Ped endo journal scan

Non-autoimmune, insulin-deficient diabetes in children and young adults in Africa: evidence from the Young-Onset Diabetes in sub-Saharan Africa (YODA) cross-sectional study

Katte JC, Squires S, Dehayem MY, Balungi PA, Padoa CJ, Sengupta D, et al. Lancet Diabetes Endocrinol. 2025 Sep;13(9):745-753. doi: 10.1016/S2213-8587(25)00120-2. PMID: 40706606.

Objective: The objective of this study was to assess whether clinically diagnosed type 1 diabetes (T1D) occurring in children and young adults from sub-Saharan Africa is of autoimmune origin and whether the phenotype and genetic susceptibility differ from T1D in other populations.

Study Methodology and Results: This was an observational, cross-sectional study (Young-Onset Diabetes in sub-Saharan Africa [YODA]), which included participants from Cameroon, Uganda, and South Africa who were of self-reported Black African ethnicity and had been clinically diagnosed with T1D at younger than 30 years of age and treated with insulin. The study included data from Black South African participants from a previous multicenter T1D study. Islet autoantibodies to glutamic acid decarboxylase (GADA), islet cell antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) were analyzed along with assessment of random C-peptide levels. Genetic susceptibility to T1D was assessed using a genetic risk score (GRS). Genetic data were compared to genotype array data from population controls from Uganda, Cameroon, and Black South Africans. The findings from the study were compared with data from participants from the SEARCH for Diabetes in Youth (SEARCH) study in the USA. The study enrolled 1072 participants, of which 894 were included in the analysis. The median duration of diabetes at the time of study was 5 years (interquartile range [IQR] 2–10), and 440 (49.2%) of 894 participants were female. The median age at diagnosis was 15 years (IQR 11–19), with a body mass index (BMI) of 21.7 kg/m² (19.5–24.1). Most participants (573 [71.6%] of 800) had severe insulin deficiency (plasma C-peptide <200 pmol/L). The majority (582 [65.1%] of 894) of participants from the sub-Saharan Africa cohorts were negative for islet autoantibodies. Even ‘among’ the participants within 1 year of diabetes diagnosis (n = 143), 84 (58.0%) were still islet autoantibody negative. GADA was by far the most prevalent islet autoantibody across the subSaharan African cohorts (258 [28.8%] of 894), followed by ZnT8A (86 [9.6%] of 894), and IA-2A (69 [7.7%] of 894). Islet autoantibody-positive participants had low endogenous insulin secretion, with 225 (82.7%) of 272 having plasma C-peptide concentrations of <200 pmol/L and a high genetic susceptibility to T1D compared with individuals from African population control cohorts (median GRS 11•76 [interquartile range, IQR 10.49–12.91] in islet autoantibody-positive participants versus 8.50 [7.05–9.76] in controls; P < 0.0001). Participants who were islet autoantibody negative had a markedly lower GRS for T1D than those with islet autoantibody positive status (median GRS 9.66 [IQR 7.77–11.33] vs. 11.76 [10.49–12.91]; P < 0.001). Although substantially reduced in comparison with autoantibody-positive participants, the GRS for T1D in this autoantibody-negative group was higher than in a control population without diabetes (P < 0.0001). Although participants without islet autoantibodies had higher plasma C-peptide concentrations (103 [8–308]) than those with autoantibodies (25 [3–145]) P < 0•0001, most autoantibody-negative participants were severely insulin deficient, and almost all had C-peptide below the range seen in type 2 diabetes (T2D, expected plasma C-peptide in T2D >600 pmol/L). BMI was not significantly different between the groups, suggesting that malnutrition was not a contributor. However, parental history of diabetes was significantly more common in the islet autoantibody-negative group. Genetic risk of T2D was not enriched in those with negative islet autoantibodies (median GRS 17.15 [IQR 16.95–17.38]) compared with control participants (GRS 17.22 [16.99–17.44]) or those with positive islet autoantibodies (GRS 17.22 [17.06–17.38]). On comparing data with the SEARCH study, black SEARCH participants who were autoantibody negative had a markedly lower GRS for T1D than those who were autoantibody positive (median 10.41 [IQR 8.65–12.22] vs. 12.31 [10.78–13.31]; P = 0.0006), consistent with findings in the sub-Saharan Africa cohorts.

