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We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection. [ABSTRACT FROM AUTHOR]

Background: In 21-hydroxylase deficiency (21-OHD), there is an influence of genotype on the severity of external genitalia virilization. However, females carrying mutations predicting a similar impairment of enzymatic activity present a wide variability of genital phenotypes. In such cases, interindividual variability in genes related to the sex steroid hormone pathway could play a role. Objective: To evaluate the influence of POR, HSD17B5 and SRD5A2 variants on the severity of external genitalia virilization in 21-OHD females. Design and Patients: Prader stages were evaluated in 178 females with 21-OHD from a multicenter study. The 21- OHD genotypes were divided into two groups according to their severity: severe and moderate. The influences of the POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants on the degree of external genitalia virilization were analyzed. Results: The POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants were found in 25, 33, 17, 1, and 31% of the alleles, respectively. In uni- and multilinear regression, HSD17B5 c.-210A>C has a significant influence on the degree of external genitalia virilization. This variant was also identified with a higher frequency in the most severely virilized females. Conclusion: We demonstrated that a variant in the promoter region of HSD17B5 related to fetal androgen synthesis influences the genital phenotype in 21-OHD females. [ABSTRACT FROM AUTHOR]

Background: Mature cystic teratomas are the most common form of ovarian tumor in children and adolescents. These tumors are mostly benign and non-secreting. Virilization from an ovarian teratoma is exceptionally rare in pediatrics. Equally rare is the association of ovarian teratomas with auto-immune encephalitis. Methods: We describe the case of a 15-year-old girl with menstrual abnormalities and virilization, who had a past medical history of encephalitis of an unknown etiology 16 months prior to presentation. Results: Endocrine evaluation revealed an elevated serum testosterone and 17-hydroxy progesterone. A large left ovarian tumor was seen on a CT scan. Surgical excision revealed a mature cystic teratoma containing 6 liters of clear fluid with high androgen levels. Antibodies to the N-methyl-D-aspartate receptor of the hippocampus were detected in pre-operatively archived serum, but undetectable 6 months postoperatively. Immunohistochemistry studies on the tumor sections revealed that the antibodies in the patient’s serum reacted with areas of the tumor expressing the N-methyl-D-aspartate receptor. Postoperatively, the patient’s menstrual cycles became regular and her behavioral problems resolved. Her testosterone levels fell precipitously as well. Conclusion: Both virilizing mature cystic teratomas and teratoma-associated encephalitis are extremely rare in the pediatric population. We report on the first instance of these 2 rare entities occurring in the same patient. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Adenomas of the adrenal gland are rare causes of virilization in childhood. Case Report: A girl aged 2 years and 4 months presented with pubarche, distinct clitoral hypertrophy, tall stature, and increased height velocity. Plasma testosterone and dehydroepiandrosterone were elevated. Androgens remained unchanged after adrenocorticotropic hormone, and dexamethasone administrations. Ultrasound examination and magnetic resonance imaging indicated an extra-adrenal mass adjacent to the left adrenal gland, which was removed by endoscopic surgery. However, plasma androgens remained elevated and 131I-iodomethyl-norcholesterol scintigraphy revealed tracer enhancement in the right adrenal gland, which was consecutively removed. Virilization regressed after extirpation of the adenomas and height velocity normalized. Results: Histology revealed a circumscribed adenoma in the right adrenal gland and an epithelial mass with adrenal cortical cells in the left-sided ectopic tumor. In the ectopic tumor, melanocortin 2 receptor expression was augmented threefold compared to the control, indicating adrenal origin. Conclusions: In this young girl, virilization is due to concomitant ectopic and intra-adrenal adenomas of the adrenal cortex. By melanocortin 2 receptor expression, it was confirmed that the ectopic adenoma derived from the adrenal cortex. Specific scintigraphy, if available, assists in allocating the source of androgen hypersecretion. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Hyperandrogenism is a rare symptom of juvenile ovarian granulosa cell- tumors (JGCTO). This study aimed to determine whether hyperandrogenism was related to overexpression of SOX9, decreased expression of FOXL2 or absent aromatase expression in tumor with particular scheme of expression of P450scc and P450c17α. Methods: Through a nationwide study including the French Society of Pediatric Oncology, 6/30 patients with JGCTO presented with clinical hyperandrogenism and high plasma testosterone. Tumor specimens underwent immunofluorescence (SOX9, FOXL2) and immunochemistry (aromatase, P450scc, P450c17α). Results were compared with patients without hyperandrogenism. Results: SOX9 was expressed in the granulosa cell nucleus in 2/6 cases but also in 9/24 tumors without hyperandrogenism (p = n.s.). FOXL2 was absent or decreased in 3/6 cases of JGCTO with hyperandrogenism with no statistical difference from the group without this symptom. In 6/6 patients, the intratumoral expression of aromatase was absent (n = 5) or dramatically reduced (n = 1). In contrast, 15/24 patients without virilization exhibited conserved aromatase expression in their tumor (p < 0.05). A variable number of tumoral cells expressed P450scc while some interstitial cells were focally immunopositive for P450c17α. Conclusion: Unusual virilization in girls with JGCTO is not explained by a dysregulation in SOX9 or FOXL2 expression, but is related to a localized defect of aromatase expression in granulosa cells and to the ability of interstitial cells to produce testosterone. [ABSTRACT FROM AUTHOR]

