Undiagnosed RASopathies in infertile men.

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 in 1,000. Patients are typically identified in childhood based on diverse characteristic features, including cryptorchidism (CR) in >50% of affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0-39 million), we hypothesized that men seeking infertility management include cases with undiagnosed RASopathies. Likely pathogenic or pathogenic (LP/P) variants in 22 RASopathy-linked genes were screened in 521 idiopathic SPGF patients (including 155 CR cases) and 323 normozoospermic controls using exome sequencing. All 844 men were recruited to the ESTonian ANDrology (ESTAND) cohort and underwent identical andrological phenotyping. RASopathy-specific variant interpretation guidelines were used for pathogenicity assessment. LP/P variants were identified in PTPN11 (two), SOS1 (three), SOS2 (one), LZTR1 (one), SPRED1 (one), NF1 (one), and MAP2K1 (one). The findings affected six of 155 cases with CR and SPGF, three of 366 men with SPGF only, and one (of 323) normozoospermic subfertile man. The subgroup "CR and SPGF" had over 13-fold enrichment of findings compared to controls (3.9% vs. 0.3%; Fisher's exact test, p = 5.5 × 10-3). All ESTAND subjects with LP/P variants in the Ras/MAPK pathway genes presented congenital genitourinary anomalies, skeletal and joint conditions, and other RASopathy-linked health concerns. Rare forms of malignancies (schwannomatosis and pancreatic and testicular cancer) were reported on four occasions. The Genetics of Male Infertility Initiative (GEMINI) cohort (1,416 SPGF cases and 317 fertile men) was used to validate the outcome. LP/P variants in PTPN11 (three), LZTR1 (three), and MRAS (one) were identified in six SPGF cases (including 4/31 GEMINI cases with CR) and one normozoospermic man. Undiagnosed RASopathies were detected in total for 17 ESTAND and GEMINI subjects, 15 SPGF patients (10 with CR), and two fertile men. Affected RASopathy genes showed high expression in spermatogenic and testicular somatic cells. In conclusion, congenital defects in the Ras/MAPK pathway genes represent a new congenital etiology of syndromic male infertility. Undiagnosed RASopathies were especially enriched among patients with a history of cryptorchidism. Given the relationship between RASopathies and other conditions, infertile men found to have this molecular diagnosis should be evaluated for known RASopathy-linked health concerns, including specific rare malignancies.

[A Case of Testicular Torsion of Retractile Testis Requiring Orchidectomy].

We report a case of testicular torsion in an 8-year-old who was referred to our hospital for right groin pain. He was diagnosed with right retractile testis during a 12-month check-up. However, instead of performing orchiopexy, he was placed under observation until the age of 5, after which he did not seek medical attention. Physical examination revealed swelling and tenderness in the right inguinal region and no palpable testis in the right scrotum. Ultrasound and computed tomography revealed right testicular torsion, and emergency surgery was performed. Intraoperative findings revealed a dark and ischemic testis that was twisted at 180°in the right inguinal region. There was no improvement in blood flow even after the testicular torsion was released; therefore, right orchidectomy with left orchiopexy was performed. Although the incidence of testicular torsion is higher in patients with an undescended testis than in those with a normally positioned scrotal position testis, reports of testicular torsion associated with a retractile testis are rare.

Immediate Versus Delayed Surgical Management of Infant Cryptorchidism With Inguinal Hernia.

INTRODUCTION: Cryptorchidism is commonly treated with orchiopexy at 6-12 months of age, often allowing time for undescended testicle(s) (UT) to descend spontaneously. However, when an inguinal hernia (IH) is also present, some surgeons perform orchiopexy and inguinal hernia repair (IHR) immediately rather than delaying surgery. We hypothesize that early surgical intervention provides no benefit for newborns with both IH and UT. METHODS: The Nationwide Readmissions Database was used to identify newborns with diagnoses of both IH and UT from 2010 to 2014. Patients were stratified by management: IHR performed on initial admission (Repair) or not (Deferral). Demographics, outcomes, and complications were compared. Results were weighted for national estimates. RESULTS: We analyzed 1306 newborns (64% premature) diagnosed with both IH and UT. IHR was performed at index admission in 30%. Repair was more common in premature babies (43% vs. 8% full-term, p < 0.001) and patients with congenital anomalies (33% vs. 27% without congenital anomaly, p = 0.012). There was no difference in readmission rates. Repair patients had higher rates of orchiectomy than did Deferral. No Deferral patients were readmitted for bowel resection, and <1% were readmitted for orchiectomy or hernia incarceration. CONCLUSION: In newborns with UT and IH, immediate repair is not associated with improved outcomes. Even with incarceration on initial presentation, rates of readmission with incarceration or bowel compromise for patients who undergo Deferral of surgery are minimal. Moreover, Repair newborns have higher rates of orchiectomy. We found no benefit to early operative intervention; thus, we recommend waiting until 6-12 months of age to reassess for surgery. LEVEL OF EVIDENCE: Level III TYPE OF STUDY: Retrospective Comparative Study.

