Late diagnosis of the X-linked MCT8 deficiency (Allan-Herndon-Dudley syndrome) in a teenage girl with primary ovarian insufficiency.

OBJECTIVES: To report an unusual case of MCT8 deficiency (Allan-Herndon-Dudley syndrome), an X-linked condition caused by pathogenic variants in the SLC16A2 gene. Defective transport of thyroid hormones (THs) in this condition leads to severe neurodevelopmental impairment in males, while heterozygous females are usually asymptomatic or have mild TH abnormalities. CASE PRESENTATION: A girl with profound developmental delay, epilepsy, primary amenorrhea, elevated T3, low T4 and free T4 levels was diagnosed with MCT8-deficiency at age 17 years, during evaluation for primary ovarian insufficiency (POI). Cytogenetic analysis demonstrated balanced t(X;16)(q13.2;q12.1) translocation with a breakpoint disrupting SLC16A2. X-chromosome inactivation studies revealed a skewed inactivation of the normal X chromosome. CONCLUSIONS: MCT8-deficiency can manifest clinically and phenotypically in women with SLC16A2 aberrations when nonrandom X inactivation occurs, while lack of X chromosome integrity due to translocation can cause POI.

Very elevated serum copeptin concentrations occur in a subset of healthy children in the minutes after phlebotomy.

OBJECTIVES: Although AVP and its surrogate, copeptin, are mainly regulated by osmotic and volume stimuli, their secretion is also elicited by stress and growth hormone (GH) stimulating agents. The aim of this report is to describe unusual patterns of copeptin response in a subset of children undergoing GH stimulation tests (GH-ST). METHODS: We conducted a secondary analysis of a cohort of 93 healthy short children with no polydipsia, polyuria or fluid/electrolyte abnormalities, undergoing GH-ST with intravenous arginine, insulin, oral clonidine, or L-Dopa/carbidopa in various combinations. Serum copeptin concentrations were measured 1-3 min after phlebotomy (0 min) and at 60, 90, 120 min during GH-ST. RESULTS: In 85 subjects (normal response group, NRG) serum copeptin concentrations increased from a 0 min median of 9 pmol/L (IQR 6, 11.5) (all values ≤21) to a median peak between 60 and 120 min of 22 (IQR15, 38) pmol/L, which varied depending on the stimulating agent. Conversely, in the eight outliers, copeptin concentrations decreased gradually from a median of 154 (IQR 61, 439) pmol/L (all ≥40 pmol/L) to values as low as 14 % of the basal value, by 120 min. Test-associated anxiety was described in 17 subjects in the NRG (20 %) and five of the outliers (63 %). CONCLUSIONS: A distinctive pattern of very elevated serum copeptin concentrations occurred in 9 % of children undergoing GH-ST, similar to reports in previous pediatric studies. Etiology may include pain or stress of phlebotomy. This phenomenon should be recognized for proper interpretation of copeptin values in children.

Current State of Pediatric Reference Intervals and the Importance of Correctly Describing the Biochemistry of Child Development: A Review.

Importance: Appropriately established pediatric reference intervals are critical to the clinical decision-making process and should reflect the physiologic changes that occur during healthy child development. Reference intervals used in pediatric care today remain highly inconsistent across a broad range of common clinical biomarkers. Observations: This narrative review assesses biomarker-specific pediatric reference intervals and their clinical utility with respect to the underlying biological changes occurring during development. Pediatric reference intervals from PubMed-indexed articles published from January 2015 to April 2021, commercial laboratory websites, study cohorts, and pediatric reference interval books were all examined. Although large numbers of pediatric reference intervals are published for some biomarkers, very few are used by clinical and commercial laboratories. The patterns, extent, and timing of biomarker changes are highly variable, particularly during developmental stages with rapid physiologic changes. However, many pediatric reference intervals do not capture these changes and thus do not accurately reflect the underlying biochemistry of development, resulting in significant inconsistencies between reference intervals. Conclusions and Relevance: There is a need to correctly describe the biochemistry of child development as well as to identify strategies to develop accurate and consistent pediatric reference intervals for improved pediatric care.

Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study.

CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Pediatric Patient With Altered Mental Status and Hypoxemia: Case Report.

Childhood cases of myxedema coma are extremely rare. We report a case of a 5-year-old girl transferred to a tertiary care pediatric emergency department with hypoxemia and altered mental status and diagnosed with severe hypothyroidism and myxedema coma in the setting of acute influenza infection. Although it is rare, myxedema coma must remain in the differential diagnosis for altered mental status and organ dysfunction in the pediatric population.