Introduction: 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency and lipoid congenital adrenal hyperplasia (CAH) are rare disorders of steroidogenesis that result in impaired synthesis of all adrenal and gonadal hormones. Affected males typically present with ambiguous genitalia and concurrent mineralocorticoid and glucocorticoid deficiency. Distinguishing between these two conditions is crucial, as their management strategies differ. Case: We report a 24-year-old male, born to non-consanguineous parents, who was clinically diagnosed with 3β-HSD deficiency during infancy. He presented at day 40 of life with ambiguous genitalia, bilateral undescended testes, and generalized hyperpigmentation. His family history was significant for an elder brother with salt-losing CAH. Initial biochemical evaluation confirmed primary adrenal insufficiency and primary hypogonadism. Notably, his steroid precursors, dehydroepiandrosterone sulfate (DHEAS) and 17-hydroxyprogesterone, were suppressed. A karyotype confirmed 46,XY. In the absence of genetic testing at that time, a clinical diagnosis of 3β-HSD deficiency was made, and he was commenced on mineralocorticoid and supraphysiological glucocorticoid replacement. He underwent bilateral orchidopexy and hypospadias repair in childhood. Pubertal induction was required, followed by maintenance testosterone therapy. Upon transitioning to adult care, a review of his biochemical profile, particularly suppressed DHEAS, which is inconsistent with 3β-HSD deficiency, raised the suspicion of a more proximal defect, such as lipoid CAH. Differentiation is imperative, as lipoid CAH requires only physiological glucocorticoid replacement, whereas 3β-HSD deficiency often needs higher doses to suppress adrenocorticotropic hormone and DHEAS. To resolve this diagnostic uncertainty and guide longterm therapy, the patient was referred for genetic studies. Conclusion Differentiating 3β-HSD deficiency from lipoid CAH is important, as both have similar clinical presentation. The absence of elevated steroid precursors, particularly DHEAS, should raise suspicion of a more proximal defect. Given the different aims of glucocorticoid therapy, establishing a precise diagnosis through genetic studies is essential to guide clinical management and minimize the morbidity associated with supraphysiological corticosteroid dosing.
Pheochromocytoma ; Mutation

Introduction: Non-diabetic hypoglycemia in older adults warrants careful evaluation across insulin-mediated and noninsulin-mediated causes. We present a challenging case of insulin autoimmune syndrome (IAS; Hirata’s syndrome). Case: An 85-year-old female presented with severe hypoglycemia (capillary blood glucose [CBG] 1.8 mmol/L) with reduced consciousness, preceded by 2 months of recurrent dizziness relieved by food intake. Appetite and weight were stable. Past medical history included stage 3 chronic kidney disease and osteoporosis, but no diabetes. Medication review revealed a recent 2-week course of traditional supplement, long-term Neurobion®, but no agents with recognized hypoglycemic potential. Physical examination showed a moderately built elderly female with a body mass index of 24.3 kg/m² and no Cushingoid features. Recurrent hypoglycemia (CBG nadir 1.5 mmol/L) occurred in both fasting and postprandial states, fulfilling Whipple’s triad. Baseline investigations showed an estimated glomerular filtration rate of 42 mL/min/1.73 m², AM cortisol of 700 mmol/L, and unremarkable liver and thyroid function tests. During a hypoglycemic episode (CBG 2.3 mmol/L), plasma insulin and C-peptide were inappropriately raised at 203.6 mU/L (reference interval [RI]: 3.0– 25.0) and 33 ng/mL (RI: 0.9–7.1), respectively, confirming endogenous hyperinsulinemic hypoglycemia. Polyethylene glycol precipitation showed 21% insulin recovery, raising suspicion for an autoimmune cause. Elevated insulin autoantibodies (175 AU/mL; RI <20) confirmed IAS. Computed tomography of the abdomen and endoscopic ultrasound excluded a pancreatic neuro-endocrine tumor. Nutritional management comprising frequent low glycemic index feeds and uncooked cornstarch was commenced. Diazoxide 100 mg TDS caused fluid overload and severe hyponatremia, while hypoglycemia persisted at lower doses, necessitating discontinuation. Subcutaneous octreotide 100 mg QID was required to control hypoglycemia. Prednisolone 30 mg BD improved glycemic stability. Insulin autoantibodies titer remained 175 AU/mL at 2 weeks; reassessment was conducted at 4 weeks with consideration for biologics if persistent. : doses, necessitating discontinuation. Subcutaneous octreotide 100 mg QID was required to control hypoglycemia. Prednisolone 30 mg BD improved glycemic stability. Insulin autoantibodies titer remained 175 AU/mL at 2 weeks; reassessment was conducted at 4 weeks with consideration for biologics if persistent. Conclusion Endogenous hyperinsulinemic hypoglycemia, after excluding insulinoma, should raise suspicion for IAS. Management includes removing triggers, supportive care, and immunomodulatory therapy in severe cases.

Introduction: Vitamin D-dependent rickets type 2 (VDDR2) is traditionally defined by biallelic vitamin D receptor (VDR) mutations causing resistance to 1,25(OH)₂D. We describe a case of the classical VDDR2 phenotype with a single VDR mutation and an interesting physiological adaptation. Case: A female diagnosed with rickets at age three presented with a femoral fracture, severe short stature, hypocalcemia (2.1 mmol/L; NR 2.35–2.70), hypophosphatemia (0.8 mmol/L; NR 1.5–2.10), and evidence of renal phosphate wasting (TMP/GFR 0.5 mmol/L; NR 1.5–2.4). Biochemistry showed markedly elevated alkaline phosphatase (1,227 IU/L; NR 50–136) and secondary hyperparathyroidism (20.7 pmol/L; NR 0.8–7.8). Despite hypocalcemia, 1,25(OH)₂D was significantly elevated (>450 pmol/L; NR 60–150), consistent with VDDR2. There was no initial family history; however, subsequent evaluation of her mother—prompted by the patient’s diagnosis—revealed a similar biochemical profile, along with short stature (142 cm) and a history of multiple fractures. Genetic analysis in both individuals identified a heterozygous missense mutation in exon 10 of the VDR gene, affecting the ligand-binding domain, supporting a pattern of dominant inheritance. The patient was treated with cholecalciferol (1,200 IU daily), calcitriol (5–6 µg daily), and calcium carbonate (2,000 mg daily). Although biochemical responsiveness to therapy was evident, poor adherence resulted in suboptimal metabolic control throughout childhood and adolescence, including a second fracture at age 15 and a final adult height of 124 cm. Notably, calcium and phosphate levels progressively normalized after puberty, with sustained biochemical stability despite the patient omitting the treatment. Conclusion This case provides two important insights. First, it represents the fourth reported case worldwide demonstrating a dominant-negative effect of a VDR gene mutation, whereby a single mutant receptor interferes with wildtype VDR function. Second, it highlights postpubertal calcium adaptation, in which vitamin D–independent intestinal absorption may restore mineral homeostasis, and disease severity can attenuate over time through adaptive physiological mechanisms.
Calcium ; Mutation ; Vitamin D ; Rickets

Introduction: Primary hyperparathyroidism (PHPT) is a common disorder that typically leads to increased bone turnover and reduced bone mineral density (BMD). Osteopetrosis, in contrast, is a rare, inherited disorder of defective osteoclast function, resulting in diffusely sclerotic but structurally fragile bones. The coexistence of both conditions is rare and can significantly alter the expected skeletal phenotype of PHPT. Case: We report a 77-year-old female with a previous history of resected ovarian carcinoma in remission, chronic iron deficiency anemia, and hypothyroidism. During a hospital admission for a lacunar infarct, an incidental finding of sclerotic skull lesions on computed tomography (CT) brain prompted further investigation. She had no history of fractures, hearing impairment, or family history of parathyroid or bone disorders. Biochemistry revealed parathyroid-dependent hypercalcemia with normal renal function. Bone turnover markers showed a normal resorption marker (BCTx) but an elevated formation marker (P1NP), with a mildly raised alkaline phosphatase. A sestamibi scan localized a probable left upper parathyroid adenoma, despite a negative neck ultrasound. Skeletal survey unexpectedly revealed widespread osteosclerosis of the skull, spine, and long bones, with a markedly elevated BMD on densitometry. Review of prior imaging confirmed that these sclerotic changes predated her current presentation, having been present on CTs from over a decade ago. Recurrent malignancy was excluded with repeat imaging and tumor markers. A diagnosis of PHPT secondary to parathyroid adenoma, coexisting with underlying, previously unrecognized osteopetrosis, was made. The patient declined both recommended parathyroidectomy and genetic studies. Conclusion This case demonstrates a rare coexistence of two pathologies with opposing effects on bone metabolism. The underlying osteopetrosis, characterized by defective osteoclasts, likely rendered the patient’s osteoclasts resistant to the catabolic effects of elevated PTH. This resulted in an atypically normal bone resorption marker and an unexpectedly high BMD, despite the diagnosis of PHPT.
Bone Density' ; Hyperparathyroidism ; Primary Osteopetrosis

