About a case of familial hypocalciuric hypercalcemia (FHH) type 3 with neurological involvement

2019 ◽  
Author(s):  
Guechot Helene Hoth ◽  
Florence Kohler ◽  
Linda Humbert ◽  
Maxime Kwapich ◽  
Odou Marie Francoise ◽  
...  
Keyword(s):  
Neurological Involvement ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Type 3

scholarly journals SAT-361 Familial Hypocalciuric Hypercalcemia Type 3: AP2S1 Mutation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sarah Elizabeth Kerut ◽  
Licy L Yanes Cardozo
Keyword(s):  
Vitamin D ◽  
Primary Hyperparathyroidism ◽  
Parathyroid Gland ◽  
Genetic Mutation ◽  
Urinary Calcium ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Dexa Scan ◽  
High Calcium ◽  
History Of ◽  
Type 3

Abstract Background: Familial hypocalciuric hypercalcemia (FHH) type 3 can appear similar to primary hyperparathyroidism and make the diagnosis of etiology of hypercalcemia challenging. Clinical Case: A 45-year-old man with hypertension and glaucoma was evaluated in clinic for hypercalcemia. His calcium was 12.3 mg/dL (8.4–10.2), PTH 41.9 pg/mL (15–65), Vitamin D 14.8 ng/mL (6.6–49) and phosphorus 1.7 mg/dL (2.7–4.5). He denied history of thiazide diuretic use, fragility fracture, nephrolithiasis and family history of calcium disorders. Further workup revealed normal kidney function, undetectable PTH related peptide and dual-energy x-ray absorptiometry (DEXA) scan with a T-score of -3.3 at spine L1-L4, -2.7 at femoral neck and -2.1 at distal one-third forearm. A 24-hour urine collection revealed a urinary calcium of 42.4 mg/24-hour (100–300) and calcium: creatinine clearance ratio of 0.003. Diagnosis of primary hyperparathyroidism was made despite low urinary calcium as this was thought to be due to vitamin D deficiency. Sestamibi scintigraphy and four-dimensional computed tomography did not localize a parathyroid adenoma, however, the patient was sent to surgery for four gland parathyroid exploration for primary hyperparathyroidism in setting of high calcium and young age with evidence of end-organ failure of osteoporosis. During surgery, three large abnormal parathyroid glands were identified and one normal parathyroid gland. Patient had a three-gland parathyroidectomy with intraoperative drop in PTH by 26.5%. Pathology returned as benign parathyroid tissues. After surgery, patient had persistently elevated calcium level of 12.6 mg/dL and an inappropriately non-suppressed PTH. He was then started on bisphosphonate and cinacalcet for osteoporosis and hypercalcemia, respectively and sent for genetic testing of FHH. His CASR gene was negative but his AP2S1 gene was positive which confirmed the diagnosis of FHH type 3. His calcium responded well to cinacalcet and repeat DEXA scan showed stability of bone mineral density in spine and hip after two years of treatment with bisphosphonate therapy. Conclusion: Familial hypocalciuric hypercalcemia type 3 is caused by an inactivating mutation in the AP2S1 gene. This gene encodes the adaptor-related protein complex 2, sigma 1 subunit which is located downstream from calcium-sensing receptor. This genetic mutation can appear similar to primary hyperparathyroidism in that it produces high levels of calcium and PTH and low phosphorus. Hypercalcemia, however, persists despite removal of parathyroid gland. This genetic mutation can be treated with cinacalcet in patients with high levels of calcium (>1 upper limit of normal) or symptoms of hypercalcemia.

scholarly journals MON-539 Mice Harboring a Germline Heterozygous AP2S1 Mutation, Arg15Leu, Are a Model for Familial Hypocalciuric Hypercalcemia Type 3 (FHH3)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Fadil Hannan ◽  
Victoria Stokes ◽  
Caroline Gorvin ◽  
Tertius Hough ◽  
Gemma Codner ◽  
...  
Keyword(s):  
Familial Hypocalciuric Hypercalcemia ◽  
Type 3

scholarly journals Clinical and Biochemical Features in a Case of Familial Hypocalciuric Hypercalcemia Type 3 with AP2S1 Gene Mutation in Codon Arg15His

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Mohamed Aashiq ◽  
Asma Jassim Malallah ◽  
Farheen Khan ◽  
Maryam Alsada
Keyword(s):  
Clinical Features ◽  
Protein Complex ◽  
Heterozygous Mutation ◽  
Missense Mutations ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Related Protein ◽  
Benign Condition ◽  
Sigma 1 ◽  
Type 3 ◽  
Biochemical Features

Familial hypocalciuric hypercalcemia (FHH) is usually a benign condition divided into three types. FHH-3 occurs in about 20% of the cases and is caused due to missense mutations in AP2S1 (adaptor-related protein complex 2 subunit sigma 1) involving the codon Arg15 (p.R15). We report a case of FHH-3 with a heterozygous mutation in the AP2S1 gene on chr19_47349359 C>T, c.44G>A, p.Arg15His. There are a handful of reports describing the clinical features in patients diagnosed with FHH-3. Herein, we describe the laboratory and clinical features associated with a case of FHH-3 with mutation in the Arg15His codon of the AP2S1 gene.

scholarly journals Gaucher Disease and Cancer: Concept and Controversy

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Francis Y. M. Choy ◽  
Tessa N. Campbell
Keyword(s):  
Gaucher Disease ◽  
Wide Spectrum ◽  
Treatment Options ◽  
Substrate Reduction Therapy ◽  
Neurological Involvement ◽  
Enzyme Replacement ◽  
Skeletal Disease ◽  
Increased Risk ◽  
Risk Of Malignancy ◽  
Type 3

