RESUMEN
We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic ß cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in ß-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient's pancreas than in control subjects but there was no difference in the proportion of ß cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.
Asunto(s)
Glucoquinasa , Hipoglucemia , Adulto , Glucoquinasa/genética , Glucoquinasa/metabolismo , Glucosa , Humanos , Hipoglucemia/genética , Insulina/metabolismo , Secreción de Insulina , MasculinoRESUMEN
Central hypothyroidism is a condition where there is (qualitatively or quantitatively) TSH deficiency, leading to reduced thyroid hormone production. In such patients, serum TSH does not accurately reflect the adequacy of thyroxine replacement, as the log-linear relationship between thyrotropin (TSH) and free thyroxine (FT4) is lost. We aimed to prospectively determine the optimal physiological FT4 treatment range for children treated for primary hypothyroidism, based on their serum TSH concentrations. This information could be used to guide optimal therapy for all children on thyroxine replacement, including those with central hypothyroidism. In total, sixty children (median age: 11 years, range: 11 months to 18 years) were recruited over 21 months. They were prescribed a stable dose of thyroxine for at least 6-8 weeks prior to a thyroid function test that consisted of serum TSH, FT4 and free triiodothyronine (FT3) measurements. The serum sample for the thyroid function tests was collected before ingestion of the daily dose, i.e. the trough concentration, and measured using Beckman Coulter UniCel DxI 800 instrument, Siemens Advia Centaur, Roche Cobas, Abbott Architect, Ortho Clinical Diagnostics Vitros 5600 (Ortho-Clinical Diagnostics, Raritan, NJ) platforms. The FT4 and FT3 reference intervals showed significant inter-method difference. The lower limit of the FT4 reference intervals were generally shifted mildly higher when the TSH concentration of the children were restricted from 0.5-5.0 mIU/L to 0.5-2.5 mIU/L. By contrast, the upper limit of the FT3 and FT4 reference intervals were relatively stable for the different TSH concentrations. Assay-specific target ranges for optimal thyroxine therapy are required until FT4 assay standardisation is realised.
Asunto(s)
Bioensayo , Monitoreo de Drogas , Terapia de Reemplazo de Hormonas , Tiroxina/sangre , Triyodotironina/sangre , Adolescente , Niño , Femenino , Humanos , Masculino , Valores de ReferenciaRESUMEN
AIM: To assess the current protocol of metabolic bone disease (MBD) at three Monash Health neonatal units (Melbourne, Australia). METHODS: Retrospective audit of 171 infants born at <32 weeks' gestation over 18 months. Mean gestational age was 28.6 ± 2.1 weeks, and birthweight was 1190 ± 374 g. Risk factors of MBD include intra-uterine growth retardation (n = 33, 19.3%), maternal pre-eclampsia (n = 17, 9.9%), necrotising enterocolitis (n = 9, 5.4%) and medications like methylxanthines (94.2%; mean 54.8 days), diuretics (38.6%; mean 49.2 days) and glucocorticoids (5.3%; mean 35 days). RESULTS: In total, 84.8% infants had an initial MBD screen (mean age 36.3 days), with 45% having repeated monitoring (mean age 71.9 days), and 14.2% had initial alkaline phosphatase levels >500 U/L, decreasing to 10.1% on follow-up. All infants received additional vitamin D supplementation of 400 IU/day, phosphate of 25.1% (n = 43) and calcium of 19.9% (n = 34). Fractures were identified from clinical documentation in 2.9% (n = 5) of infants. Stratifying into phosphate-treated and untreated groups revealed significant differences (P < 0.001) for gestational age and birthweight: 26.7 ± 1.7 weeks/918 ± 272 g for treated versus 29.2 ± 1.9 weeks/1283 ± 359 g for untreated. In the phosphate-treated group, improvement was seen in mean alkaline phosphatase (pre-treatment 467 ± 204 U/L and post-treatment 342 ± 221 U/L, P < 0.01) and mean phosphate levels (1.8 ± 0.4 vs. 2.2 ± 1.0 mmol/L, P < 0.01). Linear growth difference between phosphate-treated (n = 10) and untreated groups (n = 24) was insignificant at >6 months of age (P = 0.13), although this may reflect limited data. CONCLUSION: Adequate first-line supplementation with vitamin D and phosphate appeared to improve biochemical markers of MBD, but given the observational nature of this study, further longitudinal/prospective studies are required to confirm these findings.