Introduction: Gender-affirming hormone therapy (GAHT) for transgender women utilizes estrogen and an anti-androgen like cyproterone acetate (CPA) which can both lead to hyperprolactinemia. Although mild prolactin elevations are common, the development of prolactinomas in transgender women on GAHT is rare. Case: A 23-year-old trans-woman on self-purchased estradiol hemihydrate (17β-estradiol) 4 mg and CPA 12.5 mg daily for GAHT presented with galactorrhea. Investigations revealed markedly elevated prolactin at 2,369 mIU/L and elevated estradiol at 848 pmol/L. A pituitary magnetic resonance imaging (MRI) identified a 0.4 × 0.5 cm microprolactinoma. She declined clinical advice to reduce her medication dose and continued on the same treatment. In the subsequent year, her peak prolactin was 1,383 mIU/L, and a repeat MRI showed the microprolactinoma remained stable. She continues to be on close clinical monitoring. Transgender females experience approximately a fourfold higher rate of developing prolactinomas. The patient’s choice to persist with GAHT reflects the challenges in managing gender dysphoria alongside medical complications. A recent paper by BJ Nolan et al. suggests using prolactin levels exceeding 2,000–3,000 mIU/L to guide further investigations including a pituitary MRI to rule out a prolactinoma. In most cases, the serum prolactin levels will return to the normal range with a reduction or discontinuation of the GAHT. Normalization of prolactin levels have been reported after gonadectomy and CPA cessation in transgender females on GAHT, which suggests that CPA usage may be associated with higher risk of hyperprolactinemia compared to estrogen therapy. Conclusion This case highlights that GAHT can lead to development of prolactinomas. Prolactin monitoring and MRI investigations should be reserved for symptomatic patients, and for those with significantly elevated or increasing prolactin levels. While treatment using dopamine agonists have been reported, this case demonstrates that conservative management and close monitoring can be a viable approach for structurally stable microprolactinomas.
Female ; Prolactinoma ; Transgender Persons

Introduction: Empty sella (ES) is characterized by herniation of the subarachnoid space into the sella turcica, leading to pituitary flattening. Although often considered incidental, ES is increasingly recognized as a radiological marker of idiopathic intracranial hypertension (IIH) which classically presents with headache and visual loss. Importantly, IIH may also present with otolaryngological manifestations such as pulsatile tinnitus, hearing loss, and vertigo. Audiovestibular symptoms have been reported in up to 88.9% of patients with primary ES, with sensorineural hearing loss being the most frequent, while pulsatile tinnitus occurs in approximately 58% of IIH cases. Case: A 51-year-old female presented with 3 months of progressively worsening headaches, rapid deterioration of left-sided hearing, and a 20-kg weight gain over 1 year. Audiometry confirmed moderate left sensorineural hearing loss. Examination revealed a normotensive female with a body mass index of 35 kg/m² and diplopia on left upward gaze without evidence of ophthalmoplegia. The rest of the neurological examination was unremarkable. There was no evidence of papilledema or Cushingoid features. Repeat magnetic resonance imaging brain in 2025 showed persistent partial ES and loss of the posterior pituitary bright spot without an intracranial mass lesion or venous sinus thrombosis. There was no biochemical evidence of hypopituitarism or Cushing’s syndrome. Autoimmune markers were unremarkable. Lumbar puncture demonstrated a mildly elevated opening pressure of 23 mmHg with normal CSF composition. Based on the clinical and radiological findings, early IIH was diagnosed. She was treated with acetazolamide, and prescribed tirzepatide for weight reduction, resulting in improvement in headache and tinnitus. Conclusion IIH can manifest with partial ES and audiovestibular symptoms related to raised intracranial pressure. Early recognition is important, and IIH should be suspected in patients with pulsatile tinnitus or progressive sensorineural hearing loss. Acetazolamide and weight management remain the mainstay of treatment, with emerging evidence supporting a potential role for glucagon-like peptide-1 receptor agonists in reducing intracranial pressure.
Pseudotumor Cerebri ; Tinnitus ; Hearing Loss