Background: We present a 12-year-old girl with a 5-year history of progressive virilization. Results: Regarding elevated plasma levels of 17-hydroxyprogesterone (17-OHP) and androgens, normal ultrasound and CT scan of ovaries and adrenal glands, the nonclassic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency was presumed the cause of virilization. As the glucocorticoid therapy did not normalize high levels of 17-OHP and androgens, and the DNA analysis did not demonstrate a mutation causing CAH, a laparotomy was performed. Near the right ovary a tumor was found and extirpated. Pathohistological studies determined it to be a rare steroid cell tumor, ‘not otherwise specified’. Within the next months the signs of virilization resolved and menarche occurred. Conclusions: Steroid cell tumor should be considered in differential diagnosis of virilization in childhood. Regarding the age of our patient and pathohistological findings of the tumor, her prognosis is favorable.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aim: 11-β-hydroxylase deficiency (11βOHD) is caused by CYP11B1 gene defects and leads to congenital adrenal hyperplasia associated with hypertension. Recently, a novel L299P mutation has been described in a compound heterozygous male individual. We observed two 46,XX siblings with a homozygous L299P mutation and investigated the functional properties of this CYP11B1 variant. Patients: The index patient from a consanguineous Turkish family showed complete external virilization and was diagnosed incidentally at the age of 19 months during hospital admission for severe combined bacterial (urosepsis) and viral (CMV and EBV) infection. The younger sibling was diagnosed at the age of 5 months. Their genital phenotype was identical and both demonstrated borderline elevated blood pressure. Results: Biochemical findings revealed 11βOHD. A homozygous L299P mutation of the CYP11B1 gene was detected. In vitro expression studies performed in HCT116 cells showed a markedly decreased CYP11B1 activity in the L299P mutant (1.6 ± 0.8%) for the conversion of 11-deoxycortisol to cortisol. Conclusions: Our study provides clear data on the functional properties and clinical phenotype in 46,XX individuals homozygous for this point mutation. Adrenal insufficiency might have contributed to the severe infectious disease that was present in the index patient at diagnosis. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Premature pubarche is associated with conditions such as virilizing congenital adrenal hyperplasia, androgen-secreting tumors, and exogenous exposure to androgen products. We describe the clinical and hormonal features of a series of children who were referred to endocrine evaluation due to premature pubarche. Methods: This is a retrospective case series study of 14 children with premature pubarche and/or virilization. Five were unintentionally exposed to testosterone gel (parental use). Nine patients were intensely exposed to diaper rash prevention creams. Clinical and laboratory data were revised. Results: Moderate to severe virilization was detected in the 5 patients (2 boys and 3 girls) who were exposed to testosterone gel. These patients had pubic hair development associated with clitoromegaly (3/3), penile enlargement (2/2), and accelerated growth (5/5). Testosterone levels were elevated in 4/5 patients associated with normal prepubertal gonadotropin levels and adrenal androgen precursors. The 9 children who were intensely exposed to diaper rash prevention creams had mild pubarche (intermediate hair) without any other clinical manifestation of pubertal development. Three of them exhibited pubic hair thinning after cream withdrawal. Conclusion: Unintentional topical androgen exposure or the intense use of diaper rash prevention cream should be ruled out in children with precocious pubarche and/or virilization signs to avoid misdiagnosis and expendable investigation. [ABSTRACT FROM AUTHOR]

Introduction: The variants in the zinc finger (ZF) domains 1–3 in WT1 are one of the major causes of 46,XY disorders of sex development (DSD). Recently, variants in the fourth ZF (ZF4 variants) were reported to cause 46,XX DSD. However, all the 9 patients reported were de novo, and no familial cases were identified. Case Presentation and Results: The proband (16-year-old social female) had a 46,XX karyotype with dysplastic testes and moderate virilization in genitalia. A ZF4 variant, p.Arg495Gln, in WT1 was identified in the proband, her brother, and mother. The mother did not show any virilization with normal fertility, and the 46,XY brother developed normal puberty. Conclusion: The phenotypic variations due to the ZF4 variant are extremely broad in 46,XX cases. [ABSTRACT FROM AUTHOR]

