Pseudohypoparathyroidism

Abstract

Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the Gsα/cAMP/PKA signaling pathway by parathyroid hormone (PTH) and other hormones that interact with Gsa-coupled receptors. Proximal renal tubular resistance to PTH and thus hypocalcemia and hyperphosphatemia, frequently in presence of brachydactyly, ectopic ossification, early-onset obesity, or short stature are common features of PHP. Registries and large cohorts of patients are needed to conduct clinical and genetic research, to improve the still limited knowledge regarding the underlying disease mechanisms, and allow the development of novel therapies.

Keywords: Acrodysostosis; Brachydactyly; Early-onset obesity; GNAS; PTH resistance; Pseudohypoparathyroidism; Subcutaneous ossifications.

Fig. 1.

Subcutaneous ossifications in patients with PHP1A or POH. All patients presented carry a loss-of-function mutation at the coding sequence of the GNAS gene. (A–C) Different features of subcutaneous ossifications in infants; note the red/purple color of the lesions. (D–F) Subcutaneous ossifications in children and adolescents. Small lesions become more pale. (G, H) Organized painful ossification below the heel; surgical excision was performed and the ossification did not recur. (I) Severe extended ossification of the foot and ankle, one part is extruding white material. (J) Painful ossification surrounding the metatarsal joint of the second toe.

Fig. 2.

Growth and weight charts of a boy who was referred at the age of 12 months because of an excessive weight gain. Elevated TSH and PTH at the time of referral led to genetic analyses that identified a GNAS mutation on exon 7. (A) growth and weight charts. (B) Body mass index chart.

Fig. 3.

Cranial circumference chart (A) and craniosynostosis (B) of a young girl with a maternally inherited GNAS deletion removing GNAS exons 1 and 2, and a severe PHP1A phenotype. The computed tomography scan was done at the time of the first surgery. Note the fusion of the coronal and sagittal sutures, and the cupper beaten aspect of the skull.