Summary

Primary hyperparathyroidism (PHP) is the most common aetiology for hypercalcaemia. The incidence of PHP in pregnant women is reported to be 8/100 000 population/year. It presents a threat to the health of both mother (hyperemesis, nephrolithiasis) and fetus (fetal death, congenital malformations, and neonatal severe hypocalcaemia-induced tetany). However, there is a lack of clear guidance on the management of primary hyperparathyroidism in pregnancy. In this study, we describe the case of a 26-year-old female patient who presented with severe hypercalcaemia secondary to PHP and underwent successful parathyroid adenectomy under local anaesthesia.

Learning points

• Primary hyperparathyroidism is a rare complication in pregnancy, but the consequences for mother and fetus can be severe.

• A perceived risk of general anaesthesia to the fetus in the first trimester has resulted in a general consensus to delay parathyroid surgery to the second trimester when possible – although the increased risk of fetal loss may occur before planned surgery.

• If the patient presents with severe or symptomatic hypercalcaemia, minimally invasive surgery under local anaesthetic should be considered regardless of the gestational age of the pregnancy.

Summary

Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency due to T-box transcription factor-19 (TBX19 mutation) (MIM 201400; ORPHA 199296) usually presents in the neonatal period with severe hypoglycemia, seizures, and sometimes prolonged cholestatic jaundice. We report a case with an unusual presentation that delayed the diagnosis. A 9-month-old female patient with no relevant personal history was admitted to the emergency department due to a hypoglycemic seizure in the context of acute gastroenteritis. There was rapid recovery after glucose administration. At age 4, she presented with tonic-clonic seizures, fever, and gastrointestinal symptoms and came to need support in an intensive care unit. Low serum cortisol was documented and hydrocortisone was initiated. After normalization of inflammatory parameters, the patient was discharged with hydrocortisone. The genetic investigation was requested and compound heterozygous mutations in TBX19 were detected. This is a rare case of presentation of TBX19 mutation outside the neonatal period and in the setting of acute disease, which presented a diagnostic challenge.

Learning points

• Congenital isolated adrenocorticotrophic hormone deficiency due to TBX19 mutation usually presents with neonatal hypoglycemia and prolonged cholestatic jaundice.

• An uneventful neonatal period, however, does not exclude the diagnosis as the disease may be asymptomatic at this stage.

• In the context of idiopathic hypoglycemia, even in the context of acute disease, hypocortisolism must always be excluded.

• Genetic evaluation should be performed in cases of congenital central hypocortisolism to allow proper counselling.

Summary

Subacute thyroiditis is an inflammatory disorder of the thyroid gland that has previously been described following viral illnesses and occasionally post vaccination such as influenza vaccine. 2021 was a revolutionary year for the development of SARS-CoV-2 vaccinations with multiple different vaccines now available. There are increasing numbers of case reports of thyroiditis following these vaccinations. We report a case of a 50-year-old female who developed subacute thyroiditis 6 days post ChAdOx1 nCoV-19 vaccine (AZD1222 produced by AstraZeneca Vaxzevria). The initial thyrotoxic phase was followed by overt hypothyroidism. This resolved spontaneously within 5 months without levothyroxine replacement. We hope that our case will add to the growing literature of cases of thyroiditis occurring after multiple different types of SARS-CoV-2 vaccination and create awareness of this rare but treatable adverse effect. We also review the literature on the proposed mechanisms behind this adverse effect.

Learning points

• Subacute thyroiditis is an inflammatory disorder of the thyroid gland that can occur after a viral illness or vaccination against certain infections.

• Subacute thyroiditis is a rare adverse effect that has been reported to occur after different types of SARS-CoV-2 vaccinations.

• Subacute thyroiditis post vaccination is relatively straightforward to manage, with some patients requiring non-steroidal anti-inflammatory drugs and beta-blockers, while more severe cases may require corticosteroid therapy. This adverse effect should not dissuade vaccination use at a population level.

• There are many postulated mechanisms for the development of subacute thyroiditis following vaccination including the presence of the ACE-2 receptor for SARS-CoV-2 on the thyroid gland, an inflammatory/immune response as is seen in COVID-19 infection itself and molecular mimicry between SARS-CoV-2 spike protein and healthy thyroid antigen.

