Congenital hypogonadotropic hypogonadism (CHH) is a rare group of disorders of gonadotropin deficiency, either isolated or as a part of multiple pituitary hormone deficiencies (MPHD). We aimed to describe the spectrum of presentation, diagnosis, and management practices of CHH spanning 30 years at an Australian tertiary paediatric centre. This is a retrospective cohort study of patients with CHH seen at the Children's Hospital at Westmead between January 1994 and December 2024 (n = 96, 66% male), categorised by diagnostic subtypes: Kallmann Syndrome (KS), normosmic HH, MPHD and other syndromes (including CHARGE). RESULTS: In patients with KS (n = 31, 87% male), the most common presenting features were micropenis and/or cryptorchidism (45%) or pubertal delay (45%), with two peak ages of presentation: 0.6 [IQR 0.3-0.8] and 14.6 [11.5-15.7] years. Patients with MPHD (n = 23, 52% male) presented with neonatal hypoglycaemia in 52%. Comorbidities stratified by diagnostic subtypes (KS, MPHD, and other syndromes) included hearing impairment (10%, 4%, 100%), visual impairment (7%, 17%, 77%), cardiac anomalies (3%, 9%, 77%), and intellectual disability (13%, 26%, 46%). Genetic testing was performed in 32% in 1995-2009 vs 66% in 2010-2024. Pathogenic gene variants associated with HH were found in 61% of those tested, including CHD7 (n = 10), ANOS1 (n = 4), and FGFR1 (n = 3). Pubertal induction was commenced in males at a mean age of 14.1 ± 1.6 years using testosterone (n = 27 oral; 14 intramuscular; 1 subcutaneous) or gonadotropins (n = 5), and in females, at a mean age of 14.6 ± 1.8 years using oestradiol (n = 21 oral; 8 transdermal) ± progesterone. CONCLUSIONS: CHH is a heterogeneous group of disorders, with varying prevalence of associated comorbidities according to diagnostic subtypes. Our data highlight the paediatric-specific modes of presentation of CHH, and in KS, the bimodal distribution of age at presentation in males and the under-representation and delayed diagnoses in females. Despite advances in genetics in the past three decades, there remain areas for further research in the diagnostics and therapeutics of CHH in the paediatric age group.
PURPOSE:To comprehensively reassess the clinical and metabolic significance of the luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio in women with polycystic ovary syndrome (PCOS), and to investigate whether it is associated with a clinical and hormonal pattern consistent with a possible neuroendocrine-dominant subgroup, distinguishable from insulin-related metabolic presentation. DESIGN:Observational cross-sectional study. METHODS:This retrospective cross-sectional study included 316 women diagnosed with PCOS according to the Rotterdam criteria at a tertiary university hospital. Patients were categorised based on their LH:FSH ratio (using a cut-off of 2) and their PCOS phenotypes (Phenotypes A, B, C, and D). Clinical, hormonal, and metabolic parameters, including anti-Müllerian hormone (AMH) levels and ovarian volume, were compared across groups. RESULTS:Among 316 patients, 18.35% had an LH:FSH ratio >2. A strong positive correlation was found between LH:FSH ratio and AMH levels (r = 0.65, p < 0.001), and a significant correlation was observed with ovarian volume (r = 0.20, p = 0.001) and polycystic ovarian morphology (mean LH:FSH 1.59 vs. 1.15, p < 0.001). Patients with phenotype D (OA + PCOM, non-hyperandrogenic PCOS) exhibited the highest LH:FSH ratio (1.75 ± 0.87). Higher LH:FSH ratios were associated with oligo/amenorrhea (1.59 vs. 1.22, p < 0.001), anovulation (1.66 vs. 1.16, p < 0.001), and lower midluteal progesterone (ρ = -0.28, p < 0.001), but not with serum androgens or Ferriman-Gallwey scores. Weak positive correlations were observed with insulin levels (ρ = 0.18, p = 0.022) and HOMA-IR (ρ = 0.18, p = 0.021), but no significant associations were found with BMI, glucose tolerance, or lipid profile. CONCLUSION:A high LH:FSH ratio is associated with a clinical and hormonal pattern-including elevated AMH levels, prominent PCOM, and anovulation-that may be consistent with a neuroendocrine-dominant presentation of PCOS, rather than metabolic or androgenic disturbances. If confirmed by prospective studies, this association could inform more individualised therapeutic approaches.