Deficiency of 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) is a rare type of congenital adrenal hyperplasia (CAH), causing impaired steroid hormone production in both adrenals and gonads. Phenotype ranges, according to the genetic defect, from the salt-wasting form in both sexes to undervirilization in males and virilization in females. We present a 13-month-old male infant who was admitted to the hospital with signs of adrenocortical insufficiency and genital ambiguity. Clinical presentation, hormonal profile, laboratory evaluation, and karyotype were suggestive of the salt-wasting form of CAH due to 3βHSD2 deficiency. Mutational analysis revealed a missense mutation c.776C>T (p.Thr259Met), inherited by the mother, and a frameshift deletion c.818-819delAA (p.Lys273ArgFs*7), inherited by the father. Both mutations are considered pathogenic. To our knowledge this is the first case of an undervirilized male infant with salt wasting bearing this pathogenic frameshift deletion p.Lys273ArgFs*7 in compound heterozygosity with the missense mutation p.Thr259Met. [ABSTRACT FROM AUTHOR]

Background: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed “minipuberty” of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. Methods: We measured serum total T and free T in saliva using liquid chromatographytandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1–6 months, and in 12 adolescents, aged 11–17 years. Results: Total serum T in all infants was, as expected, high (172 ± 78 ng/dL) while salivary T was low (7.7 ± 4 pg/mL or 0.45 ± 0.20%). In contrast, salivary T in the adolescents was much higher (41 ± 18 pg/mL or 1.3 ± 0.36%) in relation to their total serum T (323 ± 117 ng/dL). We provide for the first time reference data for salivary T in infants. Conclusion: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance. [ABSTRACT FROM AUTHOR]

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3-4.6 cm. If Ox dosages <0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization (including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated, or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03-0.05 mg/kg/day starting from the age of 8-10 years onwards can be considered. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Although it was common in the 1970s–1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. Methods: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. Results: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4–5 breast development at the last assessment. Conclusion: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor. [ABSTRACT FROM AUTHOR]

Introduction and Objective: Prenatal suspicion of disorders/differences of sex development (DSDs) is a relatively new phenomenon. The aim of this study was to review the prenatal findings of DSD cases postnatally diagnosed in our tertiary referral center. Methods: We evaluated 57 DSD cases with sex ambiguity who had undergone prenatal ultrasound with phenotypic sex assessment and/or cell-free fetal DNA (cffDNA) for genotypic sex assessment. Results: Prenatal cffDNA had been performed in 32 cases, being positive (suggestive of male genotypic sex) in 26 and negative (suggestive of female genotypic sex) in 6. Five with cffDNA negative had a prenatal ultrasound indicating female external genitalia, in turn, in those with cffDNA positive, only two had a prenatal ultrasound indicating male external genitalia. Our postnatal data showed that when external genitalia were female or poorly virilized, prenatal ultrasound indicated female sex, but in cases of higher degree of virilization, ultrasound showed similar rates of male, female, or undetermined sex. Regarding the karyotype, our data showed those with XY karyotype had positive cffDNA, those with XX karyotype had negative cffDNA, and all five with sex chromosome anomalies had positive cffDNA because they were 45,X/46,XY. We suggested an algorithm to investigate these cases during gestation, including evaluation of uterus, fetal growth, and malformations. Conclusion: We suggest that the parents should be counseled prenatally by a dedicated multidisciplinary team with experience in DSD management and evaluated as soon as possible after birth. [ABSTRACT FROM AUTHOR]

The goals of this presentation are to review the essential roles of aromatase, estrogens and the estrogen receptor in pubertal growth. Estrogen deficiency due to mutations in the aromatase gene (CYP19) and estrogen resistance due to disruptive mutations in the estrogen receptor gene have no effect on normal male sexual maturation in puberty. However, they lead to absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, continued growth into adulthood and very tall adult stature in both sexes. Gonadotropin and androgen levels are elevated in patients with either estrogen deficiency (aromatase deficiency) or estrogen resistance (estrogen receptor mutation). Glucose intolerance, hyperinsulinemia and lipid abnormalities are also present. Skeletal integrity is compromised. Increased bone turnover, reduced bone mineral density and osteoporosis develop in both sexes. Sexual orientation is appropriate in males and females. In females, aromatase deficiency in the ovary causes pubertal virilization and multicystic ovaries because of elevated gonadotropins and androgens. Simultaneously, secondary sexual maturation fails to occur. Placental aromatase deficiency results in virilization of the mother and her female fetus because of the accumulation of potent androgens which are not converted to estrogens. The male fetus has normal genitalia.In conclusion, estrogens are essential for normal female secondary sexual maturation, bone maturation, epiphyseal fusion, pubertal growth spurt and achievement of normal bone mineral mass. Estrogens also influence insulin sensitivity and lipid homeostasis. However, estrogens do not appear to be essential for fetal survival, placental growth, or female sexual differentiation. [ABSTRACT FROM AUTHOR]

