Testicular Regression Syndrome Research Articles

Testicular Regression Syndrome: Histopathological Evaluation of 20 cases from Rural India with Review of Literature

ABSTRACT Context: Testicular regression syndrome (TRS), clinically termed “vanishing testes,” is a condition with atrophy of testes in late fetal or early neonatal life. The spermatic cord ends blindly or into a small fibrovascular nubbin. Histopathology reveals a fibrovascular nodule with associated hemosiderin-laden macrophages and dystrophic calcification. Few cases show the presence of seminiferous tubules and germ cells. The presence of germ cells is associated with the risk of developing a testicular germ cell tumor. Aims: To study the histopathological features of testicular nubbins and to determine the presence of germ cells and associated neoplasm. Settings and Design: It is a retro-prospective observational study carried out on patients referred to a pediatric surgical pathology center in Miraj, who were clinically diagnosed with undescended testis, over a period of 1 year. Data were collected after the study was approved by the IEC-MGCH on December 19, 2022. Materials and Methods: Twenty patients diagnosed with cryptorchidism, undescended testis, or atrophic testis were included. Findings of hematoxylin and eosin-stained slides of each case were noted, and Prussian Blue (special staining) was performed in four cases. Statistical analysis used: As this is a descriptive observational study, simple arithmetic calculations were performed. No unique statistical analysis was performed. Results: Among twenty cases of vanishing testes syndrome, 20 cases showed fibrovascular tissue only, and 1 case showed the presence of seminiferous tubules with Sertoli cells. Conclusions: Vanishing testes syndrome is a rare condition that is difficult to diagnose on clinical examination, and a definitive diagnosis may be missed if the pathologist is unaware of the condition. Also, there is a risk of germ cell tumor if there are residual germ cells in the testicular nubbin.

Bilateral Congenital Anorchidism: Case Study

Embryonic testicular regression syndrome (ETRS) or congenital bilateral anorchidism (CBA) is a highly rare syndrome defined by the complete absence of testicular tissue in a patient with a male karyotype. The phenotype varies depending on when gonadal regression occurs in utero. Clinically, a micropenis, hypoplastic scrotum, empty, without perceived testicles are observed. Hormonal assessments reveal collapsed or completely absent testosterone levels and AMH (anti-Mullerian hormone) levels. Diagnosis is confirmed by laparoscopic exploration. Management relies on androgen supplementation and placement of testicular prostheses.

P-51 Association of Bardet-Biedl syndrome with differences of sex development and pituitary hypoplasia

Abstract Introduction Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder involving hypogonadism manifested by cryptorchidism, micropenis and/or delayed puberty Clinical Case We report the case of a 13-year-old child, who was consulted for obesity and whose physical examination showed major signs of SBB: global obesity, polydactyly, learning difficulties and visual disorders. Genital examination revealed a 1 cm genital tubercle with a single orifice and two genital swelling without palpable gonads. Biological investigations revealed hypogonadotropic hypogonadism, corticotropic insufficiency, low AMH with a non- stimulable HCG test and a 46XY male karyotype. Pelvic MRI did not show any gonads or internal genitalia but noted ectopy and malrotation of the right kidney. The diagnosis of a testicular regression syndrome is very likely in this case. At the fundus photography: presence of bilateral retinal dystrophy with high myopia. At the hypothalamohypophyseal level: a strong pituitary hypoplasia was objectified. Conclusion BBS is a rare autosomal recessive multisystem ciliopathy. The incidence of BBS is 1 in 150,000–160,000 in Europe and North America. BBS is caused by a dysfunction of the gene coding for proteins that are implicated in the function of the primary cilia and in important signaling pathways. The core features of the syndrome include retinal degeneration, obesity, polydactyly, cognitive impairment, renal anomalies and urogenital malformations. To date, pathogenic variants in 26 genes have been shown to be involved in the molecular basis of this rare ciliopathy. To our knowledge, only one study conducted on 11 children with BBS found among them 7 cases of pituitary abnormalities, 4 of which showed hypoplasia. While no association with a testicular regression syndrome has been described. This makes our patient the first described association of these 3 pathologies.