Colorectal cancer (CRC) remains a major global health concern, and experimental animal models continue to play a key role in understanding its development and in evaluating preventive and therapeutic strategies. Among these, the 1,2-dimethylhydrazine (DMH)-induced rat model is widely used; however, substantial variability in dosing regimens and study design has limited consistency across studies. The present systematic review aimed to synthesize existing evidence on DMH-induced colorectal carcinogenesis in rats, with particular attention to how dose, duration, and route of administration influence pathological outcomes. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science from January 2010 to December 2025. Eligible studies were screened and analyzed based on predefined inclusion criteria. Data were extracted on induction protocols, histopathological findings, and study characteristics. Across the 430 included studies, notable heterogeneity was observed in experimental protocols. Nevertheless, certain patterns emerged. Higher-dose, shorter-duration regimens were more frequently associated with early preneoplastic lesions such as aberrant crypt foci (ACF), whereas lower-dose, longer-duration protocols tended to be linked with more advanced tumor development. Subcutaneous administration appeared to provide more consistent results compared to other routes. These findings suggest that the choice of protocol should be guided by the intended stage of carcinogenesis under investigation. Importantly, the interpretation of these findings should be approached with caution. Many studies lacked detailed reporting of methodological parameters, and quantitative synthesis was limited by incomplete data. As such, the proposed framework should be viewed as a practical guide rather than a definitive standard. In conclusion, DMH-induced CRC models in rats remain valuable but highly sensitive to experimental design. Greater standardization and more rigorous reporting are needed to improve reproducibility and strengthen the translational relevance of future studies.
BACKGROUND:Alemtuzumab (Lemtrada) is highly effective for selected relapsing multiple sclerosis (MS) but can cause autoimmune thyroid dysfunction (AITD). Our aim was to retrospectively review patients and the monitoring of their thyroid function tests (TFTs) during and after treatment with alemtuzumab. We wanted to summarise the incidence and characterise the nature of TD in our Northern Ireland (NI) cohort. METHODS:Data was obtained from the NI Disease Modifying Treatment (NIDMT) database for all patients with relapsing remitting MS receiving alemtuzumab in the period between 2015 and 2024. Patients were identified and data collected retrospectively from clinical records. Data collected included dates of alemtuzumab treatment, TFT monitoring results, subsequent follow up and any thyroid treatment required. Demographic and clinical data were obtained from the Northern Ireland Electronic Care Record (NIECR)-an electronic healthcare record. RESULTS:168 patients (female n = 114, male n = 54) received alemtuzumab between 2015 and 2024 in Northern Ireland, with a follow-up period of approximately 60 months. On most recent follow up, TD occurred in 45.8% (n = 77) patients. The spectrum of thyroid disorders observed post-alemtuzumab was diverse; Graves' disease and thyroiditis were the most common thyroid disorders, each affecting 10.7% (n = 18) of patients. Thyroiditis with positive thyroid stimulating receptor antibodies (TRAb) occurred in 7.7% (n = 13), followed by Hashimoto's disease 7.1% (n = 13), with both ab-negative hypothyroidism 6.0% (n = 10) and hyperthyroidism 3.0% (n = 5). Two patients had pre-existing thyroid dysfunction hypothyroidism n = 1 and hyperthyroidism n = 1. Baseline thyroid autoantibody status showed a strong association with TD. Women were twice as likely as men to develop TD following Alemtuzumab treatment. Neither age nor MS duration significantly influenced the risk of TD. TD was diagnosed as early as 12 months after initiating treatment, with the latest diagnosis being made 56 months after. CONCLUSION:The frequency of Alemtuzumab-induced TD in our cohort was similar to that reported in other literature and the nature of TD varied with a number of patients fluctuating between dysthyroid states. This data highlights the importance of close surveillance for TD due to the risk of complex, late-onset autoimmunity.
