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Open access

Clare Miller, Agnieszka Pazderska, John Reynolds, Patricia Gou, Barbara Dunne, Kealan McElhinney, and Lisa Owens


A 53-year-old female presented to a tertiary ophthalmology referral centre complaining of unilateral painless loss of vision. Subsequent assessment revealed malignant hypertension causing right-sided cystoid macular oedema. During the course of secondary hypertension workup, she was diagnosed with a 7.8 cm phaeochromocytoma which was resected. Testing for a panel of all predisposing phaeochromocytoma-causing variants using next-generation sequencing resulted in the diagnosis of a novel SDHD variant.

Learning points

  • Screening for secondary causes of hypertension is indicated when there is evidence of hypertension-mediated end-organ damage ().

  • Testing for a predisposing variant should be considered in all patients with phaeochromocytoma or paraganglioma due to the high heritability rate and prevalence of somatic variants (, , ).

  • Novel variants are commonly uncovered in the Succinate Dehydrogenase (SDH) subunit; proving pathogenicity is a complex, time-consuming process and one challenge of next-generation sequencing ().

  • SDHB immunohistochemistry as a tool for demonstrating pathogenicity is associated with reduced sensitivity when assessing SDHD variants (, ).

Open access

Annabelle M Warren, Peter R Ebeling, Vivian Grill, Ego Seeman, and Shoshana Sztal-Mazer


Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended.

Learning points

  • Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss.

  • Antiresorptive therapy is contraindicated in HPP.

  • Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis.

  • Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory.

  • Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly.

  • Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

Open access

Ryizan Nizar, Nathan W P Cantley, and Jonathan C Y Tang


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

Open access

Ziad Hussein, Marta Korbonits, Stephanie E Baldeweg, and Teng-Teng Chung


We observed a novel therapeutic response with cabergoline in a male patient with a dopamine-secreting head and neck paraganglioma (HNPGL), macroprolactinoma and germline succinate dehydrogenase C mutation (SDHC). The macroprolactinoma was treated with cabergoline which gave an excellent response. He was found to have raised plasma 3-methoxytyramine of 1014 pmol/L (NR: 0–180 pmol/L); but it was unclear if this was a drug-induced phenomenon from dopamine agonist (DA) therapy. Cabergoline was stopped for 4 weeks and the 3-methoxytyramine level increased significantly to 2185 pmol/L, suggesting a biochemical response of his HNPGL. Subsequently, Gallium-68 Dotatate PET and MRI (Gallium-68 Dotatate PET/MRI) demonstrated a second lesion in the sacrum. Both the HNPGL and metastatic sacral deposit received external beam radiotherapy with a good biochemical and radiological response.


Our case report highlights the rare potential of germline SDHC mutations causing metastatic paraganglioma and concurrent pituitary tumours. Cabergoline treatment may lower elevated 3-methoxytyramine levels and, therefore, mask the biochemical evidence of metastatic disease but also may have therapeutic relevance in dopamine-secreting pheochromocytomas/paragangliomas (PPGLs).

Learning points

  • Several neuroendocrine tumours (NETs) express dopamine D2 and D4 receptors. In this case report, cabergoline significantly reduced plasma 3-methoxytyramine level in a patient with functional HNPGL. Cabergoline might have therapeutic relevance in dopamine-secreting PPGLs.

  • Paragangliomas associated with SDHC mutation classically present with asymptomatic non-functional HNPGL and have rare metastatic potential.

  • The association of pheochromocytoma or paraganglioma and pituitary adenoma is now a well-described rare association (<1%), designated as the three P association. While the three P association is most commonly seen with succinate dehydrogenase B and D mutations, it has also been described in patients with SDHA and SDHC mutations.

  • Cabergoline treatment may lower elevated 3-methoxytyramine levels and mask the biochemical evidence of metastatic disease. Regular functional imaging with Gallium-68 Dotatate PET/MRI provides better evidence of metastatic disease.

Open access

Vinaya Srirangam Nadhamuni, Donato Iacovazzo, Jane Evanson, Anju Sahdev, Jacqueline Trouillas, Lorraine McAndrew, Tom R Kurzawinski, David Bryant, Khalid Hussain, Satya Bhattacharya, and Márta Korbonits


A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare.

Learning points

  • It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation ().

  • Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis.

  • Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.

Open access

Su Ann Tee, Paul Brennan, and Anna L Mitchell


Marfan syndrome is an autosomal dominant multisystem disorder that has an estimated incidence of 1 in 5000. It is caused by mutations in the FBN1 gene, which encodes the extracellular matrix protein type 1 fibrillin. Familial hypocalciuric hypercalcaemia (FHH), also inherited in an autosomal dominant pattern, is a rare benign disorder characterised by hypercalcaemia, hypocalciuria and relative hyperparathyroidism with normal or high plasma PTH levels, with an estimated incidence of between 1 in 10 000 to 1 in 100 000. We report a unique case of a 26-year-old man referred for investigation of hypercalcaemia, who also had clinical features of Marfan syndrome but no previous genetic investigations. Calculated fractional urinary excretion of calcium was low (0.0005) following correction of vitamin D deficiency, raising the possibility of FHH. Genetic testing for Marfan syndrome and FHH, via a hyperparathyroidism multiplex gene panel test, revealed a novel truncating variant in the FBN1 gene (c.8481T>G; p.(Tyr2827Ter)), consistent with Marfan syndrome; and a pathogenic truncating variant in the CaSR gene (c.741dupT; p.[Asp248Ter]), which confirmed the diagnosis of FHH. The patient’s mother was subsequently found to have mild hypercalcaemia (adjusted calcium 2.76 mmol/L) and is also heterozygous for the same CaSR mutation. Genetic testing of his father confirmed the presence of the same FBN1 gene mutation. This case illustrates the importance of making robust diagnoses in the era of modern genomic medicine, confirming FHH as the cause of hypercalcaemia means that no treatment is warranted and the patient can be reassured.