Introduction: Hurthle cell adenoma is a rare benign thyroid neoplasm that can only be diagnosed through histopathological examination. Hurthle cell neoplasm typically presents as nonfunctioning cold nodule on thyroid scintigraphy. We report a rare case of Hurthle cell adenoma presenting with thyroid storm, with unusual findings of “cold” within “hot” thyroid nodule on scintigraphy. Case: A 73-year-old male with hypertension, chronic kidney disease, coronary artery disease, and Parkinson’s disease presented to the emergency department with fever and diarrhea. His temperature was 38.4°C, heart rate 106 bpm, and blood pressure 138/75 mmHg, with atrial fibrillation and signs of heart failure. The Burch-Wartofsky score was 50, consistent with thyroid storm. Laboratory tests revealed free thyroxine 4 37.8 pmol/L (NR 11.5–22.7), free thyroxine 3 5.6 pmol/L (NR 3.5–6.5), and thyroid-stimulating hormone <0.01 mIU/L (NR 0.55– 4.78). Thyroid autoantibodies, including anti-thyroid peroxidase, anti-thyroglobulin, and thyroid-stimulating immunoglobulins, were negative (<0.10 IU/L). The thyroid storm was precipitated by invasive Klebsiella syndrome with endophthalmitis and lung and liver abscess. He was treated with Lugol’s iodine, corticosteroid, antibiotics, and carbimazole. Ultrasound thyroid revealed a mixed cystic-solid nodule in the left thyroid lobe, measuring 2.3 × 3.3 × 4.3 cm (TIRADS category 3). Technetium-99m thyroid scintigraphy demonstrated a hyperfunctioning left thyroid nodule with a focal intranodular cold spot measuring 5.0 × 3.7 cm. Fine needle aspiration cytology of the nodule was benign follicular cells. Following stabilization with anti-thyroid treatment, he underwent left hemithyroidectomy. Histopathology examination revealed a Hurthle cell adenoma without capsular or vascular invasion. Postoperatively, he remained clinically euthyroid. Surveillance ultrasound performed 8 months later showed a normal right thyroid lobe, and lifelong surveillance was planned. Conclusion This case illustrates a rare and unusual presentation of thyroid storm caused by a toxic Hurthle cell adenoma containing an intranodular cold spot on scintigraphy. To our knowledge, only one similar case has been reported in the literature, and our case is the first to present with thyroid storm.
Oxyphil Cells ; Thyroid Crisis ; Adenoma

Introduction: Thyroid hormone resistance syndrome (THR) is a disorder characterized by reduced responsiveness of target tissues to thyroid hormones with non-suppressed thyroidstimulating hormone (TSH) despite elevated free thyroxine 4 (FT4). Diagnosing and managing THR in athyreotic patients, however, is challenging; indeed, TSH levels post thyroidectomy for Differentiated Thyroid Carcinoma in patients with THR have been reported to reach levels as high as 112.59 mIU/L despite high-dose thyroxine-suppressive therapy. This case highlights the complexities in diagnosing Resistance to Thyroid Hormone (RTH) post-thyroidectomy. Case: A 63-year-old female with end-stage renal failure (ESRF) on hemodialysis and prior parathyroidectomy for tertiary hyperparathyroidism underwent total thyroidectomy in 1997 for presumed benign goiter. Following surgery, she demonstrated persistently elevated TSH, ranging from 93.2 to 670.4 mIU/L (0.55–4.78 mIU/L), with normal to mildly elevated FT4 levels, ranging from 17 to 35 pmol/L (11.5–22.7 pmol/L), while on thyroxine replacement doses as low as 0.86 ug/kg. Discordant thyroid function tests (TFTs) were consistent across different assay platforms. Polyethylene glycol precipitation excluded macro-TSH interference. Intermittent levothyroxine increments suppressed TSH but led to thyrotoxic symptoms, including weight loss, heat intolerance, insomnia, and fragility fracture. Uncontrasted pituitary magnetic resonance imaging (risk of nephrogenic systemic fibrosis with gadolinium in ESRF) showed a small pituitary gland without adenoma, excluding TSH-oma. T3 suppression test was relatively contraindicated due to her advanced age and co-morbidities. There was no family history of thyroid disorder; the patient’s only child had a normal TFT, and her parents/siblings could not be tested. A working diagnosis of RTHβ was made. She declined genetic testing for RTH. She is currently on levothyroxine 50 mcg OD (1.07 ug/kg) with FT4 16.1 pmol/L and TSH 562 mIU/L with no symptoms/signs of hypo or hyperthyroidism. Conclusion This case highlights the diagnostic challenges in managing possible RTHβ post-total thyroidectomy. Treatment should be guided by clinical status and target of mid-to-normal FT4 rather than TSH to avoid iatrogenic thyrotoxicosis.
Thyroidectomy ; Thyroid Hormones