BACKGROUND:Preclinical studies suggest a novel aldosterone regulation pathway: the mineralocorticoid receptor (MR) on the adrenal cortex is a part of an MR-mediated ultra-short feedback loop regulating aldosterone production. Activation of MR on the adrenal decreases aldosterone; blockade of the MR increases aldosterone. Whether this regulatory pathway exists in humans is unknown. METHODS:This was a double-blinded, 3-way crossover study of 23 healthy participants on a low sodium diet (10 mEq/day). Participants received three study drugs in random order: MR antagonist (eplerenone), MR agonist (fludrocortisone), and placebo. Study drugs were administered at 6:30AM on three separate days with 48 h between each administration. After 90 min, participants received sequential infusions of angiotensin-II (ANGII) for 45 min followed 60 min later by cosyntropin for 45 min. Aldosterone was measured before and after each infusion. Multi-level mixed effects linear regression was used to analyze the data. RESULTS:The change in aldosterone between baseline and post-cosyntropin infusion was greater after treatment with eplerenone as compared to placebo (5.16 ± 2.01 ng/dL, p = 0.01). There were no differences with fludrocortisone as compared to placebo. With ANGII stimulation, there were no differences in the change in aldosterone with either eplerenone or fludrocortisone versus placebo. CONCLUSIONS:In humans, MR antagonist treatment led to a greater increase in aldosterone in response to cosyntropin stimulation as compared to placebo, but not after ANGII stimulation. Future studies are needed to investigate the presence of a MR-mediated ultra-short feedback loop at the level of the adrenal gland regulating aldosterone production in humans. CLINICAL TRIAL REGISTRATION NUMBER:NCT02871648.
The spleen is usually viewed as a hematologic, vascular and immune organ, but rarely within lipid-associated disease. This review proposes splenic steatopathy as a provisional clinical and experimental framework rather than an established diagnosis or a splenic equivalent of fatty liver disease. Evidence is organized into pre-splenic drivers, intra-splenic pathology and post-splenic consequences. Upstream drivers include metabolic dysfunction-associated steatotic liver disease, obesity, severe hypertriglyceridemia, lysosomal storage disorders, drug-induced phospholipidosis, altered lymphatic lipid handling and portal-hemodynamic stress. Spleen-level findings include altered volume, attenuation, stiffness or metabolic activity; lipid-laden histiocytes; lysosomal or phospholipid storage; and immune-cell remodeling. Potential downstream relevance includes cytopenias, immune dysfunction, infection vulnerability, diagnostic redirection, cancer-associated immune biology and perioperative risk. Human evidence currently consists mainly of observational imaging studies and rare tissue reports; animal studies provide mechanistic support, while several proposed clinical links remain hypotheses. No validated diagnostic criteria, imaging thresholds or biomarkers currently exist. The framework may help distinguish unexplained splenomegaly from common mimics and, if validated, support long-term risk stratification for infection and malignancy in patients with metabolic liver disease. Future studies should prioritize spleen-specific imaging methods, tissue-imaging correlation, lipidomics, immune phenotyping and prospective outcome validation.