Higher prevalence of benign tumors in men with testicular tumors and history of treated cryptorchidism.

OBJECTIVES: To identify if surgically treated cryptorchidism correlated with testicular tumor pathology at presentation. MATERIALS AND METHODS: An institutional database of patients treated for testicular cancer between 2003 and 2020 was reviewed. Inclusion criteria included orchiectomy patients. Exclusion criteria included unknown cryptorchidism history or pathology or laterality of orchiectomy. Data collection included demographics, surgical history, and tumor marker status. RESULTS: A total of 435 patients were included. Thirty-three of these patients had a history of UDT. There was no statistical difference in age at orchiectomy, laterality of orchiectomy, or lymphovascular invasion with regard to UDT history. There was a statistical difference in tumor pathology after orchiectomy, P = 0.03. On secondary analysis, benign pathology was significantly more common in patients with a history of UDT (15.2%) than without (4.7%), P = 0.01. Mixed GCT was also found at a significantly lower rate in patients with a history of UDT (18.2%) compared to those with no history of UDT (37.3%), P = 0.03. There were no statistically significant differences in other pathology. CONCLUSION: Previous studies have shown that there is a greater rate of seminoma in patients with testicular cancer in an undescended testis. This study shows that in patients with a history of UDT compared to those without a history of UDT, there is a greater percentage of patients with benign testicular masses after orchiectomy. Guideline based practices including monthly self-examination and testis-sparing surgery for appropriate patients may reduce rates of radical orchiectomy for benign tumors.

Echidna Splenule: A Case Study of Continuous Splenogonadal Fusion.

Splenogonadal fusion (SGF) is a rare congenital anomaly of an aberrant accessory spleen-gonad connection. We present a rare case of continuous splenogonadal fusion in a full-term male with a left undescended testis, multiple congenital limb anomalies, and syndromic facies. Diagnostic laparoscopy revealed the "Echidna Splenule," a snake-like intraperitoneal splenule coursing from the spleen along the left paracolic region and engulfing an atrophic intra-abdominal testis preventing spontaneous descent and distally herniating into the left open internal inguinal ring. The atrophic testis and Echidna Splenule were resected. Splenogonadal fusion should be considered in children with left undescended testis and concomitant limb and facial anomalies.

Prevalence of urologic sequelae and bladder and bowel dysfunctions in patients with congenital Zika syndrome: A multicenter evaluation of the Zika virus bladder and bowel sequelae assistance network.

INTRODUCTION: Neurogenic bladder was first confirmed as a urological sequela of Congenital Zika Syndrome (CZS) in 2018. Further clinical-epidemiological evidence also confirmed neurogenic bowel dysfunction and cryptorchidism. To strengthen the care for these children, the Congenital Zika Virus Bladder and Bowel Sequelae Network (RASZ in Brazilian) was created, including six integrated centers in Brazil. This article represents the initial outcome of the efforts by RASZ. OBJECTIVE: To evaluate the prevalence of bladder and bowel dysfunction, cryptorchidism and other urological sequelae related to CZS in cohorts attended in six Brazilian states. STUDY DESIGN: Observational, prospective, multicenter study including children with CZS assisted in one of six RASZ collaborative centers between June 2016 and February 2023. Data were collected from patient's first assessment using the same protocols for urological and bowel evaluation. Categorical variables were analyzed by frequency of occurrence and numerical variables by mean, median, and standard deviation. The study was approved by the Research Ethics Committees of each center, all parents/caregivers provided written informed consent. RESULTS: The study included 414 children aged 2 months to 7 years (mean 2.77 years, SD 1.73), 227 (54.8 %) were male and 140 (33,8 %) referred urological and bowel symptoms on arrival. Prevalence of both urological and bowel sequelae was 66.7 %, 51 % of children aged 4 years and older had urinary incontinence (UI). UTI was confirmed in 23.4 % (two presented toxemia) and among males, 18.1 % had cryptorchidism. Renal ultrasonography, performed in 186 children, was abnormal in 25 (13.4 %), 7 had hydronephrosis. Among the 287 children who performed urodynamics, 283 (98.6 %) were altered: 232 had a lower bladder capacity, 144 a maximum bladder pressure of ≥40 cm H2O, and 127 did not satisfactorily empty their bladder. DISCUSSION: A higher prevalence of NLUTD, neurogenic bowel and cryptorchidism was confirmed in children with CZS. Early diagnosis and appropriate treatment, including a multidisciplinary approach, may reduce the risk of UTIs, UI and kidney damage. A limitation of the study was the inability of children to complete the protocol, specifically urodynamic evaluation, and ultrasonography. In both exams, the percentage of abnormal cases was higher than that expected in the normal population. CONCLUSION: A 66,7 % prevalence of combined urological sequelae and bladder-bowel dysfunction related to CZS was confirmed in patients evaluated in six Brazilian cohorts. The most frequent changes were related to NLUTD, neurogenic bowel, and cryptorchidism. Prevalence may be underestimated due to access restrictions to diagnostic tests.

[Hormonal and genetic causes of cryptorchidism].

Cryptorchidism is the most frequent congenital disorders of the reproductive system, is present in 2-3% of term newborn boys. Genes involved in embryonic testicular migration are known but their role in cryptorchidism development are not investigated enough. Genetical causes of cryptorchidism are identified in 5-7% of patients. The article contains data on the role of insulin-like peptide 3 and its receptor, anti-Müllerian hormone, gonadotropins, androgens in embryonic testicular migration. INSL3 and AMH are presented as markers of testicular dysfunction associated with cryptorchidism. Hypogonadotropic hypogonadism is also associated with cryptorchidism and can be diagnosed based on it. Results of modern investigations determine the necessary of hormonal and genetical examination of patients with isolated cryptorchidism to detect causes of cryptorchidism and manage of patients.

Laparoscopic totally extraperitoneal exploration of intra-abdominal testis, orchidectomy and inguinal hernia repair in an adult patient.

The presence of undescended testis predisposes to the development of an inguinal hernia due to the persistent processus vaginalis. This coexistence is not very rare in the paediatric population. Here, we report an adult man who presented with inguinal hernia and an intra-abdominal testis and successfully underwent an extended totally extraperitoneal (e-TEP) approach for extraperitoneal exploration of the testis in the left iliac fossa, and orchidectomy along with inguinal hernia repair. Review of the literature revealed only two case reports in which TEP has been used in the treatment of undescended testis in adults, and in both cases, the testes were intracanalicular. This case, as per our extensive bibliographical research, is the first reported case of an intra-abdominal testis, with descent arrested at the iliac fossa, explored using e-TEP along with inguinal hernia repair. Such minimally invasive procedures may be offered to the patients without the risks of intraperitoneal entry.

[Clinical, genetic, and pathological analysis in 165 children with disorders of sex development]. / 165ä¾‹å„¿ç«¥æ€§å‘è‚²å¼‚å¸¸ç–¾ç— çš„ä¸´åºŠã€é—ä¼ å­¦ä¸Žç— ç†å­¦åˆ†æž.

OBJECTIVES: To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD). METHODS: A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022. RESULTS: Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46,XX DSD, 34 cases (26.8%) of 46,XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45,X karyotype (11/57, 19%) and 45,X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants. CONCLUSIONS: Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities are common phenotypes in children with DSD. 45,X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes.

Cryptorchidism (Undescended Testicle).

Cryptorchidism refers to an undescended testicle, the most common genitourinary malformation in male children. It is diagnosed with history and physical examination findings, and primary care physicians play a key role in the early identification of the condition. Early surgical intervention reduces the risk of testicular cancer and preserves fertility. Patients should be referred for surgical intervention at six months of age or at the time of diagnosis if the child is older. After surgery, patients require lifelong surveillance and counseling regarding fertility implications and increased risk of testicular conditions. Patients with bilateral undescended testicles that are nonpalpable should undergo endocrinologic evaluation for sexual development disorders. Retractile testicles are a variant of cryptorchidism and should be monitored annually until puberty, when acquired ascent becomes unlikely due to greater testicular volume. Based on expert opinion, all patients with a history of cryptorchidism should undergo annual clinical examination and be taught self-examination techniques for early detection of testicular cancer.

Where is the testis? The role of ultrasound and diagnostic laparoscopy for Crossed Testicular Ectopia (CTE): Case report and review of literature.

Crossed Testicular Ectopia (CTE) or transverse testicular ectopia is an anecdotic urogenital anomaly in which both testes are located on the same side, generally associated with a patent processus vaginalis (PPV). The condition can be detected by ultrasound. Nevertheless, the diagnosis is often missed preoperatively and CTE is recognized intraoperatively. Controversy exists regarding management and the role of diagnostic laparoscopy. The surgical technique depends on the anatomy of vas, vessels and testis found on surgical exploration. Diagnostic laparoscopy can be useful to rule out a vanishing testis and detect Müllerian remnants. We present the case of 8-months infant with no palpable testis on the right side and no signs of inguinal hernia, reporting the management and reviewing the scarce existing literature in this regarding. KEY WORDS: Crossed Testicular Ectopia, Laparoscopy, Ectopia, Testis, Transverse Testicular Ectopia, Urogenital Abnormalities.

Analysis of factors associated with undescended testis in patients with congenital diaphragmatic hernia.

PURPOSE: This study aimed to investigate the incidence and clinical factors associated with undescended testes (UDT) in patients with congenital diaphragmatic hernia (CDH). METHODS: We retrospectively reviewed the incidence of UDT in male neonates admitted to our institution and underwent surgery for CDH between January 2006 and December 2022. Patients were divided into two groups based on the presence or absence of UDT, and risk factors for UDT were compared between the two groups. RESULTS: Among the 66 male neonates with CDH, 16 (24.2%) developed UDT. Patients with UDT had a significantly smaller gestational age (p = 0.026), lower birth weight (p = 0.042), and lower Apgar score at 1 min (p = 0.016) than those without UDT. They had a significantly higher incidence of large diaphragmatic defects (p = 0.005), received more patch closures (p = 0.020), had a longer mechanical ventilation period (p = 0.034), and longer hospital stay (p = 0.028). Multiple logistic regression analysis revealed that large diaphragmatic defect was an independent risk factor for UDT (adjusted odds ratio of 3.87). CONCLUSION: CDH and UDT are strongly correlated. In patients with CDH, the incidence of UDT was related not only to patients' prematurity but also to the large diaphragmatic defect. Large diaphragmatic defect is an independent risk factor for UDT in patients with CDH.

Male Infertility and the Risk of Developing Testicular Cancer: A Critical Contemporary Literature Review.

Background and Objectives: The relationship between male infertility (MI) and testicular cancer (TC) is bilateral. On one hand, it is well-established that patients diagnosed with TC have a high risk of pre- and post-treatment infertility. On the other hand, the risk of developing TC in male infertile patients is not clearly defined. The objective of this review is to analyze the histopathological, etiological, and epidemiological associations between MI and the risk of developing testicular cancer. This review aims to provide further insights and offer a guide for assessing the risk factors for TC in infertile men. Materials and Methods: A comprehensive literature search was conducted to identify relevant studies discussing the relationship between MI and the risk of developing TC. Results: The incidence rates of germ cell neoplasia in situ (GCNIS) appear to be high in infertile men, particularly in those with low sperm counts. Most epidemiological studies have found a statistically significant risk of developing TC among infertile men compared to the general or fertile male populations. The concept of Testicular Dysgenesis Syndrome provides an explanatory model for the common etiology of MI, TC, cryptorchidism, and hypospadias. Clinical findings such as a history of cryptorchidism could increase the risk of developing TC in infertile men. Scrotal ultrasound evaluation for testis lesions and microlithiasis is important in infertile men. Sperm analysis parameters can be useful in assessing the risk of TC among infertile men. In the future, sperm and serum microRNAs (miRNAs) may be utilized for the non-invasive early diagnosis of TC and GCNIS in infertile men. Conclusions: MI is indeed a risk factor for developing testicular cancer, as demonstrated by various studies. All infertile men should undergo a risk assessment using clinical examination, ultrasound, and semen parameters to evaluate their risk of TC.

