The accuracy of computed tomography (CT) parameters in the preoperative diagnosis of benign adrenal lesions, such as adrenal schwannoma (AS) and adrenal ganglioneuroma (AG), has not been systematically studied. Hence, we aimed to analyze CT features of AS/AG to distinguish them from other lipid-poor, poor-washout adrenal masses. Description of our AS/AG cohort, along with systematic review of literature for histopathologically confirmed AS/AG and available CT characteristics (providing unenhanced, early venous, and delayed venous phase attenuation). These were compared with our previously published cohort of other lipid-poor, poor-washout adrenal masses (n = 47). The cohort included AS (n = 30; literature:25, our center:5), AG (n = 27; literature:25, our center:2). AS and AG were similar, except AG patients were younger (28 vs. 49.5 years, p = 0.003). All AS and 92.5

OBJECTIVE:Gonadal dysgenesis (GD) due to NR0B1 duplication is a subset of 46,XY disorder of sexual differentiation (DSD) characterised by variable external genitalia phenotypes ranging from complete GD (CGD) to partial GD (PGD) and may have syndromic associations. The DSD-phenotype spectrum and its correlation with genotype have not been systematically studied. DESIGN:A systematic review of 46,XY GD with NR0B1 duplication (n = 47, including two patients from our centre) was conducted to understand DSD phenotypes and their genotypic correlations. RESULTS:Large and submicroscopic duplications were observed in 61.7% and 38.3%, respectively, and maternal inheritance (asymptomatic carriers, except one) was reported in 63.3%. Median age at presentation was 1.0 (birth to 38) years, and syndromic manifestations were the cause in 55.3% and gonadal dysfunction-related symptoms in 42.5%. CGD, PGD, and typical male genitalia were seen in 66%, 27.7%, and 6.4%, respectively. Gender incongruence and fertility (except for one reported paternity) have not been reported. Gonadoblastoma and gonadal germ cell cancer were noted in 17% (median age: 11 years) and 2.1% (15 years of age) of cases, respectively. Compared with submicroscopic duplications, large duplications were associated with earlier presentation (0.7 vs. 15 years; p = 0.008) and higher prevalence of syndromic features (96.6% vs. 22.2%; p = 0.0001), while external genital phenotype, cryptorchidism, presence of mullerian structures, and gonadoblastoma rates were comparable. CONCLUSIONS:46,XY GD phenotype with NR0B1 duplication does not correlate with duplicated segment size. A delineated spectrum of gonadal dysfunction, gender identity, fertility, and gonadal malignancy risk presented here can help to optimise patient management.

In 3β-Hydroxysteroid dehydrogenase type-2 (3β-HSD2) deficiency, the gonadal phenotypic spectrum and its correlation with genotype are unclear. We describe our center’s experience and perform a systematic review. Retrospective record review of five 3β-HSD2 deficiency probands from our center, along with per-patient data analysis of reported probands, was conducted to understand the genotype and gonadal phenotype correlation. Probands were subgrouped based on karyotype and residual enzyme activity (REA) of the genetic variant. Of 128 probands, subgroups were: 46,XY REA ≤ 2

OBJECTIVE:Persistent or recurrent primary autoimmune hypophysitis (PAH) is a rare disease, and the role of non-glucocorticoid (GC) immunosuppressive therapy (NGIT) such as azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), methotrexate (MTX), infliximab (IFX), and tacrolimus (TAC) has not been systematically studied. DESIGN:A systematic review of post-GC persistent or recurrent PAH managed with NGIT (n = 29, including two patients from our centre) was conducted to assess the effectiveness and safety of NGIT in this subset of patients. RESULTS:The majority of patients (62.1%) had recurrent disease after an initial response to GC therapy, and the remaining patients had persistent disease (37.9%). Most of the patients (75.8%) received a single NGIT agent (AZA: 14, MMF: 4, RTX: 3, MTX: 1), while the remaining seven patients received multiple NGITs in a sequential manner (AZA→RTX: 4, AZA→MMF→TAC: 1, MMF→IFX: 1, MTX→IFX→RTX: 1). In the majority (59.1%), NGIT was administered concomitantly with GC. The median (IQR) duration of NGIT use was 10.5 (4.0-24.2) months. Overall, clinical, hormonal, and radiological PAH remission was observed in ~91%, ~26%, and ~72%, respectively. Radiological response was best with RTX (100%, 8/8), followed by MMF (~66%, 4/6) and AZA (~37%, 7/19). Overall, adverse events (MMF: alopecia, hepatitis; IFX: pulmonary aspergillosis; AZA: hepatitis, leucopenia) were observed in ~20%. CONCLUSION:NGITs are effective treatment modalities for post-GC therapy persistent or recurrent PAH. Given the heterogeneity of treatment regimens and limited data, larger studies are needed to determine the optimal agent, timing, and duration of NGIT.

