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Open access

Maria P Yavropoulou, Efstathios Chronopoulos, George Trovas, Emmanouil Avramidis, Francesca Marta Elli, Giovanna Mantovani, Pantelis Zebekakis and John G Yovos

Summary

Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology.

Learning points:

  • We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A.

  • Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling.

  • GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Open access

C Kamath, J Witczak, M A Adlan and L D Premawardhana

Summary

Thymic enlargement (TE) in Graves’ disease (GD) is often diagnosed incidentally when chest imaging is done for unrelated reasons. This is becoming more common as the frequency of chest imaging increases. There are currently no clear guidelines for managing TE in GD. Subject 1 is a 36-year-old female who presented with weight loss, increased thirst and passage of urine and postural symptoms. Investigations confirmed GD, non-PTH-dependent hypercalcaemia and Addison’s disease (AD). CT scans to exclude underlying malignancy showed TE but normal viscera. A diagnosis of hypercalcaemia due to GD and AD was made. Subject 2, a 52-year-old female, was investigated for recurrent chest infections, haemoptysis and weight loss. CT thorax to exclude chest malignancy, showed TE. Planned thoracotomy was postponed when investigations confirmed GD. Subject 3 is a 47-year-old female who presented with breathlessness, chest pain and shakiness. Investigations confirmed T3 toxicosis due to GD. A CT pulmonary angiogram to exclude pulmonary embolism showed TE. The CT appearances in all three subjects were consistent with benign TE. These subjects were given appropriate endocrine treatment only (without biopsy or thymectomy) as CT appearances showed the following appearances of benign TE – arrowhead shape, straight regular margins, absence of calcification and cyst formation and radiodensity equal to surrounding muscle. Furthermore, interval scans confirmed thymic regression of over 60% in 6 months after endocrine control. In subjects with CT appearances consistent with benign TE, a conservative policy with interval CT scans at 6 months after endocrine control will prevent inappropriate surgical intervention.

Learning points:

  • Chest imaging is common in modern clinical practice and incidental anterior mediastinal abnormalities are therefore diagnosed frequently.

  • Thymic enlargement (TE) associated with Graves’ disease (GD) is occasionally seen in view of the above.

  • There is no validated strategy to manage TE in GD at present.

  • However, CT (or MRI) scan features of the thymus may help characterise benign TE, and such subjects do not require thymic biopsy or surgery at presentation.

  • In them, an expectant ‘wait and see’ policy is recommended with GD treatment only, as the thymus will show significant regression 6 months after endocrine control.

Open access

Alejandro García-Castaño, Leire Madariaga, Sharona Azriel, Gustavo Pérez de Nanclares, Idoia Martínez de LaPiscina, Rosa Martínez, Inés Urrutia, Aníbal Aguayo, Sonia Gaztambide and Luis Castaño

Summary

Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene.

Learning points:

  • Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism.

  • Large deletions or duplications in the CASR gene can be detected by the MLPA technique.

  • Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.

Open access

Bidhya Timilsina, Niranjan Tachamo, Prem Raj Parajuli and Ilan Gabriely

Summary

A 74-year-old woman presented with progressive lethargy, confusion, poor appetite and abdominal pain. She was found to have non-PTH-mediated severe hypercalcemia with renal failure and metabolic alkalosis. Extensive workup for hypercalcemia to rule out alternate etiology was unrevealing. Upon further questioning, she was taking excess calcium carbonate (Tums) for her worsening heartburn. She was diagnosed with milk-alkali syndrome (MAS). Her hypercalcemia and alkalosis recovered completely with aggressive hydration along with improvement in her renal function. High index of suspicion should be maintained and history of drug and supplements, especially calcium ingestion, should be routinely asked in patients presenting with hypercalcemia to timely diagnose MAS and prevent unnecessary tests and treatments.

Learning points:

  • Suspect milk-alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements.

  • Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome.

  • Milk-alkali syndrome may cause severe hypercalcemia in up to 25–30% of cases.

Open access

Benjamin Kwan, Bernard Champion, Steven Boyages, Craig F Munns, Roderick Clifton-Bligh, Catherine Luxford and Bronwyn Crawford

Summary

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members.

Learning points:

  • ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.

  • In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.

  • CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.

  • Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.

Open access

E Mogas, A Campos-Martorell, M Clemente, L Castaño, A Moreno-Galdó, D Yeste and A Carrascosa

Summary

Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results.

Learning points:

  • Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity.

  • Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed.

  • Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients.

  • Treatment has been well tolerated and no side effects have been detected.

