Diagnosis and Treatment > Signs and Symptoms
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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:
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We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A.
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Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling.
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GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.
Department of Endocrinology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
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Department of Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
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Department of Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia
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The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
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Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
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Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
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Department of Endocrinology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
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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:
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ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.
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In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.
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CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.
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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.