OBJECTIVE:To characterize the clinical, biochemical, radiological, and surgical profile of Cushing disease in a large tertiary-care cohort, with emphasis on age-stratified differences. METHODS:This retrospective observational audit included 277 patients with confirmed Cushing disease managed at a high-volume tertiary-care center between 2006 and 2025. Baseline clinical, biochemical, metabolic, radiological, and outcome data were extracted from the time of initial evaluation at our center, generally during diagnostic confirmation and before definitive therapy. Hormonal parameters were assessed using electrochemiluminescence immunoassay, and bone mineral density was evaluated using dual-energy X-ray absorptiometry only in a clinically selected subset. Surgical outcomes were assessed based on early postoperative cortisol levels, with remission defined as morning cortisol < 138 nmol/L. RESULTS:The cohort demonstrated a marked female predominance (71.8%), with most patients presenting in the third and fourth decades. Classical cushingoid features were highly prevalent, including weight gain (79.4%), centripetal obesity (62.5%), hyperpigmentation (61.0%), and proximal myopathy (60.6%). Exploratory age-stratified patterns were observed in selected clinical and biochemical variables. Younger patients showed a relatively higher recorded frequency of dermatological and reproductive manifestations, including striae, acne, and menstrual irregularities, whereas the recorded burden of cardiometabolic comorbidities at tertiary-care assessment, including hypertension (70.8%) and diabetes mellitus (48.0%), was higher in older age groups. Body mass index and blood pressure also varied across age groups, although these findings should be interpreted cautiously because of the retrospective design, unequal age-stratum sizes, and absence of adjustment for multiple comparisons. Biochemically, median cortisol levels were elevated across the cohort, with exploratory variation across age groups. Higher cortisol concentrations were observed in younger patients, while adrenocorticotropic hormone levels remained comparable across age decades. Bone mineral density was available in a clinically selected subset of 78 patients. Within this DXA subset, reduced bone density was frequent; however, these findings were not extrapolated to the entire cohort. Transsphenoidal surgery was the primary treatment modality. Numerically similar early remission proportions were observed in microadenomas (72.7%) and macroadenomas (72.2%) in this cohort, with no clear descriptive age-related pattern in early postoperative outcomes. Early biochemical remission was observed in 166/233 surgically treated patients (71.2%), while 67/233 patients (28.8%) had persistent disease. Relapse was assessed only after documented initial remission and occurred in 22/166 patients (13.3%). CONCLUSION:This large single-center cohort demonstrates substantial recorded clinical and cardiometabolic burden at tertiary-care assessment in Cushing disease. Exploratory age-stratified patterns were observed in clinical phenotype and cortisol profile, while numerically similar early remission proportions were observed across tumor-size categories in descriptive analyses. Bone-density findings apply only to the DXA subset, and non-uniform follow-up limits robust assessment of long-term recurrence.
OBJECTIVE:Kisspeptin-1 and Kisspeptin-54 are key regulators of the hypothalamic-pituitary-gonadal axis and may play a role in male reproductive function. This study aimed to evaluate the association between seminal plasma kisspeptin levels and male infertility, and to examine their relationships with semen parameters and oxidative stress markers. DESIGN:Retrospective cross-sectional study. METHODS:Fifty men attending an in vitro fertilization centre were classified into normozoospermia (n = 20), oligoasthenoteratozoospermia (OAT) (n = 18) and azoospermia (n = 12) groups according to WHO 2021 criteria. Seminal plasma Kisspeptin-1 and Kisspeptin-54 levels were measured using ELISA. Oxidative stress parameters, including total antioxidant capacity (TAC), total oxidant capacity (TOC) and oxidative stress index (OSI), were assessed using spectrophotometric methods. Correlation and regression analyses were performed to evaluate associations between variables. RESULTS:Kisspeptin-1 and Kisspeptin-54 levels showed a progressive decrease with increasing infertility severity (normozoospermia→OAT→azoospermia; p < 0.05). Both kisspeptins were positively associated with sperm concentration and progressive motility, and negatively associated with TOC and OSI (p < 0.01). TAC levels were higher in normozoospermic men, whereas oxidative load was increased in azoospermic individuals. Regression analyses indicated that seminal kisspeptin levels were significantly associated with sperm concentration and progressive motility. Parallel alterations in kisspeptin levels and oxidative stress markers suggest a relationship between these peptides and the seminal microenvironment. CONCLUSIONS:Seminal plasma kisspeptin levels are associated with semen quality and oxidative stress parameters in male infertility. These findings suggest that kisspeptin may represent a potential biomarker candidate for the evaluation of male infertility, although further validation is required.
