 36 months of treatment, patients with PSIS who underwent MHRT had slightly lower BMD than those in the control group. Multiple linear regression models revealed a positive association between the Z-score values for the lumbar spine with treatment duration (r = 0.453, P < .001), insulin-like growth factor-1 (IGF-1) standard deviation score (SDS) values (r = 0.248, P = .038), and total testosterone level (r = 0.260, P = .036) and a positive association between the Z-score values for the femoral neck with treatment duration (r = 0.425, P < .001) and IGF-1 SDS values (r = 0.338, P = .009). CONCLUSION: Collectively, long-term MHRT improves bone density in patients with PSIS to the normal range. A combination of recombinant human growth hormone replacement is more beneficial to the BMD than non-recombinant human growth hormone treatment. Moreover, serum IGF-1 contributes to femoral and lumbar mineralization, whereas serum testosterone plays a role in lumbar mineralization.

Case Report: Novel Compound Heterozygotic Variants in PPP2R3C Gene Causing Syndromic 46, XY Gonadal Dysgenesis and Literature Review.

Purpose: Patients with syndromic 46, XY disorders/differences of sex development (DSD) are characterized by gonadal and phenotypic genders inconsistent with their chromosomal sexes as well as abnormalities of multiple extragonadal organs. They are caused by mutations in specific genes, which are expressed in the affected organs and regulate their development, and over fourteen genes have been identified. In this study, we aimed to determine the underlying cause of a patient with syndromic 46, XY DSD and review the clinical presentations and genetic findings of all reported similar cases. Methods: Whole-exome sequencing (WES) was performed to find a molecular cause of the patient. In silico tools were used to analyze the pathogenicity of the variants. Reports of cases with similar clinical features and involved genes were summarized by searching through PubMed/MEDLINE using keywords "PPP2R3C" or "G5PR" and "46,XY disorders of sex development". Results: Compound heterozygous variants (p.F229del/p.G417E) in PPP2R3C were identified in the 24-year-old female by WES and verified by Sanger sequencing. The patient presents complete testicular dysgenesis, low birth weight, facial deformity, cubitus valgus, and decreasing number of CD19+ B lymphocytes and CD4+ T lymphocytes. A total of thirteen 46, XY DSD cases with four homozygous PPP2R3C mutations (p.Leu103Pro, p.Leu193Ser, p.Phe350Ser, and p.Ser216_Tyr218dup) have been reported previously, and their clinical manifestations are roughly similar to those of our patient. Conclusion: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis, which broadened the pathogenic variants spectrum of PPP2R3C. The typical phenotype of PPP2R3C mutation is complete 46, XY gonadal dysgenesis with multiple extragonadal anomalies, including facial deformities, skeletal system abnormalities, muscle abnormalities, impaired nervous system, impaired hearing and vision, heart and kidney anomalies, and gastrointestinal dysfunction.

Growth Hormone Is Beneficial for Induction of Spermatogenesis in Adult Patients With Congenital Combined Pituitary Hormone Deficiency.

Background: Gonadotropins are effective in inducing spermatogenesis in patients with congenital combined pituitary hormone deficiency (CCPHD). Data on recombinant human growth hormone(rhGH) adjuvant treatment to improve gonadotropin-induced spermatogenesis are limited. Design and Setting: This retrospective study included 60 male patients with CCPHD on a relatively large case series in a single center from mainland China. Twenty-nine patients who received gonadotropin therapy alone were defined as the Gn group, while 31 patients treated with a combination of rhGH and gonadotropins were defined as GH/Gn group. Results: Spermatogenesis rate was 96.77% (30/31) and 62.07% (18/29) in the GH/Gn and Gn group, respectively (P < 0.001). The time for initial sperm appearance in the GH/Gn group was shorter than in the Gn group (14 versus 23 months, P < 0.001). A higher level of serum testosterone was achieved in the GH/Gn group than in the Gn group (4.79 versus 3.38 ng/mL, P = 0.026). After adjustment for potential confounders, rhGH supplementation was an independent beneficial factor on spermatogenesis (HR = 2.294, 95% CI: 1.143-4.604, P = 0.019). Conclusions: rhGH induces earlier spermatogenesis in patients with CCPHD, which encourages the co-treatment with rhGH and gonadotropins in CCPHD patients.