A rare case of bilateral Vanishing Testicle Syndrome

Vanishing testicle syndrome (VTS) is due to regression of already formed testes. This could occur at any stage during or after testicular descent due any insult resulting in testicular atrophy. VTS is estimated to affect 1:1250 males. We present a rare case of a 12-year-old boy presenting with absent secondary sexual characteristics and short stature found to have bilateral vanishing testicle syndrome. His testes were impalpable at neonatal examination. At the age of 1.5 years an ultrasound scan detected the right testis in the inguinal ring, measuring 1.5 x 1 cm with features suggestive of ischaemia with likely acute or subacute torsion. The left testes was seen in the inguinal canal already atrophied by that time. Subsequently, on surgical exploration the right testis was found atrophied in the inguinal canal, and was replaced in the right sub-dartose pouch, but left testis could not be identified. Surprisingly, 4 months later laparoscopic exploration failed to identify either of the testes except for bilateral atrophied gubernaculum, indicating testicular regression. At the age of 7 years, magnetic resonance imaging confirmed the absence of either of the testes, with no remnants. On examination his height was 146.5cm, which was between the 25th and 50th percentile for that age, and below his mid-parental height range. He had no androgenic hair growth, testes were impalpable and had a prepubertal penis accounting to tanner stage of 1. He had hypergonadotrophic hypogonadism. Pubertal induction was done with testosterone injections which resulted in height gain and development of secondary sexual characteristics.Introduction: The entity Vanishing testicle syndrome (VTS) was coined by Abryaratne et al. in 1969, and is also referred to as "Testicular regression syndrome" [1][2]. The two essential diagnostic criteria are; visualizing the blind-ending spermatic vessels within the retro-peritoneum or spermatic vessels and vas deferens exiting a closed internal inguinal ring, and Testis not palpated during examination under anaesthesia[2][3]. A small fibrotic nodule or nubbin with dystrophic calcification and haemosiderin deposition is usually found at the end of the spermatic cord, with or without identifiable testicular or para-testicular structures [2][3]. Cryptorchidism is reported in 1 -4.6% full term and 1.1 -45.3% pre-mature male infants [4]. This prevalence of cryptorchidism decreases to 1 % by the age of 1 year [5]. Testes are non-palpable in 10 -20% cases of cryptorchidism, and of these VTS accounts for 35 - 60% [6] VTS occurs in < 5% cases of cryptorchidism [7]. VTS is estimated to affect 1:1250 males [8]. We present a rare case of bilateral VTS in a 12 year old boy who presented with short stature and absent secondary sexual characteristics with unpalpable testes.

DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.

The group of disorders known as 46,XY gonadal dysgenesis (GD) is characterized by anomalies in testis determination, including complete and partial GD (PGD) and testicular regression syndrome (TRS). Several genes are known to be involved in sex development pathways, however approximately 50% of all cases remain elusive. Recent studies have identified variants in DHX37, a gene encoding a putative RNA helicase essential in ribosome biogenesis and previously associated with neurodevelopmental disorders, as a cause of PGD and TRS. To investigate the potential role of DHX37 in disorders of sexual development (DSD), 25 individuals with 46,XY DSD were analyzed and putative pathogenic variants were found in four of them. WES analyses were performed on these patients. In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient; the p.(Leu467Val), predicted to be deleterious, was found together with an NR5A1 loss-of-function variant in patient 2; and, the p.(Val999Met) was identified in two unrelated patients, one of whom (patient 3) also carried a pathogenic NR5A1 variant. For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic inheritance is suggested. Our findings support the importance of DHX37 variants as a cause of disorders of sex development, implying a role in testis development.

