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Open access

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

Summary

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

Rishi Raj, Samaneh Hasanzadeh, Mitra Dashtizadeh, Mohammadreza Kalantarhormozi, Katayoun Vahdat, Mohammad Hossein Dabbaghmanesh, Iraj Nabipour, Mohammdreza Ravanbod, Majid Assadi, Basir Hashemi, and Kamyar Asadipooya

Summary

Oncogenic osteomalacia secondary to glomus tumor is extremely rare. Localization of causative tumors is critical as surgical resection can lead to a complete biochemical and clinical cure. We present a case of oncogenic osteomalacia treated with resection of glomus tumor. A 39-year-old woman with a history of chronic sinusitis presented with chronic body ache and muscle weakness. Biochemical evaluation revealed elevated alkaline phosphatase hypophosphatemia, increased urinary phosphate excretion, low calcitriol, and FGF23 was unsuppressed suggestive of oncogenic osteomalacia. Diagnostic studies showed increase uptake in multiple bones. Localization with MRI of paranasal sinuses revealed a sinonasal mass with concurrent uptake in the same area on the octreotide scan. Surgical resection of the sinonasal mass was consistent with the glomus tumor. The patient improved both clinically and biochemically postoperatively. Along with the case of oncogenic osteomalacia secondary to a glomus tumor, we have also discussed in detail the recent development in the diagnosis and management of oncogenic osteomalacia.

Learning points

  • Tumor-induced osteomalacia is a rare cause of osteomalacia caused by the secretion of FGF23 from mesenchymal tumors.

  • Mesenchymal tumors causing TIO are often difficult to localize and treat.

  • Resection of the tumor can result in complete resolution of biochemical and clinical manifestations in a very short span of time.

  • Glomus tumor can lead to tumor induced osteomalacia and should be surgically treated.

Open access

Su Ann Tee, Paul Brennan, and Anna L Mitchell

Summary

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

Jasmine Jiang Zhu, William J Naughton, Kim Hay Be, Nicholas Ensor, and Ada S Cheung

Summary

Hypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described. There are have only been two reported cases in the literature of hypercalcaemia associated with Cryptococcus infection. Although the mechanism of hypercalcaemia in these infections is not clear, it has been suggested that it could be driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas. We describe the case of a 55-year-old woman with a 1,25-OH D-mediated refractory hypercalcaemia in the context of a Cryptococcus neoformans infection. She required treatment with antifungals, pamidronate, calcitonin, denosumab and high-dose glucocorticoids. A disseminated fungal infection should be suspected in immunosuppressed individuals presenting with hypercalcaemia.

Learning point

  • In immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered as the differential diagnoses;

  • Glucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia; however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection;

  • Fluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.

Open access

Joana Lima Ferreira, Bernardo Marques, C Willemien Menke-van der Houven van Oordt, Wouter W de Herder, Tessa Brabander, and Johannes Hofland

Summary

Middle ear adenomas with neuroendocrine features (ANEF) are rare, with an estimated 150 reported cases. They usually pursue an indolent clinical course. Four reported cases of middle ear ANEF with distant metastases were treated with surgery, external beam radiation therapy (EBRT) and chemotherapy. To date, no successful systemic treatment for malignant behaviour of this rare tumour has been reported. Long-acting somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) have been used in well-differentiated metastatic neuroendocrine tumours (NETs), but their use has never been described in cases of metastatic middle ear ANEF. We report two patients with grade 1 middle ear ANEF treated with surgery and EBRT. They had stable disease for several years, until clinical symptoms appeared and extensive metastases were detected on 68Ga-DOTA0-Tyr3-octreotate (DOTATATE) PET/CT. Treatment with long-acting SSA was started, with stable disease for 1 year. Afterwards, despite undergoing local treatments, both patients presented progressive disease. Due to high-uptake metastases at 68Ga-DOTATATE PET/CT, both cases underwent four cycles of PRRT with 177Lu-DOTATATE, which secured disease control and improvement of quality of life in both. Similar to other well-differentiated NETs, SSA and PRRT could constitute efficacious therapeutic options in metastatic middle ear ANEF. Its neuroendocrine differentiation, potential to metastasize and somatostatin receptor type 2 expression prompt consideration and management of this disease as a neuroendocrine neoplasm.

Learning points

  • Our cases oppose the 2017 WHO classification of middle ear adenoma with neuroendocrine features as a benign disease.

  • This entity warrants long-term follow-up, as local recurrence or persistence of disease is reported in up to 18% of surgically treated patients.

  • PET/CT scan with 68Ga-labelled somatostatin analogues (SSA) can be used for staging of metastatic middle ear adenoma with neuroendocrine features.