Relationship between growth hormone deficiency and nonalcoholic fatty liver disease in patients with pituitary stalk interruption syndrome.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS), characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary, and an ectopic posterior pituitary, can lead to congenital combined pituitary hormone deficiency. There is a high prevalence of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD), in this population. OBJECTIVE: To investigate the characteristics of NAFLD in Chinese adult patients with PSIS and its association with growth hormone deficiency. DESIGN: Retrospective cross-sectional study in a tertiary referral center of China. PATIENTS: Adult patients with PSIS diagnosed, followed up between September 2019 and August 2021, were consecutively enrolled. MEASUREMENTS: Abdominal ultrasonography images were evaluated and noninvasive fibrosis scores were determined to assess the severity of NAFLD. Anthropometric, clinical, and biochemical parameters were compared between patients with and without NAFLD. Logistic regression was performed to assess the independent effects of insulin-like growth factor-1 (IGF-1) on NAFLD. RESULTS: A total of 93 patients (77 men, 16 women, mean age: 29.6 ± 7.1 years) were included. The prevalence of NAFLD and advanced fibrosis/cirrhosis was 50.5% and 4.3%, respectively. Insufficient hormone therapy and prominent metabolic disorders, including central obesity, dyslipidemia, insulin resistance, and metabolic syndrome, were more common in the NAFLD (+) group. After adjusting for multiple variables, IGF-1 <-2 standard deviation score (SDS) was found to be associated with an increased prevalence of NAFLD (odds ratio [OR]: 4.92, 95% confidence interval [CI]: 1.21-24.55, p = .035). Per 1 SDS increase in IGF-1 was associated with a 27% lower risk of NAFLD (OR: 0.73, 95% CI: 0.52-0.97, p = .042). CONCLUSION: NAFLD is a frequent comorbidity among Chinese adult patients with PSIS and is strongly associated with lower IGF-1 levels. Timely and appropriate hormone replacement, particularly growth hormone may contribute to decreasing the risk of NAFLD in these patients.

Efficacy of Pulsatile Gonadotropin-Releasing Hormone Therapy in Male Patients: Comparison between Pituitary Stalk Interruption Syndrome and Congenital Hypogonadotropic Hypogonadism.

OBJECTIVE: Pulsatile gonadotropin-releasing hormone (GnRH), widely used to induce spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients, can restore the pituitary-testis axis function in men with pituitary stalk interruption syndrome (PSIS). This retrospective study aimed to compare the differences in the long-term efficacy of pulsatile GnRH therapy on PSIS and CHH. METHODS: Patients with PSIS (n = 25) or CHH (n = 64) who received pulsatile GnRH therapy for ≥3 months were included in this retrospective study. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, total testosterone, and testicular size were compared. RESULTS: Baseline characteristics were comparable except for the lower basal testosterone, triptorelin-stimulated peak luteinizing hormone (LH), and follicle-stimulating hormone in patients with PSIS. With similar duration of treatment and a significantly higher GnRH dose (P < .001), small increments in LH (2.82 [1.4, 4.55] vs 5.89 [3.88, 8.02] IU/L; P < .001), total testosterone (0.38 [0, 1.34] vs 2.34 [1.34, 3.66] ng/mL; P < .001), and testicular volume (5.3 ± 4.5 vs 8.8 ± 4.8 mL, P < .05) were observed. However, spermatogenesis rate (52.0% vs 70.3%, P > .05), median time of sperm appearance (14 vs 11 months, P > .05), sperm concentration, and progressive motility were comparable. Basal testicular volume (hazard ratio, 1.13; 95% CI, 1.01-1.27) and peak LH levels (hazard ratio, 1.11; 95% CI, 1.0-1.23) were predictors for early sperm appearance. CONCLUSIONS: Pulsatile GnRH therapy can improve gonad function and induce spermatogenesis in men with PSIS. However, its efficacy may be inferior to that in CHH.

High incidence of hypertension-mediated organ damage in a series of Chinese patients with 17α-hydroxylase deficiency.

OBJECTIVE: To analyze the prevalence of hypertension-mediated organ damage (HMOD) and its relationship with enzyme activity of mutant CYP17A1 and other risk factors in patients with 17α-hydroxylase/17,20-lyase deficiency (17-OHD). METHODS: A total of 68 patients with 17-OHD were recruited in the Peking Union Medical College Hospital from 2003 to 2021. The incidence of hypertension and HMOD was respectively analyzed. CYP17A1 sequencing was performed and the enzyme activity of mutant CYP17A1 was determined by analyzing the characteristics of mutation itself and the functional data reported previously. A logistic regression model was employed to analyze the factors related to HMOD and the specific damaged organs in 17-OHD patients. RESULT(S): Sixty-five patients (95.6%) exhibited hypertension, 32 of whom were diagnosed with HMOD. c.985_987delTACinsAA (p.Y329KfsX418) (53.8%) and c.1459_1467del (p. del D487_F489) (11.4%) were the top two mutations, and no correlation was found between enzyme activity of mutant CYP17A1 and HMOD. The risk of HMOD increased by 32% for each additional year of hypertension duration, 10.2-fold for each one-grade increase in hypertension level, 2.3-fold for each grade of exacerbation of hypokalemia. CONCLUSION: Patients with 17-OHD experience a high incidence of HMOD. There was no correlation between the HMOD occurrence and enzyme activity of mutant CYP17A1. Longer duration of hypertension, more severe hypertension, and hypokalemia were independent risk factors for the occurrence of HMOD in patients with 17-OHD.

