BACKGROUND:Complete 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare autosomal recessive form of congenital adrenal hyperplasia caused by CYP17A1 variants. Large-scale studies integrating clinical, genetic, and functional data remain limited. METHODS:We recruited 113 genetically confirmed 17-OHD patients from 107 unrelated families. Comprehensive clinical manifestations, hormonal, and imaging examination data were collected. CYP17A1 variants were identified by Sanger sequencing, whole-exome sequencing or long-read sequencing. In vitro functional studies including enzyme activity assays and minigene splicing assays were performed to verify the pathogenicity of the variants. RESULTS:All patients presented as phenotypic females, with a median diagnostic age of 17 years. Hypertension (93.58%) and hypokalemia (74.31%) were the dominant clinical features, and 91.26% exhibited Tanner stage I breast development. We identified 50 pathogenic CYP17A1 variants, including 6 novel ones (c.286C>G, c.436+1G>T, c.1241C>T, c.1300C>T, c.1348C>T, c.1433G>T). The mutation spectrum was dominated by a founder hotspot, c.985_987delinsAA, accounting for 59.29% of alleles, with mutations clustering in exons 6 and 8. In vitro enzyme activity assays confirmed near-complete loss of both 17α-hydroxylase and 17,20-lyase activities in all variants except p.Val236Gly, which retained minimal residual activity. Notably, 5 variants (including 2 missense changes, c.1084C>T and c.1085G>A) were shown to disrupt normal pre-mRNA splicing in minigene assays, revealing a dual molecular mechanism of pathogenicity involving both protein dysfunction and aberrant RNA processing. CONCLUSION:This study defines the most comprehensive CYP17A1 variant spectrum for complete 17-OHD in China, identifies 6 novel pathogenic variants, and uncovers splicing disruption as an under-recognized mechanism in missense mutations. These findings expand the molecular and clinical understanding of 17-OHD, highlight the founder effect of c.985_987delinsAA in the Chinese population, and provide critical insights for genetic diagnosis and counseling.

This case report describes large areas of erythema on the face, chest, and back with relatively clear boundaries and swollen hands with scattered skin-colored papules and nodules.

Background: Limited data are available regarding the fertility-inducing treatment outcomes and spermatogenic duration in congenital hypogonadotropic hypogonadism patients carrying prokineticin receptor 2 rare sequence variants. Objectives: We aimed to delineate the rare sequence variant profiles of PROKR2 in a large Chinese cohort with congenital hypogonadotropic hypogonadism, and to characterize the associated clinical phenotypes and therapeutic outcomes. In addition, the reproductive phenotypes and therapeutic outcomes were compared between patients with congenital hypogonadotropic hypogonadism who harbored PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. Materials and Methods: Seven unrelated congenital hypogonadotropic hypogonadism probands carrying PROKR2 rare sequence variants (four with Kallmann syndrome and three with normosmic congenital hypogonadotropic hypogonadism) were included. PROKR2 variants in these patients were identified using targeted next-generation sequencing and verified using Sanger sequencing. The pathogenicity of the identified PROKR2 rare sequence variants was assessed according to the American College of Medical Genetics and Genomics guidelines. Baseline clinical characteristics and therapeutic outcomes were retrospectively evaluated and compared between patients with PROKR2 rare sequence variants and those lacking the identified rare sequence variants in established congenital hypogonadotropic hypogonadism-associated genes. Results: We identified a novel PROKR2 rare sequence variant (p.Y154*, a nonsense mutation). Four rare sequence variants were classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. Spermatogenesis was achieved in all six male patients with PROKR2 rare sequence variants who received gonadotropin therapy following an average of 1.28 years. No statistically significant differences were observed in the baseline clinical characteristics and spermatogenic outcomes between patients with PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. Conclusion: We observed a lack of evidence for a significant difference in reproductive phenotype or spermatogenic outcomes between male patients with congenital hypogonadotropic hypogonadism and PROKR2 rare sequence variants and those without identified rare sequence variants in congenital hypogonadotropic hypogonadism-associated genes, but this finding is critically limited by the small number of PROKR2 rare sequence variant carriers in our treatment cohort. The identification of a novel PROKR2 rare sequence variant expands the PROKR2 variant spectrum in patients with congenital hypogonadotropic hypogonadism.

