Summary

The spectrum of endocrine-related complications of COVID-19 infection is expanding; one of the most concerning of which is adrenal haemorrhage due to the risk of catastrophic adrenal crisis. In this study, we present a case that highlights the challenging management of a large, indeterminate unilateral adrenal mass during pregnancy and draws attention to a rare yet probably underestimated complication of COVID-19. During hospitalization for severe COVID-19 pneumonia, a 26-year-old woman was incidentally found to have a 12.5 cm heterogeneous left adrenal mass. Soon after the discovery, she became pregnant and upon referral, she was in the seventh week of gestation, without clinical or biochemical features of hormonal excess. The uncertainty of the diagnosis and the risks of malignancy and surgical intervention were discussed with the patient, and a period of radiological surveillance was agreed upon. An MRI scan performed 3 months later showed a size reduction of the adrenal lesion to 7.9 cm, which was against malignancy. A Doppler ultrasound showed a non-vascular, well-defined round lesion consistent with an adrenal haematoma, likely a complication of the recent COVID-19 infection. The multidisciplinary team recommended further radiological follow-up. The patient then spontaneously had miscarriage at 12 weeks gestation. Subsequent radiological surveillance showed a further size reduction of the adrenal lesion to 5.5 cm. The patient conceived again during follow-up, and the repeated Doppler ultrasound showed stable appearances of the adrenal mass, and thus, it was agreed to continue radiological monitoring after delivery. The pregnancy was uneventful, and the patient delivered a healthy baby. An MRI scan performed after delivery showed a stable but persistent lesion consistent with a likely underlying adrenal lesion.

Learning points

• Unilateral adrenal haemorrhage can occur as a complication of COVID-19 and should be considered in the differential diagnosis of heterogeneous adrenal masses if there is a history of recent infection.

• Management of large indeterminate adrenal masses during pregnancy poses several challenges and should be led by an experienced multidisciplinary team.

• Underlying adrenal tumours may trigger non-traumatic haemorrhages, especially if exacerbated by stressful illness.

Summary

A male phenotype accompanied by a 45,X karyotype is rare. It may occur due to Y chromosomal translocation or insertion to X/autosome. Clinical presentation may vary depending on the presence of the Y chromosomal locus and the degree of loss of autosome material. 45,X males can present with short stature and Turner syndrome phenotype due to haploinsufficiency of genes which are normally expressed in both X and Y chromosomes. The presence of the sex-determining region Y (SRY) gene leads to the differentiation of bipotential gonads to testis. Most individuals go through puberty normally, but some may need pubertal induction for delayed puberty. Rarely some can have a pubertal arrest. The risk of gonadoblastoma is minimal in these individuals due to functioning testicular tissue. The azoospermia factor (AZF) region is found on the long arm of the Yq chromosome and is needed for spermatogenesis. In a 45,X male with unbalanced translocation of Y chromosome, spermatogenesis can be affected due to the lack of AZF leading to Sertoli cell-only syndrome. This will have an implication on fertility in adult life. We present a 14-year-old boy with developmental delay, learning difficulties and subtle dysmorphic features who was diagnosed with 45,X,der(2)t(Y:2)(?:p25). Fluorescence in situ hybridisation analysis revealed translocation of SRY (Yp11.3) to the terminal part of the short arm of chromosome 2 resulting in the deletion of most of the Y chromosome (Yp11.2-q12) and part of chromosome 2(2p25.3). This is the first case where SRY translocation to chromosome 2 presents with the above clinical presentation.

Learning points

• 45,X karyotype is rare in male.

• It may occur due to SRY translocation or an insertion to X/autosome.

• SRY gene translocation to chromosome 2 has been not reported in the literature.

• Clinical presentation can be varied due to degree of loss of chromosomal material.

• Due to loss of AZF region found on the long arm of the Yq, spermatogenesis can be affected. Loss of 2p25 leads to learning difficulty and obesity.

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

Pituitary adenomas are intracranial neoplasms, usually demonstrating a benign phenotype. We present the case of 21-year-old male with an 18-month history of reduced visual function (acuity and field) in the left eye. Based on neuroimaging and endocrine profile, a giant prolactinoma causing hypogonadotropic hypogonadism was diagnosed and cabergoline was commenced. After a month of treatment, the tumour size reduced, and visual function improved to normal; however, he developed Foster Kennedy syndrome with a swollen right optic disc. After almost 1 year of follow-up, he regained full visual functioning. Two years since his diagnosis, his prolactin remains normal with no adverse effects or further visual complications.

Learning points

• Foster Kennedy syndrome is a rare entity but can be a feature of pituitary adenomas.

• Visual deterioration secondary to a compressive optic neuropathy can be reversible, provided that diagnosis and treatment are prompt.