Critical Review: This is an important study that has robustly identified that YODA is a heterogeneous disease with a novel non-autoimmune, insulin-deficient subtype which is commonly seen in this cohort. The strengths of this study include large multi-country cohorts, standardized autoantibody and genetic testing, and comparison with US SEARCH data, enhancing validity. The absence of detailed data on malnutrition-related diabetes and fibrocalcific pancreatic disease limits the ability to determine whether the observed non-autoimmune subtype represents a novel entity or a variant of previously described forms of diabetes in Africa. Similarly, the lack of mortality data introduces potential survival bias, as individuals with classic autoimmune T1D may experience higher mortality in resource-limited settings and thus be under-represented in cross-sectional cohorts. These findings have important implications for the evaluation and management of youth-onset diabetes in multi-ethnic populations, where uniform diagnostic and treatment strategies may fail to address underlying heterogeneity. Further research is essential to elucidate the etiology of this non-autoimmune, insulin-deficient subtype, including prospective studies that integrate environmental exposures, genetic susceptibility, and comprehensive phenotyping to inform tailored prevention and treatment approaches.

Growth hormone withdrawal in mid-puberty: No impact on near-adult height in adolescents with transient idiopathic GHD

Vliegenthart J, Wit JM, Bakker B, Boot AM, de Bruin C, Finken MJJ, et al. J Clin Endocrinol Metab. 2025 Nov 15:dgaf626. doi: 10.1210/clinem/dgaf626. Epub ahead of print. PMID: 41239863.

Objective: The objective of this study was to investigate if withdrawing recombinant human growth hormone (rhGH) treatment from mid-puberty onward would not have a negative effect on attained near adult height (NAH) in adolescents who, after retesting, were no longer growth hormone (GH) deficient.

Study Methodology and Results: This was a multicenter, prospective patient preference design study. The study population consisted of adolescents in mid-puberty who started rhGH treatment after the diagnosis of partial idiopathic isolated GH deficiency (IIGHD) was made and were treated for at least 3 years. Partial IIGHD was defined as the highest GH peak in 2 GH stimulation tests (GHSTs) between 1.7 and 10 µg/L (5-30 mU/L). Adolescents who exhibited a normal GH peak (6.7 µg/L = 20 mU/L) on retesting in mid-puberty were eligible for inclusion. Growth and pubertal progression were monitored every 3–4 months in the group continuing rhGH treatment (GHcont) and every 6 months in the group that discontinued rhGH treatment (GHstop). The primary outcome was the comparison of the NAH-standard deviation score (SDS) minus the conditional target height (TH) SDS. Secondary outcomes were NAH-SDS and total pubertal growth (TPG; height gain in centimeters [cm] from Tanner G2 or B2 until NAH). The study included 127 patients (95 male, 75%) for analysis, of whom 44 patients continued rhGH treatment (35%) and 83 patients stopped rhGH treatment (65%). The mean NAH-SDS minus TH-SDS in the GHcont group was −0.171 (0.60), compared to −0.177 (0.62) in the GHstop group (P = 0.96). The mean NAH-SDS in the GHcont group was −0.91 (0.76), compared to −0.78 (0.76) in the GHstop group (P = 0.35), with a mean difference of −0.13 SDS. TPG (cm height gain between the onset of Tanner G2 or B2 and NAH) was available for 118 patients (93%). The mean (standard deviation) TPG in the GHcont group was 26.10 (7.32) cm, compared to 24.63 (6.89) cm in the GHstop group (P = 0.28). The average duration of rhGH treatment was 10.3 (2.2) years in the GHcont group (10.3 [2.3] years for boys and 10.2 [1.2] years for girls) and 8.2 (1.9) years in the GHstop group (8.4 [1.9] years for boys and 7.8 [1.9] years for girls; P < 0.01).

Critical Review: This is an important study which demonstrates that discontinuing rhGH treatment at mid-puberty in previously IIGHD adolescents does not adversely affect AH outcome. The strengths of this study are that it focused exclusively on adolescents retested GH-sufficient, reducing diagnostic heterogeneity. The non-randomized patient preference design, however, does introduce the risk of potential selection bias. The overall findings from this study support stopping rhGH at mid-puberty without compromising NAH, enabling 2–3-year shorter treatment duration. This translates to substantial cost savings and lower patient burden and it could help to inform future guidelines and optimize resource allocation in pediatric endocrinology.