Summary

Necrobiosis lipoidica (NL) is a rare and chronic disease characterised by yellow-brown, atrophic, telangiectatic plaques usually located on the lower extremities, with pathological features of collagen necrobiosis and dermal inflammation. Most cases are seen in those with diabetes mellitus, particularly type 1 diabetes (T1DM), and many without diabetes have evidence of abnormal glucose tolerance or family history of autoimmune disease. In this study, we describe four patients with NL and T1DM. A common theme is late identification and delay in diagnosis. Hence, we discuss the clinical features, need for clinicopathological correlation, and the management and prognostic implications for this distinctive entity. While most remain relatively asymptomatic, others progress to debilitating disease with pruritus, dysesthesia, and pain. Pain is often intense in the presence of ulcerated plaques, a morbid complication of NL. Diagnosis requires the integration of both clinical and histopathological findings. NL has proven a challenging condition to treat, and despite the numerous therapeutic modalities available, there is no standard of care. Hence, in this study, we provide an overview of current management strategies available for NL.

Learning points

• Necrobiosis lipoidica (NL) is classically seen in patients with type 1 diabetes.

• Koebner phenomenon, defined as the appearance of new skin lesions on previously unaffected skin secondary to trauma, is a well-recognised feature in NL.

• Background skin phototype contributes to variable yellow appearance of lesions in NL.

• Diagnosis of NL requires careful clinicopathological correlation.

• NL is a chronic disease often refractory to treatment leading to significant morbidity for the patient and a management conundrum for the multidisciplinary healthcare team.

• No standard therapeutic regimen has been established for the management of NL.

Summary

Complicated Rathke’s cleft cyst (RCC) is a rare occurrence of symptomatic bleeding or growth of a previously asymptomatic (and often undiagnosed) intrasellar cyst derived from remnants of Rathke’s pouch, situated on the midline between the adeno- and neurohypophysis. Symptoms may be identical to those of pituitary apoplexy: acute onset of headache, hypopituitarism, and neurological disturbances. Both syndromes may also exhibit a similar appearance of a large haemorrhagic sellar mass at initial radiological evaluation. We report on two patients who presented with headache and complete hypopituitarism. Based on the initial MRI, they were first diagnosed with pituitary apoplexy but managed conservatively with hormone therapy alone because of the absence of severe visual or neurological threat. Upon follow-up at 4 months, clinical evolution was good in both patients but their pituitary mass had not reduced in size and, after careful radiologic reviewing, was more indicative of a large midline complicated RCC. In conclusion, the diagnosis of complicated RCC is challenging because it can mimic pituitary apoplexy clinically, biologically, and radiologically. Clinicians should distinguish between the two entities using specific radiological signs or evolution of the mass at MRI if the patient does not undergo surgery. To our knowledge, we report conservative management of this rare condition for the first time, though it seems appropriate in the absence of neurological compromise or visual compression. Long-term follow-up is however mandatory.

Learning points

• Complicated Rathke’s cleft cyst can mimic pituitary apoplexy, presenting with sudden onset of headache, hypopituitarism, and visual and neurological compromise in the most severe cases.

• At diagnosis, pituitary MRI may not be able to differentiate between the two entities, showing a large haemorrhagic mass inside the sella, with little or no normal pituitary tissue visible. Patients are often diagnosed with apoplexy at this stage and may undergo pituitary surgery.

• When surgery has not been performed initially in these patients, repeat imaging at 3–6 months is unchanged and does not show the expected involution usually seen after adenoma apoplexy.

• Conservative management with hormonal replacement seems a valid option in the absence of visual or neurological deficits that would require trans-sphenoidal surgery.