Background: Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. Case Reports: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. Conclusion: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Variations in phenotype in 21-hydroxylase deficiency (21OHD) have cautioned against initiating treatment in the absence of abnormal clinical features. We report 2 Caucasian brothers with compound heterozygous mutations of the CYP21 gene and mild clinical and biochemical features of late-presenting 21OHD. The index case presented aged 8.5 years with mild genital virilization and bone age advanced by 5 years. Elevated basal and synacthen-stimulated 17-hydroxyprogesterone (17OHP; 22.4 and 246 nmol/l) and androstenedione (10.9 and 19.9 nmol/l) levels confirmed 21OHD. His younger brother was investigated at age 7.3 years, and although examination showed normal pre-pubertal genitalia, basal and synacthen-stimulated 17OHP (32.4 and 281 nmol/l) and androstenedione (6.2 and 9.0 nmol/l) were abnormal, and bone age was advanced by 1.5 years. Because of actual or incipient virilization, both patients were treated with glucocorticoid replacement 8–12 mg/m2/day. This decision is discussed in the context of published guidelines for the management of 21OHD. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Congenital adrenal hyperplasia in females leads to virilization of external genitalia and persistent urogenital sinus. There are controversies regarding the timing and outcomes of surgery. Deferring surgeries beyond childhood is difficult to implement in conservative societies, and may result in stigmatization and distress to individuals with disorders of sexual differentiation and their families. Methods: Thirty girls with virilization due to congenital adrenal hyperplasia were admitted for single-stage feminizing genitoplasty, between 2011 and 2014. We prospectively studied the concerns and input of the families represented by the mothers. After comprehensive counselling, the mothers completed a questionnaire to clarify their priorities and concerns related to surgery. Results: Surgeries were performed at a mean age of 22 months. Most cases ranged between Prader's degrees III and IV. Egyptian families believe that early surgical reconstruction is in the best interest of their girls. They are marginally more concerned about functional outcomes and future child bearing than external appearance and cosmetic outcomes. Conclusions: Social difficulties noticeably add challenges to the management plan within conservative societies. Early genital reconstructive surgery, when reasonably indicated, needs to remain a viable option. Comprehensive psychosocial support within a multidisciplinary approach is needed to defer feminizing genitoplasty in selected cases to adolescence. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Disorders of sex development (DSD) are a heterogeneous group of rare conditions. Evidence-based treatment is challenged by a lack of clinical longitudinal outcome studies. We sought to investigate the quality of life of children with DSD other than congenital adrenal hyperplasia. Methods: The participants (aged 6-18 years) were 23 patients raised as males and 7 patients raised as females. Control data were obtained from representatives of the patients' siblings matched for age and gender. The Pediatric Quality of Life InventoryTM Version 4.0 (PedsQL) Generic Core Scales were used as the study tool. Results: In comparison with the reference data, the patient group had significantly lower overall PedsQL (p < 0.01) and school functioning (p < 0.01) scores. Also, the total PedsQL score was significantly lower in patients with DSD who were of female social sex as compared to the controls who were females. Family income, surgical procedures, degree of virilization, and mode of puberty did not influence the PedsQL scores. Conclusion: This study revealed a poorer quality of life for patients with DSD as compared compared to the age-matched control group. This highlights the need for a skilled multidisciplinary team to manage this group of patients. [ABSTRACT FROM AUTHOR]

Aromatase deficiency (AD) is a very rare disorder resulting from mutations in the CYP19A1 gene encoding aromatase, a cytochrome P450 enzyme that plays a pivotal role in androgen conversion to estrogens. AD is inherited in an autosomal recessive trait, and to date only 35 cases have been described in the literature. Herein, we depict a new patient reared as a male, who presented at the age of 21 years with no palpable testis, hypoplastic scrotum, penis-like phallus (3 cm), and penoscrotal hypospadias. The patient was born to consanguineous parents, his karyotype was 46,XX, and SRY was negative. Pelvic sonar showed a small hypoplastic uterus, and no testis could be identified. Serum testosterone was within the reference range of females along with high gonadotropins. Pathology of gonadal biopsy showed ovarian stroma negative for oocytic follicle consistent with streak gonads. All these data were suggestive of AD, which was subsequently confirmed by molecular investigation of the CYP19A1 gene. A homozygous splice site mutation in the donor splice site of exon 9 was identified, c.1263 + 1G>T. This is the first report of such a rare disorder in an Egyptian patient. Our results reinforce the importance of considering AD in patients with 46,XX disorders of sex development after ruling out congenital adrenal hyperplasia. [ABSTRACT FROM AUTHOR]

The presence of a Y chromosome in patients with Turner syndrome (TS) is a risk factor for the development of gonadal tumor and/or virilization. With conventional cytogenetic analysis, some cells containing a Y chromosome can be missed. The aim of this study was to determine the presence and incidence of Y chromosome-derived material in TS patients using PCR and the markers SRY, DYZ1, DYZ3, DYS132, ZFY, and TSPY. Fifty-five TS patients (aged 5.5-26.75 years) were analyzed. A total of 17/55 (30.9%) were Y-positive, but only 7/17 had a Y chromosome in their karyotype and underwent gonadectomy. In 2 of these patients (28.6%), histopathologic examination revealed gonadoblastoma and dysgerminoma, respectively. In 8 patients in the studied group (8/55; 14.5%), the TSPY gene was detected, and the SRY gene (or a fragment) was identified in 9(3)/55 patients. No coding region mutations were observed in these SRY-positive patients. In conclusion, we have shown a high prevalence of Y chromosomal material in TS. Y markers were also observed in patients who had no Y chromosome in their karyotype, and PCR is very precise in detecting the presence of genetic material from the Y chromosome. Further follow-up of these Y-positive TS patients is mandatory. [ABSTRACT FROM AUTHOR]