Diagnostic performance of morning serum cortisol for glucocorticoid weaning in children and adults

Arshad MF, Ahmed A, Beddows S, Marsh I, Mullamitha A, Newell-Price J, et al. Eur J Endocrinol. 2025 Oct 30;193(5):654-662. doi: 10.1093/ejendo/lvaf215. PMID: 41092479.

Objective: The study aimed to evaluate the diagnostic performance of morning serum cortisol compared with the short synacthen test (SST) in pediatric and adult cohorts with suspected glucocorticoid-induced adrenal insufficiency (GIAI).

Study Methodology and Results: In this retrospective, observational study conducted at the Sheffield Children’s and Teaching Hospitals, NHS Foundation Trust, UK; patients on long-term oral (≥5 mg prednisolone [or equivalent] for ≥4 weeks) or inhaled glucocorticoids, who underwent an SST for suspected GIAI, were identified using electronic databases. In accordance with the hospitals’ clinical protocols, patients were initially weaned to physiological replacement doses, i.e., 6–8 mg/m²/day hydrocortisone or prednisolone equivalent in children, and prednisolone 3–5 mg/day or hydrocortisone 15–25 mg/day in adults. Children and adults with morning cortisol levels <12.2 µg/dL and <12.7 µg/dL, respectively, were referred to the endocrinology unit for dynamic testing with synacthen. The procedure was performed 24 h after the last dose of prednisolone and after skipping the evening and morning doses of hydrocortisone and inhaled glucocorticoids. After obtaining a baseline serum sample for cortisol and adrenocorticotropic hormone (ACTH), synacthen was administered intravenously or intramuscularly in a dose of 145 µg/m² in children and 250 µg in adults; and blood was drawn for cortisol at 30 min. An SST with a post-synacthen cortisol of ≥15.6 µg/dL excluded GIAI and was henceforth considered “pass.” All hormone levels were assessed with modern immunoassays (Vitros 5600 [Ortho Clinical Diagnostics analyser, New York, USA] in children; Elecsys Cortisol II assay [Roche Diagnostics GmbH, Mannheim, Germany] in adults for cortisol; and Siemens Immulite 2000 chemiluminescent assay [Siemens, Frimley, United Kingdom] for ACTH). The diagnostic performance of morning cortisol, ACTH, and cortisol:ACTH for predicting a “pass” SST was evaluated using receiver operating characteristic (ROC) curve analysis, including estimation of the area under the curve (AUC), and identification of cut-offs with 95% and 99% sensitivity and specificity. To determine which of the two cortisol thresholds yielding sensitivities of 95% and 99% was clinically more appropriate, the study investigators additionally examined the outcomes of adult patients with baseline cortisol levels between the two cut-offs. Over a 5-year study period, 101 children (48.5% girls) underwent 151 SSTs at a mean (standard deviation [SD]) age of 8.5 (5.2) years. The “pass” rate of SST was 48/151 (31.8%). The majority of these children (72.2%) had been on oral corticosteroids for chiefly hematological (24.5%), respiratory (23.2%), and neonatal (13.9%) indications. The AUC (95% confidence interval [CI]) for morning cortisol, ACTH, and cortisol:ACTH was 0.79 (0.71, 0.87), 0.46 (0.36, 0.56), and 0.77 (0.70, 0.89), respectively. Serum cortisol levels with 95% and 99% sensitivities to exclude GIAI were 10.1 µg/dL and 11.5 µg/dL, respectively, while cut-offs with corresponding specificities confirming the presence of GIAI were 4.2 µg/dL and 0.7 µg/dL, respectively. Among adults (n = 237, 61.6% females, mean [SD] age 59.6 [15.1] years) who underwent 372 SSTs following exposure to primarily a combination of oral and inhaled corticosteroids (61.6%) due to respiratory (58.9%) indications, AUC (95% CI) for cortisol, ACTH and cortisol: ACTH were 0.88 (0.84, 0.91), 0.54 (0.48, 0.60) and 0.80 (0.75, 0.85). Cortisol thresholds at 95% and 99% sensitivities were 10.5 µg/dL and 12.7 µg/dL, whereas those at 95% and 99% specificities were 4.8 µg/dL and 3.2 µg/dL. Among children weaned off of glucocorticoids, no cases of adrenal crisis, adrenal insufficiency-related hospitalization, or deaths were reported for up to 12 months following treatment cessation. Fifty-one adults had morning cortisol values between the derived thresholds with 95% (10.5 µg/dL) and 99% (12.7 µg/dL) sensitivities. Forty-two (82.4%) of these patients had successfully “passed” dynamic testing with synacthen. Of the remaining nine subjects, 30 min SST cortisol was borderline (ranging from 14.4 to 15.5 µg/dL, as opposed to the pre-determined cut-off of 15.6 µg/dL) in six, all of who could be successfully weaned off of glucocorticoids over the ensuing 8–12 weeks. The remaining three patients warranted continuation of physiological replacement dose of glucocorticoids in view of either low 30 min cortisol (n = 2) or complex symptoms (n = 1). However, there was no reported case of adrenal crisis, adrenal insufficiency-related hospital admission, or death over a 12-month follow-up period.