Gaucher disease is an inherited disorder caused by a deficiency in the lysosomal hydrolase glucocerebrosidase. There is a wide spectrum of clinical presentations, with the most common features being hepatosplenomegaly, skeletal disease, and cytopenia. Gaucher disease has been classified into three broad phenotypes based upon the presence or absence of neurological involvement: Type 1 (nonneuronopathic), Type 2 (acute neuronopathic), and Type 3 (subacute neuronopathic). The two main treatment options include enzyme replacement therapy and substrate reduction therapy. Recently, discussion has escalated around the association of Gaucher disease and cancer, with conflicting reports as to whether Gaucher patients have an increased risk of malignancy. In this review, we present both the concept and controversy surrounding the association of Gaucher disease with cancer.

scholarly journals Identification of a Second Kindred with Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Narrows Localization to a <3.5 Megabase Pair Region on Chromosome 19q13.3

2010 ◽  
Vol 95 (4) ◽  
pp. 1947-1954 ◽  
Author(s):  
M. Andrew Nesbit ◽  
Fadil M. Hannan ◽  
Una Graham ◽  
Michael P. Whyte ◽  
Patrick J. Morrison ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Urinary Calcium ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Coding Region ◽  
Calcium Sensing Receptor ◽  
Single Nucleotide ◽  
Polymorphic Loci ◽  
Calcium Sensing ◽  
Serum Pth ◽  
Type 3

Abstract Context: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogenous disorder that consists of three defined types, FHH1, FHH2, and FHH3 whose chromosomal locations are 3q21.1, 19p, and 19q13, respectively. FHH1, caused by mutations of the calcium-sensing receptor (CASR), occurs in more than 65% of patients, whereas the abnormalities underlying FHH2 and FHH3, which have each been described in single North American kindreds, are unknown. Objective: The aim of this study was to determine the basis of FHH in a proband, who did not have CASR mutations, and her kindred. Patients and Methods: The proband was a 43-yr-old woman who presented with a corrected serum calcium of 2.74 mmol/liter (normal = 2.15–2.55 mmol/liter), a serum PTH of 47 pg/ml (normal = 10–65 pg/ml), and a urinary calcium clearance:creatinine clearance of 0.006. She did not have a CASR mutation within the coding region and splice sites, and 24 members from three generations of her kindred were ascertained and investigated for serum abnormalities and cosegregation with polymorphic loci from chromosomes 3q21.1 and 19q13 using leukocyte DNA. Results: Sixteen members were hypercalcemic with normal or elevated serum PTH concentrations and mild hypophosphatemia, features consistent with FHH3. Use of microsatellite and single nucleotide polymorphic loci from chromosome 19q13.3 demonstrated cosegregation with FHH in the kindred, with a peak LOD score = 5.98 at 0% recombination with D19S412. Analysis of recombinants mapped FHH to a 3.46-Mbp interval flanked centromerically by single nucleotide polymorphism rs1990932 and telomerically by D19S604. Conclusions: FHH3 may explain the calcium homeostasis disorder in those FHH patients who do not have CASR mutations.

scholarly journals Clinical Presentation and Management Approach in a Case of Familial Hypocalciuric Hypercalcemia Type 3 Due to APS21 Gene Mutation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A188-A188
Author(s):  
Sahar A Elsheikh ◽  
Henry M Blunk ◽  
Scott Wilhelm
Keyword(s):  
Case Report ◽  
Genetic Testing ◽  
Primary Hyperparathyroidism ◽  
Calcium Homeostasis ◽  
Clinical Presentation ◽  
Genetic Disorder ◽  
Management Approach ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Surgical Options ◽  
Type 3

Abstract Familial hypocalciuric hypercalcemia (FHH) is a genetic disorder caused by dysfunctional calcium homeostasis. Thus far, three types of FHH are known to be caused by mutations inCASR (FHH1), GNA11 (FHH2), and AP2S1 (FHH3). The patient in this case report is a 36-year old male that initially presented for a second opinion after being diagnosed with Primary Hyperparathyroidism(PHPT) with subsequent parathyroidectomy done at another institute, and developed recurrent symptomatic hypercalcemia. Prior to considering this patient for further surgical options, he underwent genetic testing, which revealed he had c.43C&gt;T (p.Arg15Cys) mutation in the AP2S1 gene diagnostic of Familial Hypocalciuric Hypercalcemia Type 3 (FHH3). The patient’s father and sister also have hypercalcemia, and have been offered genetic testing. There have been cases reported of patients with FHH3 that have symptomatic hypercalcemia and that have associated cognitive issues. Many patients with FHH can be misdiagnosed and may undergo unnecessary parathyroidectomy. This case report further elucidates the need to raise awareness of FHH.

scholarly journals Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3

2012 ◽  
Vol 45 (1) ◽  
pp. 93-97 ◽  
Author(s):  
M Andrew Nesbit ◽  
Fadil M Hannan ◽  
Sarah A Howles ◽  
Anita A C Reed ◽  
Treena Cranston ◽  
...  
Keyword(s):  
Familial Hypocalciuric Hypercalcemia ◽  
Type 3

scholarly journals Misleading localization by 18F-fluorocholine PET/CT in familial hypocalciuric hypercalcemia type-3: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Noha N Mukhtar ◽  
Mohei El-Din M Abouzied ◽  
Mohammed H Alqahtani ◽  
Muhammad M Hammami
Keyword(s):  
Vitamin D ◽  
Genetic Testing ◽  
Serum Calcium ◽  
Calcium Level ◽  
Renal Ultrasound ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Mineral Density ◽  
Pet Ct ◽  
Sigma Subunit ◽  
Type 3

Abstract Background Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. Case presentation A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51–2.89 mmol/L with concomitant PTH level of 58.7–94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. Conclusions In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Sign in / Sign up

Export Citation Format

Share Document