Summary

A 52-year-old female patient with breast cancer presented with a history of fatigue and malaise 1 year prior. She was diagnosed with isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) on endocrinological examination. Her pituitary gland showed normal morphology. Paraneoplastic IAD associated with breast cancer was suspected; however, immunofluorescence staining revealed no ectopic ACTH or proopiomelanocortin expression in the tumor tissue. Subsequently, the patient was diagnosed with idiopathic acquired IAD concurrent with breast cancer, ruling out paraneoplastic syndrome. Although malignancy should be considered a potential cause of IAD, not all patients with concurrent IAD and malignancy necessarily develop paraneoplastic syndrome.

Learning points

• Several adrenal insufficiency symptoms are similar to the nonspecific symptoms associated with malignancies, and therefore, the diagnosis of IAD remains challenging, especially in patients with cancer.

• When we encounter a case of IAD accompanied by a malignant tumor, it is important to suspect that paraneoplastic IAD, a novel clinical condition as secondary hypophysitis, may be the etiologic agent.

• Although malignant tumours should be considered a potential cause of IAD, not all patients with concurrent IAD and malignancy necessarily develop paraneoplastic autoimmune hypophysitis.

Summary

Multiple endocrine neoplasia type 1 (MEN1) requires a high level of suspicion, and late diagnosis can lead to dire outcomes. Genetic counselling is an important part of management, with a lack of evidence surrounding an optimal approach in Aboriginal Australian populations. Our case surrounds a remote-dwelling 48-year-old Aboriginal Australian female who was reviewed by an inpatient endocrine team in 2020 for persistent hypercalcaemia on a background of a parathyroidectomy in 2011 for primary hyperparathyroidism (PHPT), while she was admitted to a local hospital for acute chronic abdominal pain. Relevant medical history included multiple pulmonary embolisms/deep vein thrombosis, myocardial infarction, atrial fibrillation, chronic thromboembolic pulmonary hypertension, right heart failure, human T-lymphotropic virus 1, recurrent abdominal pain, and gastro-oesophageal reflux disorder. Gastroscopies from 2013 and 2015 demonstrated chronic gastritis with hundreds of gastric polyps. Subsequent laboratory studies, neuroendocrine tumour (NET) screening, and CT imaging demonstrated a recurrence of PHPT and a new diagnosis of Zollinger–Ellison syndrome. A 68-gallium-DOTATATE PET/CT was in keeping with metastatic NET. Pituitary studies were normal. Genetic testing confirmed a rare heterozygous variant of c.207dupC in exon 2 of the MEN1 gene. Treatment was symptom based due to terminal comorbidities. Genetic counselling was attempted; however, cultural and logistical barriers were identified and the family declined further testing. Unfortunately, she died in 2021 from multifactorial respiratory failure. This case highlights the need for better approaches to genetic counselling systems for remote Aboriginal Australians and emphasizes the importance of early recognition and the challenges faced in remote areas in making such rare diagnoses.

Learning points

• Remote healthcare systems often lack access to adequate specialist care, resulting in delayed diagnosis of rare conditions and leading to morbidity and mortality.

• Further research and work need to be done to provide culturally appropriate genetic counselling systems in remote Aboriginal Australians.

• A high index of suspicion is required to diagnose MEN1.

• Consider MEN1 in any patient diagnosed with primary hyperparathyroidism, with age <40, and/or with the presence of multiglandular disease or with the presence of Zollinger–Ellison syndrome.

• MEN1 may be under-recognized in Aboriginal Australians.

Summary

At the end of the 19th century, an 18-year-old lady gave birth to a well-proportioned, though very small, son. After delivery, the mother developed a full-grown beard, whereas the son always remained of small stature. The mother developed diabetes mellitus and died, aged 59, from a complicated severe cold. The son died at the age of 91 because of chronic kidney disease. The differential diagnosis in the son is isolated growth hormone deficiency. The mother might have suffered luteoma of pregnancy, polycystic ovary syndrome (PCOS), or Sertoli–Leydig cell tumor(s). The two cases are apparently coincidental/not related in pathophysiology.