OBJECTIVE:Achondroplasia is an autosomal dominant genetic disorder, characterised by distinctive growth patterns and recognisable skeletal features. This study aimed to determine the demographic and clinical characteristics, quality of life (QoL) losses, and expectations of individuals with achondroplasia in Türkiye. DESIGN:In this survey-based study, Computer-Assisted Telephone Interviewing (CATI) system was used and questions were directed to patients or their parents via phone calls. PATIENTS:A total of 140 patients with achondroplasia, of whom 50.7% were male (age range, 0-20 years) were included. MEASUREMENTS:The questionnaire forms were prepared by a committee including clinicians and the president of the Achondroplasia and Families Association. The forms included questions on sociodemographic characteristics, diagnosis and treatment, expectations from the patient association, and quality of life. RESULTS:Achondroplasia was commonly diagnosed by obstetricians (76.5%) and the patients were followed by multiple specialties. Of the patients, 10% received growth hormone treatment, and 55.7% underwent at least one surgical procedure, with 23.6% undergoing limb lengthening surgery. The main symptoms frequently/very frequently observed in the patients were: sleep-disordered breathing (40%), recurrent ear infections (32%), and frequent respiratory tract infections (28%). The primary concerns involved experiences of social exclusion due to physical appearance and together with related psychological challenges. The main expectations of the participants and parents from the association were to receive education on achondroplasia management and new treatment options, and to promote public awareness. CONCLUSIONS:Patients with achondroplasia face significant challenges in daily life, they require medical treatment and some supportive services to improve their quality of life.
CONTEXT:Variants in LHX3, encoding a LIM-homeodomain transcription factor essential for pituitary and neuronal development, are a rare cause of combined pituitary hormone deficiency (CPHD). Affected patients typically exhibit deficiencies of growth hormone (GH), thyrotropin (TSH), prolactin (PRL), and gonadotropins, often accompanied by cervical spine rigidity or sensorineural hearing loss. CASE DESCRIPTION:A 4.8-year-old boy presented with short stature and central hypothyroidism. Combined deficiencies of GH, TSH, and PRL were documented, while ACTH secretion remained intact. Cranial magnetic resonance imaging showed normal pituitary morphology. Neck mobility and audiological evaluation were unremarkable. EVALUATION:A targeted next-generation sequencing panel for panhypopituitarism was non-diagnostic. Whole-exome sequencing (WES) was performed at 10.5 years of age. RESULTS:WES identified a novel homozygous LHX3 c.575 G > A, p.(Arg192His) variant located within the homeodomain. Segregation analysis confirmed parental heterozygosity. A younger sister carrying the same homozygous variant exhibited a similar endocrine phenotype. Growth velocity normalized on recombinant human GH replacement. CONCLUSION:This case expands the phenotypic spectrum of LHX3-related CPHD by demonstrating that a homeodomain missense variant may produce isolated endocrine deficiencies without structural, auditory, or motor abnormalities, and underscores the value of serial genetic re-evaluation in unexplained CPHD.
