Disorders of sex development: challenges for the future

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Depressive and anxiety disorders and antidepressant prescriptions among insured children and young adults with congenital adrenal hyperplasia in the United States

BackgroundDysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders among individuals with congenital adrenal hyperplasia (CAH), a form of primary adrenal insufficiency.ObjectiveWe investigated the prevalence of depressive and anxiety disorders and antidepressant prescriptions in two large healthcare databases of insured children, adolescents, and young adults with CAH in the United States.MethodsWe conducted a retrospective cohort study using administrative data from October 2015 through December 2019 for individuals aged 4–25 years enrolled in employer-sponsored or Medicaid health plans.ResultsAdjusting for age, the prevalence of depressive disorders [adjusted prevalence ratio (aPR) = 1.7, 95% confidence interval (CI): 1.4-2.0, p<0.001], anxiety disorders [aPR = 1.7, 95% CI: 1.4-1.9, p<0.001], and filled antidepressant prescriptions [aPR = 1.7, 95% CI: 1.4-2.0, p<0.001] was higher among privately insured youth with CAH as compared to their non-CAH peers. Prevalence estimates were also higher among publicly insured youth with CAH for depressive disorders [aPR = 2.3, 95% CI: 1.9-2.9, p<0.001], anxiety disorders [aPR = 2.0, 95% CI: 1.6-2.5, p<0.001], and filled antidepressant prescriptions [aPR = 2.5, 95% CI: 1.9-3.1, p<0.001] as compared to their non-CAH peers.ConclusionsThe elevated prevalence of depressive and anxiety disorders and antidepressant prescriptions among youth with CAH suggests that screening for symptoms of depression and anxiety among this population might be warranted

PMM2-CDG caused by uniparental disomy: Case reportand literature review

Background Phosphomannomutase 2 deficiency (PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy. Case Presentation Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG. A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG. Conclusion Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counselingWe thank the patient described in this case report for all-owing us to share her details, and we thank C. Pérez-Cerdá of the Center of Molecular Biology-Severo Ochoa,Madrid, for her contribution. This work is funded by thegrant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute ofNeurological Diseases and Stroke (NINDS) and theNational Center for Advancing Translational Sciences(NCATS), and the Rare Disorders Consortium DiseaseNetwork (E.M. and S.K.

Variation in early number skills and mathematics achievement: Implications from cognitive profiles of children with or without Turner syndrome

Individuals with Mathematics Learning Disabilities have persistent mathematics underperformance but vary with respect to their cognitive profiles. The present study examined mathematics ability and achievement, and associated mathematics-specific numerical skills and domain-general cognitive abilities, in young children with Turner syndrome compared to their matched peers. We utilized two independent peer groups so that group comparisons would account for verbal skills, a hypothesized strength of girls with Turner syndrome, and nonsymbolic magnitude comparison skills, a hypothesized difference of girls with Turner syndrome. This individual matching approach afforded characterization of mathematics profiles of girls with Turner syndrome and girls without Turner syndrome that share potential key features of the Turner syndrome phenotype. Results indicated differences in mathematics ability and nonsymbolic magnitude comparison tasks between girls with Turner syndrome and peers with similar levels of verbal skill. Mathematics ability and mathematics achievement scores of girls with Turner syndrome did not differ significantly from their peers with similar levels of accuracy on a nonsymbolic magnitude comparison task. Cognitive correlates of mathematics outcomes showed disparate patterns across groups. These quantitative and qualitative differences across profiles enhance our understanding of variation in mathematics ability in early childhood and inform how mathematics skills develop in young children with or without Turner syndrome

Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective: Assess tildacerfont safety and efficacy. Design and setting: Two Phase 2 open-label studies. Patients: Adults with 21OHD. Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2). Main outcome measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal

Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.Glycomine, Inc. was the sponsor of this study, and was involved in the study design and in the and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Several authors of this publication are members of the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN) - Project ID No 739543.info:eu-repo/semantics/publishedVersio

Application of Deep Neural Networks as a Prescreening Tool to Assign Individualized Absorption Models in Pharmacokinetic Analysis

A specific model for drug absorption is necessarily assumed in pharmacokinetic (PK) analyses following extravascular dosing. Unfortunately, an inappropriate absorption model may force other model parameters to be poorly estimated. An added complexity arises in population PK analyses when different individuals appear to have different absorption patterns. The aim of this study is to demonstrate that a deep neural network (DNN) can be used to prescreen data and assign an individualized absorption model consistent with either a first-order, Erlang, or split-peak process. Ten thousand profiles were simulated for each of the three aforementioned shapes and used for training the DNN algorithm with a 30% hold-out validation set. During the training phase, a 99.7% accuracy was attained, with 99.4% accuracy during in the validation process. In testing the algorithm classification performance with external patient data, a 93.7% accuracy was reached. This algorithm was developed to prescreen individual data and assign a particular absorption model prior to a population PK analysis. We envision it being used as an efficient prescreening tool in other situations that involve a model component that appears to be variable across subjects. It has the potential to reduce the time needed to perform a manual visual assignment and eliminate inter-assessor variability and bias in assigning a sub-model

Short-Term PTH(1-34) Therapy in Children to Correct Severe Hypocalcemia and Hyperphosphatemia due to Hypoparathyroidism: Two Case Studies

The standard treatment of hypoparathyroidism is to control hypocalcemia using calcitriol and calcium supplementation. However, in severe cases this approach is insufficient, and the risks of intravenous (i.v.) calcium administration and prolonged hospitalization must be considered. While the use of recombinant human parathyroid hormone 1-34 [rhPTH(1-34)] for long-term control of hypocalcemia has been established, the benefits of short-term rhPTH(1-34) treatment in children have not been explored. We report two patients with hypoparathyroidism treated with rhPTH(1-34). Patient 1 is a 10-year-old female with polyglandular autoimmune syndrome type 1. Patient 2 is a 12-year-old female with hypoparathyroidism after total thyroidectomy. Both patients showed poor response to i.v. and oral calcium and calcitriol, and patient 1 did not respond to phosphate binders. Patient 1 had rapid increase in serum calcium with a decrease in serum phosphate after a 3-day course of subcutaneous rhPTH(1-34). Patient 2 had normalization of calcium and phosphate levels after a 7-day course of rhPTH(1-34). These cases support a role for rhPTH(1-34) in the acute management of hypoparathyroidism in hospitalized patients to more rapidly correct hypocalcemia and hyperphosphatemia, shorten hospitalization, and reduce the need for frequent i.v. calcium boluses