[Atypical genital development and tumor risk]. / Atypie du développement génital et risque tumoral : synthèse de la réunion scientifique du 25 mai 2018 organisée par le « Centre de référence des maladies rares du développement génital du fœtus à l'adulte ¼.

Atypical genital development (AGD), also called disorders of sex development are a set of miscellaneous pathologies who have in common a morphological and/or functional abnormality of the internal and/or external genital organs. The Chicago classification identifies 3 major groups based on karyotype, hormone balance and genetic studies. Some AGD predispose to the occurrence of tumors, mainly malignant germ cell tumors. The tumor risk depends on many factors: the type of AGD, the position of the gonad, the age of the patient, the phenotype, the function of the gonad and the presence of germ cells in the gonad. AGD with the highest tumor risk are those with gonadal dysgenesis, implying an incomplete differentiation of the bipotential gonad (dysplasia). Monitoring of patients with AGD and indication of prophylactic gonadectomies should be individualized according to tumor risk.

Perspectives in Pediatric Pathology, Chapter 5. Gonadal Dysgenesis.

One of the most challenging areas in pediatric testicular pathology is the appropriate understanding and pathological diagnosis of disorders of sexual development (DSD), and in particular, the issue of gonadal dysgenesis. Here we present the main concepts necessary for their understanding and appropriate classification, with extensive genetic correlations.

Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases.

OBJECTIVE: To determine the frequency of XY karyotypes among females with complete gonadal dysgenesis (CGD) and to investigate the frequency of both gonadal tumors and SRY mutations. DESIGN: Retrospective study based on data from all patients with CGD seen in our service from 1989 to 2010. SETTING: Clinic for disorders of sex development, University Hospital, State University of Campinas. PATIENT(S): Thirty-two patients with hypergonadotropic hypogonadism, streak gonads, internal and external female genitalia, and normal karyotype (46,XX or 46,XY); 31 were index cases and 29 did not have a previously determined karyotype. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): The percentage of XY karyotypes among patients with CGD was 34.5% (10/29). Mean age at diagnosis among XY and XX patients was 17.4 years and 19.9 years, respectively. Gonadal tumors were found in 4 of 9 XY girls, and 7 of 10 had SRY gene mutations. CONCLUSION(S): The previously unreported finding of an elevated frequency of 46,XY karyotype among patients with CGD and the high risk of gonadal neoplasia in such cases indicate that this diagnosis must be kept in mind by clinicians and strengthen the importance of karyotype analysis in females with primary hypogonadism. In addition, the frequency of SRY mutations in XY CGD might be higher than previously considered.

Nomenclature of cryptorchidism.

Despite the fact that cryptorchidism is a common congenital anomaly, our understanding of this problem is hampered by confusion and uncertainty regarding diagnosis and treatment. A major factor producing this confusion is the lack of a common terminology that describes to the reader (or listener) exactly what the author means by a given term. Herein is proposed a classification system that, if adopted and utilized, could ameliorate this problem.

[Clinical aspects of gonadal dysgenesis]. / Aspects cliniques des dysgénésies gonadiques.

Gonadal dysgenesis are classified according to the aspect of external genitalia. The group with female genitalia includes Turner's syndrome, and "pure" dysgenesis; the group with male genitalia involves Klinefelter's syndrome, XX males and may be anorchia; the group with ambiguous genitalia includes "mixed" gonadal dysgenesis, true hermaphroditism and Leydig-cell agenesis. An algorythmic approach to patients with ambiguous external genitalia is presented in order to distinguish between gonadal dysgenesis and male or female pseudohermaphroditism.

[Gonadal dysgenesis and agenesis: anatomical expression]. / Dysgénésies et agénésies gonadiques expression anatomique.