BACKGROUND:Lupus-associated hypophysitis is a rare but clinically important manifestation of systemic lupus erythematosus (SLE), characterised by heterogeneous pituitary dysfunction and inflammatory sellar changes that may mimic other pituitary disorders. Evidence is limited to isolated reports. We aimed to summarise clinical, radiological, endocrine features, management, and outcomes. METHODS:A narrative systematic review of MEDLINE, Embase, Web of Science, and Google Scholar to 10 November 2025. Reports were included if accepted SLE criteria were met and hypophysitis or hypothalamic-pituitary inflammation was attributed to SLE after exclusion of alternative sellar pathology. Demographic, clinical, endocrine, imaging, treatment, and outcome data were synthesised descriptively. RESULTS:Eleven cases (63% female; median age 23 years) were identified, most presenting at or near SLE diagnosis. Common symptoms included polyuria/polydipsia, fatigue, amenorrhoea, and headache. Arginine vasopressin deficiency (AVP-D) frequently coexisted with multi-axis anterior hypopituitarism. MRI typically demonstrated pituitary stalk thickening, gland enlargement, and loss of the posterior pituitary bright spot. High-dose glucocorticoids, with or without additional immunosuppression, led to improvement in most cases, although persistent adrenal and gonadal deficits were common; one patient died from severe hyponatraemia. CONCLUSIONS:Lupus-associated hypophysitis is a rare manifestation of SLE with heterogeneous endocrine and radiological presentations that may create diagnostic challenges. Early endocrine evaluation and pituitary imaging are important in patients with suspected hypothalamic-pituitary involvement.
BACKGROUND:Parathyroid carcinoma is a rare endocrine malignancy (< 1% of primary hyperparathyroidism and 0.005% of all cancers) that often mimics a benign adenoma, leading to diagnosis only after surgery, unless invasion or metastasis is present. OBJECTIVE:To identify distinguishing clinical, biochemical and pathological features of parathyroid carcinoma in comparison with primary parathyroid adenoma and atypical parathyroid tumor and to determine its perioperative predictors. METHODS:A retrospective analysis compared 16 histopathologically confirmed parathyroid carcinoma cases with 378 primary parathyroid adenoma and 11 atypical parathyroid tumors, evaluating and contrasting their clinical and laboratory features. RESULTS:No significant differences in age or gender were observed across groups. Parathyroid carcinoma was significantly associated with hoarseness, hypercalcaemic crisis, palpable neck mass (all p < 0.001), pancreatitis, and concomitant bone/kidney involvement (both p < 0.05). Ridge-penalized logistic regression identified hoarseness, palpable neck mass and an involved parathyroid gland weight ≥ 3 grams (g) as significant perioperative predictors of parathyroid carcinoma while adenoma diameter, serum calcium levels and intact parathyroid hormone (iPTH) were not statistically significant. ROC analysis showed parathyroid adenoma weight of ≥ 7.5 g had the highest diagnostic accuracy (75% sensitivity, 86% specificity), whereas serum calcium and iPTH exhibited only moderate diagnostic performance. Recurrence was observed in 31% of cases. CONCLUSION:Parathyroid carcinoma exhibits more severe clinical and biochemical features and greater gland weight than benign lesions. The high recurrence rate necessitates rigorous long-term surveillance. While offering a framework for preoperative risk stratification, these retrospective findings require prospective validation in larger cohorts.
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.
OBJECTIVE:Hyponatraemia is a common electrolyte disorder often driven by excess arginine vasopressin (AVP). Copeptin is a stable surrogate marker co-secreted with AVP. It is unclear whether treatment of hyponatraemia with tolvaptan, an AVP-V2 receptor antagonist, impacts copeptin. We aimed to assess the effects of tolvaptan on serum copeptin, compared to fluid restriction. DESIGN:Pre-specified secondary analysis of an open-label randomised trial comparing tolvaptan or fluid restriction for 3 days. PATIENTS:Hospitalised patients with plasma sodium (pNa) 115-130 mmol/L at a single-centre tertiary hospital in Melbourne, Australia. MEASUREMENTS:Copeptin measured at baseline and completion (Day 4, or discharge if sooner). RESULTS:Copeptin results were available in 45/54 participants, randomised to tolvaptan (n = 25) or FR (n = 20). Mean baseline copeptin was 10.4 pmol/L. pNa increased in both groups, significantly more with tolvaptan as previously reported. Copeptin remained stable after FR, but significantly increased after tolvaptan (mean adjusted difference between groups over 3 days 8.4 pmol/L, 95% CI 2.1-14.6, p = 0.01). Baseline copeptin did not predict rapid sodium rise. The rise in copeptin after tolvaptan may represent an exaggerated response to osmolality rise in these patients ('reset osmostat'), or feedback mechanisms from AVP blockade. CONCLUSION:Tolvaptan increased serum copeptin compared to fluid restriction. Further research is required to determine if there is clinical utility for measuring copeptin in hyponatraemia before it is adopted into practice. TRIAL REGISTRATION:ACTRN12619001683123.