Learning points

• Hirsutism occurring directly postpartum can have several causes.

• Patients with isolated growth hormone deficiency can live a long life without the substitution of growth hormone.

• Coincidence does not necessarily imply correlation.

• In the past, patients with endocrine disorders like severe hirsutism or small stature were employed at circuses and fairs to entertain the audience as curiosities.

Summary

The resistance to thyroid hormone syndrome (RTHβ) occurs uncommonly and requires a high level of clinical suspicion and specific investigations to reach a precise diagnosis and to avoid unnecessary and potentially harmful therapies. We report a case of a young male patient referred to our unit for SARS-CoV-2 infection and atrial fibrillation with elevated thyroid hormones and non-suppressed thyroid-stimulating hormone (TSH), for which antithyroid therapy was prescribed. A mood disorder was reported in the medical history. The family history was unknown as the patient was adopted. Thyroid-specific antibodies were undetectable, and thyroid ultrasound revealed a normal thyroid gland without nodules. After the resolution of SARS-CoV-2 infection, the diagnostic workup continued, and the pituitary MRI revealed a small area ascribable to a microadenoma. Due to atrial fibrillation, the execution of the T3 test was contraindicated. The octreotide long-acting release (LAR) test showed an initial reduction of free thyroid hormones levels at first administration, which was consistent with the presence of a TSH-secreting pituitary tumour, although an escape from the response was observed after the following two injections of octreotide LAR. Indeed, the genetic investigation revealed a variant in heterozygosity of the THRβ gene (Pro453Ser), thus leading to an RTHβ diagnosis, and, therefore, medical treatment with triiodothyroacetic acid was initiated. After 2 years from the SARS-CoV-2 infection, the patient continues the follow-up at our outpatient clinic, and no other medical interventions are needed.

Learning points

• RTHβ is a rare genetic syndrome characterised by discrepant thyroid function tests and by a dissociation between the observed hormone levels and the expected patient signs and symptoms.

• Features of thyroid hormone deficiency in TR-ß dependent tissues (pituitary gland, hypothalamus, liver and neurosensitive epithelia), as well as thyroid hormone excess in TR-α-dependent tissues (heart, bone, skeletal muscle and brain), may coexist in the same individual.

• Clinical pictures can be different even when the same variant occurs, suggesting that other genetic and/or epigenetic factors may play a role in determining the patient’s phenotype.

• Differentiating RTHβ from a TSH-secreting pituitary tumour is very difficult, especially when a concomitant pituitary adenoma is detected during diagnostic workup. The injection of long-acting somatostatin analogues can help differentiate the two conditions, but it is important to detect any interference in the dosage of thyroid hormones to avoid an incorrect diagnosis.

• Genetic testing is fundamental to prevent unnecessary and potentially harmful therapies.

• Medical treatment with triiodothyroacetic acid was demonstrated to be effective in reducing thyroid hormone excess and controlling symptoms.

Summary

Struma ovarii is an ovarian teratoma that comprises 2–5% of all ovarian teratomas. Malignant transformation of struma ovarii occurs in less than 5% of all cases, and metastatic disease is even rarer. We report two cases initially diagnosed with benign struma ovarii that presented malignant transformation, specifically highly differentiated follicular carcinoma of the ovary (HDFCO), some years after the first diagnosis. Case 1 concerns a 37-year-old female featuring HDFCO of the right ovary with multiple metastatic foci, who was diagnosed with benign struma ovarii 14 years ago. Case 2 concerns a 26-year-old female diagnosed with HDFCO of the left ovary. This patient was initially diagnosed with benign struma ovarii 6 years ago that recurred 4 years after the diagnosis. Both patients were treated with surgery, adjunctive total thyroidectomy, and radioactive iodine (¹³¹I) therapy.

Learning points

• Malignant transformation of struma ovarii is very rare (<5%).

• Diagnosis of HDFCO without extra ovarian dissemination is difficult due to the resemblance of its histological appearance with normal thyroid tissue.

• There is no consensus on the postoperative treatment of malignant struma ovarii (MSO). Clinical and histological features of MSO should be assessed for the postoperative treatment decisions.