• This case highlights the importance of frequent monitoring of visual function during follow-up of these lesions, particularly when there are deficits at diagnosis.

Summary

Milk–alkali syndrome (MAS) is a triad of hypercalcaemia, metabolic alkalosis and renal insufficiency. In this study, we present a case of milk–alkali syndrome secondary to concurrent use of over-the-counter (OTC) calcium carbonate-containing antacid tablets (Rennie®) for dyspepsia and calcium carbonate with vitamin D3 (Adcal D3) for osteoporosis. A 72-year-old woman presented with a 2-day history of nausea, vomiting, epigastric pain, constipation, lethargy and mild delirium. Past medical history included osteoporosis treated with daily Adcal D3. Initial blood tests showed elevated serum-adjusted calcium of 3.77 mmol/L (normal range, 2.2–2.6) and creatinine of 292 µmol/L (45–84) from a baseline of 84. This was corrected with i.v. pamidronate and i.v. fluids. She developed asymptomatic hypocalcaemia and rebound hyperparathyroidism. Myeloma screen, vasculitis screen and serum angiotensin-converting enzyme (ACE) were normal, while the CT of the chest, abdomen and pelvis showed renal stones but no malignancy. A bone marrow biopsy showed no evidence of malignancy. Once the delirium resolved, we established that prior to admission, she had been excessively self-medicating with over-the-counter antacids (Rennie®) as required for epigastric pain. The increasing use of calcium preparations for the management of osteoporosis in addition to easily available OTC dyspepsia preparations has made MAS the third most common cause of hypercalcaemia hospitalisations. Educating patients and healthcare professionals on the risks associated with these seemingly safe medications is required. Appropriate warning labels on both calcium preparations used in the management of osteoporosis and OTC calcium-containing preparations would prevent further similar cases and unnecessary morbidity and hospital admission.

Learning points

Summary

A 49-year-old teacher presented to his general physician with lethargy and lower limb weakness. He had noticed polydipsia, polyuria, and had experienced weight loss, albeit with an increase in central adiposity. He had no concomitant illnesses and took no regular medications. He had hypercalcaemia (adjusted calcium: 3.34 mmol/L) with hyperparathyroidism (parathyroid hormone: 356 ng/L) and hypokalaemia (K: 2.7 mmol/L) and was admitted for i.v. potassium replacement. A contrast-enhanced CT chest/abdomen/pelvis scan revealed a well-encapsulated anterior mediastinal mass measuring 17 × 11 cm with central necrosis, compressing rather than invading adjacent structures. A neck ultrasound revealed a 2 cm right inferior parathyroid lesion. On review of CT imaging, the adrenals appeared normal, but a pancreatic lesion was noted adjacent to the uncinate process. His serum cortisol was 2612 nmol/L, and adrenocorticotrophic hormone was elevated at 67 ng/L, followed by inadequate cortisol suppression to 575 nmol/L from an overnight dexamethasone suppression test. His pituitary MRI was normal, with unremarkable remaining anterior pituitary biochemistry. His admission was further complicated by increased urine output to 10 L/24 h and despite three precipitating factors for the development of diabetes insipidus including hypercalcaemia, hypokalaemia, and hypercortisolaemia, due to academic interest, a water deprivation test was conducted. An ¹⁸flurodeoxyglucose-PET (FDG-PET) scan demonstrated high avidity of the mediastinal mass with additionally active bilateral superior mediastinal nodes. The pancreatic lesion was not FDG avid. On 68Ga DOTATE-PET scan, the mediastinal mass was moderately avid, and the 32 mm pancreatic uncinate process mass showed significant uptake. Genetic testing confirmed multiple endocrine neoplasia type 1.

Learning points

• In young patients presenting with primary hyperparathyroidism, clinicians should be alerted to the possibility of other underlying endocrinopathies.

  In patients with multiple endocrine neoplasia type 1 (MEN-1) and ectopic adrenocorticotrophic hormone syndrome (EAS), clinicians should be alerted to the possibility of this originating from a neoplasm above or below the diaphragm.

• Although relatively rare compared with sporadic cases, thymic carcinoids secondary to MEN-1 may also be associated with EAS.

• Electrolyte derangement, in particular hypokalaemia and hypercalcaemia, can precipitate mild nephrogenic diabetes insipidus.