OBJECTIVE:This study aimed to evaluate the impact of pathogenic genetic variants on growth outcomes following 3 years of recombinant human growth hormone (rhGH) therapy in children born small for gestational age with persistent short stature (SGA-SS). DESIGN:A retrospective cohort study. PATIENTS:One hundred and seventy-nine SGA-SS children who underwent clinical and genetic evaluation were classified into variant-positive (n = 30) and variant-negative groups (n = 149). MEASUREMENTS:Clinical characteristics and growth outcomes were assessed over 3 years of rhGH therapy. RESULTS:At baseline, the variant-positive group had significantly lower height standard deviation score (SDS) (-2.83 vs. -2.28, p < 0.001) and higher rates of intellectual disability (36.7% vs. 7.4%, p < 0.001) and congenital anomalies (30.0% vs. 6.7%, p < 0.001). rhGH therapy promoted longitudinal growth in both groups (evaluated n = 142); after 3 years, the estimated marginal mean (EMM) of height SDS reached -1.30 ± 0.10 in the variant-positive group and -0.93 ± 0.04 in the variant-negative group. However, linear mixed model analysis revealed a progressive attenuation of incremental height SDS gain in the variant-positive group as the treatment progressed, with significant interaction estimates observed at Year 1 (Estimate -0.18), Year 2 (Estimate -0.31) and Year 3 (Estimate -0.36; all p < 0.05). CONCLUSION:As one of the first longitudinal analyses utilizing repeated-measures modelling in a genetically characterized patient population, this study demonstrates that while rhGH therapy effectively promoted linear growth in SGA-SS children, patients with a molecular diagnosis presented with lower baseline stature and an attenuated incremental growth response over time, highlighting the importance of genetic evaluation for personalized treatment strategies.
BACKGROUND:Meier-Gorlin-syndrome (MGORS) is a rare cause of primordial dwarfism stemming from pathogenic variants in genes involved in DNA replication. The classic clinical triad is microtia, absent patella and short stature. MGORS can mimic endocrine causes of short stature or delayed/atypical pubertal development. METHODS:We report two new cases of MGORS. A systematic literature search of all cases published up to 31 March 2026 was done to identify the cases reporting any endocrinopathy or hormonal therapy, focussing on growth-hormone-deficiency (GHD) and response to growth hormone (GH). RESULTS:We describe a 14 year-old girl, the first MGORS case with CDC6 variant and mammary hypoplasia. Another 11-year old boy with GMNN variant had severe short-stature with GHD and had significant height improvement with GH. Among 29 cases (out of ~150 published), the classic triad was absent in 18.5%. Short stature was almost universal (median height-Z-score -4.4), with 70% exhibiting delayed bone age, 42.9% low IGF-1 and 35.3% GHD. Among 10 GH-treated cases with response data, 6 had reported improvement in height-SDS/growth-velocity. Those with GHD and delayed bone age were more likely to benefit from GH. Among females, all post-pubertal cases had mammary hypoplasia, while 23.5% had clitoromegaly with hypoplastic labia. Among males, cryptorchidism, hypoplastic scrotum and micropenis were common. However, gonadal hormones and gonadotrophins were normal. Data on the effect of estrogen on hypoplastic mammary glands or labia was variable. CONCLUSION:MGORS should be kept in mind as a differential of multiple endocrinopathies. Cases of MGORS should undergo screening for GHD. Available data, mostly from case-reports or small series, suggest that response to GH has been reported in some individuals, particularly where GHD or delayed bone age was present, but evidence remains very limited.
