Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.

OBJECTIVE: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study. METHODS: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. RESULTS: Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included. DISCUSSION: The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study.

Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation.

INTRODUCTION: Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to multi-systemic manifestations. These disorders are categorized into various groups depending on which part of the glycosylation process is impaired. The cardiac manifestations in CDG can significantly differ, not only across different types but also among individuals with the same genetic cause of CDG. Cardiomyopathy is an important phenotype in CDG. The clinical manifestations and progression of cardiomyopathy in CDG patients have not been well characterized. This study aims to delineate common patterns of cardiomyopathy across a range of genetic causes of CDG and to propose baseline screening and follow-up evaluation for this patient population. METHODS: Patients with molecular confirmation of CDG who were enrolled in the prospective or memorial arms of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study were ascertained for the presence of cardiomyopathy based on a retrospective review of their medical records. All patients were evaluated by clinical geneticists who are members of FCDGC at their respective academic centers. Patients were screened for cardiomyopathy, and detailed data were retrospectively collected. We analyzed their clinical and molecular history, imaging characteristics of cardiac involvement, type of cardiomyopathy, age at initial presentation of cardiomyopathy, additional cardiac features, the treatments administered, and their clinical outcomes. RESULTS: Of the 305 patients with molecularly confirmed CDG participating in the FCDGC natural history study as of June 2023, 17 individuals, nine females and eight males, were identified with concurrent diagnoses of cardiomyopathy. Most of these patients were diagnosed with PMM2-CDG (n = 10). However, cardiomyopathy was also observed in other diagnoses, including PGM1-CDG (n = 3), ALG3-CDG (n = 1), DPM1-CDG (n = 1), DPAGT1-CDG (n = 1), and SSR4-CDG (n = 1). All PMM2-CDG patients were reported to have hypertrophic cardiomyopathy. Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG; left ventricular non-compaction cardiomyopathy was diagnosed in two patients, one with PGM1-CDG and one with DPAGT1-CDG; two patients, one with DPM1-CDG and one with SSR4-CDG, were diagnosed with non-ischemic cardiomyopathy. The estimated median age of diagnosis for cardiomyopathy was 5 months (range: prenatal-27 years). Cardiac improvement was observed in three patients with PMM2-CDG. Five patients showed a progressive course of cardiomyopathy, while the condition remained unchanged in eight individuals. Six patients demonstrated pericardial effusion, with three patients exhibiting cardiac tamponade. One patient with SSR4-CDG has been recently diagnosed with cardiomyopathy; thus, the progression of the disease is yet to be determined. One patient with PGM1-CDG underwent cardiac transplantation. Seven patients were deceased, including five with PMM2-CDG, one with DPAGT1-CDG, and one with ALG3-CDG. Two patients died of cardiac tamponade from pericardial effusion; for the remaining patients, cardiomyopathy was not necessarily the primary cause of death. CONCLUSIONS: In this retrospective study, cardiomyopathy was identified in ∼6% of patients with CDG. Notably, the majority, including all those with PMM2-CDG, exhibited hypertrophic cardiomyopathy. Some cases did not show progression, yet pericardial effusions were commonly observed, especially in PMM2-CDG patients, occasionally escalating to life-threatening cardiac tamponade. It is recommended that clinicians managing CDG patients, particularly those with PMM2-CDG and PGM1-CDG, be vigilant of the cardiomyopathy risk and risk for potentially life-threatening pericardial effusions. Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood. Subsequently, routine cardiac examinations every five years are advisable. Additionally, patients with diagnosed cardiomyopathy should receive ongoing cardiac care to ensure the effective management and monitoring of their condition. A prospective study will be required to determine the true prevalence of cardiomyopathy in CDG.

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

BACKGROUND: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH. METHODS: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control. RESULTS: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups. CONCLUSIONS: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

Can incorporating molecular testing improve the accuracy of newborn screening for congenital adrenal hyperplasia?

