Moyamoya syndrome in a male pseudohermaphrodite patient with congenital adrenal hyperplasia - a rare association. Case report and review of literature.

BACKGROUND AND IMPORTANCE: Moyamoya syndrome causes progressive stenosis of intracranial internal carotid arteries and may be associated with genetic disorders like Down's or Turner's syndromes. We treated a male pseudohermaphrodite patient with congenital adrenal hyperplasia (CAH) with clinical and radiological features of moyamoya vasculopathy. To our knowledge, this association has not been reported. CLINICAL PRESENTATION: The 42-year-old patient presented with an intraventicular bleed. Cerebral angiography revealed moyamoya vasculopathy. He was hypertensive and had primary amenorrhea. Secondary sexual characteristics were poorly developed and he had ambiguous genitalia. Breast development was Tanner stage 3. Investigation revealed hypokalemia. With primary amenorrhea, persistent hypokalemia, hypertension and ambiguous genitalia, CAH was considered as a possibility and confirmed on hormone profile. Karyotyping revealed 46XY pattern. Abdominal ultrasound revealed hyperplasia of the adrenal glands, absent uterus and ovaries and ectopic testicles in inguinal canals. He was put on steroids and his blood pressure controlled. CONCLUSIONS: To the best of our knowledge we report the first case of moyamoya syndrome occurring in association with CAH.

Behavioral Health Diagnoses in Youth with Differences of Sex Development or Congenital Adrenal Hyperplasia Compared with Controls: A PEDSnet Study.

OBJECTIVE: To evaluate the odds of a behavioral health diagnosis among youth with differences of sex development (DSD) or congenital adrenal hyperplasia (CAH) compared with matched controls in the PEDSnet database. STUDY DESIGN: All youth with a diagnosis of DSD (n = 1216) or CAH (n = 1647) and at least 1 outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables (1:4) with controls (n = 4864 and 6588, respectively) using multivariable logistic regression. The likelihood of having behavioral health diagnoses was examined using generalized estimating equations. RESULTS: Youth with DSD had higher odds of a behavioral health diagnosis (OR, 1.7; 95% CI, 1.4-2.1; P < .0001) and neurodevelopmental diagnosis (OR, 1.7; 95% CI, 1.4, 2.0; P < .0001) compared with matched controls. Youth with CAH did not have an increased odds of a behavioral health diagnosis (OR, 1.0; 95% CI, 0.9, 1.1; P = .9) compared with matched controls but did have higher odds of developmental delay (OR, 1.8; 95% CI, 1.4, 2.4; P < .0001). CONCLUSIONS: Youth with DSD diagnosis have higher odds of a behavioral health or neurodevelopmental diagnosis compared with matched controls. Youth with CAH have higher odds of developmental delay, highlighting the need for screening in both groups.

Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6-CDG.

Congenital disorders of glycosylation (CDG) are an expanding group of metabolic disorders that result from abnormal protein glycosylation. A special subgroup of CDG type II comprises defects in the Conserved Oligomeric Golgi Complex (COG). In order to further delineate the genotypic and phenotypic spectrum of COG complex defect, we describe a novel variant of COG6 gene found in homozygosity in a Moroccan patient with severe presentation of COG6-CDG (OMIM #614576). We compared the phenotype of our patient with other previously reported COG6-CDG cases. Common features in COG6-CDG are facial dysmorphism, growth retardation, microcephaly, developmental disability, liver or gastrointestinal disease, recurrent infections, hypohidrosis/hyperthermia. In addition to these phenotypic features, our patient exhibited a disorder of sexual differentiation, which has rarely been reported in COG6-CDG. We hypothesize that the severe COG6 gene mutation interferes with glycosylation of a disintegrin and metalloprotease family members, inhibiting the correct gonadal distal tip cells migration, fundamental for the genitalia morphogenesis. This report broadens the genetic and phenotypic spectrum of COG6-CDG and provides further supportive evidence that COG6-CDG can present as a disorder of sexual differentiation.

Establishing an Institutional Gonadal Tissue Cryopreservation Protocol for Patients with Differences of Sex Development.

