Multicenter Analysis of Cardiometabolic-Related Diagnoses in Youth with Congenital Adrenal Hyperplasia: a PEDSnet study.

CONTEXT: Small cohorts of youth with congenital adrenal hyperplasia (CAH) demonstrate increased risk of obesity and poor cardiometabolic health. OBJECTIVE: To determine the odds of cardiometabolic-related diagnoses in youth with CAH compared to matched controls in a cross-sectional analysis in a large, multisite database (PEDSnet). DESIGN: Electronic health record data (2009-2019) were used to determine odds of cardiometabolic-related outcomes based on diagnosis, anthropometric and laboratory data using logistic regression among youth with CAH vs. controls. SETTING: Six PEDSnet sites. PATIENTS OR OTHER PARTICIPANTS: Youth with CAH and >1 outpatient visit in PEDSnet (n=1,647) were propensity-score matched on 8 variables to controls (n=6,588). A subset of youth with classic CAH (n=547, with glucocorticoid and mineralocorticoid prescriptions) were matched to controls (n=2,188). INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): Odds of having cardiometabolic-related diagnoses among youth over 2 years with CAH compared to matched controls. RESULTS: Outcomes were calculated for all individuals with CAH (median age at last visit 12.9 years [7.3, 17.6]) and a subset with classic CAH (median age at last visit 11.6 years [4.7, 17.5]) compared to their matched controls. All patients with CAH had higher odds of overweight/obesity (odds ratio [95% confidence interval] 3.63 [3.24,4.07]), hypertension (3.07 [2.60,3.64]), dysglycemia (1.95 [1.35,2.82], dyslipidemia (2.28 [1.79,2.91]) and liver dysfunction (2.30 [1.91,2.76]) compared to matched controls. Patients with classic CAH had higher odds of overweight/obesity (3.21 [2.61,3.93]), hypertension (8.22 [6.71,10.08]), and liver dysfunction (2.11 [1.55,2.89]) compared to matched controls. CONCLUSIONS: Overall, youth with CAH are at increased risk of diagnoses related to worse cardiometabolic health.

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future.

Since antiquity Man has been fascinated by the variations in human (and animal) growth. Stories and art abound about giants and little people. Modern genetics have solved some of etiologies at both extremes of growth. Serious study began with the pathophysiology of acromegaly followed by early attempts at treatment culminating in modern endoscopic surgery and multiple pharmacologic agents. Virtually at the same time experiments with the removal of the pituitary from laboratory animals noted the slowing or stopping of linear growth and then over a few decades the extraction and purification of a protein within the anterior pituitary that restored, partially or in full, the animal's growth. Human growth hormone was purified decades after those from large animals and it was noted that it was species specific, that is, only primate growth hormone was metabolically active in primates. That was quite unlike the beef and pork insulins which revolutionized the care of children with diabetes mellitus. A number of studies included mild enzymatic digestion of beef growth hormone to determine if those "cores" had biologic activity in primates and man. Tantalizing data showed minimal but variable metabolic efficacy leading to the "active core" hypothesis, for these smaller peptides would be amenable to peptide synthesis in the time before recombinant DNA. Recombinant DNA changed the landscape remarkably promising nearly unlimited quantities of metabolically active hormone. Eight indications for therapeutic use have been approved by the Food and Drug Administration and a large number of clinical trials have been undertaken in multiple other conditions for which short stature in childhood is a sign. The future predicts other clinical indications for growth hormone therapy (and perhaps other components of the GH?IGF-1 axis), longer-acting analogues and perhaps a more physiologic method of administration as virtually all methods at present are far from physiologic.

Recipe for Disaster: Homemade Formula Leading to Severe Complications in 2 Infants.

Families and physicians alike benefit from the advances and ease of the Internet. Similarly, both can be unaware of harmful misinformation circulating the Web. In this article, we describe the presentation of 2 unrelated infants, within 1 week of each other, with vitamin D deficiency rickets and severe extraskeletal manifestations of hypocalcemia, including seizures and cardiac arrest, from homemade, vegan formula found through Pinterest (San Francisco, CA). Despite good parental intentions this formula did not meet macronutrient and micronutrient standards, particularly regarding vitamin D, phosphorus, and calcium content, and led to rare, life-threatening complications in both cases. Before presentation, both patients followed appropriately with their pediatrician and discussed feeding in detail, although neither family disclosed the use of homemade formula. Pediatricians must be aware of these dangerous homemade alternative formulas, consider the manner and depth of their feeding history questioning, and continue to counsel against homemade formula to prevent further harm to children.

Monozygotic twins discordant for congenital adrenal hyperplasia due to mosaicism.