BACKGROUND:Type 2 diabetes mellitus (T2DM) is associated with an increased risk of urinary tract infections, including asymptomatic forms like asymptomatic bacteriuria or asymptomatic pyuria (ASP). However, the association between ASP (defined as elevated urinary leukocyte count without symptoms) and glycemic control remains unclear. Hence, this study was conducted to determine the prevalence of ASP in patients with T2DM and evaluate its association with glycemic parameters and urinary abnormalities. METHODS:This retrospective cross-sectional study included 2843 T2DM patients attending the endocrinology outpatient department of a tertiary care center between June 2018 and May 2020. Data on urine microscopy, fasting plasma glucose, postprandial plasma glucose (PPG), and glycated hemoglobin (HbA1c) were analyzed. ASP was defined as >10 leukocytes per high-power field in urine. RESULTS:The prevalence of ASP was 14.98%, significantly higher in females than males (30.7% vs. 6.87%, P < 0.0001). Patients with ASP were older and had significantly higher PPG and HbA1c levels compared to those without ASP. Nitrituria, proteinuria, and glucosuria were also more frequent in the ASP group. Among patients with available urine cultures (n = 84), 61.9% showed significant bacterial growth, predominantly Gram-negative organisms, with Escherichia coli being the most common isolate (69.2%). A notable proportion of isolates exhibited multidrug resistance. CONCLUSIONS:ASP is present in approximately 15% of T2DM patients, with higher prevalence in females and association with poor glycemic control and urinary abnormalities. Given the substantial proportion of culture positivity and antimicrobial resistance, further studies are needed to clarify the clinical significance and management implications of ASP in T2DM.

BACKGROUND:Pseudohypoaldosteronism type 1 (PHA1) is a rare hereditary disorder characterised by aldosterone resistance leading to salt wasting, hyperkalaemia, and metabolic acidosis. Two forms are recognised: a milder renal form (PHA1A) due to NR3C2 mutations and a severe systemic form (PHA1B) caused by biallelic mutations in epithelial sodium channel (ENaC) subunit genes. Data on Indian patients are scarce. This study describes the clinical, biochemical, and molecular characteristics and treatment outcomes of children with PHA1 from South India. METHODS:This multicentric retrospective series included nine children diagnosed with PHA1 across six tertiary care centres between 2022 and 2025. Clinical and biochemical data were extracted from hospital records. Plasma renin, aldosterone, cortisol, and 17-hydroxyprogesterone were measured at presentation. Genetic testing was performed using clinical exome sequencing, and variants were classified according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS:All nine patients had the systemic form (PHA1B). The median age at presentation was 14 days (interquartile range 5.5-42.5), and parental consanguinity was present in seven (78%). All presented with hyponatraemia and hyperkalaemia (median serum sodium 124 mEq/L; potassium 8.0 mEq/L). Eight (pathogenic/likely-pathogenic: 4, supporting: 4) homozygous variants were identified in SCNN1A (n = 2), SCNN1B (n = 3), and SCNN1G (n = 3); all were novel. Six patients (67%) died, mainly due to sepsis (n = 2) or treatment discontinuation (n = 4), while three remain stable on oral sodium supplementation. CONCLUSIONS:This first multicentric South Indian series highlights exclusive reporting of PHA1B, high early mortality, and major treatment challenges. Eight novel ENaC variants expand the genetic spectrum of PHA1B in India.