Introduction: Lupus erythematosus-associated skin disease - papulonodular mucinosis (PNM) is characterized by a diffuse deposition of mucin in the dermis. The relationship between PNM and lupus erythematosus and appropriate treatment is crucial for PNM patients. Aim: To investigate the relationship between systemic lupus erythematosus (SLE) and PNM. Material and methods: We collected clinicopathological, treatment and follow-up data of 13 patients with PNM of the Chinese Academy of Medical Sciences and Peking Union Medical College from 2004 to 2024. According to the diagnostic criteria for SLE, the patients were divided into two groups: the SLE group and non-SLE group who presented with PNM as major manifestations. The similarities and differences between the two groups were summarised and compared. Results: Thirteen patients included 8 (61.5%) males and 5 (38.5%) females, who presented with generalized (61.5%) or localized (38.5%) nodules/plaques with a mean onset age of 39.8 years. Among them, 4 (33.3%) cases accorded with the diagnostic criteria for SLE. As to treatment, the SLE group adopted the regimen of systemic prednisolone, hydroxychloroquine and intralesional triamcinolone acetonide. The rest of patients all received systemic prednisolone, together with some other adjuvant therapy. They all gained improvement of varying degree and to date, no SLE symptoms have developed in 11 patients, while 2 patients have developed arthralgia, oral ulcer and alopecia. Conclusions: Although the clinical presentation varies, the SLE and non-SLE groups of PNM have similar histological features and outcomes, suggesting that these two situations are highly associated.

PURPOSE:Treatment of early post-traumatic scars with energy-based devices like plasma radiofrequency is often complicated by post-inflammatory hyperpigmentation (PIH). This study aimed to evaluate the efficacy and safety of a combination regimen of plasma radiofrequency and immediate topical application of tranexamic acid (TXA) to simultaneously address both scars and concomitant PIH. METHODS:This retrospective study included 35 patients with early post-traumatic scars and hyperpigmentation. All patients underwent three sessions of plasma radiofrequency at 6-week intervals, each followed by immediate in-office and 7-day at-home topical application of TXA. Efficacy was evaluated using the Modified Vancouver Scar Scale (mVSS), Investigator's Global Assessment (IGA), and a patient-reported Visual Analogue Scale (VAS) for satisfaction at baseline and 6 weeks after the final session. RESULTS:Significant improvements were observed in all patients. The mean mVSS score decreased from a baseline of 5.71 ± 1.47 to 2.66 ± 2.07 at the final follow-up (p < 0.001). According to IGA, 91.4% (32/35) of patients achieved moderate to excellent improvement. High patient satisfaction was reported on the VAS. No serious adverse events were observed; side effects were limited to transient erythema and edema. CONCLUSION:The combination of plasma radiofrequency with immediate topical TXA application is a safe and effective strategy for treating early scars with hyperpigmentation. This dual-action approach successfully improves scar characteristics while controlling and reversing pigmentation, offering a valuable therapeutic option to optimize outcomes with energy-based devices.

Extramammary Paget's disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential. The exact origin of the tumor is still undefined. To explore potential cellular origin-related signals and depict a relatively comprehensive cellular landscape of EMPD, we collected 50,180 cells from patients with EMPD. We detected a distinct basal keratinocyte cell population characterized by New York Breast-1 (NY-BR-1) expression, which exhibited a transcriptional trajectory toward Paget-like phenotype. We also presented a comprehensive single-cell profile of immune cells and fibroblasts in EMPD. The fibroblasts exhibited a markedly central position in outgoing and incoming signaling interactions. The upregulation of the MK pathway and the downregulation of the MIF pathway in EMPD may promote fibroblast-immune crosstalk and tumor progression. This study provided a novel perspective on potential origin-related transcriptional programs in EMPD and highlighted a global reprogramming of cell-cell communication in EMPD, driven predominantly by fibroblast-derived interactions.

Extramammary Paget's disease (EMPD) usually occurs in the apocrine gland-bearing areas, in which Paget's cells are scattered in the middle and lower epidermis, arranged singly or in clusters, and spread to all skin layers. The pathogenesis of EMPD remains unclear, and the origin of Paget's cells is still controversial. This review discusses the pathogenesis of EMPD from 4 aspects, i.e., histogenesis, driver genes, signal transduction pathways and immune environment, and focuses on relevant research progress.