Although monosomy X is the most common karyotype in patients with Turner syndrome, the presence of Y chromosome material has been observed in about 10% of patients. Y chromosome material in patients with Turner syndrome poses an increased risk of gonadoblastoma and malignant transformation. We report a woman with a diagnosis of Turner syndrome at 12 years of age, without signs of virilization and karyotype reported as 46,X,del(X)(q13). At 26 years, cytogenetic studies indicated the patient to be mosaic for monosomy X and a cell line that contained a duplicated Yq chromosome. Bilateral gonadectomy was performed and revealed streak gonads, without evidence of gonadoblastoma. Histological analysis showed ovarian stromal cells with few primordial tubal structures. FISH performed on streak gonadal tissue showed a heterogeneous distribution of SRY, with exclusive localization to the primordial tubal structures. DNA extraction from the gonadal tissue showed a 6.5% prevalence of SRY by microarray analysis, contrasting the 86% prevalence in the peripheral blood sample. This indicates that the overall gonadal sex appears to be determined by the majority gonosome complement in gonadal tissue in cases of sex chromosome mosaicism. This case also raises questions regarding malignancy risk associated with Y prevalence and tubal structures in gonadal tissue. [ABSTRACT FROM AUTHOR]

17β-hydroxysteroid dehydrogenase 3 (17β-HSD 3) deficiency is a rare cause of 46,XY disorders of sex development (DSD). At puberty, these patients experience a surge of androstenedione and also testosterone, leading to substantial virilization. The origin of testosterone synthesis in these patients remains elusive. We investigated the expression of the isoenzyme AKR1C3 (17β-HSD 5) in the testis and patient-derived genital skin fibroblasts (GSF) as well as the ability of GSF to synthesize testosterone. Supernatants of GSF cultures and serum samples of one patient before and after gonadectomy were analyzed by liquid and gas chromatography/mass spectrometry. The androgenic potential of GSF-derived supernatants was also assessed by androgen receptor-mediated transactivation of a reporter gene in transiently transfected Chinese hamster ovary cells. Although AKR1C3 is expressed both in the testes and in GSF, androstenedione is rapidly metabolized and is not synthesized to testosterone. The transactivation potential of GSF supernatants towards the androgen receptor is declining within 48 h. However, under testis-equivalent androstenedione concentration, testosterone can be synthesized in 17β-HSD 3-negative GSF. After gonadectomy, both androstenedione and testosterone decline rapidly in vivo. In 17β-HSD 3 deficiency, relevant amounts of testosterone are synthesized most probably through AKR1C3 in the testis and not peripherally in GSF. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Steroid 5α-reductase deficiency (MIM*607306) caused by mutations in the SRD5A2 gene is characterized by a predominantly female phenotype at birth and significant virilization at puberty. The undermasculinization at birth results from low dihydrotestosterone (DHT) levels during fetal development as the type 2 isoenzyme activity is reduced. In puberty, when the type 1 isoenzyme activity increases, significant virilization occurs. Most 46,XY individuals with 5α-reductase 2 deficiency develop a male gender identity. Case Report and Results: We present a case with a predominantly female phenotype and ambiguous external genitalia but a normal 46,XY karyotype. Plasma steroid analysis after β-hCG stimulation at 8 days of age revealed a steroid profile estimated as normal with a testosterone (T)/DHT ratio of 9.5 initially misleading to the exclusion of 5α-reductase deficiency. However, mutation analysis of the SRD5A2 gene revealed a homozygote point mutation (Leu55Gln) confirming the diagnosis of 5α-reductase deficiency. A male phenotype was successfully achieved by hormone treatment with T and DHT after diagnosing 5α-reductase deficiency and a masculinization operation. As a side effect skeletal age accelerated temporarily. Conclusion: In individuals with predominantly female phenotype and suspected 5α-reductase deficiency, a T/DHT ratio during the neonatal period >8.5 might point to 5α-reductase deficiency. After confirmation of the diagnosis by molecular analysis of the SRD5A2 gene, a satisfactory change to a male phenotype can be achieved by hormone treatment preceding surgery. [ABSTRACT FROM AUTHOR]