Summary

Leptin is secreted by adipocytes in response to fat storage and binds to its receptor (LEPR), which is ubiquitously expressed throughout the body. Leptin regulates energy expenditure and is anorexigenic. In this study, we describe the clinical and hormonal findings of three siblings with a personal history of rapid weight gain during the first months of life. They had delayed puberty, high levels of FSH (15.6 ± 3.7 mUI/mL; reference: 1.5–12.4) and LH (12.3 ± 2.2 mUI/mL; reference: 1.7–8.6), normal oestradiol and total testosterone and successful fertility. None of the patients had dyslipidemia, diabetes or thyroid disease. Next-generation sequencing identified a pathogenic homozygous variant c.2357T>C, p.(Leu786Pro) in LEPR. Their parents and children were heterozygous for this mutation. We compared clinical and biochemical findings of homozygous carriers with first-degree heterozygous family members and ten randomly selected patients with adult-onset morbid obesity. Homozygous carriers of the mutation had significantly higher BMI (32.2 ± 1.7 kg/m² vs 44.5 ± 7.1 kg/m², P = 0.023) and increased serum levels of leptin (26.3 ± 9.3 ng/mL vs 80 ± 36.4 ng/mL, P = 0.028) than their heterozygous relatives. Compared with the ten patients with adult-onset morbid obesity, serum levels of leptin were not significantly higher in homozygous carriers (53.8 ± 24.1 ng/mL vs 80 ± 36.4 ng/mL, P = 0.149), and thus serum levels of leptin were not a useful discriminative marker of LEPR mutations. We described a rare three-generation family with monogenic obesity due to a mutation in LEPR. Patients with early onset obesity should be considered for genetic screening, as the identification of mutations may allow personalized treatment options (e.g. MC4R-agonists) and targeted successful weight loss.

Learning points

• The early diagnosis of monogenic forms of obesity can be of great interest since new treatments for these conditions are becoming available.

• Since BMI and leptin levels in patients with leptin receptor mutations are not significantly different from those found in randomly selected morbid obese patients, a careful medical history is mandatory to suspect this condition.

• Loss of leptin receptor function has been associated with infertility. However, our patients were able to conceive, emphasizing the need for genetic counselling in affected patients with this condition.

Summary

Vasoactive intestinal peptide-secreting tumours (VIPomas) are an extremely rare form of functional pancreatic neuroendocrine tumour with an estimated annual incidence of 1 in 10 million. Associated tumour hypersecretion of other peptides, including pancreatic polypeptide (PPomas), may also be seen. These malignancies classically present with a defined triad of refractory diarrhoea, hypokalaemia and metabolic acidosis known as Verner–Morrison syndrome. Diagnosis is frequently delayed, and the majority of patients will have metastatic disease at presentation. Symptoms are usually well controlled with somatostatin analogue administration. Here we report a case of metastatic mixed VIPoma/PPoma-induced diarrhoea causing renal failure so severe that ultrafiltration was required to recover adequate renal function.

Learning points

• Profuse, watery diarrhoea is a common presenting complaint with a multitude of aetiologies. This, combined with the rarity of these tumours, makes diagnosis difficult and frequently delayed. A functional neuroendocrine tumour should be suspected when diarrhoea is unusually extreme, prolonged and common causes have been promptly excluded.

• These patients are likely to be profoundly unwell on presentation. They are extremely hypovolaemic with dangerous electrolyte and metabolic abnormalities. Aggressive initial rehydration and electrolyte replacement are imperative. A somatostatin analogue should be commenced as soon as the diagnosis is suspected.

• This is an extreme example of Verner–Morrison syndrome. We are unaware of another case where renal failure secondary to diarrhoea and dehydration was so severe that renal replacement therapy was required to restore adequate renal function, further emphasising how critically unwell these patients can be.

• Both the primary tumour and metastases showed a remarkably good and rapid response to somatostatin analogue administration. Cystic change and involution were noted on repeat imaging within days.

• Prior to his illness, this patient was extremely high functioning with no medical history. His diagnosis was an enormous psychological shock, and the consideration and care for his psychological well-being were a crucial part of his overall management. It highlights the importance of a holistic approach to cancer care and the role of the clinical nurse specialist within the cancer multidisciplinary team.

Summary

Biallelic pathological variants in the thyroid stimulating hormone (TSH) subunit β gene (TSHB) result in isolated TSH deficiency and secondary hypothyroidism, a rare form of central congenital hypothyroidism (CCH), with an estimated incidence of 1 in 65 000 births. It is characterised by low levels of free thyroxine and inappropriately low serum TSH and may therefore be missed on routine neonatal screening for hypothyroidism, which relies on elevated TSH. We describe a patient with CCH who developed recurrence of pituitary hyperplasia and symptomatic hypothyroidism due to poor compliance with thyroxine replacement. She was diagnosed with CCH as a neonate and had previously required trans-sphenoidal hypophysectomy surgery for pituitary hyperplasia associated with threatened chiasmal compression at 17 years of age due to variable adherence to thyroxine replacement. Genetic testing of TSHB identified compound heterozygosity with novel variant c.217A>C, p.(Thr73Pro), and a previously reported variant c.373delT, p.(Cys125Valfs*10). Continued variable adherence to treatment as an adult resulted in recurrence of significant pituitary hyperplasia, which subsequently resolved with improved compliance without the need for additional medications or repeat surgery. This case describes a novel TSHB variant associated with CCH and demonstrates the importance of consistent compliance with thyroxine replacement to treat hypothyroidism and prevent pituitary hyperplasia in central hypothyroidism.

