Human recombinant GH replacement therapy in children with pseudohypoparathyroidism type Ia and GH deficiency: first study on the effect on growth
Giovanna Mantovani1, Emanuele Ferrante1, Agnes Linglart5, Marco Cappa2, Mariangela Cisternino3, Mohamad Maghnie4, Paolo Beck-Peccoz1 & Anna Spada1
Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of rare metabolic disorders characterized by hypocalcemia and hyperphosphatemia due to PTH resistance. Heterozygous loss of function mutations in the gene encoding the alpha-subunit of Gs (GNAS) inherited from the mother lead to PHP type Ia. PHP type Ia (PHP-Ia) is a disease in which the physical features (short stature, obesity, round face, brachydactyly and subcutaneous ossifications) that constitute Albright hereditary osteodystrophy (AHO) are classically associated to resistance to the action of different hormones that activate Gs-coupled receptors, the hallmarks being PTH, TSH and gonadotropins. Since the identification in 2003 by us and others of GH deficiency due to resistance to GHRH in PHP-Ia patients, no study investigated the effects of recombinant human GH (rhGH) therapy on height velocity in these subjects. To address this question, 7 pre-pubertal PHP-Ia children with GH deficiency (6 girls and 1 boy, mean age 8.0±1.1 years) underwent a 3 to 7 years-treatment with standard doses of rhGH. Height and height velocity were measured before and at 6-month intervals during therapy. Nine sex and age matched children with isolated, idiopathic GH deficiency were monitored over the same period of rhGH therapy for comparison. In PHP-Ia children height SDS increased from −2.75±0.6 to −2.21±0.5 (P<0.05), height velocity (HV) from 3.2±0.9 cm/year to 8.1± 0.6 cm/y (P<0.001) and HV S.D. from −2.87±0.89 to +3.3±0.7 (P<0.001) after 12 months. Despite a non-significant reduction, the HV increase was maintained after the second and third years of therapy and started to significantly decrease at puberty when pubertal growth spurt was not observed. The response to GH treatment in terms of height S.D. and HV during the first 3 years therapy was comparable to that recorded in children with idiopathic GH deficiency Data on final height will be soon available for the majority of patients.
In conclusion, we report the first study on the efficacy of rhGH replacement therapy on height velocity in children with PHP-Ia, and provide indication that replacement treatment of GH deficiency should be started soon, due to the rather limited time window for a potentially effective therapy.