Abdominal Cryptorchidism with Complete Dissociation between the Testis and Deferent Duct Mimicking Testicular Regression Syndrome

Complete separation of the deferent duct from the epididymis in cryptorchid testes residing in the abdomen is an extremely rare variant of developmental disorders of the testis and epididymis. Available sources mention only three clinical cases similar to our observations. The unique anatomic aspects of this disorder hamper the correct diagnosis of an intra-abdominal cryptorchid testis. Two boys with nonpalpable left-sided cryptorchidism underwent diagnostic laparoscopy, revealing an intra-abdominally located testis. The epididymis was completely separated from the deferent duct, and the epididymis and testis were supplied by testicular vessels. Exploration of the inguinal canal revealed blind-ending deferent ducts. The testis was brought down through the inguinal canal and fixed in the scrotum in both boys. The follow-up examination at 6 months revealed no signs of testicular atrophy or malposition of the testis in either patient. With our observations in mind, the exclusive use of a transscrotal or transinguinal approach as the initial surgical exploration in the treatment of patients with nonpalpable forms of cryptorchidism may be inappropriate. Careful laparoscopic examination of the abdominal cavity is indispensable in children with suspected testicular regression syndrome or nonpalpable forms of cryptorchidism.

Testicular regression syndrome: A retrospective analysis of clinical and histopathological features in 570 cases

This study aimed to analyze the clinical features and pathological findings of the largest reported case series of testicular regression syndrome (TRS). Data, including age, affected side, color Doppler ultrasound results, surgical methods, intraoperative conditions, and pathological examinations, of children with unilateral TRS who were treated in our center from December 2012 to November 2021 were retrospectively analyzed. A total of 570 patients were included in this study. The mean age at surgery was 38 (range, 5-193) months. There were 457 cases (80.2%) of left TRS. Preoperative color Doppler ultrasonography found nubbins in 172 cases (30.2%). The long diameter of the contralateral testis was 17.11 (±4.22) mm, and the volume was 0.81 (±1.15) ml. The long diameter was ≥1.6 cm in 62.0% of the patients (240/387) aged ≤3 years. Laparoscopy was performed as the initial surgical step in 513 cases, of which 96.7% of the children had closed internal rings. One or more lesions of fibrosis, hemosiderin, and calcification were found in 92.4% (474/513) of the excised remnants. Germ cells were present in 16 cases (3.1%). In conclusion, TRS is more common on the left side and is usually accompanied by a closed internal ring and compensatory hypertrophy of the contralateral testis. Germ cells are only present in cases where the spermatic vessels enters the internal ring. We recommend that further exploration and excision of the remnants may not be applicable in cases where only the vas deferens has entered the internal ring.

Primary amenorrhea revealing testicular regression syndrome in two sisters

Primary amenorrhea revealing testicular regression syndrome in two sisters

Neonatal hypogonadism due to rare testicular atrophy with congenital contralateral torsion: case report

The process of sexual differentiation involves genetic, hormonal and anatomical factors, and there may be several disorders evident at birth. Congenital testicular torsion associated with atrophy contralateral gonad in phenotypically male newborns, without alteration in development of the internal and external genital organs, is a rare condition and little reported in the literature. Thereby, we sought to report and discuss the clinical case which the presence of both clinical conditions was diagnosed in the perinatal period. Hormonal production of testicular androgens is confirmed by the development of the male genital system, both internal and external. It isn’t possible to determine whether the atrophic testis was caused by extrinsic compression of the vascular bundle due to torsion of contralateral testis, or by testicular regression syndrome, in which there in involution of the organ in utero as part of presentation of gonadal dysgenesis. The twisted testicle may have been regression, without hormone production by it, or there was hormonal production of congenitally atrophied testicle and later regressed. Regardless of this fact, early diagnosis is the cornerstone of the clinical condition, since it will invariably evolve with hypergonadotropic hypogonadism, with need for multidisciplinary follow-up.

A case report of vanishing testicle: radiological diagnosis and short review

BackgroundVanishing testicular syndrome is also known as testicular regression syndrome (TRS) is due to atrophy and disappearance of testis in the fetal life after the formation of the normal testis. It is a spectrum of disorders; clinical features are depending upon the stage of fetal or early neonatal life at which function of testicles ceases.Case presentationYoung 40-year-old male patient came for a routine master health checkup. On clinical examination he had a nonpalpable left testis, Rest of the clinical examinations are unremarkable. Referred to ultrasound (USG), for testis localization reveals the absence of left testis in the left scrotal sac and inguinal canal. Further MRI of the scrotum reveals the feature of TRS.ConclusionTRS in the 4th-decade adult is rarely reported in the literature. The asymptomatic presentation shows the least possibility of neoplasm in TRS patients.