High prevalence of hypertension and target organ damage in patients with 11ß-hydroxylase deficiency.

BACKGROUND: Prevalence of hypertension and hypertension-mediated organ damage (HMOD) had not been well studied in patients with 11ß-hydroxylase deficiency (11ß-OHD). OBJECTIVE: The study was to assess the prevalence and risk factors of hypertension and HMOD in patients with 11ß-OHD. DESIGN: Retrospective cohort analysis in a single medical centre. PATIENTS: Twenty-eight patients with 11ß-OHD were recruited between January 2003 and June 2021, and their diagnosis had been confirmed by Sanger sequencing. MEASUREMENTS: Blood pressure and clinical indicators for the assessment of HMOD occurrence were collected from the medical records. Medication adherence of antihypertensive drugs and glucocorticoids were determined by the patients' biochemistry. Logistic regression was used to identify factors associated with HMOD. RESULTS: Prevalence of hypertension and HMOD in the cohort was 100% and 50%, respectively. The kidneys (71.43%) are the organ most commonly damaged by high blood pressure, followed by the heart (64.29%), eyes (57.14%) and brain (21.43%). Risk factors of HMOD were hypokalemia (odds ratio [OR]: 9.16; 95% confidence interval [CI]: 1.634-51.43; p = .012), blood pressure ≥ 180/110 mmHg (OR: 22.0, 95% CI: 3.08-157.34; p = .002) and irregular glucocorticoid use (OR: 3.18, 95% CI: 1.13-8.98; p = .021). Blood pressure ≥ 180/110 mmHg was an independent predictor for HMOD. CONCLUSION: Hypertension and HMOD are prevalent in patients with 11ß-OHD in our study. These findings illustrate the importance of early HMOD evaluation and optimal glucocorticoid medication in 11ß-OHD patients.

The underlying cause of the simple virilizing phenotype in patients with 21-hydroxylase deficiency harboring P31L variant.

Objective: To analyze the relationship between genotype and phenotype in 21-Hydroxylase deficiency patients harboring P31L variant and the underlying mechanism. Methods: A total of 29 Chinese patients with 21-OHD harboring P31L variant were recruited, and the detailed clinical features of the patients were extracted and analyzed retrospectively. The TA clone combined with sequencing of the region containing the promotor and exon1 of CYP21A2 was performed to determine whether the variants in promotor and P31L aligned in cis. We further compared the clinical characteristics of 21-OHD patients between the promoter variant group and no promoter variant group. Results: Among the 29 patients diagnosed with 21-OHD harboring P31L variant, the incidence of classical simple virilizing form was 62.1%. Thirteen patients owned promoter variants (1 homozygote and 12 heterozygote) and all exhibited SV form. The promoter variants and the P31L variant were located in the same mutant allele as validated by TA cloning and sequencing. There were statistically significant differences in clinical phenotype and 17-OHP level between the patients with and without promoter region variations (P<0.05). Conclusion: There exists high incidence (57.4%) of SV form among the 21-OHD patients harboring P31L variant, and the underlying mechanism is partially due to both the promoter variants and P31L aligning in cis on one allele. Further sequencing of promoter region will provide important hints for the explanation of phenotype in patients harboring P31L.

[SARS-CoV-2 damages male fertility: How and why].

The male reproductive system has a structural basis for being invaded by the SARS-CoV-2 virus. Existing evidence shows that SARS-CoV-2 can cause substantial damage to testicular tissues, pituitary-testicular axis hormone homeostasis, and production and quality of sperm in male patients. Local inflammation of the testis, cytokine storm and fever are considered to be the potential pathogenic factors for testis injury. COVID-19, as a rapidly spreading disease, requires close attention for its impact on the male reproductive system.

Gonadotropin Therapy Once a Week for Spermatogenesis in Hypogonadotropic Hypogonadism.