PURPOSE: Many individuals with differences of sex development experience subfertility. We describe a novel gonadal tissue cryopreservation protocol for those individuals. MATERIALS AND METHODS: Before 2018 patients with differences of sex development electing gonadal tissue cryopreservation were enrolled in a cancer focused protocol. Thereafter, our hospital developed a protocol specifically for these patients undergoing gonadectomy due to neoplasia risk. Protocol development steps and procedures are reported. A retrospective chart review was conducted for patient characteristics and cryopreservation choices. RESULTS: During the institutional review board approval process there were multidisciplinary meetings with stakeholders. The main concerns discussed included preoperative counseling, pathological evaluation and final tissue disposition. Detailed multidisciplinary preoperative counseling is provided regarding potential gonadal tissue cryopreservation for patients undergoing gonadectomy. For enrolled patients the gonad is bisected after removal, with half being sent to pathology and half being processed for cryopreservation. If neoplasia is noted, cryopreserved tissue is recalled for further pathological analysis. Postoperative counseling is performed after pathology results are available, and the final gonadal tissue cryopreservation decision is made. During the study period 7 patients with 5 diagnoses and a median age of 10.99 years (IQR 1.29 to 14.84) elected to attempt gonadal tissue cryopreservation. Of the patients 4 (57%) had germ cells and elected to store tissue. CONCLUSIONS: Gonadal tissue cryopreservation at the time of gonadectomy is feasible for patients with differences of sex development at risk for gonadal neoplasia. The protocol described represents a template for institutions wishing to offer gonadal tissue cryopreservation to patients electing gonadectomy. More than half of patients thus far have cryopreserved gonadal tissue.

Rare and special robotic surgery indications in the pediatric population: ectopic organs and differences of sexual development.

BACKGROUND AND OBJECTIVE: Differences of sexual development (DSD) affect the development of internal reproductive organs and external genitalia. Ectopic kidney is a rare and challenging pathology causing amongst others incontinence and recurrent urinary tract infections. Those pathologies may in certain cases be an indication for surgery. This manuscript aims to evaluate the role of robot-assisted laparoscopy in the surgical treatment of patients with ectopic kidneys or DSD. MATERIALS AND METHODS: A prospective database is maintained in a tertiary referral center with all robotic surgeries performed in children. From this database, a prospective series of robot-assisted resection of embryologic remnants located in the pelvis was extracted: resection of a prostatic utricle cyst, removal of ectopic non-functional kidneys, and resection of a hemi-uterus. RESULTS: From an initial database including 72 patients, six patients met the inclusion criteria. Three male patients presenting with utricle cysts, two young girls presenting with ectopic kidneys, and one young boy with pelvic embryological remnants of the uterus, were further evaluated. CONCLUSION: Surgical treatment of patients with DSD is safe, feasible, and a good indication for robot-assisted laparoscopic surgery, as both deep dissection and reconstruction in a limited surgical field are requested.

A Rare Case of Infertility: SRY Positive 46, XX Testicular Disorder of Sexual Differentiation.

Aim To highlight the complexity of infertility causes by describing the rare case of a man with a testicular disorder of sexual differentiation. Diagnosis A 33 years old Caucasian male presented with a 3-year-old history of primary infertility. His investigations revealed a low testosterone and a raised LH and FSH levels. A sample sent for sperm analysis revealed azoospermia. Chromosomal analysis and karyotyping revealed a 46 XX SRY positive karyotype. Treatment The patient was initiated on testosterone replacement and on calcium/vitamin D supplements. Conclusion Fertility evaluation requires complex assessments and a broad knowledge of possible causes.

Predictors of Psychosocial Distress in Parents of Young Children with Disorders of Sex Development.

PURPOSE: We evaluated demographic, financial and support predictors of distress for parents of young children with disorders of sex development including atypical genital development, and characterized early parental experiences. This work extends our previous findings to identify those parents at risk for distress. MATERIALS AND METHODS: Participants included mothers (76) and fathers (63) of a child (78) diagnosed with disorders of sex development characterized by moderate to severe genital atypia. Parents completed a demographic questionnaire, measures of anxious and depressive symptoms, quality of life, illness uncertainty and posttraumatic stress symptoms, and rated their satisfaction with the appearance of their child's genitalia. RESULTS: Depressive and posttraumatic stress symptoms of caregivers were comparable to standardized norms while levels of anxious symptoms were below norms. A subset of parents reported clinically elevated symptoms. Overall 26% of parents reported anxious symptoms, 24% reported depressive symptoms and 17% reported posttraumatic stress symptoms. Levels of illness uncertainty were lower than those of parents of children with other chronic illnesses. Differences by parent sex emerged, with mothers reporting greater distress. Lower income, increased medical care and travel expenses, and having no other children were related to increased psychosocial distress. CONCLUSIONS: Early psychosocial screening is recommended for parents of children with disorders of sex development. Clinicians should be aware that financial burden and lack of previous parenting experience are risk factors for distress.

