Prepubertal XY gonadal dysgenesis

Two children had prepubertal XY gonadal dysgenesis. A 7-year-old girl with clitoral enlargement had a left ovarian tumor that contained a dysgerminoma; the right gonad proved to be a gonadoblastoma. The second child (a 2-year-old girl) showed poor physical development and slight virilization of the genitalia. Her bilateral dysgenetic gonads were removed at exploratory laparotomy. The occurrence of gonadal tumors in XY gonadal dysgenesis is increased. It is probably related to the hypergonadotropinism existing from childhood as well as to genetic predisposition of the cryptorchid testis in the presence of a Y chromosome. Our first patient is one of the youngest who had XY gonadal dysgenesis iwth gonadoblastoma reported. The indication of prophylactic gonadectomy in XY gonadal dysgenesis is emphasized.     

Alopecia universalis congenita,XY gonadal dysgenesis and laryngomalacia: a novel malformation syndrome

We report on five individuals with the following consistent findings: alopecia universalis congenita, XY gonadal dysgenesis and laryngomalacia persisting beyond infancy. The clinical presentation of the XY gonadal dysgenesis was ambiguous genitalia, appearing as male or, more commonly, female. In one affected individual müllerian structures were present. The affected individuals come from two unrelated families. While in the first family the two affected individuals come from two related sibships, three affected individuals come from one sibship in the second family. Parents of affected individuals in the three sibships are first cousins. To our knowledge, this association has not been reported before. We speculate that the mode of inheritance of this disorder is autosomal recessive with probable sex limitation.     

Disorders of gonadal development: a broad clinical, cytogenetic and histopathologic spectrum

The most complicated group of sexual differentiation disorders is that of gonadal development. Disorders of gonadal development form a wide clinical, cytogenetic and histopathological spectrum. There are still some unsolved difficulties of diagnosis, development of malignancy and the sex rearing of these patients. We reviewed 23 cases of gonadal developmental disorders among 169 patients with ambiguous genitalia or delayed puberty. Among 169 patients, 87 patients were 46,XY disorders of sex development (DSD), 59 patients were 46,XX DSD without disorders of gonadal development and the remaining 23 patients had disorders of gonadal development. Nine of these 23 patients were diagnosed as 46,XY gonadal dysgenesis, 7 patients had ovotesticular DSD, 5 patients had 45,X/46,XY mixed gonadal dysgenesis. Fourteen patients with disorders of gonadal development had genital ambiguity, 5 patients had a female genital phenotype with a palpable gonad and/or delayed puberty. Four patients had the male genital phenotype. Disorder of gonadal development is a very important clinical problem with different aspects of diagnosis, treatment, rearing sex and prophylaxis. Each patient should be evaluated individually employing a multidiciplinary approach.     

Mixed gonadal dysgenesis. Apropos of a series of 21 cases

Twenty-one cases of mixed gonadal dysgenesis referred at age 1 to 16 years are studied. External genitalia were in most cases of types III-IV, with a small penis and posterior hypospadias, asymmetrical genital folds containing an externalized testis on one side. The internal genitalia varied according to the degree of dysgenesis of the gonads, and included an uterus and/or a vagina in 18 among the 21 cases. A chromosomal mosaicism XO/XY or XX/XY was found in 11 patients, the other 10 having a normal 46 XY caryotype. Pubertal follow-up was obtained in 10 cases, and showed always a male sexual development, without possibility to exactly evaluate the function of the testis. Choosing the sex assignment is relatively easy in newborns or infants with mixed gonadal dysgenesis. It relies more on anatomy (size of corpora cavernosa, feasibility of urethroplasty or vaginoplasty) than on the results of hormonal measurements. The presence of an Y chromosome is not by itself an argument to choose the male sex. In most cases, the choice of the female sex is the easiest and relies on strong clinical arguments, but it leads unavoidably to suppress both the testis and the dysgenetic gonad.     

Recurrence of a dysgerminoma in Frasier syndrome

Mestrallet G, Bertholet‐Thomas A, Ranchin B, Bouvier R, Frappaz D, Cochat P. Recurrence of a dysgerminoma in Frasier syndrome.
Pediatr Transplantation 2011: 15:e53–e55. © 2010 John Wiley & Sons A/S. Abstract: FS is an inherited disease characterized by male pseudohermaphroditism and glomerular involvement leading to end‐stage renal disease during adolescence or early adulthood (J Pediatr 1964:64:740). The FS phenotype in 46,XY patients consists of female external genitalia, gonadal dysgenesis, high risk of gonadoblastoma, and development of renal failure in the second decade of life. FS is caused by heterozygous mutation in intron 9 of the WT1 leading to a change in splicing that results in loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/?KTS isoforms that is critical for proper gonadal and renal development (Nat Genet 1997:17:467; Hum Mol Genet 1998:7:709). We report on a patient followed for FS revealed by acute peritoneal syndrome because of ovarian dysgerminoma. Therapeutic options had led to an unusual course with recurrent neoplastic disease after renal transplantation.     

WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review

Aim: The Wilms’ Tumour gene is thought to have tumour suppressor activity and to play an important role in nephrogenesis, genitourinary development, haematopoiesis and sex determination. WT1 mutations will impair gonadal and urinary tract development and have been demonstrated to cause syndromes of WAGR, Denys–Drash and Fraiser. Methods: To elucidate the role of constitutional mutations of WT1, in the expression of the different clinical feature, we describe a 14‐year‐9‐month nonmosaic XY sex‐reversed woman with pure gonadal dysgenesis (46, XY karyotype, completely female external genitalia, normal Mullerian ducts, absence of Wolffian ducts, streak gonads) who had right kidney removed at 7 months of age because of Wilms’ tumour and was diagnosed as secondary thrombocytopenia (Plt 60–80 × 10⁹/L) since she was 4 years old. We sequenced the genomic DNA of all the 10 exons of the WT1 in which mutations may occur in proposita. Results: A new de novo insertion mutation in the first exon was found. A ‘GCCGCCTCACTCC’ is inserted between codon 138 and 139, resulting in the creation of a stop codon and a truncated protein. Conclusion: The present data provide further evidence to support the role of WT1 in diverse cellular functions.     

Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment. Conclusion: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.     

Association d''une dysgénésie gonadique mixte et d''une forme non classique de bloc de la 21-hydroxylase

Background.

The rare association of mixed gonadal dysgenesis and non classical congenital hyperplasia by 21-hydroxylase deficiency poses the problem of their respective responsability in the development of sexual ambiguity.

Case report.

In a newborn with ambiguous genitalia, blood 17-OH progesterone was moderately elevated (3.9 to 14.1 ng/mL) leading to the diagnosis of non-classical 21 hydroxylase deficiency. Molecular studies later confirmed this diagnosis. However, the presence of a palpable gonad and the caryotype (45 X/46 XY mosaicism) indicated a mixed gonadal dysgenesis as the cause of sexual ambiguity. Histological examination revealed the presence of a testis and a streak gonad.

Conclusion.

This observation emphasizes the need for a complete clinical and biological analysis in all newborns with sexual ambiguity.     

Carcinoma in situ of the testis in children with 45,X/46,XY gonadal dysgenesis

The frequency of gonadal tumors in intersex patients with a karyotype including a Y chromosome is very high. In other at-risk groups, testicular germ cell tumors have been shown to be preceded by carcinoma in situ (CIS) changes. We investigated gonadal tissue from four children, aged 1 month to 18 years, with 45,X/46,XY gonadal dysgenesis, and with male or ambiguous genitalia, for the presence of CIS germ cells. Twelve gonadal biopsies and gonadectomy specimens were analyzed by means of conventional histology and densitometric DNA measurements. CIS changes were detected in specimens from all four patients, and aneuploid DNA distributions of the CIS germ cells confirmed the malignant potential of these cells. In one case, electron microscopic analysis revealed the same ultrastructural features of the CIS germ cells as previously described in seminoma cells. These observations indicate that in all patients with 45,X/46XY gonadal dysgenesis and a male phenotype, gonadal biopsies should be considered as soon as the syndrome is diagnosed. We believe that the finding of CIS warrants gonadectomy.     

Gender role across development in adults with 46,XY disorders of sex development including perineoscrotal hypospadias and small phallus raised male or female

Self-rated degree of femininity and masculinity across development were evaluated for 40 adults affected by 46,XY disorders of sex development (DSDs) who presented at birth with a small phallus and perineoscrotal hypospadias, raised either male (n = 22) or female (n = 18). Most participants were confirmed or presumed to be affected by partial androgen insensitivity syndrome (n = 14), partial gonadal dysgenesis (n = 11), or were considered to have a poorly defined case of 46,XY DSD including ambiguous external genitalia (n = 15). Participants retrospectively evaluated their degree of masculinity and femininity during their childhood, adolescence, adulthood, and in the past 12 months of filling out a questionnaire pertaining to their psychosexual development. Participants raised male reported more masculinity than those raised female due to an increase in masculinization during adolescence and adulthood. Participants raised male also reported less femininity than those raised female throughout development. Participants raised female reported more femininity than those raised male due to an increase in feminization during adolescence and adulthood. Participants raised female also reported less masculinity than those raised male throughout development. These data support the proposition that some aspects of gender role (GR), such as masculinity and femininity, are capable of proceeding along female- or male-typic patterns depending on sex of rearing among individuals affected by specific types of 46,XY DSD. Furthermore, regardless of male or female rearing, GR increasingly corresponds with assigned sex as individuals proceed through sexual maturity and into adulthood. These results are consistent with the idea that socialization/learning contributes to GR development in humans in addition to data from others demonstrating endocrine influences.     