Introduction:Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterised by hyperandrogenism and ovulatory dysfunction. Nonclassic congenital adrenal hyperplasia (NCCAH) is an important differential diagnosis, but its prevalence in Indian women remains unclear. Previous North Indian studies reported variable rates using less specific assays. This study aimed to determine the prevalence and clinical characteristics of NCCAH among hyperandrogenemic South Indian women with PCOS. Methods:This cross-sectional study was conducted at a tertiary care centre in South India (January 2019 to December 2022). Women aged ≥18 years meeting Androgen Excess Society criteria for PCOS were included. Hyperandrogenemia was defined as serum total testosterone >0.55 ng/ml by chemiluminescent immunoassay. All participants underwent serum steroid profiling 60 minutes after Acton Prolongatum-stimulation using liquid chromatography-tandem mass spectrometry. The serum steroid levels of women with PCOS were compared with those of healthy volunteers. Results:Of 182 screened women, 128 were diagnosed with PCOS. Acton Prolongatum-stimulated steroid profiling was performed in 120 women. Three (2.5%) were diagnosed with congenital adrenal hyperplasia (CAH)-two with classic 21α-hydroxylase deficiency (21OHD) and one with 11β-hydroxylase deficiency. All three showed severe hirsutism, clitoromegaly and severe hyperandrogenemia (>1.5 ng/ml). None were diagnosed with nonclassic 21OHD. Compared with controls, PCOS women had significantly higher testosterone and androstenedione levels with no significant difference in other steroid levels. Conclusions:NCCAH is rare among South Indian women with PCOS, whereas the simple virilising form of classic CAH may often mimic PCOS. Severe hyperandrogenism distinguishes CAH from PCOS and helps prioritise them for CAH screening.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a rare condition caused by pathogenic ALB variants, typically involving Arg242. We describe 2 Indian families with FDH. Case 1 showed elevated total (TT4) and free thyroxine (fT4) with normal thyroid-stimulating hormone (TSH). Her 2 children displayed a similar pattern. All 3 had ∼2-6-fold TT4 and 2-4-fold fT4 elevations on Roche COBAS and Beckman ACCESS assays, while Ortho VITROS reported low-normal fT4 and Abbott ARCHITECT showed minimal or no hormone elevation. Genetic analysis identified a novel heterozygous ALB variant, p.Asn415Ile. Case 2 was evaluated after markedly high TT4 was detected during routine screening. He demonstrated 11-13-fold TT4 elevation on most assays, except Ortho VITROS, and only a modest increase on Abbott ARCHITECT. Genetic testing confirmed the p.Arg242Ser ALB variant. To conclude, we report a novel ALB variant and show that Abbott ARCHITECT exhibits the least assay interference among the contemporary immunoassay platforms in FDH.

CONTEXT:The overnight dexamethasone suppression test (ODST) is precise and highly sensitive; however, its specificity ranges from 80% to 90%. OBJECTIVE:To assess whether late-afternoon overnight dexamethasone suppression (ODS) cortisol and morning/late-afternoon ODS ACTH measurements improve ODST accuracy. METHODS:Prospective, single-center study included healthy adults (n = 60), combined oral contraceptive pill (COCP) users (n = 29), chronic kidney disease (CKD, n = 29), treatment-naïve ACTH-dependent Cushing syndrome (A-CS, n = 33), posttreatment Cushing disease in remission (CD-R, n = 23) or persistence (CD-P, n = 31). Participants underwent the standard 1-mg dexamethasone suppression test; blood samples were collected at 8 to 9 Am for cortisol, ACTH, dexamethasone and at 3 to 4 Pm for cortisol and ACTH. RESULTS:ODS 4 Pm cortisol was significantly lower than 8 Am in healthy adults (P = .003), COCP (P < .001), CKD (P < .001), and CD-R (P = .001), whereas this difference was not significant in treatment-naïve A-CS and CD-P. ODS 8 Am and 4 Pm cortisol (cutoff: 1.8 μg/dL) showed high specificity in healthy adults (95% and 100%), but its specificity was low in COCP (55% and 79%) and CKD (17% and 52%). ODS 8 Am and 4 Pm ACTH (cutoff: 10 pg/mL) showed high specificity in healthy adults (95%, 100%), COCP (100%, 100%), and CKD (96.6%, 100%), with 100% sensitivity for diagnosing A-CS. The diagnostic accuracy of ODS 4 Pm cortisol, ODS 8 Am ACTH, and ODS 4 Pm ACTH in differentiating CD-R from CD-P was 98.1%, 81.5% and 81.5%, respectively. CONCLUSION:Late-afternoon cortisol measurement is a novel modification that enhances ODST specificity. ACTH measurement was particularly useful in COCP and CKD. Before widespread integration in clinical practice, further validation is required.