Genotype-phenotype correlation, gonadal malignancy risk, gender preference, and testosterone/dihydrotestosterone ratio in steroid 5-alpha-reductase type 2 deficiency: a multicenter study from Turkey.

BACKGROUND: Studies regarding genetic and clinical characteristics, gender preference, and gonadal malignancy rates for steroid 5-alpha-reductase type 2 deficiency (5α-RD2) are limited and they were conducted on small number of patients. OBJECTIVE: To present genotype-phenotype correlation, gonadal malignancy risk, gender preference, and diagnostic sensitivity of serum testosterone/dihydrotestosterone (T/DHT) ratio in patients with 5α-RD2. MATERIALS AND METHODS: Patients with variations in the SRD5A2 gene were included in the study. Demographic characteristics, phenotype, gender assignment, hormonal tests, molecular genetic data, and presence of gonadal malignancy were evaluated. RESULTS: A total of 85 patients were included in the study. Abnormality of the external genitalia was the most dominant phenotype (92.9%). Gender assignment was male in 58.8% and female in 29.4% of the patients, while it was uncertain for 11.8%. Fourteen patients underwent bilateral gonadectomy, and no gonadal malignancy was detected. The most frequent pathogenic variants were p.Ala65Pro (30.6%), p.Leu55Gln (16.5%), and p.Gly196Ser (15.3%). The p.Ala65Pro and p.Leu55Gln showed more undervirilization than the p.Gly196Ser. The diagnostic sensitivity of stimulated T/DHT ratio was higher than baseline serum T/DHT ratio, even in pubertal patients. The cut-off values yielding the best sensitivity for stimulated T/DHT ratio were ≥ 8.5 for minipuberty, ≥ 10 for prepuberty, and ≥ 17 for puberty. CONCLUSION: There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.

Surgical management of hypospadias in cases with concomitant disorders of sex development.

INTRODUCTION: To review the surgical treatment of hypospadias (HP) associated with disorders of sex development (DSD). PATIENTS AND METHODS: HP cases were assessed for DSD by gross examination for atypical external genitalia, and assessment of hormone levels and karyotype. There were 58 HP cases with concomitant DSD treated between 1999 and 2017. DSD classification, type of HP, sex assignment, hormonal abnormality, surgical strategy, and post-urethroplasty complications (post-UPC) were reviewed. RESULTS: DSD were sex chromosome abnormalities (n = 4), 46,XY (n = 51), 46,XX (n = 1), and 47,XY + 21 (n = 2). HP was perineal: (n = 26), scrotal: (n = 16), penoscrotal: (n = 15), and midshaft: (n = 1); repair was primary (n = 6) or staged (n = 52). Mean age at final urethroplasty (UP) was 4.12 ± 0.21 years; all cases had soft tissue interposition at UP. At mean follow-up 5.16 ± 0.56 years after final UP, observed post-UPC (n = 8; 13.8%) were urethral stenosis (n = 3), urethral diverticulum (n = 2), urethrocutaneous fistula (n = 2), and curvature (n = 1). Mean onset of post-UPC was 1.24 ± 0.77 years (range 0.1-6.3). The second half of our cases (n = 29; treated 2015 ~) had significantly less post-UPC (0/29; 0%) than the first half (8/29; 27.6%) (p = 0.0075). CONCLUSIONS: Although UP for HP + DSD was formidably challenging, we achieved a significant decrease in post-UPC through a combination of surgical techniques and experience.

A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development.

Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist.

Presence of Germ Cells in Disorders of Sex Development: Implications for Fertility Potential and Preservation.

PURPOSE: We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future fertility potential is possible. We hypothesized that germ cells are present but vary by age and diagnosis. MATERIALS AND METHODS: We reviewed histology from patients with disorders of sex development who underwent gonadectomy/biopsy from 2002 to 2014 at a single institution for pathological classification of the gonad, composition of gonadal stroma and germ cell presence. RESULTS: A total of 44 patients were identified and germ cells were present in 68%. The presence and average number of germ cells per mm2 were analyzed by gonad type and diagnosis. By gonad type all ovotestes, most testes, ovaries and dysgenetic testes, and 15% of streak gonads had germ cells present. By diagnosis germ cells were present in all patients with complete androgen insensitivity syndrome, Denys-Drash syndrome, SRY mutation, mixed gonadal dysgenesis, ovotesticular conditions and StAR (steroid acute regulatory protein) deficiency, in some patients with persistent müllerian duct syndrome, XO/XY Turner syndrome and disorders of sex development not otherwise specified, and in none with complete or partial gonadal dysgenesis. Germ cells were present in the gonads of 88% of patients 0 to 3 years old, 50% of those 4 to 11 years old and 43% of those older than 12 years. CONCLUSIONS: Germ cells were present in the majority of our cohort and the presence decreased with age. This novel, fertility driven evaluation of germ cell quantity in a variety of disorders of sex development suggests that fertility potential may be greater than previously thought. Further studies must be done to evaluate a larger population and examine germ cell quality to determine the viability of these germ cells.

