Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a GNAS mutation

Abstract

Germline loss-of-function GNAS mutations are associated with multiple phenotypes, depending on the parental origin of the mutant allele. Here, we describe an infantile lethal form of atypical pseudohypoparathyroidism type 1a or 1c with severe Albright's hereditary osteodystrophy phenotype, underlying the extremely variable expressivity of this syndrome.

Keywords: Albright's hereditary osteodystrophy; GNAS mutation; inactivating PTH/PTHrP signaling disorders; pseudohypoparathyroidism; severe phenotype.

Figure 1

The growth curves of our patient illustrate the severe failure to thrive, which is more pronounced for the height (A) than for the weight (B) and the head circumference (C). The last two parameters tend to normalize with time, contrary to the height. This disharmonic evolution leads to an increasing body mass index (D), which reaches values of morbid obesity after the age of 2 y

Figure 2

Proband's hand X‐rays at 1.5 mo (A) and 22 mo (B), showing brachymetacarpy and brachydactyly, which are more obvious with age. At 22 mo, the bone age was estimated to be delayed by 1 y. Proband's knee X‐rays at 1.5 mo (C), showing no distinctive sign of acroscyphodysplasia

Figure 3

Proband's clinical phenotype: (A) At birth, he had a short stature and moderate facial dysmorphism (short nose with anteverted nostrils, mandibular hypoplasia, and full cheeks). At 16 mo (B1‐2) and at 27 mo (C1‐2, D, E), he showed severe growth retardation, obesity, facial dysmorphism (round face, extremely short nose, prominent tongue, full cheeks), short neck, brachydactyly, and edema of the hands and feet

Figure 4

The c.691C>T, p.Arg231Cys mutation in the GNAS gene (NM_000516.4) was detected in the patient's lymphocytes (A), but was absent in the maternal (B) and paternal (C) blood samples

Figure 5

The arginine concerned by the c.691C>T, p.Arg231Cys mutation is highly conserved through the species in the amino acid sequence of the G alpha subunit (reference of the human protein sequence: NP_000507.1)