PURPOSE:Congenital or juvenile-onset hypothyroidism presenting in adulthood is rare but clinically important and may provide a unique opportunity to explore the effects of long-standing hypothyroidism from childhood. Here, we describe five such cases and analyze their unique features. METHODS:This retrospective study includes five cases of congenital (n = 2) or probable juvenile-onset (n = 3) primary hypothyroidism presenting in adulthood, identified at a tertiary healthcare center in South India. We noted the clinical manifestations, laboratory and radiological (roentgenograms and magnetic resonance imaging) investigations, and treatments offered from the record review. RESULTS:All five patients (age: 18-34 years) exhibited severe short stature and impaired puberty. Four patients had myxedematous features, while one patient presented with a marasmic appearance. Bone maturity was delayed in all cases, with epiphyseal dysgenesis, metaphyseal sclerosis, persistent Wormian bones, flattened vertebrae, and pericardial effusion in one or more patients. Uncommon radiological observations included cortical thickening of long bones, dislocation of dysgenetic femoral head epiphyses, and extensive vascular calcification of superficial femoral arteries in one or more patients. One each exhibited pituitary hyperplasia, partial empty sella, enlarged pituitary with a concave superior margin and a normal-sized pituitary gland. CONCLUSIONS:Alongside the well-known effects on growth, puberty, epiphyses, growth plates, and vertebrae, the cases highlight the unique impacts of long-standing pediatric-onset hypothyroidism on cortical thickness, vascular calcification and pituitary.

ObjectivesPreoperative alpha blockade is recommended for phaeochromocytomas and paragangliomas (PPGLs), whereas evidence for calcium channel blockers remains limited. This study evaluated perioperative haemodynamic outcomes with first-line amlodipine for preoperative blockade and identified predictors of intraoperative haemodynamic instability (iHDI). Methods/designIn this monocentric retrospective study, 35 operated PPGL patients who received preoperative first-line amlodipine (July 2021–March 2024) were analysed. Continuous intraoperative arterial pressure recordings were analysed for episodes and duration of hypertension, hypotension, and iHDI. Biochemical phenotype and tumour characteristics were assessed as predictors. ResultsThe cohort (median age: 32 years; 60% female) included 32 phaeochromocytomas and 3 sympathetic paragangliomas. Germline variants were detected in 20/34 tested patients (cluster 1: 11; cluster 2: 9). Amlodipine up to 20 mg was tolerated in all except two, with a median of 7 days to reach BP targets. Median iHDI duration was 6.67% (0–16.4). On linear regression, log-transformed plasma free metanephrine (PFMN) independently predicted iHDI duration (β = 2.26, P = 0.027). Patients with adrenergic phenotype (n = 13) exhibited a longer duration of SBP ≥ 160 mmHg (14 vs 1 min), a higher peak SBP (201 vs 160 mmHg), and a higher nitroglycerine dose (659 vs 59.6 μg) than those with noradrenergic phenotype. Postoperative hypotension (37.1%) was associated with a higher plasma free normetanephrine level (3,440 vs 1,242.9 ng/L) and a larger tumour size (5.1 vs 4.2 cm). No perioperative mortality occurred. ConclusionFirst-line amlodipine blockade was effective in preventing iHDI in PPGLs. Plasma free metanephrine and normetanephrine correlated with intraoperative hypertension and postoperative hypotension, respectively.

