Classic features of inactivating PTH/PTHrP Signaling Disorder 2 or 3 (iPPSD2, iPPSD3), i.e. former pseudohypoparathyroidism include multi-hormone resistance, short stature, subcutaneous ossifications, brachydactyly, and early-onset obesity and a molecular defect at the GNAS region. In addition, patients may present with less-known features including craniosynostosis (CSO).
Objective: To describe the prevalence of CSO in a cohort of 90 iPPSD2 and iPPSD3 patients, followed in one reference center. To describe the characteristics of the CSO in 8 iPPSD2 patients, recruited from 3 reference centers with data about the iPPSD2 disease.
Results: Six out of 71 iPPSD2 (8.4%) and none of the 19 iPPSD3 patients, had CSO. 7/8 and 1/8 patients with CSO carried a maternal and a paternal GNAS mutation, respectively. The 7 patients with CSO (table 1) and a maternal GNAS mutation, presented with a severe iPPSD2 phenotype associated to the typical PTH resistance. We characterized cognitive impairment in 8/8, sleep disturbances in 6/8, and congenital hypothyroidism in 4/8. CSO was discovered before the diagnosis of iPPSD2 in 4/8.
|GNAS mutation||Origin||Age at diagnostic iPPSD2 (years)||Hormonal resistances||Chiari 1 anomaly||CSO||Synostosis sutures||Age at diagnostic CSO (years)|
|1||Exon 1||Novo||0.5||PTH, TSH||yes||complex||Sagittal-coronal||4.9|
|2||Intron 5||Novo||3||PTH, TSH, Gonadotrophins||no||complex||Sagittal||antenatal|
|3||Exon 7||-||7||PTH, TSH||-||complex||pansynostosis||<2|
|4||Intron 3||mat||0.1||PTH, TSH||no||complex||Sagittal-lambdoid||1|
|5||Exon 11||mat||0.5||PTH, TSH, Gonadotrophins||yes||complex||pansynostosis||1.5|
|6||Exon 5||mat||0||PTH, TSH||no||simple||Coronal||6.5|
|8||Exon 7||Novo||2||PTH, TSH, ACTH||yes||complex||Sagittal-coronal||<2|
Comments: In this large cohort of iPPSD2 and 3 patients, we found a significant prevalence of CSO. CSO seems associated with disease severity. As it was detected only in patients with loss-of-function in the GNAS gene, it is likely that the impaired PTH/PTHrP in skull bone is involved. Our findings have clinical relevance. We suggest that regular head circumference-for-age, and, if necessary, fundus oculi, should be performed in children with iPPSD2. Furthermore, CSO could be the first manifestation of iPPSD2, raising the need for calcium homeostasis evaluation in children with CSO of unknown origin. Early diagnostic and follow-up of these complex patients may improve their clinical care.
19 Sep 2019 - 21 Sep 2019