A novel mutation in the AMHR2 gene, resulting in persistent Müllerian duct syndrome presenting with bilateral cryptorchidism and obstructed inguinal hernia.

OBJECTIVES: To highlight important clinical aspects of Persistent Müllerian duct syndrome (PMDS). PMDS belongs to the group of differences of sex development. It is attributed to mutations in genes encoding for the anti-Müllerian hormone or its type II receptor (AMHR2) and inherited via an autosomal recessive transmission. CASE PRESENTATION: An 18-day-old male infant with known bilateral cryptorchidism, presented with left-sided obstructed inguinal hernia. The diagnosis of PMDS was considered during inguinal exploration as both testes together with uterus and fallopian tubes were recognized in the hernial sac. Histology confirmed the presence of Müllerian-derived tissues. Genetic testing revealed two different mutations of the AMHR2 gene, both with autosomal recessive transmission: a frequently encountered deletion of 27 pairs bases on exon 10 of this 11 exon gene and a novel deletion of 2 pairs bases on exon 6. CONCLUSIONS: This case is notable being the rarest type of PMDS, that of transverse testicular ectopia and associated with a novel AMHR2 gene mutation.

Testicular malignancy in persistent Mullerian duct syndrome: Experience from an apex cancer center with review of literature.

OBJECTIVES: Persistent Mullerian duct syndrome (PMDS) is a rare disorder of sexual differentiation resulting from aberrations in the Mullerian inhibiting factor (MIF) pathway, with consequent failure of regression of fetal Mullerian duct. The concomitant association of undescended testis increases the likelihood of developing testicular tumors in these patients. Due to its rarity, clinic-pathologic and treatment outcome data on testicular cancer in PMDS is sparse. We present our institutional experience and review published literature on testicular cancer in PMDS. MATERIAL AND METHODS: We retrospectively queried our institutional testicular cancer database for all patients with a diagnosis of testicular cancer and PMDS, between January 1980 and January 2022. Additionally, a Medline/PubMed search was performed for English language articles published during the same time period. Data on pertinent clinical, radiologic, and pathologic disease characteristics were abstracted, in addition to treatment received and outcomes. RESULTS: Of 637 patients treated for testicular tumors during the specified time period in our institution, 4 patients had a concomitant diagnosis of PMDS. Testicular tumor was pathologically confirmed as seminoma in 3, 1 had mixed germ cell tumor. All patients in our series presented with stage 2B or higher disease and required chemotherapy, either in the neoadjuvant or adjuvant setting, in addition to surgery. With a mean follow up of 67 months, all patients were disease free. Medline/PubMed search retrieved 44 articles (49 patients) of testicular tumors associated with PMDS, with majority (59%) presenting with a large abdominal mass. Only 5 cases (10%) had a preceding history of appropriately managed cryptorchidism. CONCLUSIONS: Testicular cancer in PMDS usually presents in adults with advanced stage disease resulting from neglected or inadequate management of cryptorchidism. Appropriate management of cryptorchidism in childhood is likely to decrease malignant degeneration, if not, enable early-stage diagnosis.

[A Case of Intra-Abdominal Testicular Cancer Occurring from an Overlooked Intra-Abdominal Testis in Undescended Testicular Surgery].

Here, we report an adult case of intra-abdominal testicular cancer after surgical treatment of an undescended testis in infancy. A 36-year-old male patient was accidentally diagnosed with a tumor in the pelvic cavity by ultrasonographic examination. He had hematuria and the human chorionic gonadotropin beta subunit level was slightly elevated. T2-weighedmagnetic resonance imaging revealed a well-defined and highly intense mass. Since these findings suggested intra-abdominal testicular cancer, laparoscopic surgery was performed to remove the mass. Laparoscopy revealed an intra-abdominal tumor accompanied by a looping vas deferens entering the left inguinal canal. The distal part of the looping vas had already been removed from the external inguinal ring. The pathological findings revealed a pT1 seminoma. The patient has been recurrence-free for 12 months. The present case implies the importance of careful investigation and treatment for intra-abdominal testicular cancer, since intra-abdominal testis might have been overlooked at the time of surgery for undescended testis.