Undescended testis: What paediatricians need to know.

Undescended testis (UDT) occurs when something goes wrong with testicular descent from high in the abdominal cavity to the scrotum. Normal descent occurs in two steps, with the transabdominal phase controlled by a new testicular hormone, insulin-like hormone 3, and the inguinoscrotal phase controlled by androgens. The latter phase requires a complex process of migration from the inguinal abdominal wall to the scrotum and is commonly defective, leading to the high incidence (2-4%) of UDT at birth. The clinical examination of babies and infants aims to confirm the persistence of congenital UDT by 3-6 months, so surgery can be optimally timed at 6-12 months. For those boys who develop acquired UDT later in childhood, the 'ascending' testis often needs surgery between 5 years and 10 years, so all boys should be screened again for UDT at school entry.

Coexistence of Trisomy 13 and SRY (-) XX Ovotesticular Disorder of Sex Development.

INTRODUCTION: Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation characterized by the presence of both testicular and ovarian tissue in an individual and the majority of cases have been reported with 46,XX karyotype. In 46,XX cases, testicular differentiation may occur due to the translocation of SRY to the X chromosome or to an autosome. CASE REPORT: Herein, we present a female newborn with a combination of trisomy 13 and SRY (-) XX OT-DSD. CONCLUSION: Trisomy 13 is a relatively common and well-known chromosomal disorder in which disorders of sexual differentiation are not frequent. In the absence of SRY, overexpression of pro-testis genes, or decreased expression of pro-ovarian/anti-testis genes have been suggested as underlying mechanisms of testicular formation. The findings in this patient were suggestive of an underlying genomic disorder associated with FGF9 and/or SPRY2.

Crustacean intersexuality is feminization without demasculinization: implications for environmental toxicology.

The dysfunction associated with intersexuality in vertebrates and molluscs is often a serious threat to ecosystems. Although poorly understood, crustacean intersexuality is associated with contamination and includes forms linked to increased sex-ratio distorting parasites at polluted sites. Despite the importance of crustaceans for monitoring vulnerable aquatic habitats, little is known about the molecular basis of this abnormal sexual differentiation and any associated sexual dysfunction. To increase the relevance of crustaceans to environmental toxicologists, we comprehensively analyzed gene expression in amphipods presenting parasite- and nonparasite-associated intersexuality. Our findings reveal existing vertebrate biomarkers of feminization should not be applied to crustaceans, as orthologous genes are not induced in feminized amphipods. Furthermore, in contrast to vertebrates, where feminization and intersexuality is often associated with deleterious demasculinization, we find males maintain masculinity even when unambiguously feminized. This reveals a considerable regulatory separation of the gene pathways responsible for male and female characteristics and demonstrates that evidence of feminization (even if detected with appropriate biomarkers) is not a proxy for demasculinization in crustaceans. This study has also produced a comprehensive spectrum of potential molecular biomarkers that, when combined with our new molecular understanding, will greatly facilitate the use of crustaceans to monitor aquatic habitats.

Loss-of-function mutation in GATA4 causes anomalies of human testicular development.

Approximately 1 of every 250 newborns has some abnormality of genital and/or gonadal development. However, a specific molecular cause is identified in only 20% of these cases of disorder of sex development (DSD). We identified a family of French origin presenting with 46,XY DSD and congenital heart disease. Sequencing of the ORF of GATA4 identified a heterozygous missense mutation (p.Gly221Arg) in the conserved N-terminal zinc finger of GATA4. This mutation was not observed in 450 ancestry-matched control individuals. The mutation compromised the ability of the protein to bind to and transactivate the anti-Müllerian hormone (AMH) promoter. The mutation does not interfere with the direct protein-protein interaction, but it disrupts synergistic activation of the AMH promoter by GATA4 and NR5A1. The p.Gly221Arg mutant protein also failed to bind to a known protein partner FOG2 that is essential for gonad formation. Our data demonstrate the key role of GATA4 in human testicular development.