Context: Steroid 17α-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol, and excessive mineralocorticoid action. The clinical symptoms of hypocortisolemia are subtle. Aim: The clinical, biochemical, and molecular characteristics of patients with 17OHD were evaluated to determine the factors influencing the time of diagnosis and the management. Patients and Methods: Clinical data, steroid profiles by liquid chromatography-tandem mass spectrometry, and Sanger sequencing of the CYP17A1 gene was evaluated in 12 patients with 17OHD diagnosed between 2004 and 2020. Results: Median age of diagnosis was 13.9 (range: 0.04–29.5) years. Ten of 12 patients had 46,XY karyotype. Except for one boy with partial 17OHD, all patients had female external genitalia hence raised as females. The clinical presentation of 17OHD was earlier (median age: 7 years) in patients, who presented with severe hypertension, atypical genitalia, or positive family history (n = 6, 50%) than those without (median age: 15.3 years; p = 0.0005). The latter group presented with amenorrhea (n = 6, 50%). Steroid profile of patients uniformly showed a typical pattern of 17OHD regardless of the age at diagnosis. Serum gonadotropin concentrations were elevated in patients >12 years (n = 7), normal in pre-adolescents (n = 4), and low in a patient, who had a digenic inheritance of homozygous CYP17A1 and KISS1R mutations. Conclusions: Early clinical presentation and diagnosis in 17OHD are associated with symptomatic hypertension in both 46,XX and 46,XY patients or inadequate virilization of external genitalia in 46,XY partial 17OHD. In the absence of these, the clinical presentation is at late pubertal ages at which time amenorrhea and elevated gonadotropins are the hints for diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of pubertal induction with testosterone on bone health, body composition, and motor function in boys with Duchenne muscular dystrophy (DMD) receiving long-term glucocorticoid. Study Design: A retrospective, observational, pre-post study investigating the impact of testosterone therapy on bone mass accrual, vertebral fracture incidence, body composition, motor function, and quality of life in boys with DMD. All those boys aged ≥14 years, on chronic steroid therapy, who had delayed puberty, and were receiving oral testosterone or oral and then transitioned to intramuscular testosterone, to complete virilization, were included. Prior/concomitant zoledronic acid use was included. The primary outcome was lumbar spine areal bone mineral density (BMD LS). Results: Puberty was induced, using oral testosterone undecanoate in 16 individuals, 10 of whom had transited to intramuscular testosterone at time of assessment. Median age at testosterone onset was 14.5 years (range 14–17.7). Median duration of testosterone therapy was 2.5 years (range 1.0–4.5). There was statistically significant increase in median BMD LS (0.523–0.700, p < 0.001) and median annualized percentage change of BMD LS (–1.34 to +10.08%, p < 0.001), with median Tanner stage 4 at evaluation (range 2–4). Ten of 14 assessed had no progression in vertebral fractures. Fat mass index (FMI) standard deviation score (SDS), lean body mass index (LBMI) SDS, and percentage change of FMI and LBMI were statistically unchanged. Cardiac function remained stable. Motor function in non-ambulatory individuals with Egen Klassifikation scores improved in 7 of 8. Conclusion: Testosterone for delayed puberty acted as an adjunct to bisphosphonates to increase bone density and stabilize vertebral fracture in most boys with DMD. [ABSTRACT FROM AUTHOR]

11β-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia, resulting in virilization, glucocorticoid deficiency and hypertension. There have been no previous reports in the literature of a successful pregnancy in a severely affected female. We report the first successful pregnancy resulting in a live birth for a female with 11β-hydroxylase deficiency and outline management issues from preconception to successful birth. We also report 2 novel mutations in the CYP11B1 gene leading to 11β-hydroxylase deficiency. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children’s Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone than their white counterparts (p = 0.055). There was an equal sex ratio in both the I2 splice (12 female/14 male) and I172N (5 female/6 male) groups. However, in the Null group, the ratio was 4.0 (20 female/5 male; p = 0.003), suggesting that some Null male infants perish before being clinically detected to have CYP21 deficiency. Our findings strongly support the need for implementation of a neonatal screening programme for CAH in the UK which may reduce the male infant mortality. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes. Summary: In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation. Key Message: We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels – especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins – and karyotyping. [ABSTRACT FROM AUTHOR]

Introduction: Steroid 5-alpha reductase deficiency (5α-R2D) is a rare condition caused by genetic variants that reduce the activity of the enzyme that converts testosterone into dihydrotestosterone. The clinical spectrum of 5α-R2D is known to overlap with other 46,XY differences of sex development (DSD) such as androgen insensitivity or gonadal dysgenesis. However, the clinical trajectories of the aetiologies can differ, with 5α-R2D presenting its own challenges. Methods: In this study, we have collated clinical information for five individuals with variants in SRD5A2 identified using research genetic testing in an Australian paediatric setting. Results: We describe how a genetic finding resolved or confirmed a diagnosis for these individuals and how it guided clinical management and family counselling. Conclusion: This work highlights the importance of early genetic testing in children born with 46,XY DSD where it complements traditional first-line testing. [ABSTRACT FROM AUTHOR]

