Fluidity models in ancient Greece and current practices of sex assignment.

Disorders of sexual differentiation such as androgen insensitivity and gonadal dysgenesis can involve an intrinsic fluidity at different levels, from the anatomical and biological to the social (gender) that must be considered in the context of social constraints. Sex assignment models based on George Engel's biopsychosocial aspects model of biology accept fluidity of gender as a central concept and therefore help establish expectations within the uncertainty of sex assignment and anticipate potential changes. The biology underlying the fluidity inherent to these disorders should be presented to parents at diagnosis, an approach that the gender medicine field should embrace as good practice. Greek mythology provides many accepted archetypes of change, and the ancient Greek appreciation of metamorphosis can be used as context with these patients. Our goal is to inform expertise and optimal approaches, knowing that this fluidity may eventually necessitate sex reassignment. Physicians should provide sex assignment education based on different components of sexual differentiation, prepare parents for future hormone-triggered changes in their children, and establish a sex-assignment algorithm.

Evidence-Based Management of Patients with 45,X/46,XY Gonadal Dysgenesis and Male Sex Assignment: from Infancy to Adulthood.

45,X/46,XY gonadal dysgenesis is a disorder of sexual differentiation with a wide clinical presentation, ranging from Turner-like females to individuals with genital ambiguity to azoospermic but otherwise normal-appearing males. Hence, patients can be assigned female or male sex. Female patients are managed according to the Turner Syndrome Guidelines, whereas males are managed on a case-by-case basis. Male patients present with multiple medical challenges: undervirilization, hypogonadism, gonadoblastoma risk, and short stature. Many require surgeries and hormonal treatments that are time-sensitive and irreversible. Nonetheless, these therapeutic decisions are made without evidence-based guidelines. This review describes the medical concerns and possible interventions in male patients with 45,X/46,XY dysgenesis for each stage of development. Interventions should be addressed within a patient-centered framework by a multidisciplinary team and after thorough discussion with the family. We use the GRADE system to appraise the existing evidence and provide recommendations based on the available evidence.

Androgen Insensitivity Syndrome: Management Considerations from Infancy to Adulthood.

Androgen insensitivity syndrome (AIS) is an undervirilization syndrome in individuals with 46, XY karyotype. The undervirilization can be complete feminization or incomplete virilization with grades of ambiguity. AIS is caused by mutations in the androgen receptor, resulting in resistance to the physiologic activities of androgens. Differing degrees of resistance lead to three phenotypes: a complete form with female-appearing external genitalia, a partial form with a wide range of virilization, and a mild form with only minor undervirilization. AIS presents different challenges depending on whether resistance is complete or partial. Challenges include sex assignment, which impacts other medical decisions such as gonadectomy, hormonal replacement, and other surgical interventions. This review describes medical, psychosocial, and ethical concerns for each stage of development in complete and partial AIS, from the neonatal period to adulthood. These aspects of care should be addressed within an ethical framework by a multidisciplinary team, with the patients and families being the stakeholders in the decision-making process. We use the GRADE system when appropriate to appraise the existing evidence and provide recommendations and guidelines for management of AIS and appropriate transition of patients from pediatric to adult care.

Association of immunohistochemical markers with premalignancy in Gonadal Dysgenesis.

BACKGROUND: Gonadal dysgenesis (GD) is associated with increased risk of gonadal malignancy. Determining a patient's risk and appropriate timing of gonadectomy is challenging, but immunohistochemical markers (IHM) may help establish the diagnosis of malignant germ cell tumors (GCT). Our objective was to identify the prevalence of specific IHM expression in patients with GD and determine if the patterns of expression can help identify malignancy versus pre-malignancy state. We evaluated the published literature using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system to provide recommendations on the predictive role of IHM in the detection of germ cell malignancy. METHODS: The data for this retrospective study included karyotype, gonadal location, external masculinization score, age at time of gonadectomy or biopsy, microscopic description and diagnosis of gonadal tissue, and immunohistochemical staining, including octamer binding transcription factor (OCT) 3/4, placental-like alkaline phosphatase (PLAP), ß-catenin, alpha-fetoprotein (AFP), and stem cell factor receptor CD117 (c-KIT). Patients with complete or partial GD who had undergone gonadectomy or gonadal tissue biopsy were included. RESULTS: The study included 26 patients with GD, 3 of whom had evidence of GCT (11.5 %, gonadoblastoma, dysgerminoma): 2 had Swyer syndrome, 1 had 46,XY partial GD. One patient with XY partial GD had gonadoblastoma-like tissue. All 4 patients (15 %) had strong expressions of 4 tumor markers (OCT 3/4, PLAP, ß-catenin, CD117), as did 5 other patients (19 %, ages 2-14 months) without GCT: 4 had XY GD, 1 had 46,XX GD. ß-catenin was expressed in 96 % of patients in a cytoplasmic pattern, CD117 in 78 %, OCT 3/4 in 55 %, PLAP in 37 %, and AFP in 1 patient (4 %). Tumor marker expression was not specific for ruling out malignancy in patients <1 year. CONCLUSIONS: In patients older than 1 year, expression of all three markers (OCT 3/4, PLAP, CD117) may be instrumental in the decision-making process for gonadectomy, even in the absence of overt germ cell malignancy. Our literature review suggests that OCT 3/4 expression is most helpful in predicting risk of malignancy. Additional criteria are needed to stratify risk in patients younger than 1 year of age, as these markers are not reliable in that age group.