Bilateral sertoli and interstitial cell tumours in abdominal testes of a goat with polled intersex syndrome (PIS).

An 8-year-old, mixed breed, polled goat was presented for evaluation of male-like behaviour. Clinical findings included clitoromegaly, a heavily muscled neck, pronounced beard, and erect dorsal guard hairs, which are phenotypic characteristics commonly observed in intersex animals. Transrectal ultrasonography revealed the presence of two abdominal masses caudolateral to the uterine horns. Serum concentration of estradiol was elevated. Genetic evaluation was compatible with polled intersex syndrome defined by an XX karyotype without a Y chromosome or SRY gene. Based on gross and histologic evaluation, the abdominal masses were determined to be intra-abdominal testes, each of which was effaced by Sertoli cell and interstitial (Leydig) cell tumours. The Sertoli cell tumours (SCTs) represented two unique histologic patterns. Regardless of pattern, neoplastic Sertoli cells were consistently lipid laden and positive for vimentin. Interstitial cell tumours (ICTs) were negative for vimentin. Clinical and histopathologic findings suggest that prolonged exposure to steroids secreted by neoplastic Sertoli cells contributed to virilization. In addition, results from immunohistochemistry indicated that vimentin may be a valuable immunodiagnostic tool for differentiation between interstitial and Sertoli cell tumours in goats.

Increased occurrence of disorders of sex development, prematurity and intrauterine growth restriction in children with proximal hypospadias associated with undescended testes.

PURPOSE: Proximal hypospadias represents 20% of hypospadias cases, which are considered to have a higher incidence of associated urological, nonurological, developmental and sexual development disorders, and chromosomal anomalies. We compared associated anomalies in boys with proximal hypospadias and undescended testis with those in boys with proximal hypospadias and descended testes. MATERIALS AND METHODS: We reviewed the medical records of 69 boys who underwent 2-stage hypospadias repair for proximal hypospadias at a single institution during the 11-year period of 2001 to 2011. Collected data included demographics, birth history, associated urological and extra-urological anomalies, karyotype analysis and gonad palpability. Patients were divided into group 1-those with proximal hypospadias and undescended testis, and group 2-those with proximal hypospadias and descended testes. Statistical analysis was performed using the 2-tailed Fisher exact test. RESULTS: There were 17 patients (25%) in group 1 with a median age of 2.2 years and 52 in group 2 (75%) with a median age of 2 years. Children in group 1 had a higher incidence of XY nondysgenetic testicular sexual development disorder (8 vs 11, p = 0.06), premature birth (9 vs 10, p = 0.01) and intrauterine growth restriction (8 each) than children in group 2 (p = 0.01). CONCLUSIONS: Prematurity and intrauterine growth restriction are significantly associated with proximal hypospadias and undescended testis. Also, due to the 28% incidence of an underlying sexual development disorder, male infants with proximal hypospadias should undergo multidisciplinary evaluation.

A patient with a unique frameshift mutation in GPC3, causing Simpson-Golabi-Behmel syndrome, presenting with craniosynostosis, penoscrotal hypospadias, and a large prostatic utricle.

We present a Hispanic male with the clinical and molecular diagnosis of Simpson-Golabi-Behmel syndrome (SGBS). The patient was born with multiple anomalies not entirely typical of SGBS patients, including penoscrotal hypospadias, a large prostatic utricle, and left coronal craniosynostosis. In addition, he demonstrated endocrine anomalies including a low random cortisol level suspicious for adrenal insufficiency and low testosterone level. To our knowledge, this is the first report of a prostatic utricle in SGBS and the second report of craniosynostosis. The unique disease-causing mutation likely arose de novo in the mother. It is a deletion-insertion that leads to a frameshift at the p.p. S359 [corrected] residue of GPC3 and a premature stop codon after five more amino acids. p. S359 [corrected] is the same residue that is normally cleaved by the Furin convertase, although the significance of this novel mutation with respect to the patient's multiple anomalies is unknown. We present this case as the perinatal course of a patient with unique features of SGBS and a confirmed molecular diagnosis.

Ambiguous genitalia and hypertension in a patient with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is an uncommon condition. Its clinical presentation with hypertension is rare. Deficiency of the steroid 11-beta-hydroxylase accounts for less than 10% of CAH. We report a case of a 19-year-old patient who presents with hypertension with ambiguous genitalia secondary to adrenal steroidogenesis dysfunction. We also discuss the defects in adrenal steroidogenesis and clinical phenotypes of CAH.