Clinical severity of 21-hydroxylase deficiency (21-OHD) is primarily determined by the CYP21A2 genotype and residual enzymatic activity of mutant CYP21A2. However, CYP21A2 variants often lack functional characterization, and the pathogenic contribution of multiple variants arranged in cis remains poorly understood. We aimed to determine the residual 21-hydroxylase activity of 11 rare CYP21A2 variants, assess the combined functional impact of cis-configured double variants, and refine genotype-phenotype correlations. Among 713 patients with 21-OHD, 14 carried rare CYP21A2 variants. Targeted long-read sequencing was used to resolve allele structures and phase variants. Pathogenicity was evaluated using conservation analysis, in silico prediction, enzyme activity assays, and minigene-based splicing analysis. Clinical data were reviewed to examine genotype-phenotype correlations. We identified 11 CYP21A2 variants in 14 patients, including 10 missense variants and one deep intronic variant (c.738 + 75 C > T); four were novel (p.Ile173Phe, p.Gly179Glu, p.Asp259Val, p.Pro361Leu). Two cis-configured double-variant alleles were confirmed: p.[His63Leu; Val70Leu] and p.[Thr124Ile; Ile173Asn]. Functional assays showed that all 10 missense variants exhibited reduced activity across both substrate conversions. Both cis-configured double-variant alleles showed greater functional impairment than their corresponding single variants, a pattern consistent with a cumulative functional effect. The intronic variant c.738 + 75C > T caused partial intron 6 retention (73-bp insertion), with a predicted frameshift and likely nonsense-mediated decay. Overall concordance between genotype and phenotype was 71.4

We report on two patients with a c.844C>T variant in TINF2 demonstrating distinct phenotypes of classic dyskeratosis congenita (DC) and a novel linear hypermelanosis in narrow bands similar to mosaic DC. The first patient presented with classic features of DC linked to a germline mutation, while the second exhibited extensive linear hypermelanosis in narrow bands similar to the pigmentary lesions attributed to somatic mosaicism. These findings underscore the critical role of genetic analysis, particularly in affected tissues, for understanding mosaic dermatoses. Our report expands the phenotypic spectrum of DC and sheds light on the molecular mechanisms underlying mosaic congenital dyschromatosis.

BackgroundPrevious studies showed the prevalence of melasma, plateau facial telangiectasia, and vitiligo varied in different regions but were absent in high-altitude areas.AimsTo investigate the prevalence of three common pigmented skin disorders (melasma, plateau facial telangiectasia, and vitiligo) among the general population in Lhasa, aiming to provide a scientific basis for their prevention and management in high-altitude areas.MethodsFrom May 2021 to October 2021, multistage stratified cluster random sampling was conducted in Lhasa to carry out a questionnaire and a second on-site physical examination, and the results were statistically analyzed.ResultsThe study included 4988 participants, revealing a prevalence of 14.94% for melasma, 17.14% for plateau facial telangiectasia, and 0.38% for vitiligo. Notably, the prevalence of melasma and plateau facial telangiectasia were significantly higher among women, particularly those aged 31-50 years, compared to men. Urban residents also showed a higher prevalence than their rural counterparts.ConclusionsOur study concludes that the prevalence of the three pigmented skin disorders in Lhasa is notably higher than in lower-altitude areas, with UV radiation being a significant risk factor. Our findings underscore the need for enhanced public health interventions, including screening, education, and prevention efforts, to mitigate the impact of these skin disorders in high-altitude regions. Our research contributes valuable insights toward the understanding and management of pigmented skin disorders in such unique environments. It may also provide an easy-to-use epidemiological survey method for socioeconomically underdeveloped areas.

CONTEXT:21-Hydroxylase deficiency (21-OHD) is caused by pathogenic variants in CYP21A2. High homology between CYP21A2 and its pseudogene CYP21A1P causes mismatches, leading to deletions and CYP21A1P/CYP21A2 chimeras. OBJECTIVE:To detect chimeric CYP21A1P/CYP21A2 in 21-OHD patients using long-read sequencing (LRS) and analyze genotype-phenotype correlations. METHODS:From 2015 to 2023, 869 21-OHD patients were enrolled at Peking Union Medical College Hospital, with 113 identified harboring CYP21A2 large deletion. Long-range PCR and LRS were used to identify the types of CYP21A1P/CYP21A2 chimeric. Haplotype analysis explored founder effects, and in vitro assays assessed the functional impact of novel mutations. Clinical data were retrospectively collected and patients were classified into 4 groups based on genotypes and residual enzyme activity to study genotype-phenotype correlations. RESULTS:Ten types of chimeric CYP21A1P/CYP21A2 genes were identified across 119 alleles, including a novel type, CH-10. The most common, CH-1, accounted for 50.4% of all types. Haplotype analysis of 24 SNPs within CYP21A1P/CYP21A2 CH-1 revealed 25 haplotypes, with haplotype 11 being the most prevalent. Variants p.L100P and p.L301V of CYP21A2 showed enzyme activities of 1.36 ± 0.44% or 1.63 ± 0.19% for 17-hydroxyprogesterone to 11-deoxycortisol, and 1.36 ± 0.58% or 3.99 ± 1.09% for progesterone to 11-deoxycorticosterone, respectively, linked to the simple virilizing type. Genotype-phenotype consistency rates were 78.6% to 84% across the 4 groups. CONCLUSION:LRS is a comprehensive genetic testing method for 21-OHD patients, effectively detecting both CYP21A2 gene variants and CYP21A1P/CYP21A2 chimeric gene types. This study expands the CYP21A2 variant spectrum by identifying a novel chimera. Haplotype analysis revealed diverse haplotypes for each chimeric gene type, suggesting the absence of a common founder effect. The strong genotype-phenotype correlation aids genetic counseling and supports personalized treatment.