For an adrenal incidentaloma with indeterminate imaging characteristics, urine multisteroid profiling is suggested for diagnosing adrenocortical carcinoma (ACC). Data on the utility of serum steroid metabolomics in this context is limited to a few studies. Here, we present data of 62 adult patients with indeterminate unilateral adrenal masses (size ≥ 3 cm and basal attenuation ≥10HU) where baseline serum liquid chromatography-tandem mass spectrometry (LC-MS/MS) multisteroid profiling was available. Logistic regression was used to identify the key steroid signature for differentiating ACC from other non-ACC adrenal masses. Among 62 patients (median age: 41 years, 31 males), 37 (59.6 %) had ACC. The non-ACC cohort (n = 25) comprised pheochromocytoma (n = 9), adrenocortical adenoma (n = 8), metastases (n = 4), schwannoma (n = 2), ganglioneuroma (n = 1), and lymphoma (n = 1). Tumour size was significantly larger in the ACC cohort (9.9 vs 7.0 cm; p < 0.001) than the non-ACC cohort. Nine of 13 steroids were significantly elevated in ACC: 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (S), cortisone (E), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulphate (DHEAS) in both sexes, as well as testosterone (T) in females and progesterone (P4) in males. After excluding sex-dependent steroids, univariate analysis yielded six significant steroids (17OHP, S, E, A4, DHEA, and DHEAS). A multivariate logistic regression model with backward elimination identified A4, S, and DHEAS as the best discriminators (AUC:0.923), with a cutoff of 0.52 yielding 83.8 % sensitivity and 96 % specificity for diagnosing ACC. Our study results suggest serum LC-MS/MS profiling of three steroids (A4, S, and DHEAS) provides a non-invasive approach to distinguish ACC from other indeterminate adrenal masses.

OBJECTIVES:Ovotesticular disorders of sex development (OT-DSD) are rare disorders that constitute ∼5 % of all DSDs. Data on long-term outcomes with respect to gender identity, gonadal malignancy, pubertal/adulthood gonadal and sexual functions are scarce. METHODS:This retrospective study, reports the long-term outcomes of patients with OT-DSD from a single centre in western India. RESULTS:Fifteen patients (14: 46XX, 1: 46XX/46XY) with atypical genitalia and diagnosed as OT-DSD (unilateral-OT with contralateral ovary: 8, bilateral-OT: 3, lateral gonads: 4) were followed up for a median duration of 8.25 (2.1-28) years. 14/15 patients underwent gonadectomy (bilateral in 4). Sex of rearing was male in 14, and none reported gender incongruence/dysphoria. Nine adult males had varied concerns, including gynecomastia (n=9), periodic hematuria (n=3), periodic abdominal pain (n=3), acute abdomen (n=1), hypogonadism requiring testosterone replacement (n=8), genitoplasty-related complications (n=3; urethral fistula in one and poor urine stream requiring intermittent catheterisation in two), short stature [median final height SDS: -2.3 (-3.0 to -0.5)]. Two males reported having sexual relationships. Overall gonadal malignancy rate was 6.6 % (1/15), it was seen in the only patient raised as female (46, XX) who presented at 20.7 years with a right adnexal mass (dysgerminoma from the ovotestes) and primary amenorrhoea. She underwent right gonadectomy and is currently on estrogen and progesterone replacement. CONCLUSIONS:Majority of patients with OT-DSD were reared as males and had a male gender identity, most had short final height and adulthood hypogonadism. Although the risk of gonadal malignancy is low, it cannot be ruled out even in 46XX karyotype. These observations will help in counselling families with affected members.

OBJECTIVES:We report two cases of 46,XY siblings with pontocerebellar hypoplasia type 7 (PCH7) and conduct a systematic literature review for genetically confirmed PCH7 cases, focusing on phenotypic characteristics, particularly gonadal parameters, and associated genotypic data. CASE PRESENTATION:Two 46,XY siblings diagnosed with PCH7 were reviewed. Both exhibited hypoplastic male external genitalia, absent uterus, and cryptorchid testes, confirmed through histological assessments showing dysgenesis. A systematic literature search revealed an additional 26 cases of 46,XY PCH7, with neurological involvement noted in all cases except one. The external genitalia were described as abnormal (17/23); however, few of these were hypoplastic male type on pictorial review. Nonlocalized testes (5/5) and absent uterus (4/7) on ultrasonography, elevated FSH (7/7), and low testosterone (3/3) were observed. Besides a novel variant (p.Ile133Thr) in Indian siblings, a total of 25 variants in TOE1 were identified with no specific genotype-phenotype correlation. CONCLUSIONS:Testicular development was defective in all PCH7 patients but was variable, with the predominant phenotypic manifestation being testicular regression syndrome/partial gonadal dysgenesis with Müllerian duct regression (TRS/PGD-MDR).

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors with a prevalence of less than 0.05%. Being rather uncommon, they pose significant diagnostic challenges as the symptom complex is nonspecific. We present a clinical review based on the published literature and our center's experience in managing pheochromocytoma and paragangliomas over the past two decades. At the onset, summaries of three representative pheochromocytoma and paraganglioma cases are provided to highlight common diagnostic challenges. A holistic approach, combining biochemical evaluation with particular attention to pretest probability, accurate interpretation of imaging data, and differentiation from other adrenal masses, can aid in establishing the diagnosis and guiding appropriate management. Thus, the careful selection and interpretation of clinical, biochemical and imaging parameters are essential to improve diagnostic accuracy and optimize patient management.

INTRODUCTION:Corticotropin (adrenocorticotropic hormone (ACTH))-stimulated blood steroid profile is useful in the diagnosis of rare adrenal disorders but their utility is limited due to lack of assay- and population-specific reference ranges. Hence, we conducted this study to establish the reference ranges for basal and ACTH-stimulated blood steroid profiles in Indian women of reproductive age. METHODS:This cross-sectional study included 30 apparently healthy female volunteers aged 18-40 years. Blood samples were collected during the early follicular phase of the menstrual cycle at baseline and 60 minutes after intramuscular administration of 250 µg of ACTH 1-24. Serum steroid levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS:After ACTH stimulation, 11-deoxycorticosterone (24.8±19.4 ng/dl from 2.44±0.8 ng/dl, 10.16-fold), corticosterone (from 226.0±184.0 to 2159.0±779.0 ng/dl, 9.55-fold) and 11-deoxycortisol (from 47.4±52.4 to 344.7±246.0 ng/dl, 7.28-fold) demonstrated greater than seven-fold elevation whereas 17α-hydroxyprogesterone (from 38.0±39.0 ng/dl to 129.0±75.0 ng/dl, 3.39-fold), dehydroepiandrosterone (from 340.0±221.8 to 998.0±580 ng/dl, 2.94-fold), cortisol (from 10.90±3.80 to 24.72±4.46 µg/dl, 2.27-fold) and aldosterone (from 6.65±5.19 to 13.88±8.11 ng/dl, 2.09-fold) showed 2-3.5-fold elevation. CONCLUSIONS:This study presents reference ranges for baseline and ACTH-stimulated steroid panels in Asian Indian women of reproductive age and summarises the available blood steroid profiles for reproductive-age women from the literature.

Introduction:Hypophosphatasia (HPP) is a rare disorder, with only two genetically proven cases reported from India. Here, We report five Indian patients with genetically proven hypophosphatasia and describe their clinical, biochemical, and genetic profiles. Methods:The study included patients with genetically proven hypophosphatasia managed at different healthcare centers in South India. The participants' case records were reviewed, and relevant phenotypic and genotypic information was collected and analyzed. Results:Case 1 presented at 4 months of age for failure to thrive, found to have persistent hypercalcemia for which she received bisphosphonate therapy. A low alkaline phosphatase was recognized later. Case 2 presented during adolescence with bilateral genu valgus and delayed dentition with classical tongue-like translucencies on radiology and low alkaline phosphatase. Genetic evaluation in cases 1 and 2 revealed compound heterozygous variants in the ALPL gene. Case 1 received asfotase alfa with remarkable improvement in growth. Case 3 presented with multiple vertebral fractures at 33 years of age whereas cases 4 (42 years) and 5 (63 years) presented with musculoskeletal pains with delayed diagnosis for 8 and 13 years, respectively. Cases 3-5 had heterozygous variants in the ALPL gene. Conclusions:In the largest case series of hypophosphatasia from India, we report five cases of hypophosphatasia with two novel variants. Our study emphasizes the need to increase awareness regarding the disease to improve its early diagnosis and also, the need to form strategies to reduce the challenges in obtaining enzyme replacement therapy for hypophosphatasia in India.