• TSH suppression and thyroglobulin level measurements are necessary for patient follow-up.

Summary

Thyroid metastases from nonthyroidal malignancies (NTMs) represent a diagnostic challenge, often displaying heterogeneous clinical manifestations. These metastases are rare but significant, accounting for approximately 2% of thyroid malignancies. Distinguishing them from primary thyroid malignancies is challenging due to the lack of specific ultrasound features, and the ultrasound-based risk stratification systems offer limited utility in such cases. Fine needle aspiration cytology is crucial for definitive diagnosis, yet it may not always provide accurate results. In this case report, we describe a unique instance of thyroid metastases originating from renal cell carcinoma, emphasizing the complexities in diagnosis and the importance of considering oncological conditions when assessing thyroid masses. Awareness of thyroid metastasis from NTMs, particularly in cases of diffuse thyroid hypoechogenicity and hypothyroidism, is essential for clinicians in their diagnostic approach.

Learning points

• Thyroid metastases from nonthyroidal malignancies are diagnostic challenges due to their heterogeneous clinical presentations, often mimicking primary thyroid malignancies.

• Thyroid metastases from nonthyroidal malignancies are relatively rare, but they still account for approximately 2% of thyroid malignancies.

• It is fundamental to consider oncological conditions when assessing thyroid masses, especially in cases of diffuse thyroid hypoechogenicity, hypothyroidism, and history of other tumors.

• Thyroid presentation is quite similar to that of autoimmune hypothyroidism, endocrinologists must be aware of the possibility of thyroid hypofunction due to the massive invasion of the parenchyma.

Summary

Bardet–Biedl syndrome (BBS) is a rare, autosomal recessive, multisystem non-motile ciliopathy of progressive onset. It is primarily characterised by rod–cone dystrophy, early-onset obesity and related complications, postaxial polydactyly, renal and genitourinary abnormalities, learning disabilities, and hypogonadism. The diagnosis is based on Beales’ modified diagnostic criteria. We present a case of two monozygotic female twins, 17 years of age at presentation, referred for obesity since childhood. The initial hormonal work-up was negative and no dysmorphic features were noted. They were diagnosed with exogenous obesity. However, after ophthalmologic problems became apparent, rod–cone dystrophy was observed and genetic testing was performed. A mutation in the BBS2 gene led to the diagnosis of BBS, although the full diagnostic criteria were not met. This case not only highlights the need to raise awareness for BBS but also exposes two limitations of the current diagnostic standard. The first limitation is the low sensitivity of the clinical diagnostic model, due to the progressive onset and the high variability of the syndrome. The second limitation is the unclear role of genetic testing. As genetic testing becomes more widely available, genetic diagnosis preceding clinical diagnosis will become more common, leading to a diagnostic conundrum. We propose an update of the diagnostic model. A less strict application in the presence of confirmed genetic mutations should be applied, as this could facilitate earlier diagnosis and intervention. This is important because therapeutic agents are being developed that could have a significant impact on quality of life and prognosis.

Learning points

• Due to the low prevalence, the significant inter-and intrafamilial variation, and the slowly evolving phenotype, monogenic forms of obesity such as Bardet–Biedl syndrome are difficult to diagnose. Despite advances in the understanding of the presentation, pathophysiology and access to accurate genetic characterisation, a substantial number of diagnoses are still made by ophthalmology, as recognition of BBS in other departments of medicine, remains limited.

• Clinical diagnosis of BBS is based on Beales’ modified diagnostic criteria which require the presence of four primary features or three primary features plus two secondary features. This model has its limitations. Due to the progressive onset of clinical symptoms, patients generally do not meet the diagnostic criteria early in life, leading to a delay in diagnosis. In addition, the role of genetic testing remains controversial. However, as it becomes more widely available, genetic diagnosis may precede a full clinical diagnosis.

• BBS has an impact on the quality of life and prognosis of both the patient and the family. Obesity management strategies are an important part of the multidisciplinary approach, as there is no cure available. Setmelanotide has shown promising results in a phase 3 trial, but its effect in clinical practice remains unproven.

