The newborn infant with atypical genitalia presents a challenging clinical scenario and requires expert input. There have been appreciable advances in our knowledge of the underlying causes that may lead to a mere difference or a more serious disorder of sex development (DSD), the natural history of conditions, as well as the short and long-term complications of these conditions themselves, together with the clinical interventions that are associated with these conditions. With this information, the DSD expert can be more confident when discussing options with the parents of the newborn infant. By working within a multidisciplinary team, the expert should be able to support the family whilst individualising the management plan so that it is also cognizant of the shifts in societal attitudes and expectations around concepts of diversity and openness. It is, therefore, likely that the practice of assigning sex, especially in those cases where sex assignment is unclear on expert assessment, will continue to show temporal, social and geographical variations. It is imperative that clinical data for rare conditions such as these are collected in a standardized format and shared through a common registry so that any evidence that is used for future shifts in practice has a stronger foundation than that which is currently available.

Objectives: To determine trends in clinical practice for individuals with DSD requiring gonadectomy. Design: Retrospective cohort study. Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist center; and location of center from cases reported to the International DSD Registry and who were over 16 years old in January 2019. Results: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centers. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centers in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n=311, p<0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centers, 17 (5%) at 9 centers had undergone gonadectomy before their first presentation to the specialist center. Median age at gonadectomy of cases from high income countries and low/middle income countries (LMIC) was 13.0 yrs (0.1, 68) years and 16.5 yrs (1, 28), respectively (p<0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

Disorders of sex development (DSDs) are a genetically and clinically heterogeneous group of congenital conditions of the urogenital tract and reproductive system. Time and spatially controlled transcription factors, signal molecules, and an array of different hormones are involved in the development of sex characteristics, and variations in their pathways and actions are associated with DSD. These conditions may be caused by numerical or structural variations in sex chromosomes as well as autosomes, variations in genes involved in gonadal and/or genital development, and changes in gonadal and/or adrenal steroidogenesis. Endogenous or exogenous (maternal) and possibly endocrine disruptors may also interfere with genital development.

Background: Type 1 diabetes mellitus (T1DM) is the life-threatening chronic disease if left without appropriate clinical care and self-management. Diabetes places a burden on family life and daily routine that can be reduced by a proper disease management program. Extensive research studies are conducted for the estimation of pediatric quality of life (PedsQL) in the medical and psychosocial care of diabetic children. Objectives: To evaluate the quality of life of children 8-12 y/o with T1DM, to compare PedsQL perceived by their parents, to understand influence of gender and other factors on PedsQL and disease management. Methods: Children with T1DM were identified and recruited from the pediatric endocrinology department registries. We used the validated adapted pediatric quality of life inventory 3.0 diabetes module of the child (ages 8-12) and parent reports. Obtained scales were compared between children and parents as well as between the two genders. Results: A total of 132 T1DM children and their primary caregivers participated in the study. The mean age of the children was 6.82 ± 2.17 years. Girls had higher (17.82 ± 1.59) body mass index (BMI) than boys (17.1 ± 1.95; OR = 0.72; P value 0.021). Mean levels of HbA1C were different in genders: 9 ± 1.78 for girls and 7.93 ± 1.0 for boys (P < 0.001). Diet habits of diabetic children with uneducated primary caregiver have not been changed (P value 0.0138) and these children more often experienced hypoglycemia (P < 0.001). Regular exercising had positive effect on level of HbA1C (7.8 ± 0.82 versus 8.93 ± 1.73) (P value 0.003). In a comparison of PedsQL scores between boys and girls, we have found significant differences in 17 items and in 15 items between child and parent. Conclusions: In 8-12 y/o group of T1DM children, girls seem to be more sensitive towards pain and difficulties associated with the disease, boys experienced more difficulties related to treatment compliance and parents' involvement. Primary caregivers mostly underestimated the child's PedsQL.