Gonadectomy in conditions affecting sex development: a registry-based cohort study.

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 centre; and location of centre 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 centres. 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 centres 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 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (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.

A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD.

R-spondin proteins are secreted agonists of canonical WNT/ß-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat-containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease.

Two novel mutations in the EIF2AK3 gene in children with Wolcott-Rallison syndrome.

Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, epiphyseal dysplasia, and other multisystemic clinical manifestations. We described two novel mutations in the EIF2AK3 gene in two consanguineous families with WRS from Brazil and Morocco. We have observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398 (Gln398Stop). Both of his parents were found to be heterozygous for the mutation. We detected in both parents of case 2, a deceased Moroccan girl, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (p.Pro285AlafsX3). Both cases 1 and 2 had neonatal diabetes mellitus, multiple epiphyseal dysplasia, and growth delay, and presented episodes of acute hepatic dysfunction. Case 1 presented central hypothyroidism, developmental delay, and mild mental retardation. Case 2 presented a fatal episode of acute renal failure. The clinical phenotype associated with the syndrome can be variable, but a combination of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and hepatic and/or renal dysfunction is the mainstay of diagnosis.

Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis.

OBJECTIVES: To describe the history, mechanisms, and consequences of cystic fibrosis (CF)-related diabetes, from childhood to early adulthood. STUDY DESIGN: Pancreatic beta-cell function was estimated from the plasma insulin/glucose ratios during oral glucose tolerance test (total area under the curve and deltaI(30-0min)/G(30min), homeostasis model assessment [HOMA]%B), insulin sensitivity with the HOMA%S index, in 237 children with CF (109 boys, 128 girls). Progression of glucose metabolism abnormalities was evaluated by analysis for interval censored data; rates of pulmonary transplantation and death by Kaplan-Meier analysis. RESULTS: Impaired glucose tolerance was found in 20% of patients at 10 years, 50% at 15 years, 75% at 20 years, 82% at 30 years; for diabetes, >20% at 15 year, 45% at 20 years, 70% at 30 years; for insulin treatment, 30% at 20 years, 40% at 30 years. Early impairment was associated with lower survival rates and higher rates of lung transplantation. The area under the curve(glucose) correlated with decreased body mass index and height. Decrease in early insulin secretion (deltaI(30-0min)/G(30min)) was associated with impaired glucose tolerance, in all estimates of insulin secretion with diabetes. HOMA%S did not differ between the groups. Increased inflammation correlated with insulin resistance and impaired glucose tolerance. CONCLUSIONS: CF-related diabetes, mainly because of beta-cell deficiency, is frequent early in life and associated with impaired nutritional state and growth, increased rates of terminal respiratory failure, and death.