OBJECTIVE: Hypogonadotropic hypogonadism (HH) can be caused by congenital HH (CHH), pituitary stalk interruption syndrome (PSIS), and pituitary injury (acquired HH). Gonadotropin therapy, typically administered every other day or twice a week, is commonly used to promote spermatogenesis. The aim of this retrospective study was to evaluate the efficacy of weekly gonadotropin therapy on spermatogenesis in patients with HH (n = 160). METHODS: The patients' diagnoses include Kallmann syndrome (KS) (n = 61), normosmic CHH (nCHH) (n = 34), PSIS (n = 48), and acquired HH (n = 17). The rate of successful spermatogenesis and median time to achieve spermatogenesis among these 4 subgroups were compared as well as between a weekly group (n = 95) and a twice-a-week group (n = 223) of CHH patients. RESULTS: Once-a-week gonadotropin therapy resulted in 74% (119/160) of HH patients achieving spermatogenesis with significantly increased testicular volume and total testosterone levels (P < .001). The median period of spermatogenesis was 13 (interquartile range[IQR] 11.4-14.6) months. Larger basal testicular volume (P = .0142) was an independent predictor for earlier sperm appearance. Six spontaneous pregnancies occurred. Compared with the twice-a-week regimen for spermatogenesis, the weekly injection group had a similar median time of sperm appearance (14 [IQR, 11.6-16.4] vs 15 [IQR, 13.5-16.5] months), success rate (78% [74/95] vs 64% [143/223]), sperm concentration (20.9 [IQR, 5.0-46.3] vs 11.7 [IQR, 2.1-24.4] million/mL), and progressive sperm motility (40.8 ± 27.3% vs 36.9% ± 20.2%). CONCLUSION: Weekly gonadotropin therapy is effective in inducing spermatogenesis, similar to that of twice-a-week therapy. A larger basal testicular size was a favorable indicator for earlier spermatogenesis.

Novel rare variants in FGFR1 and clinical characteristics analysis in a series of congenital hypogonadotropic hypogonadism patients.

OBJECTIVE: We aimed to analyse FGFR1 rare variants in a series of Chinese congenital hypogonadotropic hypogonadism (CHH) patients. In addition, we intended to understand the clinical characteristics and the response to treatment of CHH patients with FGFR1 rare variants. PATIENTS AND METHODS: A total of 357 CHH patients were recruited at Peking Union Medical College Hospital. We used Sanger sequencing to analyse FGFR1 gene. In silico analysis was carried out to study the pathogenicity of novel missense variants. The clinical, endocrinological and therapeutic effects from patients carrying FGFR1 rare variants were analysed retrospectively. RESULTS: Thimissense mutations.rty patients in this series were found to harbour 29 FGFR1 rare variants, with 8 recurrent and 21 novel variants. After comprehensive analysis, 18 out of 21 novel variants were classified as likely pathogenic (LP) ones. These variants are widely spread throughout the FGFR1 gene and almost all FGFR1 functional domains, which exhibited no hot spot. Cryptorchidism, cleft palate and dental abnormality incidence in this CHH series that possessed FGFR1 LP variants were approximately 38.5%, 7.6% and 3.8%, respectively. Among patients who accepted the fertility-promoting treatment, 8 out of 10 patients succeeded in spermatogenesis. CONCLUSIONS: Eighteen novel LP variants were found to expand the spectrum of FGFR1 rare variants. In CHH patients possessing FGFR1 variants, we found that the rate of spermatogenesis was high following fertility-promoting therapy and the existence of cryptorchidism may represent the underlying factors which affect spermatogenesis.

Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics.

Purpose: CHD7 rare variants can cause congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome. We aimed to summarize the genotype and phenotype characteristics of CHH patients with CHD7 rare variants. Methods: Rare sequencing variants (RSVs) were detected by Sanger sequencing in a series of 327 CHH patients and were interpreted and grouped according to the American College of Medical Genetics and Genomics (ACMG) guideline. Detailed phenotyping and genotype-phenotype correlation were analyzed. Results: The RSV detection rate was 11.01% (36/327) in the CHH patients. We identified 30 RSVs and 19 of them were novel. Following ACMG criteria, three variants were pathogenic (P), 4 were likely pathogenic (LP), 3 were of uncertain significance with paradoxical evidence (US1), and 20 were of uncertain significance without enough evidence (US2). All patients (4/4, 100%) with P or LP variants manifested extragonadal symptoms. Conclusion: Addition of 19 novel CHD7 variants expanded the spectrum of variants, and pathogenic or likely pathogenic RSVs were more likely to cause syndromic CHH. For CHH patients carrying CHD7 RSVs, detailed genotyping and phenotyping can facilitate clinical diagnosis and therapy.