EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence.

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.

Low Vitamin D Levels are Associated With Need for Surgical Correction of Pediatric Fractures.

BACKGROUND: There is growing concern over the relationship between the severity of pediatric fractures and low vitamin D [25-hydroxyvitaminD (25(OH)D)] status. OBJECTIVE: Compare 25(OH)D levels and lifestyle of children with fractures to nonfracture controls to determine if 25(OH)D levels are associated with fractures and if there is a 25(OH)D fragility fracture threshold. METHODS: Pediatric fracture and nonfracture controls were included. Bone health survey and medical record data were analyzed. Fractures were categorized using the Abbreviated Injury Scale (AIS). AIS 3 fractures were identified as fractures that required surgical intervention. Univariate and multivariable ordinal regression analyses were performed to identify potential risk factors for increased fracture severity. RESULTS: A total of 369 fracture patients and 662 nonfracture controls aged 18 years and younger were included. Both groups' 25(OH)D levels were comparable. 25(OH)D was 27.5±8.9 in the fracture group compared with 27.4±9.1 ng/mL in nonfracture controls (P=0.914). AIS 3 fractures had lower 25(OH)D levels (24.6±9.3 ng/mL) versus AIS 1 and 2 (30.0±10.8 and 28.3±8.4, respectively, P=0.001). Univariate correlations for AIS severity were found with age (P=0.015) and outdoor playtime (P=0.042). Adjusted odds ratios for 25(OH)D levels <12 ng/mL was 55.4 (P=0.037), 25(OH)D between 12 and 20 ng/mL was 6.7 (P=0.039), 25(OH)D between 20 and 30 ng/mL was 2.8 (P=0.208), and 25(OH)D between 30 and 40 was 1.7 (P=0.518). CLINICAL RELEVANCE: Occurrence of a pediatric fracture was not associated with 25(OH)D levels in our study. However, children with lower vitamin D levels were found to be at higher risk for more severe fractures. Early evidence suggests that the target serum level for 25(OH)D should be at least 40 ng/mL in patients less than 18 years of age as the relative risk of more severe fractures increased as 25(OH)D levels decreased <40 ng/mL. LEVEL OF EVIDENCE: Level III.

Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative.

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH.