E-Poster 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Atypical presentations of FHH– not so benign? (#78)

Albert Kim 1 2 , Ashley Crook 3 , Michael Field 3 , Mathilda Wilding 3 , Lyndal Tacon 1 2 , Roderick Clifton-Bligh 1 2
  1. Department of Endocrinology, Diabetes and Metabolism, Royal North Shore Hospital, St Leonards, NSW, Australia
  2. Faculty of Medicine & Health, University of Sydney, NSW 2600, Australia
  3. Department of Cancer Services, Northern Sydney Local Health District Familial Cancer Service, Royal North Shore Hospital, St Leonards, NSW, Australia

Familial Hypocalciuric Hypercalcaemia(FHH) is an inherited disorder of calcium homeostasis due to inactivating mutations of the CASR gene.FHH individuals typically have mild hypercalcaemia, hypocalciuria and normal parathyroid hormone(PTH) levels and no specific treatment is required1.Atypical presentations with parathyroid adenomas have been previously reported2.We describe two families in whom CASR variants were identified following presentation with hyperparathyroidism.

Case 1

48year-old female presented with hypercalcaemia, elevated PTH and fractional urinary excretion of calcium of0.014. She had previous nephrolithiasis and underwent resection of a parathyroid adenoma with normalisation of her serum calcium.Her eldest daughter was also diagnosed with primary hyperparathyroidism and 3-gland parathyroidectomy revealed hyperplasia. Her serum calcium also normalised post-operatively.Her father also has a history of multigland hyperparathyroidism and nephrolithiasis. A previously described heterozygous CASR variant c.2449G>A,p.Val817Ile)was detected by next-generation sequencing. All four of her children have been confirmed to carry this CASR variant and are under surveillance.

Case 2

45year-old male with long standing hypercalcaemia was diagnosed with primary hyperparathyroidism and underwent resection of an adenoma,with normalisation of calcium postoperatively. A novel likely pathogenic heterozygous CASR variant(c.205C>A, p.Arg69Ser)was detected by next-generation sequencing and further testing of his family members is in progress.

More than 130 different pathological variants of CASR have been reported with heterogeneous clinical manifestations2. FHH variants have been located in the transmembrane3 and intracellular4 domains leading to impaired intracellular signalling. In-vitro studies of CASR variants have demonstrated altered cell surface expression and shifts in the dose-response curve leading to impaired signalling activity5,and this may be more severely impaired in the parathyroid relative to the kidneys6. This may explain the atypical findings of parathyroid adenomas,correction of hypercalcaemia following parathyroidectomy,hypercalciuria and nephrolithiasis observed in our cases. These cases highlight the heterogeneity of familial hypercalcaemic syndromes and the overlap in clinical features between FHH and primary hyperparathyroidism.

 

 

 

 

 

 

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