Is Routine Excision of Dysplastic Testicular Remnants/Nubbins Associated with Nonpalpable Testis Necessary? Is Routine Fixation of Contralateral Solitary Testis Indicated? A Survey on the Prevalent Practice among Indian Pediatric Surgeons.

Dysplastic nubbin also referred to as testicular regression syndrome (TRS) is found in 5% of cases of the Non palpable testis (NPT). There is no consensus on the excision of the above and fixation of the contralateral solitary testis. We aimed to survey the prevalent practice of the same among members of the Indian Association of Pediatric Surgeons (IAPS). A structured questionnaire was sent through group e-mail and social media platforms to IAPS members to identify their practices in management. A total of 132 surgeons responded to the questionnaire. Excision of intra-abdominal and inguinoscrotal TRS remnants was practiced by 84% (95% confidence interval [CI] 77%-89%) and 82% (95% CI 74%-87%). Fixation of contralateral solitary testis was practiced by 62% (95% CI 53%-70%) in the above scenario. Among the respondents, 30% reported encountering torsion of solitary testis during their career and this experience was a significant factor (P = 0.01) in deciding contralateral orchidopexy. Scrotal infection/necrosis was not encountered by a majority (72%) and it was not a deterrent factor in preventing contralateral orchidopexy (P = 0.68). The majority of pediatric surgeons favored the removal of intra-abdominal/inguinoscrotal TRS remnants identified during laparoscopy for NPT. A majority favored sutureless fixation of the contralateral solitary testis.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Ectopic Testis and Its Relationship to Testicular Microlithiasis

Testicular microlithiasis (TM) has been defined as 5 or more echogenic petechial foci in a single view of a testicular ultrasound. Most cases are asymptomatic and are only found incidentally when testicular ultrasound is indicated for other conditions. The aim of our study is to evaluate the prevalence of testicular microlithiasis in children with ectopic testis and their association with testicular tumor. Methods:It is a retrospective study involving 8 patients who were diagnosed with TM in the pediatric surgery department of Monastir over a period of 16 years from 2003 to 2019. Results:The average age of children was 6.8 years old. The most common indication for US was cryptorchidism (5 patients); The most common other indications were scrotal pain (1 patient) and testicular mass (1 patient). Two boys had bilateral microlithiasis. We opted for orchidopexy in 6 children with undescended testes. Orchiectomy was indicated for testicular tumour in one case and for testicular regression syndrome in the other case. Two patients had pathologic confirmation of testicular microlithiasis. Patients follow-up was done by tumor marker assay and scrotal Doppler ultrasound. None of these patients developed testicular tumors with mean follow-up of two 2 years. Conclusion: Recent studies found that testicular ultrasonography for cryptorchidism will reveal a 10% incidence of TM in the ectopic testis. The incidence of malignant transformation in a cryptorchid testis associated with microlithiasis is approximately twofold to threefold greater than that of the normal cryptorchid testis. So, we currently recommend the perform intermittent radiologic surveillance for these population.

SUN-027 Testicular Regression Syndrome, an Underdiagnosed Cause of Hypergonadotropic Hypogonadism

