Dental and craniofacial features associated with GNAS loss of function mutations

Eur J Orthod. 2020 Nov 3;42(5):525-533. doi: 10.1093/ejo/cjz084.


Background: Pseudohypoparathyroidism (PHP, OMIM #103580) is a very rare disease (incidence 0.3-1/100,000). Heterozygous inactivating mutations involving the maternal GNAS exons 1-13 that encodes the alpha subunit of the stimulatory G protein (Gsα) cause inactivating parathyroid hormone (PTH)/PTHrP signalling disorder type 2 (iPPSD2 or PHP type 1A), which is characterized by Albright hereditary osteodystrophy and resistance to multiple hormones that act through the Gsα signalling pathway (including PTH, thyroid-stimulating hormone, and α-melanocyte-stimulating hormone). To date, little information is available on craniofacial features in patients with PHP. The small number of patients studied in previous reports as well as the lack of molecular characterization of the patients may have precluded the detection of specific orofacial manifestations in the different PHP subtypes.

Materials/methods: We conducted a systematic analysis of dental and craniofacial features in 19 patients with iPPSD2 and maternal GNAS inactivating mutations to assess the frequency and specificity of the anomalies.

Results: Facial examinations showed reduced vertical, sagittal, and transverse development of the mid-facial structures. Intraoral and radiographic examinations revealed that 89 per cent of the patients had at least one dental anomaly, including tooth submergence leading to severe infraocclusion in 83 per cent of cases. Craniofacial analysis of lateral cephalometric radiographs also showed a significant alteration in the development of the cranial base and maxillary and mandibular structures in these patients.

Conclusions: Patients with iPPSD2 and maternal GNAS mutations had specific craniofacial alterations and dental abnormalities. These specific defects should be assessed in order to provide appropriate dental and orthodontic care to these patients. (clinical trial registration: 1920371 v 0, French Nationale Data Processing and Liberties Commission - CNIL).

MeSH terms

  • Chromogranins / genetics
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Humans
  • Loss of Function Mutation*
  • Mutation
  • Pseudohypoparathyroidism* / genetics


  • Chromogranins
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs