A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin.

Isolated ACTH deficiency (IAD) is a life-threatening condition, particularly in the neonatal period, while a main consequence of undiagnosed isolated ACTH deficiency in survivors is cognitive impairment. TBX19 is involved in the differentiation and proliferation of corticotropic cells and TBX19 mutations are responsible for more than 60% of neonatal cases of IAD. We describe a new variant of the main TBX19 transcript (NM 005149.3, c.840del (p.(Glu280Asp fs*27)), classified as pathogenic, whose pathogenicity is assumed to be due to nonsense mediated decay leading to non-expression of T-box transcription factor TBX19. Moreover we summarize the TBX19 mutations published as individual cases since our last large cohort. Interestingly, this pathogenic variant was identified in four patients from three apparently unrelated families. Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect. Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients.

Two Novel Cases of Resistance to Thyroid Hormone Due to THRA Mutation.

Resistance to thyroid hormone alpha (RTHα) is a rare and under-recognized genetic disease caused by mutations of THRA, the gene encoding thyroid hormone receptor α1 (TRα1). We report here two novel THRA missense mutations (M259T, T273A) in patients with RTHα. We combined biochemical and cellular assays with in silico modeling to assess the capacity of mutant TRα1 to bind triiodothyronine (T3), to heterodimerize with RXR, to interact with transcriptional coregulators, and to transduce a T3 transcriptional response. M259T, and to a lower extent T273A, reduces the affinity of TRα1 for T3. Their negative influence is only reverted by large excess of T3. The severity of the two novel RTHα cases originates from a reduction in the binding affinity of TRα1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TRα1 mutants in the presence of T3.

Evaluation of flash glucose monitoring after long-term use: A pediatric survey.

AIMS: To understand the opinions of children with type 1 diabetes about their everyday use of flash glucose monitoring. (FGM). METHODS: Children with type 1 diabetes using the FreeStyle Libre® FGM system and/or their parents were surveyed in several French medical centers between December 2016 and June 2017, regardless of their treatment regimen and metabolic control. RESULTS: Of the 347 patients recruited, 79.5% had been using the sensor for more than three months (average usage time: 285 days). The main reported motivations for initiating this type of monitoring were to avoid finger prick pain (for 85.9% of patients) and to allow parents to check nocturnal glucose levels (60.8%). Two-thirds of respondents experienced difficulties, mainly the sensor falling off (47.6%), measurement discrepancies (25.1%) and cutaneous reactions (22.2%); 89.5% changed their habits: 70.6% took more scans, 37.2% corrected their hyperglycemia more promptly, and 37.5% used trends to adjust their insulin dosage. About one-third of the study group (35.1%) experienced lower HbA1c levels, and two thirds (67.1%) were satisfied with the device. CONCLUSIONS: Our results show that FGM is a widely accepted option for self-monitoring diabetes, but that specific training is required to improve its use for insulin dosage adjustment and metabolic results.

Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

BACKGROUND: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D. METHODS: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods. RESULTS: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age. CONCLUSIONS: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas. TRIAL REGISTRATION: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.