Puberty Today, Gone Tomorrow: Transient Refractory Central Precocious Puberty in a Toddler with End-Stage Kidney Disease.

Novel Insights: - There are only three reported cases of precocious puberty in boys with CKD - Hypothalamic dysfunction due to uremia, and disordered renal clearance of LH, may lead to central precocious puberty, which resolves after uremia is corrected, e.g., after kidney transplant. - Increased drug clearance via peritoneal dialysis and/or an effect of uremia may lead to a sub-optimal response to leuprolide therapy. - Further studies are needed to characterize the relationship of CKD and peritoneal dialysis on puberty. INTRODUCTION: The onset of puberty is typically delayed in children with chronic kidney disease (CKD), with only three reported cases of precocious puberty in boys with CKD. CASE PRESENTATION: We report the case of a boy with end-stage kidney disease secondary to posterior urethral valves who, while undergoing peritoneal dialysis, presented at 17 months with central precocious puberty characterized by clinical signs of testicular and penile enlargement, pubic hair, and acne; rapid linear growth with advanced bone age; and pubertal luteinizing hormone (LH) and testosterone levels. Monthly leuprolide injections were commenced at 24 months with no pubertal or biochemical suppression thereafter, along with continued rapid bone-age advancement through 32 months. He then received a deceased-donor kidney transplant at 33 months of age, with good graft function. Within 2 months, he was noted to have prepubertal GnRH-stimulated LH and testosterone levels. Leuprolide injections were discontinued at that time with no further progression of puberty. The patient is now 48 months with minimal further bone-age advancement, and consistently prepubertal LH and testosterone levels. CONCLUSION: Our case demonstrates the development of precocious puberty due to premature activation of the hypothalamic-pituitary-testicular axis, presumably secondary to uremia and/or disordered renal clearance of gonadotropins, which was refractory to standard management with a gonadotropin-releasing hormone agonist, perhaps due to excessively rapid removal by peritoneal dialysis and/or the uremic state itself. Kidney transplantation led to a correction of uremia and a return to the prepubertal state.

Early anthropometric indicators of type 2 diabetes mellitus.

PURPOSE OF REVIEW: With the rapidly increasing incidence of type 2 diabetes mellitus (T2DM) in youth (as in adults), it is critical to recognize phenotypic markers that can help predict and potentially prevent its onset, and reduce the associated burden of the disease for patients, families, and society. In this review, we summarize the most recent literature characterizing growth, puberty, and body composition in youth at risk for or who have T2DM. RECENT FINDINGS: There is an inverse, nonlinear relationship between birth weight and future risk of developing T2DM. Height seems to have an inverse correlation with risk for diabetes. Earlier onset of puberty in males and females is associated with the T2DM phenotype. While adiposity is a known correlate of T2DM, visceral adiposity as represented by waist circumference has emerged as one of the key determinants of T2DM in population-based studies globally. Thresholds for body mass index vary across ethnicities in predicting risk for T2DM, depending on genetic factors and fat-distribution profiles. SUMMARY: Emerging links between T2DM and dysregulated parameters of growth and development highlight the importance of early recognition of modifiable risk factors and the creation of individualized screening protocols. VIDEO ABSTRACT: http://links.lww.com/COE/A31.

Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series.

CONTEXT: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes. METHODS: We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts. RESULTS: Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated. CONCLUSIONS: Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8.

Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.