ABSTRACTObjectiveThis study aimed to evaluate the long‐term effects of hormone therapies on the body composition, adipokines and metabolic parameters of adult men with congenital hypogonadotropic hypogonadism (CHH).MethodsSixty‐six patients with CHH and 21 healthy controls were recruited. Patients were divided into untreated (n = 33) and treated (n = 33) groups based on hormone therapy history. Body composition was assessed using dual‐energy X‐ray absorptiometry (DXA), and adipokines and metabolic parameters were measured in all participants.ResultsCompared to the healthy control group, patients in the treated group had lower serum testosterone levels (p < 0.001), increased body fat percentage (BFP) and visceral adipose tissue (VAT) volume, decreased lean soft tissue (LST) and bone mineral content (BMC) (p < 0.05), increased serum leptin levels accompanied by decreased adiponectin (ADP) (p < 0.05), higher HOMA‐IR with lower QUICKI (p < 0.05). Compared to the untreated group, patients in the treated group (therapy duration 4.8 ± 2.3 years) had higher serum testosterone levels (p < 0.001), decreased BFP and VAT volume, increased LST and BMC (p < 0.05), decreased serum leptin levels (p < 0.001), and decreased HOMA‐IR accompanied by increased QUICKI (p < 0.05). Among them, VAT volume, LST, BMC, HOMA‐IR and QUICKI reached healthy control levels (p > 0.05). Multiple stepwise linear regression analysis showed serum testosterone levels were negatively correlated with BFP (β = −0.564, p < 0.001) and VAT volume (β = −0.260, p = 0.045), positively correlated with LST (β = 0.305, p = 0.018) and BMC (β = 0.423, p = 0.001). Serum testosterone levels were independently negatively correlated with leptin levels (β = −0.277, p = 0.004).ConclusionsPatients with untreated CHH had impaired body composition, adipokines and metabolic parameters. While hormone therapies can improve body composition and glucolipid metabolism in patients with CHH, this imperfect treatment does not fully rescue body composition abnormalities when compared to healthy individuals. Abnormal metabolic parameters in patients with CHH are associated with increased fat mass and abnormal serum leptin level. Serum testosterone levels were independently negatively correlated with leptin levels.

OBJECTIVES:Limited data exist on growth-promoting factors beyond growth hormone and insulin-like growth factor 1. This study aimed to identify factors associated with growth in patients with pituitary stalk interruption syndrome (PSIS). METHODS:This retrospective cross-sectional study included 62 adult patients with PSIS between January 2021 and September 2024. Demographic data, metabolic parameters, and hormone statuses were compared. Binary logistic regression was used to assess the relationships among hyperinsulinemia, hyperprolactinemia, sex hormone replacement history, thyroxine replacement history and 1) height attainment within or above the target height and 2) height ≥ -2 SD. RESULTS:A total of 62 patients (53 males and 9 females) were included, with a median age of 30.5 years (range: 26.0-32.4). Twelve patients achieved their target height, while the remaining patients did not. Hyperprolactinemia in adult patients with PSIS was positively associated with height attainment within or above the target height (odds ratio [OR] 6.4, 95% CI: 1.6-24.7, P = .007), and this association remained after adjustment for multiple confounders (OR 6.89, 95% CI: 1.19-40.81, P = .032). Additionally, hyperprolactinemia showed a positive association with height ≥ -2 SD (OR 10.5, 95% CI: 2.8-38.5, P < .001), which also remained after adjusting for confounders (OR 13.8, 95% CI: 2.5-77.6, P = .003). These associations were consistently observed in male patients. CONCLUSIONS:Hyperprolactinemia was associated with height attainment within or above the target height and in Chinese adult patients with PSIS. Additionally, a significant correlation was observed between hyperprolactinemia and height ≥ -2 SD.

Vitiligo has a significant impact on a substantial number of individuals worldwide. Traditional Chinese medicine has a long history of serving as a therapeutic treatment for vitiligo. Nevertheless, given the increasing volume of research on the utilization of traditional Chinese medicine for vitiligo treatment, it is imperative to conduct a comprehensive review that elucidates the efficacy of Chinese traditional medicine and other active ingredients in the treatment of vitiligo. This paper presents a comprehensive overview of the clinical preparations used to treat vitiligo, while also highlighting the potential monomers and extracts derived from traditional Chinese medicine for vitiligo treatment. A thorough analysis of the pharmacological effects of traditional Chinese medicine on vitiligo treatment will provide valuable insights and reliable information for the development of new treatment strategies.

BACKGROUND:17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare subtype of congenital adrenal hyperplasia caused by homozygous or compound heterozygous pathogenic variants in the CYP17A1 gene. PURPOSE:This study aimed to identify and characterize pathogenic variants in individuals with 17-OHD and to classify and validate the pathogenicity of novel variants. METHODS:Variants were identified via targeted long-read sequencing (TLRS) of the entire CYP17A1 gene in enrolled 17-OHD patients. The American College of Medical Genetics and Genomics (ACMG) guidelines were employed to assess the pathogenicity of novel variants. Minigene splicing assays were utilized to determine the impact of variants on RNA splicing. RESULTS:This study encompassed 26 patients with 17-OHD, detecting 2 trans pathogenic variants per patient using the TLRS method. A total of 20 pathogenic variants in the CYP17A1 were identified, with variant c.985_987delinsAA being the most frequent (28/52 alleles), followed by variant c.1459_1467del (4/52 alleles). Five novel variants including c.280T > C, c.470T > A, c.636_637del, c.866A > G, and c.1095del, were classified as pathogenic/likely pathogenic ones according to ACMG criteria. The minigene splicing assays revealed c.866A > G in exon 5 causes a frameshift due to a 104 base pair deletion, while c.470T > A generates 2 transcripts, with the vast majority spliced like the wild-type and a small fraction lacking 35 base pairs in the 5' flank of exon 3. CONCLUSION:The TLRS can determine the cis/trans orientation of 2 distant variants. Five novel pathogenic variants were reported, broadening the spectrum of the CYP17A1 pathogenic variants. The variant c.866A > G, located deep in the exon, affects gene function through mechanisms of aberrant splicing.

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.

Abstract Purpose Kallmann syndrome is a rare disease characterized by delayed puberty, infertility and anosmia. We report the clinical and genetic characteristics of four patients with Kallmann syndrome who presented with Klinefelter syndrome or primary testicular disease and defined a new type of hypogonadism as mixed hypogonadism. Methods Clinical data and examinations were obtained, including laboratory examination and magnetic resonance imagination (MRI) of the olfactory structures. Idiopathic hypogonadotropic hypogonadism (IHH) related genes were screened by next generation sequencing (NGS). Results Four patients with Kallmann syndrome were included. Patient 1–3 had co-existence with Klinefelter syndrome and showed hypogonadotropic hypogonadism. Patient 1 was complicated with germinoma. Patient 4 had a history of hypogonadotropic hypogonadism and cryptorchidism, and then gradually converted to hypergonadotropic hypogonadism during follow-up. 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 IHH or gonadotropin levels decrease in patients with Klinefelter syndrome.

Vitiligo is the most common disorder of depigmentation, which is caused by multiple factors like metabolic abnormality, oxidative stress and the disorders of immune. In recent years, several studies have used untargeted metabolomics to analyze differential metabolites in patients with vitiligo, however, the subjects in these studies were all in plain area. In our study, multivariate analysis indicated a distinct separation between the healthy subjects from plateau and plain areas in electrospray positive and negative ions modes, respectively. Similarly, a distinct separation between vitiligo patients and healthy controls from plateau and plain areas was detected in the two ions modes. Among the identified metabolites, the serum levels of sphingosine 1-phosphate (S1P) were markedly higher in vitiligo patients compare to healthy subjects in plain and markedly higher in healthy subjects in plateau compare to those in plain. There are significant differences in serum metabolome between vitiligo patients and healthy subjects in both plateau and plain areas, as well as in healthy subjects from plateau and plain areas. S1P metabolism alteration may be involved in the pathogenesis of vitiligo.