State of the art review in hypospadias: challenges in diagnosis and medical management.

Hypospadias is a common congenital malformation in males, the cause of which may be genetic, hormonal, or environmental, although it usually is idiopathic or possibly multifactorial. Determining the optimal diagnostic testing and management remains a challenge. Hypospadias is corrected with surgery, and androgen therapy often is used preoperatively as an adjunctive therapy, although its use, timing, and effectiveness are unclear. No standardized approach has been established for the diagnostic testing for hypospadias or for preoperative androgen therapy. We reviewed current literature and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence and provide recommendations for a diagnostic testing algorithm from an endocrine and genetic perspective and for the optimal use of preoperative androgen therapy. These recommendations are an important step towards standardizing the use of diagnostic testing and the management of patients with hypospadias.

State of the art review in gonadal dysgenesis: challenges in diagnosis and management.

Gonadal dysgenesis, a condition in which gonadal development is interrupted leading to gonadal dysfunction, is a unique subset of disorders of sexual development (DSD) that encompasses a wide spectrum of phenotypes ranging from normally virilized males to slightly undervirilized males, ambiguous phenotype, and normal phenotypic females. It presents specific challenges in diagnostic work-up and management. In XY gonadal dysgenesis, the presence of a Y chromosome or Y-chromosome material renders the patient at increased risk for developing gonadal malignancy. No universally accepted guidelines exist for identifying the risk of developing a malignancy or for determining either the timing or necessity of performing a gonadectomy in patients with XY gonadal dysgenesis. Our goal was to evaluate the literature and develop evidence-based medicine guidelines with respect to the diagnostic work-up and management of patients with XY gonadal dysgenesis. We reviewed the published literature and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system when appropriate to grade the evidence and to provide recommendations for the diagnostic work-up, malignancy risk stratification, timing or necessity of gonadectomy, role of gonadal biopsy, and ethical considerations for performing a gonadectomy. Individualized health care is needed for patients with XY gonadal dysgenesis, and the decisions regarding gonadectomy should be tailored to each patient based on the underlying diagnosis and risk of malignancy. Our recommendations, based on the evidence available, add an important component to the diagnostic and management armament of physicians who treat patients with these conditions.

Guidelines for evaluating and managing children born with disorders of sexual development.

Children born with disorders of sexual differentiation (DSD) pose numerous challenges for the parents, family, and treating physicians. The pediatrician is usually the first medical contact for newborns with DSD or for toddlers and children who present with DSD at a later time. Several years ago, we formed a Gender Medicine Team (GMT) at Baylor College of Medicine and Texas Children's Hospital (TCH) to explore and evaluate the most appropriate management strategies, which had long been a matter of concern and contention. Subsequently, the GMT, composed of experts in the fields of endocrinology, ethics, genetics, gynecology, psychology, pediatric surgery, and urology, formed a Task Force to evaluate the information available from our own experiences and from reviews of the literature. Utilizing the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system to assess the evidence and recommendations, the Task Force developed a consensus statement for clinical management of DSD and for making appropriate sex assignments.

Consensus in Guidelines for Evaluation of DSD by the Texas Children's Hospital Multidisciplinary Gender Medicine Team.

The Gender Medicine Team (GMT), comprised of members with expertise in endocrinology, ethics, genetics, gynecology, pediatric surgery, psychology, and urology, at Texas Children's Hospital and Baylor College of Medicine formed a task force to formulate a consensus statement on practice guidelines for managing disorders of sexual differentiation (DSD) and for making sex assignments. The GMT task force reviewed published evidence and incorporated findings from clinical experience. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to assess the quality of evidence presented in the literature for establishing evidence-based guidelines. The task force presents a consensus statement regarding specific diagnostic and therapeutic issues in the management of individuals who present with DSD. The consensus statement includes recommendations for (1) laboratory workup, (2) acute management, (3) sex assignment in an ethical framework that includes education and involvement of the parents, and (4) surgical management.

Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation.

We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient's clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant's hypothalamic-pituitary-thyroid axis to thyroid hormone replacement.