Learning points

  • Familial hypocalciuric hypercalcaemia (FHH) should always be excluded during the investigation of hypercalcaemia by measuring urinary calcium: creatinine clearance ratio.

  • Diagnosing FHH is important as the condition is benign and misdiagnosing patients with primary hyperparathyroidism could potentially lead to unnecessary morbidity from parathyroid surgery.

  • Genetic testing is increasingly available for a variety of inherited conditions including Marfan syndrome and FHH. Patients who present with clinical features suggestive of a particular genetic condition should undergo prompt, appropriate confirmatory testing wherever possible.

  • Taking a thorough family history is vital when assessing patients presenting with endocrine conditions, as this could prompt cascade testing and appropriate genetic counselling where necessary.

Open access

Laura Marino, Andrea Messina, James S Acierno, Franziska Phan-Hug, Nicolas J Niederländer, Federico Santoni, Stefano La Rosa, and Nelly Pitteloud


Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens.

Learning points

  • N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome.

  • Surgical removal of testosterone-producing gonads can result in loss of libido.

  • Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS.

  • A previously unreported AR mutation – p.Glu2_Met190del (c.2T>C) – is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.

Open access

David Joseph Tansey, Jim John Egan, Michelle Murray, Katie Padfield, John Conneely, and Mensud Hatunic


Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications – amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182–867) as well as elevated metanephrines (MN) of 793 pmol/L (61–377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient’s blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential.

Learning points

  • Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1–1.0% of all secondary hypertension cases.

  • Secondary causes should be investigated in cases where:

  • Patient is presenting <20 years of age or >50 years of age,

  • There is refractory hypertension, or

  • There is serious end-organ damage present.

  • Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms.

  • Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour.

  • Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration.

  • There is a possibility of relapse so high-risk patients require life-long follow-up.

Open access

Angelika Mohn, Nella Polidori, Chiara Aiello, Cristiano Rizzo, Cosimo Giannini, Francesco Chiarelli, and Marco Cappa


Adrenoleukodystrophy is a peroxisomal X-linked recessive disease caused by mutations in the ABCD1 gene, located on the X-chromosome (Xq28). Gene mutations in patient with adrenoleukodystrophy induce metabolic alterations characterized by impaired peroxisomal beta-oxidation and accumulation of very long chain fatty acid (VLCFA) in plasma and in all tissues. Although nutritional intervention associated with a various mixture of oil prevents the accumulation of VLCFA, to date no causal treatment is available. Therefore, haematopoietic stem cell transplantation (HSCT) and gene therapy are allowed only for very early stages of cerebral forms diagnosed during childhood.We reported a case series describing five family members affected by X-linked adrenoleukodystrophy caused by a novel mutation of the ABCD1 gene. Particularly, three brothers were affected while the sister and mother carried the mutation of the ABCD1 gene. In this family, the disease was diagnosed at different ages and with different clinical pictures highlighting the wide range of phenotypes related to this novel mutation. In addition, these characteristics stress the relevant role of early diagnosis to properly set a patient-based follow-up.

Learning points

  • We report a novel mutation in the ABCD1 gene documented in a family group associated to an X-ALD possible Addison only phenotype.

  • All patients present just Addison disease but with different phenotypes despite the presence of the same mutations. Further follow-up is necessary to complete discuss the clinical development.

  • The diagnosis of ALD needs to be included in the differential diagnosis in all patients with idiopathic PAI through accurate evaluation of VLCFA concentrations and genetic confirmation testing.

  • Early diagnosis of neurological manifestation is important in order to refer timely to HSCT.

  • Further follow-up of these family members is necessary to characterize the final phenotype associated with this new mutation.

Open access

Mariana Aveiro-Lavrador, Adriana De Sousa Lages, Luísa Barros, and Isabel Paiva


Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway leading to impaired corticosteroid biosynthesis. Depending on the extension of enzyme defect, there may be variable severities of CAH – classic and non-classic. We report the case of a 37-year-old male patient with a previously unknown diagnosis of classic CAH referred to Endocrinology evaluation due to class III obesity and insulin resistance. A high diagnostic suspicion was raised at the first Endocrinology consultation after careful past medical history analysis especially related to the presence of bilateral adrenal myelolipomas and primary infertility. A genetic test confirmed the presence of a variant of the CYP21A2 in homozygous with an enzymatic activity of 0–1%, corresponding to a classic and severe CAH form. Our case represents an unusually late definitive diagnose of classic CAH since the definition was established only during adulthood in the fourth decade of life. The missing diagnosis of classic 21 hydroxylase deficiency during infancy led to important morbidity, with a high impact on patients’ quality of life.

Learning points

  • Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive enzyme disorders responsible for an impaired cortical adrenal hormonal synthesis.

  • CAH may be divided into two major forms: classic and non-classic CAH.

  • If untreated, CAH may be fatal or may be responsible for important multi-organ long-term consequences that can be undervalued during adulthood.

  • Adrenal myelolipomas are associated with chronic exposure to high ACTH levels and continuous androgen hyperstimulation typically found in undertreated CAH patients.

  • Testicular adrenal rest tumours (TART) and primary infertility can be the first manifestation of the disease during adulthood.