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Different AHO phenotype in a Chinese family with a novel GNAS missense variant: a case report | Italian Journal of Pediatrics


PHP1a is a clinical entity mainly caused by maternally transmitted heterozygous inactivating molecular defects of the GNAS gene, leading to impaired G protein-coupled receptor (GPCR) signaling [7]. Here, we report a Chinese boy with clinical features of AHO (early-onset obesity, round face, short neck, shortened fifth metacarpal bone, developmental retardation, but without short stature and subcutaneous calcifications), and resistance to PTH, TSH and ACTH. A novel heterozygous missense variant in exon 13 of GNAS gene was identified in the proband by WES and Sanger sequencing demonstrated that the proband inherited the variant from his mother, in whom it was “de novo”, since it was not present in her parents.

The distinctive phenotype of PHP-Ia versus PPHP is the result of the Gsα preferential expression from the maternal allele in specific hormone target tissues, so pathogenic variants on the active maternal allele lead to severe Gsα deficiency, whereas the same variants on the relatively inactive paternal allele have little effect on Gsα expression [5]. The proband was diagnosed with PHP1a, whereas his mother, who carried the same mutation, was diagnosed of PPHP, because she had a partial AHO phenotype (short stature and brachydactyly) and no hormone resistance. Therefore, we hypothesized that she carried her de novo GNAS variant in her paternal allele.

Cho et al. [8] reported a girl with PHP1a who inherited a heterozygous missense variant in GNAS gene from her mother with PPHP, both reported to be obese. Classically, the obesity in AHO for PHP1a and PPHP has been thought to be similar. However, in this report, the proband had accelerated weight gain during the first 7 months of life that led to severe obesity. For the proband’s mother, the clinical features of AHO included short stature but no obesity. Animal studies have shown that when the mutant GNAS allele is maternal in origin, obesity is usually present, and often severe, but when the mutant allele is paternal in origin, obesity is not frequent [9]. Clinical investigations also indicate that obesity in the AHO phenotype is significantly more common in PHP1a than in PPHP [5]. The early-onset obesity in PHP1a but not in PPHP could be explained by the evidence that Gsα is imprinted in the paraventricular nucleus of the hypothalamus [10], since maternal Gsα variant impaired the Gsα-coupled melanocortin 4 receptor (MC4R) signaling, MC4R pathogenic variants are a common genetic cause of early-onset obesity [7].

Short stature has been considered as one of the most common features of the AHO phenotype in PHP1a. However, in our family, the proband has normal stature, whereas his mother was short. The pathogenetic mechanism of reduced growth in PHP1a was initially thought to be due to GH deficiency caused by GHRH resistance [11]. However, a study showed that in a cohort of ten children with PHP1a and inactivating GNAS variants, the height and growth velocity did not significantly differ between GH-deficient and GH-sufficient subjects [12]. The clinical variability of height in children with GNAS inactivation variants could be explained by the effect of Gsα on GPCR signaling. Since GNAS inactivation variants impair MC4R signaling, even with the suppression of GH release, MC4R deficiency result in accelerated growth [13]. So impaired MC4R signaling may counterbalance the negative effect of partial GH deficiency of growth in early childhood, whereas between 12 and 18 years of age, reduced final height is the result of reduced pubertal growth spurt, which is caused by reduction in Gsα expression impairing the GHRH receptor signaling.

Heterotopic ossifications have been described as part of the phenotype of AHO [6], presenting in patients with either PHP1a or PPHP. It is known that the prevalence of subcutaneous ossifications is approximately the same in both PHP1a and PPHP [14]. Due to the same heterozygous insertion variant in GNAS gene, both mother with PPHP and her daughter with PHP1a presented with cerebral calcifications [15]. Whereas the proband in this study presented with mild intracerebral calcifications, and his mother had not heterotopic ossifications. The intrafamilial difference in heterotopic ossifications with the same GNAS gene pathogenic variant add further evidence to the variable AHO.

To the best of our knowledge, no cases with different AHO phenotypes between PHP1a and PPHP caused by the same GNAS pathogenic variant have been reported among members of the same family. In summary, we report a Chinese boy infant with PHP1a and his mother with PPHP, in whom a novel missense GNAS pathogenic variant was identified, but their AHO phenotypes were quite different. The variant in this case has not been reported in the literature, and further expands the heterogeneous phenotype of AHO due to a novel GNAS pathogenic variant.



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