BACKGROUND: Single-tier newborn screening (NBS) for CAH using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24-48 hours produces a high false-positive rate (FPR). 2nd tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multi-tier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the 1st tier 17OHP cutoff to minimize missed cases. METHODS: Created a Minnesota-specific CYP21A2 pathogenic variants panel; develop a rapid, high-throughput multiplex, allele-specific-primer-extension assay; perform 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based two-tier protocol and a molecular-based multi-tier NBS protocol, applied post-hoc. RESULTS: CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. Centers for Disease Control and Prevention (CDC) created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68,659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A three-tier protocol with a lower 1st-tier steroid cutoff, 2nd-tier 21-variant CYP21A2 panel and 3rd-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs and 3 TPs. CONCLUSIONS: Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.

A complement C4-derived glycopeptide is a biomarker for PMM2-CDG.

BACKGROUNDDiagnosis of PMM2-CDG, the most common congenital disorder of glycosylation (CDG), relies on measuring carbohydrate-deficient transferrin (CDT) and genetic testing. CDT tests have false negatives and may normalize with age. Site-specific changes in protein N-glycosylation have not been reported in sera in PMM2-CDG.METHODSUsing multistep mass spectrometry-based N-glycoproteomics, we analyzed sera from 72 individuals to discover and validate glycopeptide alterations. We performed comprehensive tandem mass tag-based discovery experiments in well-characterized patients and controls. Next, we developed a method for rapid profiling of additional samples. Finally, targeted mass spectrometry was used for validation in an independent set of samples in a blinded fashion.RESULTSOf the 3,342 N-glycopeptides identified, patients exhibited decrease in complex-type N-glycans and increase in truncated, mannose-rich, and hybrid species. We identified a glycopeptide from complement C4 carrying the glycan Man5GlcNAc2, which was not detected in controls, in 5 patients with normal CDT results, including 1 after liver transplant and 2 with a known genetic variant associated with mild disease, indicating greater sensitivity than CDT. It was detected by targeted analysis in 2 individuals with variants of uncertain significance in PMM2.CONCLUSIONComplement C4-derived Man5GlcNAc2 glycopeptide could be a biomarker for accurate diagnosis and therapeutic monitoring of patients with PMM2-CDG and other CDGs.FUNDINGU54NS115198 (Frontiers in Congenital Disorders of Glycosylation: NINDS; NCATS; Eunice Kennedy Shriver NICHD; Rare Disorders Consortium Disease Network); K08NS118119 (NINDS); Minnesota Partnership for Biotechnology and Medical Genomics; Rocket Fund; R01DK099551 (NIDDK); Mayo Clinic DERIVE Office; Mayo Clinic Center for Biomedical Discovery; IA/CRC/20/1/600002 (Center for Rare Disease Diagnosis, Research and Training; DBT/Wellcome Trust India Alliance).

Practice Variation among Pediatric Endocrinologists in the Dosing of Glucocorticoids in Young Children with Congenital Adrenal Hyperplasia.

A Pediatric Endocrine Society (PES) Drugs and Therapeutics Committee workgroup sought to determine the prescribing practices of pediatric endocrinologists when treating children <10 years of age with congenital adrenal hyperplasia (CAH). Our workgroup administered a 32-question online survey to PES members. There were 187 respondents (88.9% attending physicians), mostly from university-affiliated clinics (~80%). Ninety-eight percent of respondents prescribed the short-acting glucocorticoid hydrocortisone to treat young children, as per the Endocrine Society CAH Guidelines, although respondents also prescribed long-acting glucocorticoids such as prednisolone suspension (12%), prednisone tablets (9%), and prednisone suspension (6%). Ninety-seven percent of respondents indicated that they were likely/very likely to prescribe hydrocortisone in a thrice-daily regimen, as per CAH Guidelines, although 19% were also likely to follow a twice-daily regimen. To achieve smaller doses, using a pill-cutter was the most frequent method recommended by providers to manipulate tablets (87.2%), followed by dissolving tablets in water (25.7%) to create a daily batch (43.7%) and/or dissolving a tablet for each dose (64.6%). Thirty-one percent of providers use pharmacy-compounded hydrocortisone suspension to achieve doses of <2.5 mg. Our survey shows that practices among providers in the dosing of young children with CAH vary greatly and sometimes fall outside of the CAH Guidelines-specifically when attempting to deliver lower, age-appropriate hydrocortisone doses.