Critical Review: This study derives and validates morning cut-off values for cortisol in children and adults being weaned off of long-term supraphysiological glucocorticoids. In doing so, it addresses a major dilemma faced by clinicians across specialties who must manage patients, children and adults alike, with corticosteroids in varying doses and through different routes. Guidelines for the evaluation and management of GIAI frequently include SST at steps such as when cortisol levels are deemed equivocal. This may overburden the healthcare system, as patients with no other endocrine issues are often referred to endocrinologists for performing SSTs. The results of this study not only inform screening for GIAI with the help of a single morning blood draw for cortisol but they also validate modern immunoassays, which are more readily available and far cheaper than LCMS/MS. The investigators go beyond statistical assessment to establish clinically meaningful cortisol cut-offs based on follow-up outcomes of adult patients. Notwithstanding the immense potential of its results, the study does have certain limitations, including its retrospective design, and uncertain applicability in settings with more diverse glucocorticoid usage (harnessing routes such as intra-articular, intranasal and topical) and slightly different ACTH doses (125 µg in children <2 years, 250 µg in children ≥2 years vs. 145 µg/m² used in the present study). The study would have also benefited from the inclusion of protocols used for early steroid weaning (for minimizing the emergence of glucocorticoid withdrawal syndrome) and the average durations at which study participants were successfully weaned off of their medications (for real-world patient prognostication). Nonetheless, this represents robust and clinically relevant research whose outcomes may significantly alleviate the burden of following up patients with long-term exposure to glucocorticoids.

Treatment of children and adults with X-linked hypophosphatemia with calcitriol alone: A prospective, open-label study

Mitchell D, Jordan M, Gehman S, Rudolph S, Jüppner H, Misra M, et al. J Clin Endocrinol Metab. 2025 Oct 24:dgaf585. doi: 10.1210/clinem/dgaf585. Epub ahead of print. PMID: 41137448.

Objective: The objective of the study was to assess serum markers of mineral metabolism, nephrocalcinosis, kidney function, growth, radiographic evidence of rickets, and skeletal microarchitecture following a 12-month trial of calcitriol monotherapy in children and adults with X-linked hypophosphatemic rickets (XLH).