Short stature in children with an apparently normal male phenotype can be caused by 45,X/46,XY mosaicism and is susceptible to growth hormone treatment

Girls with unexplained short stature are routinely screened for the presence of Ullrich-Turner syndrome by clinical examination, laboratory tests, and karyotyping. In this study, we performed chromosomal analysis in boys to explore the role of 45,X/46,XY mosaicism for short stature in males. Short-term effects of growth hormone treatment in male 45,X/46,XY individuals were compared retrospectively to those in female patients. We report six boys with a normal-appearing male phenotype and 45,X/46,XY mosaicism, four of whom were diagnosed postnatally because of short stature. Two boys were diagnosed prenatally by amniocentesis. Five boys were short and were treated with growth hormone (0.04–0.05 mg/kg per day) in analogy to girls with Ullrich-Turner syndrome and gonadal dysgenesis. With the exception of one patient in whom treatment was initiated only at the age of 14.6 years, the male patients with 45,X/46,XY mosaicism responded to short-term growth hormone treatment similarly to females with an increasing height SDS. Conclusion:45,X/46,XY mosaicism remains undetected in some short boys because this group is not routinely karyotyped. We recommend chromosomal analysis of boys with otherwise unexplained short stature who are short for their families. Growth hormone treatment should be offered to short boys with 45,X/46,XY mosaicism and a predicted adult height below the mid-parental range within clinical trials.Abbreviations FSH follicle stimulation hormone - GH growth hormone - IGF-I insulin-like growth factor 1 - IGFBP-3 insulin-like growth factor binding protein-3 - LH luteinising hormone - MPH mid-parental height     

Gender identity reversal in an adolescent with mixed gonadal dysgenesis

We describe a patient who was assigned female at birth because of genital ambiguity without performing further diagnostic procedures and presented at the age of 13-1/2 years because of her strong desire to change her legal sex. Karyotype was 46,XY; clinical, endocrinological, radiological and surgical work-up revealed hypergonadotropic hypogonadism and mixed gonadal dysgenesis. Gender identity reversal was performed after extensive psychological testing and adaptation of living circumstances resulting in a successful integration as a male with normal psychological and social functioning. In several surgical procedures, the streak gonad, the nonfunctional testis, and the rudimentary uterus were removed, and a penis was reconstructed from a penisoid with chorda and hypospadias. Our patient supports the idea that gender identity is imprinted prenatally by hitherto poorly understood mechanisms and that sex assignment in infants with ambiguous genitalia needs careful consideration of not solely endocrinological and anatomical data.     

Nephropathy gonadal dysgenesis--or incomplete Drash syndrome?]

This is a report about a phenotypical normal girl with nephropathy and gonadal dysgenesis. At the age of 2 years 8 months she presented with steroid resistant nephrotic syndrome. Focal segmental glomerulosclerosis was found by biopsy. Because of delayed puberty karyotyping was performed, which revealed 46 XY. Thirteen years after onset of proteinuria she reached end stage renal failure. Gonadal dysgenesis and nephropathy are often indistinguishable from incomplete Drash syndrome. Children with early nephropathy of unknown origin or gonadal dysgenesis should be observed for development of Wilms tumor. When chronic nephropathies are present in girls, karyotyping should be considered.     

Mixed gonadal dysgenesis in a patient with de novo tas(Y;19)(p11.3;q13.4) and 45,X mosaicism

We report a patient with a de novo telomeric association between chromosomes 19 and Y in conjunction with mixed gonadal dysgenesis. The patient was first admitted to the clinic because of abnormal external genitalia. Laparoscopic evaluation revealed (1) a rudimentary uterus, one fallopian tube, and a small gonad resembling an ovary on the right side, and (2) an immature fallopian tube, a vas deferens, and a gonad resembling a testis on the left side. Conventional cytogenetic analysis performed on cultivated peripheral blood cells, and tissue obtained from the phallus and a gonadal structure which resembled a testis revealed two different cell lines with the 46,X,tas (Y;19)(p11.3;q13.4) and 45,X karyotype. Y chromosome microdeletion analysis showed that the patient did not have any genomic deletions in the AZFa, b, c, or SRY regions on the long arm of the Y chromosome. This is the first report of a patient with mixed gonadal dysgenesis that is accompanied by a telomeric association between chromosomes 19 and Y with 45,X mosaicism.     