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

Background: Dysfunction 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. Objective: We 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. Methods: We 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. Results: Adjusting 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. Conclusions: The 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.

Sex non-specific growth charts and potential clinical implications in the care of transgender youth.

Introduction: The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) created separate growth charts for girls and boys because growth patterns and rates differ between sexes. However, scenarios exist in which this dichotomizing "girls versus boys" approach may not be ideal, including the care of non-binary youth or transgender youth undergoing transitions consistent with their gender identity. There is therefore a need for growth charts that age smooth differences in pubertal timing between sexes to determine how youth are growing as "children" versus "girls or boys" (e.g., age- and sex-neutral, compared to age- and sex-specific, growth charts). Methods: Employing similar statistical techniques and datasets used to create the CDC 2000 growth charts, we developed age-adjusted, sex non-specific growth charts for height, weight, and body mass index (BMI), and z-score calculators for these parameters. Specifically, these were created using anthropometric data from five US cross-sectional studies including National Health Examination Surveys II-III and National Health and Nutrition Examination Surveys I-III. To illustrate contemporary clinical practice, we overlaid our charts on CDC 2000 girls and boys growth charts. Results: 39,119 youth 2-20 years old (49.5% female; 66.7% non-Hispanic White; 21.7% non-Hispanic Black) were included in the development of our growth charts, reference ranges, and z-score calculators. Respective curves were largely superimposable through around 10 years of age after which, coinciding with pubertal onset timing, differences became more apparent. Discussion: We conclude that age-adjusted, sex non-specific growth charts may be used in clinical situations such as transgender youth in which standard "girls versus boys" growth charts are not ideal. Until longitudinal auxological data are available in these populations, our growth charts may help to assess a transgender youth's growth trajectory and weight classification, and expectations surrounding these.

Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia.

CONTEXT: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. METHODS: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. CONCLUSION: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Case Report: Anastrozole as a monotherapy for pre-pubertal children with non-classic congenital adrenal hyperplasia.

Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy unless they develop symptoms of hyperandrogenemia. The current practice is to treat symptomatic children with hydrocortisone aimed at suppressing excess adrenal androgen production irrespective of the child's level of endogenous cortisol production. Once on hydrocortisone therapy, even children with normal cortisol production require stress dosing. Some children with NC-CAH may present with premature adrenarche, growth acceleration, and advanced bone age, but with no signs of genital virilization and normal endogenous cortisol production. In these cases, an alternative therapy to hydrocortisone treatment that does not impact the hypothalamic-pituitary-adrenal axis, but targets increased estrogen production and its effects on bone maturation, could be considered. Aromatase inhibitors (AIs), which block the aromatization of androgen to estrogen, have been used off-label in men with short stature to delay bone maturation and as an adjunct therapy in children with classic CAH. The use of AI as a monotherapy for children with NC-CAH has never been reported. We present three pre-pubertal female children with a diagnosis of NC-CAH treated with anastrozole monotherapy after presenting with advanced bone age, early adrenarche, no signs of genital virilization, and normal peak cortisol in response to ACTH stimulation testing. Bone age z-scores normalized, and all three reached or exceeded their target heights. Monotherapy with anastrozole can be an effective alternative in slowing down bone maturation and improving height outcomes in children with NC-CAH and normal adrenal cortisol production.

Interpretation of Steroid Biomarkers in 21-Hydroxylase Deficiency and Their Use in Disease Management.

