ESPE Abstracts (2019) 92 FC6.6

Craniosynostosis in Inactivating PTH/PTHrP Signaling Disorder 2: A Non-Classical Feature to Consider

Isolina Riaño-Galan1,2,3, Anya Rothenbuhler4,5, Yahya Debza6, Anna Barosi6,7,5, Giovanna Mantovani8, Guiomar Perez de Nanclares9, Agnès Linglart6,7,5


1Pediatric Endocrinology. Pediatrics. Hospital Universitario Central de Asturias, Oviedo, Spain. 2University of Oviedo, Oviedo, Spain. 3Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain. 4APHP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, filière OSCAR and Plateforme d´éxpertise Maladies Rares Paris-Sud, Le Kremlin Bicètre, France. 5APHP, Department of Endocrinology and Diabetology, Bicêtre Paris Sud hospital, Le Kremlin Bicètre, France. 6APHP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, filière OSCAR and Plateforme déxpertise Maladies Rares Paris-Sud, Le Kremlin Bicètre, France. 7INSERM U1169, Hôpital Bicêtre, Le Kremlin Bicètre, France. 8Fondazione IRCCS Ca´Granda Ospedale Maggiore Policlinico, Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. 9Molecular (Epi)Genetics Laboratory, bioAraba National Health Institute, OSI Araba University Hospital, Vitoria-Gasteiz, Spain


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.

Table 1.- Characteristics of the 8 patients (4 females) with craniosynostosis (CSO) and iPPSD2
GNAS mutationOriginAge at diagnostic iPPSD2 (years)Hormonal resistancesChiari 1 anomalyCSOSynostosis suturesAge at diagnostic CSO (years)
1Exon 1Novo0.5PTH, TSHyescomplexSagittal-coronal4.9
2Intron 5Novo3PTH, TSH, GonadotrophinsnocomplexSagittalantenatal
3Exon 7-7PTH, TSH-complexpansynostosis<2
4Intron 3mat0.1PTH, TSHnocomplexSagittal-lambdoid1
5Exon 11mat0.5PTH, TSH, Gonadotrophinsyescomplexpansynostosis1.5
6Exon 5mat0PTH, TSHnosimpleCoronal6.5
7Exon 1-1.5nonosimpleCoronal<1
8Exon 7Novo2PTH, TSH, ACTHyescomplexSagittal-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.

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