Introduction: Long-term antithyroid drug (LT-ATD) has emerged as a feasible treatment strategy for patients who decline radioactive iodine (RAI) or thyroidectomy for relapsed or refractory Graves’ disease (GD). Benefits include faster achievement of euthyroidism, lower risk of hypothyroidism, a more favorable cardiovascular profile, and avoidance of surgical risks. Although fluctuations in thyroid status may occur despite good compliance, thyroid storm is exceedingly rare in patients on LT-ATD. While there is no specific data on the incidence of thyroid storm in this cohort, surveys suggest an overall low incidence (0.2–0.76 cases per 100,000 annually). We report a patient with stable GD who developed a thyroid storm despite more than 10 years of LT-ATD. Case: A 40-year-old female was diagnosed with GD 11 years earlier during pregnancy. Treatment was stopped at 25 weeks’ gestation, but she relapsed at 7 months postpartum and was started on carbimazole. She declined RAI or surgery following a relapse and remained on carbimazole 5–10 mg daily, with good compliance. She presented with a 1-day history of fever, cough, rhinorrhea, diarrhea, and palpitations. She was compliant with carbimazole 5 mg daily. On presentation, BP was 132/70 mmHg, HR 140 bpm, temperature 38.5°C, and SpO2 98% on air. She was alert without agitation, had a diffuse goiter, mild proptosis, and conjunctival injection, with otherwise normal findings. Electrocardiogram showed sinus tachycardia. Laboratory investigations demonstrated mild transaminitis, leukocytosis, markedly elevated free T4 (>154 pmol/L), suppressed thyroid-stimulating hormone (<0.008 mIU/L), and elevated thyroid-stimulating immunoglobulin (2.25 IU/L, reference <0.55). Thyroid function tests 1 month ago was normal. Her Burch-Wartofsky score was 60, consistent with thyroid storm, likely precipitated by upper respiratory tract infection. She improved with treatment and was discharged with carbimazole 30 mg daily with planned tapering, subsequently agreeing to RAI as definitive treatment. Conclusion Infection may trigger thyroid storm despite good compliance with LT-ATD. Patients should be counselled regarding this risk and advised to seek early medical attention if thyrotoxic symptoms recur.
Antithyroid Agents ; Thyroid Crisis

Introduction: Macro-thyroid-stimulating hormone (macro-TSH) is a rare complex formed by monomeric TSH with anti-TSH autoantibodies. Macromolecules of TSH are not renally excreted due to its large size, leading to elevated TSH measurements without clinical consequences. This rare condition frequently mimics subclinical hypothyroidism, often leading to misdiagnosis and inappropriate levothyroxine therapy. Case: A 17-year-old female with major depressive disorder was biochemically diagnosed with subclinical hypothyroidism (TSH 39.06 mIU/L, free thyroxine 4 12.9 pmol/L, antithyroid peroxidase negative) and commenced on levothyroxine. Over 5 years, her TSH levels heavily fluctuated (0.48–82.59 mIU/L) and remained persistently elevated with high-normal free T4 levels despite treatment adherence. An endocrinology consult was obtained, and clinical evaluation revealed a clinically asymptomatic and euthyroid patient, with no family history of thyroid disease or supplement use, and there was no goiter. Assay interference was excluded by analyzing her thyroid function tests on a different platform, which yielded similar biochemical results. Subsequently, a polyethylene glycol (PEG) precipitation test was performed. Her pre-PEG TSH of 29.24 mIU/L decreased significantly to 2.78 mIU/L post-PEG. This yielded a remarkably low TSH recovery rate of 9.5%, strongly indicating the presence of macroTSH. Levothyroxine was then stopped, and she remained clinically euthyroid. Conclusion While gel filtration chromatography remains the gold standard for diagnosing this condition, PEG precipitation is a more accessible, cost-effective, and reliable screening method in clinical practice. A TSH recovery rate below 20% is considered highly suggestive of macro-TSH. Clinicians should maintain a high index of suspicion for macro-TSH in asymptomatic patients presenting with isolated TSH elevations that do not respond to thyroxine therapy. Prompt recognition prevents misdiagnosis and avoids the potential risks of unnecessary thyroid hormone replacement.
Hypothyroidism ; Thyrotropin