Learning points

• Pathogenic variants in the TSH subunit β gene (TSHB) are rare causes of central congenital hypothyroidism (CCH).

• c.217A>C, p.(Thr73Pro), is a novel TSHB variant, presented in association with CCH in this case report.

• Thyroxine replacement is critical to prevent clinical hypothyroidism and pituitary hyperplasia.

• Pituitary hyperplasia can recur post-surgery if adherence to thyroxine replacement is not maintained.

• Pituitary hyperplasia can dramatically reverse if compliance with thyroxine replacement is improved to maintain free thyroxine (FT4) levels in the middle-to-upper normal range, without the need for additional medications or surgeries.

Summary

The coexistence of neurofibromatosis type 1 (NFT1) and Turner syndrome (TS) has only been reported in a few patients and may represent a diagnostic challenge. We describe the case of a 16-year-old girl, with a prior clinical diagnosis of NFT1, who was referred to Endocrinology appointments for the etiological study of primary amenorrhea. Evaluation of the anterior pituitary function was requested and hypergonadotropic hypogonadism was detected. During the etiological study, a 45X karyotype was found and TS was diagnosed. The fact that NFT1 can also be associated with short stature, short broad neck and hypertelorism was likely responsible for TS being diagnosed in late adolescence. As both TS and NFT1 are relatively common genetic disorders, it is important to be alert to the possibility that the presence of one disease does not invalidate the other.

Learning points

• The concomitant presence of two syndromes in the same patient is unlikely and represents a diagnostic challenge.

• Some phenotypic characteristics and clinical manifestations may be shared by several syndromes.

• Some syndromes, such as neurofibromatosis type 1 may have very heterogeneous presentations.

• It is important to be alert to the characteristics that are not explained by the initial diagnosis.

• If such features are present, diagnostic work-up must be performed regardless of the initial syndromic diagnosis.

Summary

Central diabetes insipidus (CDI) is a rare manifestation of acute myeloid leukemia (AML) with unclear etiology. When present, CDI in AML has most often been described in patients with chromosome 3 or 7 aberrations and no abnormalities on brain imaging. In this case, we present a woman with newly diagnosed AML t(12;14)(p12;q13) found to have diabetes insipidus (DI) with partial anterior pituitary dysfunction and abnormal brain imaging. While in hospital, the patient developed an elevated serum sodium of 151 mmol/L with a serum osmolality of 323 mmol/kg and urine osmolality of 154 mmol/kg. On history, she reported polyuria and polydipsia for 5 months preceding hospitalization. Based on her clinical symptoms and biochemistry, she was diagnosed with DI and treated using intravenous desmopressin with good effect; sodium improved to 144 mmol/L with a serum osmolality of 302 mmol/kg and urine osmolality of 501 mmol/kg. An MRI of the brain done for the assessment of neurologic involvement revealed symmetric high-T2 signal within the hypothalamus extending into the mamillary bodies bilaterally, a partially empty sella, and loss of the pituitary bright spot. A pituitary panel was completed which suggested partial anterior pituitary dysfunction. The patient’s robust improvement with low-dose desmopressin therapy along with her imaging findings indicated a central rather than nephrogenic cause for her DI. Given the time course of her presentation with respect to her AML diagnosis, MRI findings, and investigations excluding other causes, her CDI and partial anterior pituitary dysfunction were suspected to be secondary to hypothalamic leukemic infiltration.

Learning points

• Leukemic infiltration of the pituitary gland is a rare cause of central diabetes insipidus (CDI) in patients with acute myeloid leukemia (AML).

• Patients with AML and CDI may compensate for polyuria and prevent hypernatremia with increased water intake.

• AML-associated CDI can require long-term desmopressin treatment, independent of AML response to treatment.