INTRODUCTION: Genotype-phenotype discordance occurs occasionally in congenital adrenal hyperplasia (CAH). Its causes are largely unknown. We describe a case of monochorionic, diamniotic twins with discordant clinical presentations of CAH, and show evidence for this being due to mosaicism resulting from a postzygotic full gene deletion of CYP21A2 prior to twinning. CASE DESCRIPTION: A 7-day-old 36-week gestation female infant (Twin A) presented to the emergency department with elevated 17-hydroxyprogesterone (17-OHP). Her identical twin (Twin B) had normal 17-OHP on newborn screening. Both twins showed signs of virilization, more pronounced in Twin B. Molecular genetic testing of both twins and their parents showed a WT paternally-inherited CYP21A2 and a maternally-inherited copy containing the c.293-13C>G mutation. Both twins were also found to have a 5'-CYP21A1P/CYP21A2-3' hybrid (product of the common 30-kb deletion), derived from the deletion of the paternally-inherited CYP21A2. Neither mother nor father carried the deletion. CONCLUSIONS: The genetic findings are consistent with mosaicism for two CYP21A2 cell lines in both twins. The first cell line is expected, based on parental results, while the second line is due to a postzygotic full gene deletion of the paternally-inherited WT CYP21A2. The resultant genotype, compound heterozygosity for c.293-13C>G and a CYP21A2 full gene deletion, is consistent with a salt-wasting CAH phenotype. Differential distribution of the second cell line between the twins is most likely the cause for their discrepant phenotypes. We believe this is the first report of somatic CYP21A2 mosaicism, and represents a novel cause for discrepant CAH phenotypes in monozygotic twins.

Ezh2 Mutations Found in the Weaver Overgrowth Syndrome Cause a Partial Loss of H3K27 Histone Methyltransferase Activity.

Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome. Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function. Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos. Results: A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation. Conclusion: We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

The role of ¹²³I imaging in the evaluation of infants with mild congenital hypothyroidism.

BACKGROUND/AIMS: Controversy exists regarding the diagnosis and treatment of mild congenital hypothyroidism (MCH). We studied the value of (123)I imaging in patients with MCH. METHODS: Retrospective chart review of infants and children <4 years of age who underwent (123)I imaging: group 1 = MCH [thyroid-stimulating hormone (TSH) <25 µIU/ml, normal free T4/T3], group 2 = severe congenital hypothyroidism (TSH ≥25 µIU/ml), and group 3 = MCH in infancy imaged after treatment withdrawal at age 3 years. Data collected included 4- and 24-hour (123)I uptake, TSH, free T4/total T3 at imaging, age at imaging, and levothyroxine (L-T4) dose at 1 year of. RESULTS: Thirty-six patients underwent (123)I imaging. In group 1 (n = 20, median TSH: 8.49 µIU/ml), 85% had abnormal imaging consistent with dyshormonogenesis. Two patients were referred after 1 year of age. The median age at imaging for the remaining 18 patients was 54 days. Median L-T4 dose at 1 year of age for these 18 patients was 2.8 µg/kg, which is consistent with dyshormonogenesis. Ninety-one percent of group 2 (n = 11, median TSH: 428.03 µIU/ml) had abnormal imaging. The median age at imaging was 13 days. Four patients in group 3 had abnormal (123)I imaging and restarted treatment. CONCLUSION: (123)I imaging is a valuable tool for evaluation, diagnosis, and treatment of MCH.

Growth and growth disorders in children and adolescents.

Evaluation of a child's growth is one of the most important aspects of the general pediatric visit. Concerns about abnormal growth are the leading reasons general pediatricians refer patients to a pediatric endocrinologist. There is wide variation in normal growth patterns and an even greater variety of conditions that manifest with growth abnormalities. Here, we review patterns of normal growth in the pediatric and adolescent populations. We then review abnormal patterns of growth that require further evaluation and possible treatment.

Update on Turner and Noonan syndromes.

Turner syndrome (TS) and Noonan syndrome (NS) have short stature as a constant feature; however, both conditions can present clinicians with a challenging array of genetic, cardiovascular, developmental, and psychosocial issues. In recent years, important advances have been achieved in each of these areas. This article reviews these two syndromes and provides updates on recent developments in diagnostic evaluation, growth and development, psychological issues, and treatment options for patients with TS and NS.

Down syndrome and thyroid function.

Thyroid dysfunction in children with Down syndrome (DS) can occur as early as birth. As children with DS age, their risk for thyroid autoimmunity manifested as autoimmune hypothyroidism or Graves disease increases. The optimal timing and method for thyroid screening in children with DS remains controversial. The American Academy of Pediatrics recommends annual screening in this population. Consensus is needed to establish working definitions of euthyroidism and mild hypothyroidism in all infants, but especially in those with DS.