OBJECTIVE:Radiotherapy (RT) is an established second-line treatment in adult Cushing disease (CD). Data on pituitary RT in childhood and adolescent-onset CD is scarce. This study aims to demonstrate the effectiveness and long-term safety of fractionated conformal-RT (CRT) in childhood and adolescent-onset CD patients. METHODS:This single-center retrospective study included 34 out of 108 CD patients (<20 years at presentation) who underwent first-line, second-line (post-first transsphenoidal-surgery), or third-line (post-second transsphenoidal-surgery) CRT between 1994 and 2024, with a minimum 1-year follow-up post-CRT. RESULTS:Data from 34 patients (21 males, 7 prepubertal, and 24 microadenomas) with post-CRT median follow-up of 74.5 (34.5-127.3) months were analyzed. Post-CRT, 25/34 (73.5%) patients (overall cohort) achieved remission at 16.5 (8.75-39.25) months, with remission rates of 60%, 93.8%, and 53.8% in first, second, and third-line CRT, respectively. Younger age at CD diagnosis was an independent predictor of remission (HR: 0.805, P = .02). Relapse occurred in 6/25 (24%) at 19.0 (18.3-30.3) months. Ketoconazole use predicted relapse post-CRT (P = .006). Growth hormone deficiency occurred in 17/20 (85%), and 29/34 (41.4%) patients had low insulin-like growth factor-1 levels. New-onset hypogonadotropic hypogonadism (HH) and central hypothyroidism (CHT) occurred in 3/24 (12.5%) and 4/24 (16.7%) patients, respectively. Older age at CD diagnosis (17.5 vs. 13.0 years; P = .02) and at CRT administration (23 vs. 14 years; P = .04) predicted new-onset HH and/or CHT post-CRT. CONCLUSION:Our study illustrates the favorable remission rates post-CRT in childhood and adolescent CD, with lower rates of new-onset HH/CHT. Ongoing monitoring is required, as relapse can occur in one-fourth of cases.

The prevalence of congenital hypothyroidism (CH) in infants of mothers with hypothyroidism has been described but a comprehensive prevalence estimation is lacking. The comprehensive analyses of subtyping, quantum of excess risk in comparison to those born to euthyroid mothers and association with thyroid antibodies are also lacking. This systematic review and meta-analysis aimed to estimate the pooled prevalence of CH in infants born to mothers with hypothyroidism. PubMed database was searched from inception to February 2025 using the search terms’ ((congenital hypothyroidism) and (maternal hypothyroidism)) or (mothers with hypothyroidism)’. Of 2097 initially identified articles, 18 met inclusion criteria, encompassing 11,242 infants of mothers with hypothyroidism. CH diagnoses were classified as transient (TCH) or permanent (PCH). The overall pooled prevalence of CH among infants of mothers with hypothyroidism was 0.003767 (95 % CI: 0.001796–0.005637). TCH accounted for Prevalence of TCH was 0.001867 (95 % CI: 0.000674–0.003060) whereas that of PCH was 0.001429 (0.000386–0.002473). Infants of hypothyroid mothers exhibited significantly increased risk of CH (OR: 3.48, 95 % CI: 1.25–9.65) than those of euthyroid mothers. Maternal thyroid antibody status (TPOAb positivity) did not significantly influence CH prevalence (OR: 0.97, 95 % CI: 0.19–4.81). In conclusion, infants of mothers with hypothyroidism have a substantially higher prevalence (1 in 265) than that reported in the general population. The risk was also 3.5 times higher in the systematic review. However, no association between maternal thyroid antibodies and CH was observed, emphasizing a need to explore alternative pathogenetic mechanisms.