Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings.

SUMMARY: Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. LEARNING POINTS: IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.

A rare coexistence of Behcet's disease and Graves' thyrotoxicosis in a young man: a case report.

Behcet's disease is a recurrent systemic vasculitic disorder. It manifests most commonly in the form of skin lesions, oral and genital ulcers and uveitis. Graves' thyrotoxicosis is an autoimmune disorder characterized by excessive production of thyroid hormones. We present a case of a 41-year-old male of Turkish descent who had symptoms of arthralgia, rash, palpitations and weight loss. Bloods tests showed raised inflammatory markers and biochemical evidence of severe autoimmune thyrotoxicosis. The patient was HLA-B51-negative, and pathergy test was inconclusive. A diagnosis of Behcet's disease was made on constellation of clinical symptoms. The patient was treated with carbimazole and prednisolone followed by azathioprine. The coexistence of Behcet's disease and Graves' disease in the same patient is very rare. Further studies are required to determine if there is a pathological association between these two conditions.

Leucine-rich glioma-inactivated protein 1 (LGI-1) mediated limbic encephalitis associated with syndrome of inappropriate antidiuretic hormone secretion: a case report.

Autoantibodies to leucine-rich glioma-inactivated protein 1 (LGI-1) are associated with inflammation of the limbic system. Faciobrachial dystonic seizures are pathognomonic for LGI1-antibiodies and their treatment with immunotherapy is effective in seizure control with a potential to prevent cognitive decline. We report a 57-year-old man who presented to the emergency department with recurrent seizures, visual hallucinations and severe memory impairment over a seven-week period; he reported a background of alcohol excess. Initial investigations revealed hyponatremia, indicating syndrome of inappropriate anti-diuretic hormone secretion. Magnetic resonance imaging of the brain revealed bilateral asymmetrical high-T2 and low-T1 signal in the medial temporal lobes. Serum immunofluorescence assay tested positive for LGI-1 antibody. Patient responded to treatment with levetiracetam, intravenous methylprednisolone and five plasma exchange sessions. Patient remains on a maintenance dose of prednisolone and azathioprine. It is imperative that clinicians recognize signs of autoimmune encephalitis in order to curb long-term sequelae and improve clinical outcomes.

A novel CASR variant in a family with familial hypocalciuric hypercalcaemia and primary hyperparathyroidism.

SUMMARY: Familial hypocalciuric hypercalcaemia (FHH) is a dominantly inherited, lifelong benign disorder characterised by asymptomatic hypercalcaemia, relative hypocalciuria and variable parathyroid hormone levels. It is caused by loss-of-function pathogenic variants in the calcium-sensing receptor (CASR) gene. Primary hyperparathyroidism (PHPT) is characterised by variable hypercalcaemia in the context of non-suppressed parathyroid hormone levels. Unlike patients with FHH, patients with severe hypercalcaemia due to PHPT are usually symptomatic and are at risk of end-organ damage affecting the kidneys, bone, heart, gastrointestinal system and CNS. Surgical resection of the offending parathyroid gland(s) is the treatment of choice for PHPT, while dietary adjustment and reassurance is the mainstay of management for patients with FHH. The occurrence of both FHH and primary hyperparathyroidism (PHPT) in the same patient has been described. We report an interesting case of FHH due to a novel CASR variant confirmed in a mother and her two daughters and the possible coexistence of FHH and PHPT in the mother, highlighting the challenges involved in diagnosis and management. LEARNING POINTS: Familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (PHPT) can coexist in the same patient. Urinary calcium creatinine clearance ratio can play a role in distinguishing between PHPT and FHH. Genetic testing should be considered in managing patients with PHPT and FHH where the benefit may extend to the wider family. Family segregation studies can play an important role in the reclassification of variants of uncertain significance. Parathyroidectomy has no benefit in patients with FHH and therefore, it is important to exclude FHH prior to considering surgery. For patients with coexisting FHH and PHPT, parathyroidectomy will reduce the risk of complications from the severe hypercalcaemia associated with PHPT.

Undifferentiated Pleomorphic Sarcoma of the Hand with Lung Metastases.

Undifferentiated pleomorphic sarcoma (UPS) is a rare tumor of mesenchymal origin affecting the hand in less than 3% of cases. A 92-year-old male reported an enlarging, painless mass on his left hand of three months duration. Examination of the hand revealed a soft, non-tender, immobile mass over the wrist joint, just proximal to his thumb. Immunohistochemistry findings on ultrasound-guided biopsy were consistent with UPS. Further intractable pain, ulceration, and bleeding necessitated urgent radiotherapy, which provided no relief. This was followed by amputation above the elbow. Seven months later, the patient presented with confusion. A chest X-ray revealed extensive bilateral pulmonary metastases. In light of this result, the patient was referred to the palliative care team. UPS carries a poor prognosis, with a high risk of metastases. Early diagnosis and treatment is required for optimal clinical outcomes. Through this case, we highlight the need for a more effective treatment strategy to improve clinical outcomes.

Symptomatic hypophosphataemia after intravenous iron therapy: an underrated adverse reaction

Summary: Iron (ferric carboxymaltose) infusion therapy is used to treat severe iron deficiency which is not responding to the first-line oral iron therapy. However, it can also cause severe renal wasting of phosphate resulting in severe hypophosphataemia in some patients. Despite the growing number of case reports, this side effect is not well known to healthcare professionals. The product labelling information sheet does mention that hypophosphataemia can be a side effect, but also says that this side effect is usually transient and asymptomatic. We report a challenging case of a patient who developed severe, symptomatic and prolonged hypophosphataemia after an intravenous iron infusion for severe iron deficiency. Learning Points: Clinicians prescribing ferric carboxymaltose (Ferinject®) should be aware of the common side effect of hypophosphataemia, which could be mild, moderate or severe. Patients receiving iron infusion should be educated concerning this potential side effect. Pre-existing vitamin D deficiency, low calcium levels, low phosphate levels or raised parathyroid hormone levels may be risk factors, and these should be evaluated and corrected before administering intravenous iron. Patients may require phosphate and vitamin D replacement along with monitoring for a long period after iron infusion-induced hypophosphataemia. Every incident should be reported to the designated body so that the true prevalence and management thereof can be ascertained.

Difficult-to-treat Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with Secondary Central Nervous System Lymphoma.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is defined as hyponatremia with inappropriately concentrated urine in a euvolemic patient. SIADH is associated with a wide spectrum of clinical conditions. In the hospital, hyponatremia carries significant mortality with a prolonged duration of inpatient stay. It is imperative that the underlying cause is appropriately investigated and such patients are closely monitored. This article presents a case of difficult-to-treat hyponatremia secondary to SIADH in a patient with a rare isolated central nervous system (CNS) relapse from a non-Hodgkin's lymphoma (NHL). A relapse, particularly affecting the CNS, carries a poor prognosis. The patient was started on dexamethasone and offered treatment with methotrexate but declined. The hyponatremia failed to respond to fluid restriction and demeclocycline. The hyponatremia responded to a single dose of tolvaptan. Clinicians should have a low index of suspicion for a relapse of lymphoma as a cause of difficult to treat hyponatremia in any patient who has previously had remission from lymphoma treatment.