Purpose of reviewThe present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD).Recent findingsAlthough ALD screening has been on the list of Recommended Uniform Screening Panel since 2016, only 30 states in the United States are currently testing their newborns for this disease. Hematopoietic stem cell transplant (HSCT) remains the only successful treatment option available for early cerebral ALD but does not reverse neurological changes or affect the course of adrenal insufficiency. There remains a significant knowledge gap in our understanding and treatment of this disease. Novel therapies such as gene therapy and gene editing have shown promising results in animal models and are exciting potential treatment options for the future.Recently, the American Academy of Neurologists released their consensus guidelines on the diagnosis, surveillance, and management of ALD.SummaryEarly diagnosis and HSCT are key to improving the morbidity and mortality associated with ALD. The implementation of universal newborn screening for ALD and rigorous investigations of novel diagnostic and therapeutic agents is the need of the hour.
Background The spectrum of disorders associated with hyperinsulinemic hypoglycemia (HHI) has vastly increased over the past 20 years with identification of molecular, metabolic and cellular pathways involved in the regulation of insulin secretion and its actions. Hereditary tyrosinemia (HT1) is a rare metabolic disorder associated with accumulation of toxic metabolites of the tyrosine pathway due to a genetically mediated enzyme defect of fumarylacetoacetate hydrolase. Transient tyrosinemia of the newborn (TTN) is a benign condition with a maturational defect of the enzymes associated with tyrosine metabolism without any genetic abnormalities. Results We describe two rare cases of HHI, one in a patient with HT1 and for the first time, in a patient with TTN. Each of our patients presented in the neonatal period with persistent hypoglycemia that on biochemical evaluation was consistent with HHI. Each patient received diazoxide therapy for 3.5 months and 17 months of life, respectively and HHI resolved thereafter. Conclusion Despite the fact that HHI has been described in HT1 for several decades, no specific mechanism has been delineated. Although we considered the common embryonal origin of the liver and pancreas with the hepatotoxic effect in HT1 also impacting the latter, this was not a possible explanation for TTN. The commonality between our two patients is the accumulation of certain amino acids which are known to be insulinotropic. We therefore hypothesize that the excess of amino acids such as leucine, lysine, valine and isoleucine in our patients resulted in HHI, which was transient. Both patients responded to diazoxide. This novel presentation in TTN and the reassuring response in both HT1 and TTN to diazoxide will be useful to inform physicians about managing HHI in these patients. Further studies are required to delineate the mechanism of HHI in these infants.
Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (<1 μg/dL). Examination showed diffuse hyperpigmentation with normal male genitalia. Patient developed hyperbilirubinemia and elevated transaminase levels. GH levels of 6.8 ng/mL and 7.48 ng/mL during episodes of hypoglycemia, peak of 9.2 ng/mL with glucagon stimulation, and undetectable IGF-1 suggested GH deficiency. Thyroid function, prolactin, and gonadotropins were normal. Baseline ACTH was elevated at 4868 pg/mL, whereas serum cortisol remained undetectable with ACTH stimulation. Hydrocortisone replacement resulted in normalization of blood glucose and cholestasis with decline in ACTH level. GH therapy was not initiated, given improvement in cholestasis and euglycemia. An ACTH receptor defect was confirmed with molecular genetic testing that revealed homozygosity for a known mutation of the melanocortin 2 receptor ( MC2R ) gene. At 12 weeks, a random GH level was 10 ng/mL. IGF-1 was 75 ng/mL and 101 ng/mL at 7 and 9 months, respectively. This report describes glucocorticoid deficiency from an MC2R mutation associated with GH deficiency. With glucocorticoid replacement, GH secretion normalized. Our findings are consistent with a previously stated hypothesis that physiologic glucocorticoid levels may be required for optimal GH secretion [ 1 ].
Highlights We question certain aspects of the recent Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report (January 2022) showing a significant increase in the incidence of diabetes in children after COVID‐19 infection. We are concerned at the source of data being limited to commercial health insurances and lack of factoring race, ethnicity, social determinants of health, body mass index, type of diabetes, and viral variants in the interpretation of these data.
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