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Open access

Natassia Rodrigo, Diana Learoyd, and Sarah J Glastras

Summary

Hypercalcaemia in pregnancy is uncommon, with associated adverse obstetric and perinatal outcomes for both the mother and the fetus. Determination of causality is central to its management. Diagnostic imaging techniques are limited during pregnancy and the diagnosis is made more complex by physiological changes in calcium and vitamin D homeostasis in pregnancy. Further, therapeutic options are limited due to safety considerations for the pregnant woman and the developing foetus. Three cases of hypercalcaemia in pregnancy will be presented, highlighting the distinct aetiologies and management strategies for hypercalcaemia in pregnancy and the importance of early measurement of serum calcium in pregnancy screening.

Learning points

  • There are complex physiological changes in calcium balance in pregnancy, including increased calcium intestinal absorption and renal excretion.
  • Hypercalcaemia in pregnancy is uncommon but has important potential maternal and foetal complications, making a compelling argument for routine antenatal, calcium screening.
  • Identifying the cause of hypercalcaemia in pregnancy can be challenging due to the complex placental interplay in biochemical test interpretation and due to safety constraints restricting imaging and surgery.
  • Acute medical management of hypercalcaemia must be considered in the context of both maternal and foetal well-being, along with gestational age and specific consideration for the safety of the developing fetus in late gestation.
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

Joana Lima Ferreira, Francisco Simões de Carvalho, Ana Paula Marques, and Rosa Maria Príncipe

Summary

Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.

Learning points:

  • Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.
  • Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.
  • APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.
  • APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.
  • Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.
  • Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.
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.
Open access

Ravikumar Ravindran, Justyna Witczak, Suhani Bahl, Lakdasa D K E Premawardhana, and Mohamed Adlan

Summary

A 53-year-old man who used growth hormone (GH), anabolic steroids and testosterone (T) for over 20 years presented with severe constipation and hypercalcaemia. He had benign prostatic hyperplasia and renal stones but no significant family history. Investigations showed – (1) corrected calcium (reference range) 3.66 mmol/L (2.2–2.6), phosphate 1.39 mmol/L (0.80–1.50), and PTH 2 pmol/L (1.6–7.2); (2) urea 21.9 mmol/L (2.5–7.8), creatinine 319 mmol/L (58–110), eGFR 18 mL/min (>90), and urine analysis (protein 4+, glucose 4+, red cells 2+); (3) creatine kinase 7952 U/L (40–320), positive anti Jo-1, and Ro-52 antibodies; (4) vitamin D 46 nmol/L (30–50), vitamin D3 29 pmol/L (55–139), vitamin A 4.65 mmol/L (1.10–2.60), and normal protein electrophoresis; (5) normal CT thorax, abdomen and pelvis and MRI of muscles showed ‘inflammation’, myositis and calcification; (6) biopsy of thigh muscles showed active myositis, chronic myopathic changes and mineral deposition and of the kidneys showed positive CD3 and CD45, focal segmental glomerulosclerosis and hypercalcaemic tubular changes; and (7) echocardiography showed left ventricular hypertrophy (likely medications and myositis contributing), aortic stenosis and an ejection fraction of 44%, and MRI confirmed these with possible right coronary artery disease. Hypercalcaemia was possibly multifactorial – (1) calcium release following myositis, rhabdomyolysis and acute kidney injury; (2) possible primary hyperparathyroidism (a low but detectable PTH); and (3) hypervitaminosis A. He was hydrated and given pamidronate, mycophenolate and prednisolone. Following initial biochemical and clinical improvement, he had multiple subsequent admissions for hypercalcaemia and renal deterioration. He continued taking GH and T despite counselling but died suddenly of a myocardial infarction.

Learning points:

  • The differential diagnosis of hypercalcaemia is sometimes a challenge.
  • Diagnosis may require multidisciplinary expertise and multiple and invasive investigations.
  • There may be several disparate causes for hypercalcaemia, although one usually predominates.
  • Maintaining ‘body image’ even with the use of harmful drugs may be an overpowering emotion despite counselling about their dangers.
Open access

Anna Luiza Galeazzi Rech, Yvon Stüve, Andreas Toepfer, and Katrin E Schimke

Summary

Acute Charcot neuropathic osteoarthropathy (CN) is a clinical entity which can easily go unrecognized in its acute early stages due to lack of awareness and unspecific presentation. However, missing early diagnosis can lead to severe complications. We present the case of a 72-year-old male patient who went through the natural course of the disease unnoticed before the very eyes of his physicians leading to a tragic end. We aim to raise awareness for this rare diabetic complication, emphasizing the necessity of early diagnosis and adequate, interdisciplinary treatment.

Learning points:

  • Clinical signs and symptoms of acute Charcot neuropathic osteoarthropathy (CN).
  • Red flags.
  • Importance of early diagnosis and correct treatment.
  • Diagnostic challenges of acute CN.
  • Awareness of high morbidity and mortality.
Open access

Daniela Gallo, Sara Rosetti, Ilaria Marcon, Elisabetta Armiraglio, Antonina Parafioriti, Graziella Pinotti, Giuseppe Perrucchini, Bohdan Patera, Linda Gentile, Maria Laura Tanda, Luigi Bartalena, and Eliana Piantanida

Summary

Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders.

Learning points:

  • Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism.
  • Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions.
  • Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis.
  • A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index.
  • If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment.
  • In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.