ESPE Abstracts (2016) 86 RFC2.7

Effect of Paternal Loss-of-Function Mutations of GNAS on Growth During the Childhood: A Role for XL

Lea Chantal Tran, Anne-Claire Brehin, Nicolas Richard & Marie-Laure Kottler


CMR Phosphorus and Calcium, Department of Genetics, Caen University Hospital, Caen, Normandy, France


Background: Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia when paternally inherited. Mutations on the paternal, but not the maternal, GNAS allele are associated with intrauterine growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2–13 (including XL and Gαs) than with exon 1/intron 1 (limited to Gαs) mutations suggesting a role for XL in fetal growth. (Richard et al, 2013).

Objective and hypotheses: To assess the growth during childhood according to the mutation location.

Method: We conducted a retrospective study in patients with paternal mutations on either exon 1 (group 1: n=9) or exons 2–13 (group 2: n=19). Weight (W) and height (H) were compared to sex-specific OMS reference charts. Data were gathered into three groups depending on the age. Results were expressed as the mean of Z-score.

Results: Weight: The difference between groups 1 and 2 disappeared after birth. Despite being born with a severe IUGR, patients displayed weight-for-age values within the normal range (from −2 to +2 SD) after 10 years. Height: Patients from both groups are smaller compared to the OMS control references. Interestingly patients of group 2 remained significantly smaller than patients of group 1 (Table 1).

Table 1.
Age range (months)Group 1 (number of data) [quartile 1; quartile 3])Group 2 (number of data) [quartile 1; quartile 3])P-value
0–24−2.0 (32, [−3.1;−1.2])−3.1 (26, [−3.7;−2.1])NS
24–120−1.4 (10, [−1.5;−1.3])−1.0 (41, [−2.1;−0.1])NS
>120−1.0 (12, [−1.2;−0.1])−1.5 (29, [−2.3;−0.6])<0.05

Conclusion: Our results confirm a role for XL in the regulation of foetal growth. After birth, the patients recovered a normal weight during the first few years. Our data implicate a role for the paternal imprinting in the height in these patients.

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