Background: Testicular regression syndrome (TRS), also known as vanishing testes syndrome, is a condition of 46, XY males presenting with male phenotypic genitalia and testicular absence. Normal testes are thought to have once existed in fetal life and subsequently atrophied following a catastrophic event. It may present as partial or complete absence of testicular tissue. Fibrotic remnants are commonly found upon surgical exploration. Case: This is the case of a 20-year-old male with a birth-diagnosis of primary hypogonadism. The patient was born prematurely at 5 months following a motor vehicle accident that resulted in his mother’s death. Neonatal evaluation for cryptorchidism revealed no radiological evidence of intra-abdominal testicular mass. Referral to a pediatric-endocrinologist was done at early childhood. Testosterone replacement was started at 12 years of age and pubarche was adequate. After surgical exploration, a testicular remnant was surgically removed. Pathology report revealed fibrotic tissue, yet no histological testicular tissue was found. Due to lack of testes in the scrotum, testicular prosthesis was implanted at age 14, but the etiology of the hypogonadism was never elucidated. The patient was initially seen in our adult-endocrinology clinics at age 21. Upon evaluation, secondary sex characteristics were adequate for age. Penile length was of 3.5 inches. Bilateral testicular prostheses were palpable, and no gynecomastia was present. Despite testosterone replacement, total testosterone was 3.38 ng/ml (n; 2.41-8.27 ng/ml), FSH was 106 mIU/ml (n; 1.4-18.1 mIU/ml) and LH was 34.7 mIU/ml ml (n; 1.5-9.3 miu/ml). Based on history, laboratory workup and surgical pathology, TRS was presumed as the etiology of this patient’s hypogonadism. Testosterone therapy was adjusted to reach physiological expected levels. Conclusion: TRS is an underdiagnosed cause of hypergonadotropic hypogonadism. It is supposed that the initial embryologic development was normal, followed by a vascular accident. There is no clear recommended approach for evaluating a patient once the diagnosis of TRS is suspected. Diagnostic methods may include hormonal and karyotype testing, imaging, and surgical exploration. Furthermore, although clinical recommendations have been published for other disorders of sex development, TRS management has been understudied. Testosterone replacement therapy at the typical time of puberty ensures the development of secondary sexual characteristics, bone health and pubertal growth. Unlike Klinefelter syndrome and cryptorchidism, TRS has not been associated with increased risk of cancer. Thus, it is important to establish the etiology to avoid invasive and unnecessary workup, which will result in psychological distress and excessive healthcare costs.

Clinical and Histopathological Evaluations of Testicular Regression Syn-drome: A Case Report

BackgroundTesticular regression syndrome (TRS) is defined as the partial or total absence of testicular tissue in 46XY patients with normal external genitalia. The incidence of TRS has been reported to be less than 5% in patients with cryptorchidism. Herein, we report a case of a one-year old boy who underwent surgical exploration with an initial diagnosis of cryptorchidism.Case descriptiona one-year old male came to the outpatient clinic at Al Emadi Hospital, Doha, Qatar. Physical examination revealed normal external genitalia with palpable right testis and non-palpable left testis. The initial diagnosis was cryptorchidism. Testicular structure was not identified and a presumed testicular remnant in the left superficial inguinal ring was sent for histological examination. The histological examination revealed a fibrovascular nodule, spermatic cord structures, calcification and hemosiderin deposits supporting the diagnosis of TRS.ConclusionWhen patient fulfills clinical and pathological criteria for TRS, we should consider the possibility of orchiopexy and testicular prosthesis implantation to decrease the risk of testicular torsion and negative psychological effects.

Severe Degenerative Changes in Cryptorchid Testes in Japanese Black Cattle.

This is a histopathologic and endocrinologic study of 6 calves diagnosed with cryptorchidism. Cases 1-3 were diagnosed as resembling testicular regression syndrome. In cases 1 and 2, the extracted tissue was a small, firm, gray-white mass, and there was lack of obvious testicular tissue in case 3. Histopathologically, the excised tissue in cases 1-3 was a fibrotic testicular remnant with inflammation, mineralization, hemosiderin-laden macrophages or lipofuscin-laden macrophages, and lack of germ cells and interstitial endocrine cells. These findings were compared with cases 4-6, which were diagnosed as testicular hypoplasia due to cryptorchidism. These cases had small but otherwise grossly unremarkable intra-abdominal testicular tissue and histologically had a few germ cells and sustentacular cells with arrested spermatogenesis and an increase in interstitial endocrine cells. Cases 1-3 had more severe degenerative changes compared with cases 4-6. In case 2, the average diameter of the seminiferous tubules was much smaller than in cases 4-6, and there were few tubule cross sections. Anti-Müllerian hormone (214 pg/ml) was detected in the plasma of case 2. Based on the macroscopic and histopathologic findings as well as endocrinologic profiles, the testicular degeneration in cases 1-3 was considered similar to that of testicular regression syndrome. In this condition, it is thought that a normally developing intra-abdominal testis undergoes degeneration due to heat or a vascular disorder such as torsion.