The term of gonadal dysgenesis designates generically any anatomical alteration due to abnormal embryological development of a gonad. The spectrum of these gonadal abnormalities is large and includes the following entities: The gonadal agenesis is characterized by a rudimentary streak gonad. It is composed of a dense, hyalinized fibrous tissue in which the germ cells or the germ structures are entirely missing. Usually the gonadal dysgenesis is a bilateral and symmetrical lesion. The gonadal dysgenesis is characterized by the presence of residual germ structures (follicles or tubules). These structures can be more or less easily identified within a dense fibrous tissue. The gonadal dysgenesis alterations are often unilateral and always asymmetrical. Usually the ipsilateral gonad is a testis. The ovotestis is characterized by the coexistence within the same gonad of differentiated germ structures. Most commonly, the gonadal dysgenesis are associated with sexual chromosome abnormalities and an increased risk of neoplastic change (gonadoblastoma). This risk can reach 30% in the asymmetrical gonadal dysgenesis.

Studies on gonadal dysgenesis: variable expressivity of the XY testicular dysgenesis syndrome; two case reports.

Two adult unrelated XY phenotypically female individuals with sexual infantilism and genital ambiguity were studied. Mosaicism was ruled out by the assessment of a normal 46,XY karyotype in four different cell lines. Persistently elevated LH and FSH serum levels with concomitant normal pituitary Gn-RH responsiveness were found. Baseline serum testosterone concentrations were low, but they exhibited a slight though significant rise following HCG stimulation. Surgical and histological findings included the presence of Mullerian and Wolffian derivatives and small bilateral dysgenetic testes with absence of germ cell epithelium, scarce Sertoli cells, and hyperplastic Leydig cells. The overall data indicated an anatomo-functional testicular impairment particularly confined to the tubular compartment. By comparing the clinical and endocrine features of this incomplete form of the XY testicular dysgenesis with the complete and other unusual forms, further evidence is provided of a wide heterogeneity of the syndrome, and a more detailed classification is proposed.

The diagnosis and treatment of infants with intersex abnormalities.

Management of these children, which begins in the newborn period and often extends throughout adolescence, should be done as a team approach with pediatric surgeons/urologists and pediatric endocrinologists. Careful attention must be paid to the technical aspects of these repair to ensure successful anatomic, functional, and psychological outcome for these often difficult patients. Although this article concentrates on the technical aspects of the surgical repairs of these children, careful consideration is given to the circumstances dictating gender assignment and the factors that affect the choice and timing of operation.

Nephropathy-gonadal dysgenesis, type 2: renal failure in three siblings with XY dysgenesis in one.

The nephropathy-XY gonadal dysgenesis syndrome in a 17-year-old phenotypical female with focal glomerulosclerosis was associated with renal failure in two sisters, one with crescentic glomerulonephritis at 27 months, and one with membranoproliferative glomerulonephritis at 10 years. Neither the propositus or the siblings had the distinctive mesangial sclerosis of nephropathy-XY dysgenesis, type 1 (Drash syndrome). The association of nephropathy-XY dysgenesis with familial nephritis of heterogeneous pathology suggests that nephropathy-XY dysgenesis, type 2, may relate to separate genetic loci for XY dysgenesis and glomerulopathy or reflect a loss of protection against familial renal disease when the Y chromosome is absent or defective.

Brief historical note: the concept of "gonadal dysgenesis".

The history of gonadal by dysgenesis cautions against overinterpretation of data: The streak gonads are neither the result of dysgenesis nor of embryonic origin but represent late fetal/neonatal degeneration; the X-chromatin-negative character of the buccal smear and the frequency of color vision defects did not indicate male sex in the Ullrich-Turner syndrome but rather an XO constitution; severity of dysgenesis did not correlate with risk of gonadal neoplasia but with genotype; the gonadal lesion in the Ullrich-Turner syndrome was not due to a pituitary defect but a primary ovarian lesion; patients with the Noonan syndrome do not have the Turner phenotype. The concept of gonadal dysgenesis, introduced to Kermauner in 1912, has outlived its usefulness. Improved methods of phenotype analysis, family studies, and endocrine and cytogenetic methods have showen it to be causally and pathogenetically heterogeneous and have contributed to a better identification and delineation of the several different genetic entities which it formerly comprised.