Study Methodology and Results: In this prospective, single-arm, 12-month pilot interventional study, children and adults with a clinical and/or genetic diagnosis of XLH were recruited from multiple outpatient endocrinology clinics in the USA. Following a 2-week washout period during which all prior therapy was withheld, participants were initiated on oral calcitriol at doses of 20 ng/kg/day in children and 0.25 µg/day in adults, or at doses that were 50% higher than pre-study doses in those already receiving calcitriol. At baseline, all participants underwent biochemical assessment comprising serum calcium, phosphorus, creatinine, alkaline phosphatase (ALP), parathyroid hormone (PTH), fibroblast growth factor-23 (FGF-23), and 1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃]; urinary calcium-to-creatinine ratio; and tubular reabsorption of phosphorus (TRP). Imaging included ultrasound of the kidneys and high-resolution peripheral quantitative computed tomography (HRpQCT). Children additionally underwent anthropometric assessment (standing and sitting height Z-scores) and evaluation of rickets using plain radiographs of bilateral wrists and knees. Key exclusion criteria included hypercalcemia (average serum calcium ≥10 mg/dL) and vitamin D insufficiency [25(OH)D₃ <20 ng/mL] within the preceding 24 months, and chronic kidney disease with estimated glomerular filtration rate <60 mL/min/1.73 m². Laboratories (blood and urine) were performed at 1, 2, and 3 months for safe dose escalation, and at 4, 6, and 9 months (alongside patient evaluation) for dose de-escalation in case of hypercalcemia (serum calcium ≥0.5 mg/dL above the upper limit of normal) and/or hypercalciuria (urine calcium-to-creatinine ratio >0.4). At 12 months, the primary endpoints included changes in serum phosphorus and nephrocalcinosis in all participants, and rickets severity score in children; while secondary endpoints included changes in other markers of mineral metabolism, skeletal microarchitecture (via HRpQCT), and height Z-scores (in children). Of 82 patients who were screened, 16 (6 children and 10 adults) were enrolled while 14 (6 children and 8 adults) completed the study. Among the six children (67% females) with a mean (SD) age of 11.1 (3.6) years, three were receiving conventional therapy with calcitriol and phosphate, while three were treatment naïve. At 12 months, there was no significant change in serum phosphate (2.6 ± 0.5–2.7 ± 0.6 mg/dL; P = 0.497), nephrocalcinosis score (P = 0.274), or rickets severity score (P = 0.215), even though 2 of 4 participants with open epiphyses at 12 months showed improvement in rickets. Among other markers of mineral metabolism, a statistically significant reduction was observed in ALP (349 ± 112 to 275 ± 199 IU/L; P = 0.021), with a borderline decline in PTH (51 ± 20 to 21 ± 20 pg/mL; P = 0.065). No changes were noted in serum calcium (9.7 ± 0.3 to 9.8 ± 0.1 mg/dL; P = 0.346), creatinine (P = 0.090), FGF-23 (203 ± 189 to 205 ± 83 pg/mL; P = 0.976), 1,25(OH)₂D₃ (38.5 ± 12.5 to 50.8 ± 23.0 pg/mL; P = 0.391), urine calcium-to-creatinine ratio (0.08 ± 0.16 to 0.15 ± 0.12; P = 0.295) and TRP (89.1 ± 5.9 to 91.1 ± 3.4%; P = 0.376). Height Z-scores remained unchanged (baseline −1.5 ± 1.2; P = 0.615), whereas HRpQCT parameters that showed significant improvement were distal radial cortical bone density (P = 0.014), cortical thickness (P = 0.035), and tibial diaphyseal cortical thickness (P = 0.017). Adverse effects related to therapy included mild hypercalciuria in two patients that resolved with calcitriol dose decrements. Among the eight adults (mean age 29.2 ± 11.6 years with 88% females), six were receiving conventional therapy, one was on burosumab, and one was treatment naïve. The findings were broadly similar with significant changes noted in urine calcium-to-creatinine ratio (0.04 ± 0.05 to 0.13 ± 0.05; P < 0.001), 1,25(OH)₂D₃ (30.5 ± 12.5 to 64.3 ± 24.7 pg/mL; P = 0.021), and radial diaphyseal cortical thickness (P = 0.012).

Critical Review: The findings from this study suggest that calcitriol monotherapy may be safe and possibly efficacious in improving rickets and bone architecture in patients with XLH. Despite its many obvious drawbacks, such as a small sample size, the absence of control groups (untreated, treated conventionally with calcitriol and phosphate, and treated with burosumab), and a relatively short duration of follow-up, the study explores the promising possibility of doing away with oral phosphate; a drug which often serves as a barrier to optimal therapy of XLH, given its frequent dosing, gastrointestinal adverse effects and the potential to cause secondary and tertiary hyperparathyroidism. A randomized-controlled trial with a similar study protocol, albeit with a larger, adequately powered sample size and a longer duration of follow-up, would be ideal to replicate in settings with limited access to the highly efficacious yet prohibitively expensive burosumab therapy; and this study serves as the much-needed foundation for the same.

