A Translational Study of the Novel Dental Phenotype Associated with Familial Hypocalciuric Hypercalcemia — ASN Events
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  3. A Translational Study of the Novel Dental Phenotype Associated with Familial Hypocalciuric Hypercalcemia

A Translational Study of the Novel Dental Phenotype Associated with Familial Hypocalciuric Hypercalcemia (#175)

Amina Attia 1 , Franceska Kovaci 1 , Nicolas Obtel 1 , Anne-Laure Lakhel 1 , Albain Chansavang 2 , Frédéric Vaysse 3 , Frédérique Savagner 3 , Thomas Edouard 3 , Agnès Linglart 4 , Eric Pasmant 2 , Fadil Hannan 5 , Rajesh Thakker 6 , Jean-Philippe Bertocchio 1 7 , Catherine Chaussain 1
  1. UMR1333 Oral Health, Montrouge, France
  2. AP-HP Cochin Hospital, Paris, France
  3. CHU Toulouse, Toulouse, France
  4. AP-HP - Kremlin-Bicêtre Hospital, Le Kremlin-Bicêtre, France
  5. Nuffield Department of Women's & Reproductive Health, Oxford, United Kingdom
  6. Radcliffe University, Oxford, United Kingdom
  7. AP-HP - Hôpital de la Pitié-Salpêtrière, Paris, France

Background: Familial Hypocalciuric Hypercalcemia (FHH) is a rare autosomal dominant genetic disorder characterized by chronic PTH-dependent hypercalcemia resulting from inactivation of CASR, GNA11, or AP2S1 (FHH types 1, 2, or 3). GNA11 encodes the G-protein Gα11 coupled to CaSR. Our group recently identified enamel defects compatible with Amelogenesis Imperfecta (AI) in patients with FHH.

 

Objective: (i) To characterize the clinical and biochemical phenotypes of FHH to optimize patient follow-up and establish genotype-phenotype correlations. (ii) To investigate the dental phenotype of FHH using mouse models.

 

Methods: (i) Build a prospective cohort of patients with FHH and of their unaffected relatives. (ii) Study enamel mineralization in mouse models of FHH by micro-CT.

 

Results: A cohort of 40 patients with FHH from 29 families has been established: patients exhibited PTH-dependent hypercalcemia (comparison with unaffected relatives: calcium 2.74±0.23mM vs. 2.35±0.11mM, p<0.0001, PTH 0.79vs.0.59times the upper limit of normal range, p=0.13). Bone remodeling markers, bone mineralization, and history of nephrolithiasis do not differ significantly with their unaffected relatives. Among 32 patients with FHH who underwent dental examination, 31 presented enamel defects consistent with AI that were not observed in relatives without FHH.

Micro-CT analysis of mouse models of FHH type 2 reveals significantly lower enamel volume and density, together with a delay onset of enamel mineralization. By contrast, micro-CT analysis of the mouse models of FHH type 3 do not show the same dental phenotype despite hypercalcemia, suggesting a specific role of GNA11 in amelogenesis. 

 

Conclusion and discussion: Patients with FHH present a dental phenotype consistent with AI, which is recapitulated in mouse models of FHH type 2. Ongoing recruitment will expand the cohort to validate these findings. Further studies in mouse models will investigate the mechanisms underlying enamel defects in FHH and clarify the respective roles of CASR, GNA11, and AP2S1 in amelogenesis.