Open access

Maria P Yavropoulou, Christos Poulios, Christoforos Foroulis, Symeon Tournis, Prodromos Hytiroglou, Kalliopi Kotsa, Isaak Kessisoglou and Pantelis Zebekakis

Summary

Tumor-induced osteomalacia (TIO) is a rare form of hypophosphatemia usually caused by phosphaturic mesenchymal tumors (PMTs); the biologic behavior of PMTs is under investigation. Herein we present a case of TIO with a protracted course over 12 years leading to a fatal outcome. A 39-year-old man presented with weakness in 2004 and was found to have decreased serum phosphorus, phosphaturia and low levels of 1,25-dihydroxyvitamin D3. Four years later he developed a painful left calf mass. The lesion was resected, but recurred causing extreme pain and dysfunction. Radiological examination showed a large cluster of soft tissue tumors affecting all the muscle compartments of the calf and a smaller lesion inside the metaphysis of the tibia. Above-knee amputation was performed. Histological examination of all lesions showed a cellular spindle cell neoplasm with variously sized vessels, wide vessel-like spaces and scattered deposits of calcified extracellular material. The tumor infiltrated skeletal muscles, subcutaneous fat and the proximal end of the fibula. The tibial lesion had identical histology. Three years after the amputation the patient presented with cough and dyspnea. Radiological examination, followed by an open biopsy, showed that there were multiple metastatic nodules of PMTs in both lungs. Shortly after the diagnosis the patient died. This case illustrates that even benign cases of PMTs may lead to a fatal outcome and the classification of PMTs into benign and malignant should be reassessed in order to correspond to its biological behavior.

Learning points:

  • PMTs, aside from having locally aggressive behavior, may metastasize and cause death

  • PMTs may behave aggressively despite ‘benign’ histological findings

  • Accurate diagnosis of tumor-induced osteomalacia and patient management require a multidisciplinary approach

Open access

Cheuk-Lik Wong, Chun-Kit Fok and Vicki Ho-Kee Tam

Summary

We report a case of elderly Chinese lady with neurofibromatosis type-1 presenting with longstanding palpitation, paroxysmal hypertension and osteoporosis. Biochemical testing showed mild hypercalcaemia with non-suppressed parathyroid hormone level suggestive of primary hyperparathyroidism, and mildly elevated urinary fractionated normetanephrine and plasma-free normetanephrine pointing to a catecholamine-secreting pheochromocytoma/paraganglioma. Further scintigraphic investigation revealed evidence of a solitary parathyroid adenoma causing primary hyperparathyroidism and a left pheochromocytoma. Resection of the parathyroid adenoma and pheochromocytoma resulted in normalization of biochemical abnormalities and hypertension. The rare concurrence of primary hyperparathyroidism and pheochromocytoma in neurofibromatosis type-1 is discussed.

Learning points:

  • All NF-1 patients who have symptoms suggestive of a pheochromocytoma/paraganglioma (PPGL), even remotely, should undergo biochemical testing.

  • The initial biochemical tests of choice for PPGL in NF-1 are either plasma-free metanephrines or urinary fractionated metanephrines. Any elevations of metanephrines should be carefully evaluated for the presence of PPGLs in NF-1 patients.

  • Primary hyperparathyroidism (PHPT) is described in subjects with NF-1. Due to the lack of epidemiological and functional studies, their association is yet to be substantiated. Meanwhile, PHPT may further exacerbate the metabolic bone defect in these patients and should be treated when present according to published guidelines.

  • Coexistence of PPGL and PHPT can occur in subjects with NF-1, mimicking multiple endocrine neoplasia type 2 (MEN2).

Open access

Carine Ghassan Richa, Khadija Jamal Saad, Ali Khaled Chaaban and Mohamad Souheil El Rawas

Summary

The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution.

Learning points:

  • Learning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.

  • Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.

  • Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.

Open access

C E Stiles, R Thuraisingham, D Bockenhauer, L Platts, A V Kumar and M Korbonits

Summary

29-year-old female presenting with an 8-year history of unexplained hypomagnesaemia, which was severe enough to warrant intermittent inpatient admission for intravenous magnesium. Urinary magnesium was inappropriately normal in the context of hypomagnesaemia indicating magnesium wasting. Ultrasound imaging demonstrated unilateral renal cysts and computed tomography of kidneys, ureters and bladder showed a bicornuate uterus. Referral to genetic services and subsequent testing revealed a de novo HNF1B deletion.

Learning points:

  • HNF1B loss-of-function mutations are one of the most common monogenic causes of congenital anomalies of the kidney and urinary tract.

  • Those with HNF1B mutations may have some of a constellation of features (renal and hepatic cysts, deranged liver function tests, maturity onset diabetes of the young type 5 (MODY5), bicornuate uterus, hyperparathyroidism, hyperuricaemic gout, but presenting features are highly heterogeneous amongst patients and no genotype/phenotype correlation exists.

  • HNF1B mutations are inherited in an autosomal dominant pattern but up to 50% of cases are de novo.

  • HNF1B mutations can be part of the Chr17q12 deletion syndrome, a contiguous gene deletion syndrome.

  • Inorganic oral magnesium replacements are generally poorly tolerated with side effects of diarrhoea. Organic magnesium compounds, such as magnesium aspartate, are better absorbed oral replacement therapies.