Longitudinal characterization and sonographic staging of testicular adrenal rest tumors

Vaid S, Kulkarni S, Marko J, Sinaii N, Sukin C, Burkardt D, et al. J Clin Endocrinol Metab. 2025 Sep 8:dgaf498. doi: 10.1210/clinem/dgaf498. Epub ahead of print. PMID: 40921717.

Objective: The present study aimed at describing the natural history of testicular adrenal rest tumors (TARTs), and the factors associated with their emergence and progression in boys with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase and 11β-hydroxylase deficiencies.

Study Methodology and Results: This was a retrospective, longitudinal, observational study performed at the National Institutes of Health Clinical Center (Bethesda) in the USA. Boys with a biochemical and genetic diagnosis of CAH who were evaluated between 1988 and 2022 were included, and their electronic medical records were reviewed. These records comprised diagnostic details, anthropometric data, pubertal development, hormonal parameters (17-hydroxyprogesterone [17OHP], adrenocorticotropic hormone [ACTH], 11-deoxycortisol, androstenedione, and plasma renin activity), therapeutic steroid doses, and findings on scrotal ultrasound (performed 6-monthly in children and annually in adults) across serial follow-up visits. Thirty-six male patients with classical CAH (34 with 21-hydroxylase deficiency [salt wasting 19, simple virilizing 15; 19 with null/In2G variation and 14 with I172N variation] and 2 with 11β-hydroxylase deficiency) underwent 783 testicular ultrasounds over a mean ± SD follow-up duration of 18.4 ± 6.8 years. The median (interquartile range [IQR]) age at diagnosis was 0.1 [0.0, 3.6] years and at enrolment was 5 [3.2, 6.0] years. At study entry, median [IQR] 17OHP was 8.7 [1.6, 61.9] ng/mL, ACTH was 112.5 [22.8, 182.8] pg/mL, androstenedione was 40.0 [12.9, 122.5] ng/dL, and equivalent hydrocortisone dose was 17.1 [13.3, 18.5] mg/m²/day. Fifteen (41.7%) participants received a combination of low-dose hydrocortisone, anti-androgens, and aromatase inhibitors for a duration of 8.1 ± 2.3 years. TARTs were detected in 27 (75%) of 36 participants, of whom 13 (48%) were diagnosed prepubertally and 8 (29.6%) before the age of 10 years. Survival analysis yielded a median (95% confidence interval [CI]) age of 15.1 (12.7, 20.4) years at TART diagnosis; with those having salt wasting phenotype developing TART earlier than those with the simple virilizing phenotype (12.9 [10.8, 16.3] years vs. 17.2 [15.1, NA] years, P = 0.009). Likewise, patients with null/In2G variation had an earlier age at TART diagnosis as compared to those with the I172N variant (13.1 [11.6, 16.7] years vs. 20.4 [17.2, NA] years; P = 0.004). On serial imaging, 14/27 (51.9%) patients with TART showed radiological worsening, 8/27 (29.6%) demonstrated resolution, while 2/27 (7.4%) remained radiologically stable. Longitudinal unadjusted logistic regression analysis identified elevated ACTH, elevated 17OHP, elevated androstenedione, elevated renin, salt wasting phenotype, null/In2G genotype, younger age at diagnosis, and higher equivalent hydrocortisone doses as significant predictors of increased odds of development of TART. On longitudinal adjusted analysis, the covariates that remained significant were salt wasting phenotype (Odds ratio [OR]: 6.82, 95% CI: 2.35, 19.80; P < 0.001), higher hydrocortisone dose (OR: 1.10, 95% CI: 1.03, 1.18 mg/m²/day; P = 0.006) and elevated ACTH (OR: 1.0011, 95% CI 1.0005, 1.0017 pg/mL; P < 0.001). After excluding visits during which the patients were on anti-androgens and aromatase inhibitors, salt wasting phenotype (OR: 7.04, 95% CI: 2.37, 20.89; P < 0.001) and higher hydrocortisone dose (OR: 1.09, 95% CI: 1.01, 1.17 mg/m²/day; P = 0.022) retained statistical significance, while elevated androstenedione (OR: 2.22, 95% CI: 1.19, 4.14; P = 0.012) emerged as an additional predictor of increased odds of TART diagnosis.

