Background: FHH is a genetically heterogeneous condition mimicking primary hyperparathyroidism at the difference of low urine calcium excretion. FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. FFH 3, the rarest of the 3, is usually associated to 3 recurrent mutations affecting the arginine residue in position 15. The clinical phenotype has not been well described. We report a new case striking by the neurological involvement. Case: A 26-year old man was referred for fortuitously found hypercalcemia (135 mg/l, 3.36 mmol/l). The family history was not well known. The personal history included bilateral inguinal hernia and testicular fixation. The patient had followed a special schoolchild course because of mild cognitive impairment but was able to work and no further investigations were done. Biological assessment revealed moderately high calcium (115 mg/l, 2.86 mmol/l), low 25OHvitD3 (22 ng/ml), but normal phosphate (29 mg/l; N:245), magnesium (22 mg/l; N:2024), and PTH (54 ng/ml; N<68) blood levels, with low urine calcium excretion (63 mg/24 H; creatininuria: 0.7 g/24 H). Nevertheless, bilateral nephrocalcinosis was present on CTscan. The Tscore (DEXA) was −1.5 (vertebral) and −1 (femoral), and remained stable over time. The diagnosis of FHH1 was considered. Frequent intron 5 polymorphism and heterozygous variant of the CASR gene were identified that could not explain biological features. At 33 years old, the patient was re-referred after surgery of calcifying right hip tendonitis with very poor results confining the patient in a wheeling-chair. Besides physical inability, the patient had now overt cognitive impairment (MMS: 25/30) confirmed by a specialized neurological evaluation showing attentional and working memory disorders (MOCA 21/30) despite a normal brain MRI. He couldnt read or work anymore and couldnt remember the birth date of his 9-month old child. The NGS completion of the genetic work-up showed a AP2S1 gene heterozygous variation (exon2: c.43C>T (p.Arg15Cys) arguing for type 3 FHH.
Conclusion: Despite similar biological and genetic features (with the most frequent p.Arg15Cys mutation), the phenotype of this case was different from that one reported in one of the largest FHH3 cohort (Vargas-Poussou JCEM 2016) since our patient had nephrocalcinosis and no osteoporosis, with evolutive cognitive impairment, as reported in some other series (Szalat Endocrine 2017; 10 patients - Hannan Human Molecular genetic 2015; 17 patients). These findings suggest that AP2S1 could play a role in neural development. Cognitive impairment in FHH should orientate towards AP2S1 gene mutation.
18 - 21 May 2019
European Society of Endocrinology