Summary

A 20-year-old South Asian male presented with polyuria, polydipsia, HbA1c 81 mmol/mol, BMI 28.8 and family history of both type 1 and type 2 diabetes mellitus. As autoantibody testing was negative and c-peptide level demonstrated significant endogenous insulin secretion, type 1 diabetes was excluded. Given his age and family history, the differential diagnosis included maturity-onset diabetes of the young (MODY), a rare form of diabetes caused by a single-gene variant. A high probability of MODY was calculated and he was subsequently referred for genetic testing. Although a useful tool, the pre-test probability calculator for MODY is only validated in White Europeans. A heterogenous variant of unknown clinical significance of the NEUROD1 gene was detected, leading to gliclazide use with poor response. The patient responded well to metformin. Type 2 diabetes was considered the most likely diagnosis. This case highlights the diagnostic challenges in young patients of Asian ethnicity and the importance of interpreting genetic results of unknown significance within the clinical context. Ethnicity-specific BMI thresholds should be used when classifying patients as overweight or obese.

Learning points

• Variants of unknown significance detected by genetic sequencing should be interpreted within the context of the patient’s other clinical parameters.

• It is important to use ethnicity-specific BMI thresholds for obesity.

• Diagnosis of type 2 diabetes mellitus at younger ages is becoming increasingly common.

• The pre-test probability calculator for MODY is only validated in White Europeans; although a useful guide, results should be interpreted with caution in patients of other ethnicities.

Summary

This case report describes a rare presentation of ectopic Cushing’s syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (⁶⁸Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A ¹⁸F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous.

Learning points

• Medullary thyroid carcinoma may secrete CRH and cause ectopic CS.

• Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test.

• Plasma CRH measurements can be useful in selected cases.

Summary

Autoimmune polyglandular syndrome (APS) type 2 is characterized by the presence of Addison’s disease (AD) along with autoimmune thyroid disease and/or type 1 diabetes. APS type 2 is known as Schmidt’s syndrome when autoimmune adrenal insufficiency is associated with chronic lymphocytic thyroiditis. We report a very rare case of a 28-year-old female patient who had Schmidt’s syndrome revealed by a thyroid storm (TS) concomitant with an acute adrenal crisis. The onset of AD resulted in a surgical emergency. The patient presented with cardiogenic shock and an acute abdomen. The precipitation factor was Hashitoxicosis presented as TS. This life-threatening condition was successfully reversed with aggressive medical therapy based on antithyroid drugs and intravenous glucocorticoids. This hyperthyroid phase lasted for a period of 8 months. The patient eventually developed hypothyroidism, suggesting that Hashimoto's thyroiditis was the most likely diagnosis. She was started on levothyroxine replacement therapy and remained euthyroid on levothyroxine. The case we describe had several diagnostic pitfalls that are discussed both at the start as well as during the evolution.

Learning points

• Autoimmune diseases can appear concomitantly or succeed each other over time. The clinician must be vigilant to detect these diseases in time in order to avoid a misdiagnosis of a life-threatening emergency such as adrenal insufficiency or thyroid storm.

• Thyroid storm is an uncommon but life-threatening manifestation of hyperthyroidism. Diagnosis is dependent on clinical symptoms, and no specific laboratory tests are available.

• Glucocorticoids should be used in the treatment of thyroid storm because they have an inhibitory effect on peripheral conversion of T4 to T3.

• In patients who have severe thyrotoxicosis, especially in conjunction with hypotension, treatment with glucocorticoids has become standard practice because of the possibility of relative adrenal insufficiency or the possibility of undiagnosed Addison’s disease.

• The differential diagnosis of hyperthyroidism can be challenging. Graves’ disease can be discussed in view of the severity of the clinical presentation and the prolonged duration of the hyperthyroid phase. Hashitoxicosis is the initial hyperthyroid phase in chronic autoimmune thyroiditis. The hyperthyroid phase is always followed by definitive resolution, with persistent euthyroidism and no hyperthyroid relapses.

• Synthetic antithyroid drugs may be prescribed during the hyperthyroid phase of Hashimoto thyroiditis if the clinical presentation is severe and the duration of the hyperthyroid phase is prolonged.