Classic 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD II) deficiency causes congenital adrenal hyperplasia with glucocorticoid, mineralocorticoid, and sex steroid deficiency. We present a female patient with congenital adrenal hyperplasia detected in newborn screening due to elevated 17OHprogesterone. Female external genitalia and non-measurable androgen levels elicited the suspicion of a defect early in the steroid cascade. Two loss-of-function HSD3B2 mutations (1 novel) were detected and confirmed in silico. We argue that in a girl with glucocorticoid and mineralocorticoid deficiency without virilization, 3β-HSD II deficiency is an important differential diagnosis. 17OH-progesterone may initially be elevated due to placental and peripheral activity of 3β-HSD I, whereas dehydroepiandrosterone may not be increased. [ABSTRACT FROM AUTHOR]

Fertility remains a challenge for men with 5α-reductase-2 deficiency. Such a diagnosis was made in 2 adult brothers who are compound heterozygous for the 5α-reductase type 2 gene (SRD5A2; c.308G>C; c.689A>C). They were born with ambiguous genitalia and the male sex was assigned. Both brothers underwent reconstructive genital surgery during pediatric age and had spontaneous virilization at puberty. The older brother experienced natural conception, while the younger had a son by assisted reproductive technology. Other family members were demonstrated to be compound heterozygous or heterozygous for the same genetic variants. The older brother is the third man with 5α-reductase-2 deficiency and spontaneous paternity. The little series of men with 5α-reductase-2 deficiency and documented spontaneous or assisted paternity is reviewed. In conclusion, the possibility of fatherhood is a main indication for male sex assignment in patients with 5α-reductase-2 deficiency. [ABSTRACT FROM AUTHOR]

Prenatal treatment of congenital adrenal hyperplasia with dexamethasone (DEX) has been in use since the mid-1980s and has proven effective at reducing virilization of external genitalia in affected girls. However, multiple experimental studies on animals and clinical studies on humans show that prenatal administration of glucocorticoids may cause unwanted adverse effects which have raised concerns about the long-term safety of the treatment. The long-term outcome of prenatal DEX treatment on cognition has been investigated, but the results are still conflicting. Overall, most of the evidence points towards a negative effect on executive functions where girls seem to be more susceptible than boys. Some effects on social behavior have been observed, but results are still contradictory and treated children are mostly well adapted. Cardiovascular, renal, and metabolic function are still areas to be investigated. Larger studies are warranted to investigate areas other than cognition and behavior and to be able to draw more definitive conclusions about prenatal DEX treatment. [ABSTRACT FROM AUTHOR]

Background: Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD). Summary: Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis. Key Messages: The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood. [ABSTRACT FROM AUTHOR]

Background: 3β-hydroxysteroid dehydrogenase (3βHSD) type 2 (encoded by HSD3B2) is expressed in the adrenals and gonads. HSD3B2 mutations cause the rare form of congenital adrenal hyperplasia '3βHSD deficiency'. In its classic form, affected individuals have salt wasting early in infancy and may have ambiguous genitalia in both sexes. The presence of peripheral type 1 3βHSD often complicates the hormonal diagnosis of this disorder, in that very high 17α-hydroxypregnenolone levels can be converted extra-adrenally to 17α-hydroxyprogesterone (17OHP). Patient and Methods: A 46,XX female newborn with no signs of virilization was referred for evaluation of positive 17OHP newborn screening, and developed a salt-wasting crisis at 13 days of age. The confirmatory test revealing highly elevated 17OHP suggested a 21-hydroxylase deficiency, but sequencing of the CYP21A2 gene was not consistent. Further family history suggested a 3βHSD deficiency. The HSD3B2 gene was then sequenced. Results: The patient was homozygous for the novel nonsense mutation Q334X in the HSD3B2 gene, inherited from both parents. Conclusions: We report a novel mutation of the HSD3B2 gene, Q334X, responsible for a classic 3βHSD deficiency. The clinical and hormonal phenotypes can be complicated in this disorder, and this supports the benefits of 17OHP newborn screening to detect various forms of congenital adrenal hyperplasia. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: 3β-Hydroxysteroid dehydrogenase type II deficiency, a rare form of congenital adrenal hyperplasia, is characterized by varying degrees of salt loss and incomplete masculinization in males and mild virilization or normal external genitalia in females. The clinical signs may be difficult to recognize, increasing the risk of a neonatal adrenal crisis. In addition, elevated 17α-hydroxyprogesterone and androstenedione levels due to peripheral HSD3B1 activity may lead to a delay of the correct diagnosis and even to misdiagnosis as CYP21 deficiency. Method: We report a patient who was detected on neonatal screening for 21-hydroxylase deficiency, in part because of cross-reactivity in the commonly used assay. Results: The diagnostic difficulties in this case were overcome by the use of more specific antibodies. Conclusion: This case emphasizes the importance of confirming the etiological diagnosis with molecular genetic analyses. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The 5α-reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, playing a crucial role in male development. This enzyme is encoded by the SRD5A2 gene, which maps to chromosome 2 (2p23), consists of 5 exons and 4 introns, and encodes a 254 amino acid protein. Disruptions in this gene are the molecular etiology of a subgroup of differences of sex development (DSD) in 46,XY patients. Affected individuals present a large range of external genitalia undervirilization, ranging from almost typically female external genitalia to predominantly typically male external genitalia with minimal undervirilization, including isolated micropenis. This is an updated review of the implication of the SRD5A2 gene in 5α-reductase type 2 enzyme deficiency. For that, we identified 451 cases from 48 countries of this particular 46,XY DSD from the literature with reported variants in the SRD5A2 gene. Herein, we present the SRD5A2 mutational profile, the SRD5A2 polymorphisms, and the functional studies related to SRD5A2 variants to detail the molecular etiology of this condition. [ABSTRACT FROM AUTHOR]