Summary

A 37-year-old female of South Asian origin was referred to our diabetes clinic for evaluation of an unusual finding during her retinal screening. Her retinal blood vessels appeared white in contrast to the normal pink-red colour. She had type I hyperlipidaemia, confirmed by genotype, and was recently diagnosed with diabetes, secondary to pancreatic insufficiency, for which she had suboptimal control and multiple hospitalisations with recurrent pancreatitis. On examination, she had multiple naevi on her skin; the rest of the examination was unremarkable. The patient did not report any visual disturbances and had intact visual acuity. Investigations showed raised total cholesterol (12.5 mmol/L) and triglycerides (57.7 mmol/L). Following evaluation, the patient was diagnosed with lipaemia retinalis, secondary to type I hyperlipidaemia. The patient was managed conservatively to reduce the cholesterol and triglyceride burdens. However, therapies with orlistat, statin, fibrates and cholestyramine failed. Only a prudent diet, omega-3 fish oil, medium-chain triglycerides oil and glycaemic control optimised with insulin showed some improvements in her lipid profile. Unfortunately, this led her to becoming fat-soluble vitamin deficient; hence, she was treated with appropriate supplementation. She was also recently started on treatment with volanesorsen. Following this, her lipid parameters improved and lipaemia retinalis resolved.

Learning points

• Lipaemia retinalis is an uncommon incidental finding of type I hyperlipidaemia that may not affect vision.

• Management of associated dyslipidaemia is challenging with minimal response to conventional treatment.

• Increased awareness of lipaemia retinalis and specialist management is needed as part of regular patient monitoring and personalised management.

Summary

A 33-year-old gentleman of Egyptian heritage presented with a 21 years history of unexplained and recurrent hypercalcaemia, nephrolithiasis, nephrocalcinosis, and myocarditis. A similar history was also found in two first-degree relatives. Further investigation into the vitamin D metabolism pathway identified the biochemical hallmarks of infantile hypercalcaemia type 1 (IIH). A homozygous, likely pathogenic, variant in CYP24A1 was found on molecular genetic analysis confirming the diagnosis. Management now focuses on removing excess vitamin D from the metabolic pathway as well as reducing calcium intake to achieve serum-adjusted calcium to the middle of the reference range. If undiagnosed, IIH can cause serious renal complications and metabolic bone disease.

Learning points

• Infantile hypercalcaemia type 1 (IIH) is an autosomal recessive disorder characterised by homozygous mutations in the CYP24A1 gene that encodes the 24-hydroxylase enzyme used to convert active vitamin D metabolites such as 1,25-(OH)₂-vitamin D into their inactive form.

• IIH should be questioned in individuals presenting with a history of unexplained hypercalcaemia, especially if presenting from childhood and/or where there is an accompanying family history of the same in first and/or second degree relatives, causing complications such as nephrocalcinosis, pericarditis, and calcium-based nephrolithiasis.

• Associated biochemistry of IIH is persistent mild to moderate hypercalcaemia, normal or raised 25-(OH)-vitamin D and elevated 1,25-(OH)₂-vitamin D. An elevated ratio of 25-(OH)-vitamin D to 24,25-(OH)₂-vitamin D can be a useful marker of defects in the 24-hydroxylase enzyme, whose measurement can be facilitated through the supra-regional assay service.

• Management should focus on limiting the amount of vitamin D introduced into the body either via sunlight exposure or supplementation in addition to calcium dietary restriction to try and maintain appropriate calcium homeostasis

Summary

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10⁻⁵, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient.

Learning points

• Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases.

• In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing.

• Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.

Summary

Hypothyroidism occurring in the postpartum period can be due to pituitary or hypothalamic disease as in Sheehan’s syndrome and postpartum autoimmune hypophysitis or due to a primary thyroid disease as in postpartum thyroiditis. It is important that the correct diagnosis is ascertained because hypothalamic or pituitary disorders are often associated with other pituitary hormone deficiencies, especially life-threatening adrenal insufficiency or adrenal crisis. A combination of various symptoms and biochemical markers, especially serum thyroid-stimulating hormone levels dictate the initial diagnostic pathway. We present a case of a woman who presented with a 2-month history of tiredness and neck discomfort following delivery. A thyroid function test demonstrated results, which we initially interpreted as central hypothyroidism. Follow-up results indicated that this was in fact the transition period between the thyrotoxic phase and hypothyroid phases of postpartum thyroiditis. This case highlights the potential for diagnostic confusion between central hypothyroidism and postpartum thyroiditis.

Learning points

• Postpartum thyroiditis affects one in twenty mothers within 12 months of delivery.

• The majority of patients have transient thyrotoxicosis only, some have transient hypothyroidism only, and the rest has a triphasic pattern (thyrotoxic, hypothyroid then a euthyroid phase).

• During the transition from the thyrotoxic phase to hypothyroid phase, when serum TSH is still suppressed, the biochemical results can resemble that of central hypothyroidism.

• If central hypothyroidism is suspected, then urgent diagnostic investigations should be carried out along with the assessment of adrenal function.

• There is a potential for diagnostic confusion between postpartum central hypothyroidism and postpartum thyroiditis; however, the obstetric history, clinical symptoms, and signs (headaches, breastfeeding, goitre, etc.) and serum adrenocorticotropic levels should help with the differential diagnosis.