INTRODUCTION:Intermediate-risk papillary thyroid carcinoma (PTC) accounts for 40%-60% of newly diagnosed PTC and comprises a heterogeneous group with variable recurrence risk. The benefit of postoperative radioactive iodine (RAI) remains uncertain. OBJECTIVES:To describe features, response-to-therapy outcomes, and ATA 2025 recurrence-risk redistribution in patients with ATA 2015 intermediate-risk PTC managed without adjuvant RAI. DESIGN:Retrospective cohort study. METHODS:Adults (≥ 18 years) with ATA 2015 intermediate-risk PTC treated with total thyroidectomy (TT) or thyroid lobectomy (TL), with/without lymph node dissection, and followed for ≥ 1 year were included. Omission of postoperative RAI was based on histopathology, cervical ultrasound (US), serum thyroglobulin (Tg), and anti-thyroglobulin antibodies (TgAb) measured within 6 months postoperatively. TL patients required negative US. TT patients required negative US plus Tg < 1 ng/mL if TgAb-negative, or stable/declining TgAb if positive. Response to therapy was assessed using ATA 2015 dynamic risk stratification and reassessed with ATA 2025 criteria. RESULTS:Ninety-nine patients were included; 84 (84.8%) were women, the mean age was 40.2 ± 13.3 years, and the median follow-up was 4.8 years. Microscopic extrathyroidal extension was present in 51 (51.5%), lymph node metastases in 37 (37.4%), and extranodal extension in 4 (4.0%). By ATA 2015, 67 (67.7%) had an excellent response and 32 (32.3%) an indeterminate response; no incomplete responses or structural recurrences occurred. ATA 2025 reclassified 3 (3.0%) as low risk, 39 (39.4%) as low-intermediate, 52 (52.5%) as high-intermediate, and 5 (5.1%) as high risk. CONCLUSIONS:Selected intermediate-risk PTC patients managed without adjuvant RAI had excellent mid-term outcomes, supporting a risk-adapted de-escalation strategy.
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:Improved cancer survival rates have highlighted second primary malignancies (SPMs), with the thyroid gland being one of the most common organs developing SPMs in cancer survivors. Second primary papillary thyroid carcinoma (2-PTC) is the predominant type, yet it remains poorly understood. This study aims to delineate the clinicopathological features and survival outcomes of 2-PTC and assess the efficacy of postoperative radioactive iodine therapy (post-RAIT) in reducing mortality risks in intermediate-risk 2-PTC patients. METHODS:Using the SEER-17 database (2004-2019), we identified 6399 2-PTC patients as Cohort 1 to analyze characteristics and outcomes, and 1743 as Cohort 2 to examine post-RAIT effects. Competing risk regression models were applied to assess mortality risks from prior primary malignancies (PPMs) and other causes. Propensity score matching and stabilized inverse probability treatment weighting with 500 bootstrap samples were used for robust analysis. RESULTS:Predominant demographic characteristics of 2-PTC patients included older age, female sex, and white ethnicity. Breast (25.5%), prostate (9.8%), and skin cancer (6.7%) were the most common PPMs. Unfavorable PPMs were found in 6.3% of patients. Despite lower cumulative mortality from 2-PTC compared to PPMs and other causes, post-RAIT did not significantly reduce mortality risks in Cohort 2, even among patients aged ≥ 55 years, with clinical stage IV disease, or unfavorable PPMs. Sensitivity analyses confirmed these findings. CONCLUSION:The survival prognosis for 2-PTC patients is generally favorable, and post-RAIT does not significantly affect mortality in intermediate-risk cases, indicating a need for reevaluation of its use.