  • Unlabelled SSA and peptide receptor radionuclide therapy (PRRT) with radiolabelled SSA can be the first systemic therapeutic options for patients with advanced middle ear adenoma with neuroendocrine features.

Open access

Marina Yukina, Nurana Nuralieva, Ekaterina Sorkina, Ekaterina Troshina, Anatoly Tiulpakov, Zhanna Belaya, and Galina Melnichenko

Summary

Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS.

Learning points

  • Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood.

  • The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation.

  • The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30.

  • The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible.

  • Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

Open access

Aditi Sharma, Thilipan Thaventhiran, Suzanne Braggins, Channa N Jayasena, and Vassiliki Bravis

Summary

Infection is a common complication of advanced diabetic foot disease, increasing the risk of acute admission and amputation. It is less well-known that foot ulceration and osteomyelitis may cause bacteraemia-associated hematogenous seeding and subsequent epidural abscess formation. Here we describe the case of a 57-year-old woman with known diabetic foot ulcer with underlying osteomyelitis admitted with backpain in the absence of trauma. Her condition deteriorated secondary to overwhelming sepsis. MRI of the spine confirmed spondylodiscitis and posterior epidural collection, not amenable to surgical intervention due to patient’s comorbidities and high surgical risk. Despite prolonged antibiotic therapy, the patient died following a hospital admission lasting 2.5 months. This case highlights the importance of regular contact with diabetes foot service for optimisation and prompt treatment of diabetic foot disease, which can be an underestimated potential source of remote site invasive systemic infection. Secondly, high clinical suspicion in admitting clinicians is imperative in ensuring timely diagnosis and early intervention to minimise fatal consequences.

Learning points:

  • Approximately 10% of patients with diabetes will develop a foot ulcer in their lifetime.

  • Spondylodiscitis (incorporating vertebral osteomyelitis, spondylitis and discitis) is a rare condition and diabetes is the most common predisposing risk factor.

  • Spondylodiscitis often presents with no other symptom other than back pain. Neurological or infective symptoms can be present or absent.

  • High clinical suspicion in clinicians is imperative in ensuring timely diagnosis and early intervention to minimise devastating consequences.

Open access

Athanasios Gkirgkinoudis, Christina Tatsi, Stephanie J DeWard, Bethany Friedman, Fabio R Faucz, and Constantine A Stratakis

Summary

SOX5 plays an important role in chondrogenesis and chondrocyte differentiation. SOX5 defects in humans (often deletions) result in a Lamb-Shaffer syndrome (LSS), presenting with speech delay, behavioral problems and minor dysmorphic features. We present a patient with idiopathic short stature (ISS) who carried a heterozygous novel variant in SOX5. The patient had no dysmorphic features, but a skeletal survey revealed minor skeletal abnormalities. Laboratory and endocrine evaluation for known causes of growth disorders was negative. The missense variant in SOX5 gene (c.1783A>G, p.K595E) was de novo and was predicted to be deleterious by in silico programs. In summary, we present a patient whose presentation may provide evidence that gene defects in SOX5 may contribute to the etiology of short stature and/or mild skeletal defects beyond LSS.

Learning points:

  • We report a girl with idiopathic short stature and mild skeletal defects presenting with a de novo variant in SOX5 gene, predicted in silico to be deleterious.

  • Although SOX5 has not been previously specifically associated with short stature, several evidences support its contributing effect on dyschondrogenesis.

  • Missense variants in SOX5 gene may lead to mild phenotypes, differing from typical presentation of patients with Lamb-Shaffer syndrome.

Open access

Dured Dardari, Alfred Penfornis, and Agnes Hartemann

Summary

We report the onset of acute Charcot neuroarthropathy during pregnancy in two patients with type 1 diabetes using retrospective review of case notes. We describe for the first time the onset of acute Charcot neuroarthropathy during pregnancy in two patients with type 1 diabetes. Pregnancy may promote the onset and worsening of a number of diabetic complications. A link between pregnancy and the onset of acute Charcot neuroarthropathy is demonstrated for the first time in this report.

Learning points:

  • Patients with already diagnosed sensitive neuropathy can develop an active phase of Charcot neuroarthropathy during pregnancy.

  • The rapid correction of hyperglycaemia may induce an active phase of Charcot neuroarthropathy during pregnancy.

Open access

Mawson Wang, Benjamin Jonker, Louise Killen, Yvonne Bogum, Ann McCormack, and Ramy H Bishay

Summary

Cushing’s disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing’s disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull.

Learning points:

  • Cushing’s disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism.

  • The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30–60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas.

  • Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years.

  • Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy.

  • Overall prognosis in radiation-induced sarcoma of bone is poor.

  • Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.