45,X/46,XY mosaicism

The clinical findings in ten patients with 45,X/46,XY mosaicism are described. Three girls presented with short stature, delayed sexual development or Turner-like stigmata without signs of virilization. Bilaterally gonadoblastomas were found in two girls, and the gonads in one of these girls also contained mucinous cystadenomas. The remaining seven patients were raised as boys. Three had scrotal hypospadias and mixed gonadal dysgenesis. Three presented as male pseudohermaphrodites with scrotal or penoscrotal hypospadias and bilateral testes. One male was diagnosed in adulthood because of gynecomastia, but had normal male external genitals. The clinical findings illustrate the wide spectrum of phenotypic manifestations of 45,X/46,XY mosaicism, ranging from females with Turner-like phenotypes, phenotypic males and females with mixed gonadal dysgenesis, male pseudohermaphroditism to almost phenotypic normal males.     

Ovarian choriocarcinoma as the first manifestation of 46,XY pure gonadal dysgenesis

We report a case of 46,XY pure gonadal dysgenesis (Swyer syndrome) in a phenotypically normal 12-year-old girl with a history of vaginal bleeding and early breast development, with ovarian choriocarcinoma as the first manifestation. The clues leading to the diagnosis included the failure to establish any relationship between normal menstrual cycles postoperatively and a small remaining contralateral ovary. The correct diagnosis is important for cancer prophylaxis and hormonal replacement therapy. Prepubertal and peripubertal girls presenting with gonadal germ cell tumors should be carefully evaluated for the possibility of underlying gonadal dysgenesis. A history of vaginal bleeding or early signs of puberty does not exclude the diagnosis.     

Rudimentary testes syndrome revisited

Sixteen children who were one day to 9 years of age underwent clinical, anatomic, and hormonal study because of extreme hypoplasia of the phallus and small testes associated with normal 46XY male karyotype. Two of them were first cousins. All patients had Leydig cell deficiency. Among 15 patients who received luteinizing hormone-releasing hormone stimulation during childhood, 11 had an exaggerated response of either one or both gonadotropins. Bilateral biopsy, performed in eight patients, showed a clearly testicular structure with either scant or incompletely differentiated tubules. These characteristics allow clear differentiation from chromosomal abnormalities and malformation syndromes. It is more difficult to differentiate between rudimentary testes and primary gonadotropic deficiencies and may not be possible until the child has reached adolescence. The syndrome of rudimentary testes may be a manifestation of XY primary gonadal dysplasia, along with pure XY gonadal dysgenesis, XY hermaphroditism, XY mixed gonadal dysgenesis, and congenital anorchia, probably resulting from fetal regression of the testes. The observed familial occurrence of the syndrome of rudimentary testes, as well as of XY gonadal dysgenesis, leads to speculation about the possibility of X-linked transmission.     

Idiopathic male pseudohermaphroditism: variations in presentation and management

Male pseudohermaphroditism (MPH) is the abnormal development of genitalia in an individual with a 46,XY chromosome complement and testicular tissue. The etiology of MPH is unknown in most cases, which are defined as idiopathic. OBJECTIVE: To analyze the data for cases of idiopathic MPH. PATIENTS AND METHODS: A retrospective study of 29 patients with idiopathic MPH and no uterus. Results: Four patients had a family history of abnormal sexual development and five had low birth weight. The initial manifestations were sexual ambiguity (26), microphallus and hypospadias (2), and primary amenorrhea (1). Basal and/or stimulated testosterone concentrations showed insufficient testosterone secretion in three patients. Genitography showed a vagina in 13 patients. Male genitoplasties were performed on 21 out of the 24 patients reared as males and female genitoplasties on five patients. Histological studies of the gonads of these showed streak gonads in one, normal gonads in one and signs of testicular dysgenesis in three others. Molecular studies on the SRY gene (17) showed no mutation. CONCLUSIONS: Idiopathic male pseudohermaphroditism is a heterogeneous condition, even within families with a history of this condition. We propose a set of guidelines for the management of these patients.     

Gonadal dysgenesis with a difference

We report here an exceptional clinical finding of a 46,XY phenotypic female with complete gonadal dysgenesis, but who was found unexpectedly to have absence of the uterus and posterior vagina. Extensive review of current and past literature failed to confirm other reports of this variant form of complete gonadal dysgenesis.