The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns worldwide. Lifelong treatment consists of replacing cortisol and aldosterone deficiencies, and supraphysiological dosing schedules are typically employed to simultaneously attenuate production of adrenal-derived androgens. Glucocorticoid titration in 21OHD is challenging as it must balance the consequences of androgen excess vs those from chronic high glucocorticoid exposure, which are further complicated by interindividual variability in cortisol kinetics and glucocorticoid sensitivity. Clinical assessment and biochemical parameters are both used to guide therapy, but the specific purpose and goals of each biomarker vary with age and clinical context. Here we review the approach to medication titration for children and adults with classic 21OHD, with an emphasis on how to interpret adrenal biomarker values in guiding this process. In parallel, we illustrate how an understanding of the pathophysiologic and pharmacologic principles can be used to avoid and to correct complications of this disease and consequences of its management using existing treatment options.

Primary Adrenal Insufficiency in a Boy with Type I Diabetes: The Importance of Considering X-linked Adrenoleukodystrophy.

Primary adrenal insufficiency (PAI) is often the first clinical sign of X-linked adrenoleukodystrophy (X-ALD), a rare genetic disorder that can present with various clinical phenotypes. A subset of boys with X-ALD develop cerebral ALD (cALD), characterized by progressive central demyelination, neurocognitive decline, and ultimately death. Timely intervention with hematopoietic cell transplant (HCT) can be a life-saving therapy by stopping progression of cerebral disease. We report the case of an 11-year-old boy with type 1 diabetes mellitus who presented with PAI, growth delay, and symptoms of attention deficit hyperactivity disorder. Given his history of T1DM, his PAI was presumed to be autoimmune and he was started on hydrocortisone and fludrocortisone. Eleven months later brain magnetic resonance imaging revealed white matter hyperintensity consistent with advanced cALD. The degree of disease progression at the time of diagnosis rendered the patient ineligible for transplant and he has continued to experience progressive neurologic decline. Initial symptoms of cALD are often subtle but should not be overlooked, as early identification of X-ALD is critical to allow early intervention with lifesaving HCT. PAI typically presents prior to the onset of neurologic symptoms. All boys who present with PAI should undergo workup for X-ALD with plasma very long chain fatty acid testing, even in the setting of underlying autoimmune disease.

Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene.

The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 × 10-5 ). Using population data, we estimate that ~85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness. Newborns homozygous for this allele in the absence of other factors are at low risk of requiring clinical intervention, although more studies are required to clarify the natural history of various CD320 variants across patient populations.

Bone Age Maturation and Growth Outcomes in Young Children with CAH Treated with Hydrocortisone Suspension.

BACKGROUND: Young children with congenital adrenal hyperplasia (CAH) require small doses (0.1-1.25 mg) of hydrocortisone (HC) to control excess androgen production and avoid the negative effects of overtreatment. The smallest commercially available HC formulation, before the recent US Food and Drug Administration approval of HC granules, was a scored 5-mg tablet. The options to achieve small doses were limited to using a pharmacy-compounded suspension, which the CAH Clinical Practice Guidelines recommended against, or splitting tablets into quarters or eighths, or dissolving tablets into water. METHODS: Cross-sectional chart review of 130 children with classic CAH treated with tablets vs a pharmacy-compounded alcohol-free hydrocortisone suspension to compare growth, weight, skeletal maturation, total daily HC dose, and exposure over the first 4 years of life. RESULTS: No significant differences were found in height, weight, or body mass index z-scores at 4 years, and in predicted adult height, before or after adjusting for age at diagnosis and sex. Bone age z-scores averaged 2.8 SDs lower for patients on HC suspension compared with HC tablets (P < 0.001) after adjusting for age at diagnosis and sex. The suspension group received 30.4% lower (P > 0.001) average cumulative HC doses by their fourth birthday. CONCLUSIONS: Our data indicate that treatment with alcohol-free HC suspension decreased androgen exposure as shown by lower bone age z-scores, allowed lower average and cumulative daily HC dose compared to HC tablets, and generated no significant differences in SDS in growth parameters in children with CAH at 4 years of age. Longitudinal studies of treating with smaller HC doses during childhood are needed.

Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.

CONTEXT: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. OBJECTIVE: This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. METHODS: This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios. CONCLUSION: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.

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.