A girl aged 5 years and 6 months presented with premature thelarche in our outpatient clinic. During long-term observation, we recorded growth acceleration, advanced bone age, and elevated oestradiol levels which together were taken to confirm the diagnosis of precocious puberty. The patient was successfully treated with a gonadotropin-releasing hormone agonist, but in view of the poor growth prognosis, recombinant human growth hormone was administered concurrently. At the age of 9 years and 6 months a mild clitoris enlargement and conspicuous muscle development without any further signs of virilization were noticed. Laboratory findings showed high values for testosterone and normal basal values for 17-hydroxyprogesterone and dehydroepinadrosterone sulphate. Explorative laparotomy revealed a gonadoblastoma arising from testicular structures on the left, a female streak gonad on the right side, and normal uterus and fallopian tubes. The karyotype was 46,XY/45,X. These findings confirmed the diagnosis of mixed gonadal dysgenesis with testosterone-producing gonadoblastoma.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Androgen insensitivity syndrome (AIS) is a hereditary condition in patients with a 46,XY karyotype in which loss-of-function mutations of the androgen receptor (AR) gene are responsible for defects in virilization. The aim of this study was to investigate the consequences of the lack of AR activity on germ cell survival and the degree of testicular development reached by these patients by analyzing gonadal tissue from patients with AIS prior to Sertoli cell maturation at puberty. Twenty-three gonads from 13 patients with AIS were assessed and compared to 18 testes from 17 subjects without endocrine disorders. The study of the gonadal structure using conventional microscopy and the ultrastructural characteristics of remnant germ cells using electron microscopy, combined with the immunohistochemical analysis of specific germ cell markers (MAGE-A4 for premeiotic germ cells and of OCT3/4 for gonocytes), enabled us to carry out a thorough investigation of germ cell life in an androgen-insensitive microenvironment throughout prepuberty until young adulthood. Here, we show that germ cell degeneration starts very early, with a marked decrease in number after only 2 years of life, and we demonstrate the permanence of gonocytes in AIS testis samples until puberty, describing 2 different populations. Additionally, our results provide further evidence for the importance of AR signaling in peritubular myoid cells during prepuberty to maintain Sertoli and spermatogonial cell health and survival. [ABSTRACT FROM AUTHOR]

Introduction: Adrenal masses are a rare diagnosis in children, with bilateral masses even less common. At present, appearance of the mass on imaging and histology can give important clues to the diagnosis; however, there is significant overlap in 10–30% of cases and it can be difficult to distinguish benign from malignant adrenal masses. As a result, the clinical presentation remains a large part of the diagnostic process, as well as thorough endocrinology evaluation to determine if the tumor is functional versus nonfunctional. Case Presentation: We present a recent case of bilateral adrenal masses in a pediatric patient at our institution, with an unusual diagnosis of histiocytosis. Conclusion: In this case, the diagnosis was unclear, until genetic testing and pathology allowed for expedient diagnosis and targeted therapy for this patient. We hope that presenting this case will increase physician awareness of this condition and expedite diagnosis and treatment in other patients with this rare presentation. [ABSTRACT FROM AUTHOR]

17-β-hydroxysteroid dehydrogenase type 3 (17-β-HSD 3) deficiency is an autosomal recessive form of 46,XY disorder of sex development (DSD). To date, a total of 27 HSD17B3 gene mutations have been described in 46,XY patients exhibiting different phenotypes at birth and virilization at puberty, sometimes in association with gynecomastia. Herein, we investigate the 46,XY DSD in an Iranian family consisting of 7 siblings, 3 of which are affected and virilized at puberty. We clinically characterized these patients andperformed direct DNA sequencing of the steroid 5-α-reductase type 2 (SRD5A2) and the HSD17B3 gene, respectively. We identified a homozygous mutation in the HSD17B3 gene (R80W; c.238C>G) in all affected siblings. No mutation was detected in the SRD5A2 gene. The detected mutation in the HSD17B3 gene was previously described in a newborn child, who died from other congenital malformations, and in a 12-year-old girl. Hence, our report adds novel value to the phenotype classification of 17-β-HSD 3 deficiency. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

NR5A1 (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous NR5A1 mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with NR5A1 genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous NR5A1 genetic variants. In the boys, pathogenetic NR5A1 gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that NR5A1 gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with NR5A1 mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward. [ABSTRACT FROM AUTHOR]