Critical Review: This is the first study to systematically describe the natural history of TARTs in boys with classical CAH. With the implementation of a regular surveillance protocol from early childhood, TARTs were identified in 75% of patients by age ~24 years, with nearly half developing so before the onset of puberty. In addition to elevated ACTH and androstenedione (both biochemical markers of poor metabolic control) across follow-up periods, the clinical phenotype of salt wasting CAH also conferred an increased odds of developing TARTs, suggesting, as speculated by the investigators, that in utero hormonal alterations might influence their natural history. The limitations of the study include its retrospective nature, reviewer bias (unblinded radiologists), and paucity of data on the effects of glucocorticoid dose adjustments on TART progression. Overall, the study findings support early initiation of screening for TARTs, with the investigators further proposing a radiologic staging system to denote disease severity.

Comprehensive molecular studies in 88 Japanese patients with congenital hypogonadotropic hypogonadism

Tanikawa W, Okamoto S, Ohara O, Masunaga Y, Yamoto K, Fujisawa Y, et al. J Clin Endocrinol Metab. 2025 Oct 3:dgaf548. doi: 10.1210/clinem/dgaf548. Epub ahead of print. PMID: 41042998.

Objective: The present research was aimed at determining the genetic etiology in Japanese patients with congenital hypogonadotropic hypogonadism (CHH).

Study Methodology and Results: In this single-center study conducted at the Hamamatsu University School of Medicine and National Research Institute for Child Health and Development in Japan, 88 patients with a clinical and biochemical diagnosis of CHH were subjected to a stepwise algorithm for genetic testing. At the outset, all patients underwent targeted next-generation sequencing (NGS) covering 14 genes implicated in the causation of CHH. Subjects with no pathogenic/likely pathogenic variation on targeted NGS subsequently underwent whole exome sequencing (WES), with the initial analysis focusing on 41 genes (14 defined previously and 27 probably causative for CHH). Among patients who did not harbor pathogenic/likely pathogenic variation in any of these 41 genes, the focus was further broadened to identify variants in other unrelated genes. Finally, the frequency of rare variants among participants without pathogenic/likely pathogenic variation in either of 41 genes was compared with that observed in 100 adult control participants with proven fertility (50 unrelated parent pairs). Of 88 patients (71 males, 17 females; 82 sporadic and 6 familial cases), 58 had Kallman syndrome, and 30 had normosmic hypogonadotropic hypogonadism. Targeted NGS (14 genes) identified 25 pathogenic/likely pathogenic variants in 32 patients (ANOS1 6 variants [7 patients], CHD7 2 variants [2 patients], FGFR1 14 variants [15 patients], PROKR2 2 variants [8 patients] and SOX10 1 variant [1 patient]; with one patient having 2 variants, one each in ANOS1 and PROKR2). WES (41 genes) identified a deep intronic likely pathogenic variant in CHD7 in another patient, and WES (>41 genes) identified a pathogenic variant in ZNF462, with the phenotype of both patients in agreement with their genotypes. In summary, the yield of genetic testing was 30 (36.6%) of 82 among sporadic cases, and 4 (66.7%) of 6 among familial cases. Of the remaining 54 patients, 13 (25%) of 52 sporadic cases harbored 17 variants of uncertain significance in 12 CHHcausative and CHH-related genes (ANOS1, FGFR1, CHD7, PROKR2, IGSF10, WDR11, TAC3, FGF8, PROP1, SEMA4D, TACR3, CDH2). Among 54 patients with no pathogenic/likely pathogenic variation, the frequency of oligogenicity across the 41 CHH-causative and CHH-related genes was significantly higher than that observed among the 100 controls (P = 0.0047); and the number of rare variants per individual was similarly higher in cases than in controls (P = 0.0031).

Critical Review: The present study adds to the existing body of literature on the genetics of CHH. Although the overall yield was ~39%, evidence supporting oligogenic inheritance may further improve the diagnostic rate. An important limitation of the present research, however, is that its findings may not be generalizable to all populations, particularly those with high rates of consanguinity and endogamy, where disorders with autosomal recessive inheritance (e.g., CHH due to GNRHR variation) typically predominate.