Testicular regression syndrome: A series of 22 cases at a tertiary care hospital

Testicular regression syndrome (TRS) represents a congenital condition in which no normal testicular tissue can be identified following exploration for a clinically impalpable testis. It is seen in less than 5% of cryptorchidism cases, however accounts for 35-60% of clinically impalpable testis. To study the Clinicopathological spectrum of Testicular regression syndrome (TRS) and review the literature. Study design: The study included 22 patients with nonpalpable testis, who had undergone resection of testicular nubbins. Original diagnosis was studied in context of pathological recognition of TRS and additional sections and stains were examined. Pathological assessment included identification of epididymis and vas deferens, vascularised fibrous nodule (VFN), dystrophic calcification, hemosiderin and pampiniform plexus like veins. Stain for iron and calcium were performed. On secondary review, 21 out of 26 cases of undescended testis (UDT) showed features consistent with the diagnosis of TRS. On microscopy, VFN was observed in 17 (77.3%), calcification in 4 (18.2%), hemosiderin in 15 (68.2%), vas deferens in 13 (59%), epididymis in 11 (50%), prominent vessels in 21 (95.4%) and seminiferous tubules in 6 (27.3%) cases. The presence of dystrophic calcification and hemosiderin deposition with absent viable tissue points to the hypoxic injury to the testis. TRS theoretically carries a long-term risk for malignant degeneration therefore In the typical situation in which a blind-ending spermatic cord without viable testis is submitted for tissue analysis, it is imperative to characterize such cases as consistent with regressed testis thus eliminating the need for further surgical intervention.

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

PurposeXY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. MethodsWe performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. ResultsThirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10−10). Five variants are de novo (P value = 1.5 × 10−5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. ConclusionDHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.

Testicular Regression Syndrome: Practice Variation in Diagnosis and Management

Objective: The purpose of this study was to assess clinical practice patterns with regard to diagnosis and management of testicular regression syndrome (TRS), a condition in 46,XY males with male phenotypic genitalia and bilateral absence of testes. Methods: A retrospective review was conducted at two large pediatric academic centers to examine diagnostic and management approaches for TRS. Results: Records of 57 patients were reviewed. Diagnostic methods varied widely between patients and included hormonal testing, karyotype, imaging, and surgical exploration, with multiple diagnostic methods frequently used in each patient. Of the 30 subjects that had reached adolescence at the time of the study, 17 (57%) had gaps in care of more than 5 years during childhood. Thirty subjects had received testosterone replacement therapy at a mean age of 12.1 ± 1.0 years. Forty-seven percent had a documented discussion of infertility. Eighty-two percent discussed prosthesis placement, with 35% having prostheses placed. Twenty-three percent were seen by a psychosocial provider. The between-site differences were age at fertility discussion, age at and number of prostheses placed, and type/age of testosterone initiation. Conclusion: Our findings highlight the wide variation in diagnostic approaches, follow-up frequency, testosterone initiation, fertility counseling, and psychosocial support for patients with TRS. Developing evidence-based guidelines for the evaluation and management of TRS would help reduce inconsistencies in care and unnecessary testing. Ongoing follow-up and coordination of care, even during the years when no hormonal treatment is being administered, could lead to opportunities for psychosocial support and improved interdisciplinary approach to care. Abbreviations: AMH = antimüllerian hormone; CAH = congenital adrenal hyperplasia; DSD = differences/disorders of sex development; hCG = human chorionic gonadotropin; TRS = testicular regression syndrome.

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum.

46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). To report a gene for 46,XY GD etiology, especially for ETRS. Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. Tertiary Referral Center for differences/disorders of sex development (DSD). We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.