The Growth Hormone-Insulin-like Growth Factor Axis in Glycogen Storage Disease Type 1: Evidence of Different Growth Patterns and Insulin-like Growth Factor Levels in Patients with Glycogen Storage Disease Type 1a and 1b Daniela Melis, MD, PhD, Rosario Pivonello, MD, PhD, Giancarlo Parenti, MD, Roberto Della Casa, MD, Mariacarolina Salerno, MD, Francesca Balivo, MD, Pasquale Piccolo, PhD, Carolina Di Somma, MD, Annamaria Colao, MD, PhD, and Generoso Andria, MD, PhD Objectives To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glyco- gen storage disease type 1 (GSD1). Study design This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control sub- jects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary anti- bodies (APA). Results Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b (P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b (P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a (P = .008), 57.1% of patients with GSD1b (P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a (P = .02) and control subjects (P = .03). The GH response to the provocative test inversely correlated with the presence of APA (P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores (P = .003). Conclusion Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The ncreased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment. (J Pediatr 2010;156:663-70). G lycogen storage disease type 1 (GSD1) is an inborn disorder of glucose metabolism caused by the deficiency of micro- somal glucose-6-phosphatase (G6Pase) system. 1 Two major forms of the disease have been identified: GSD1a, which is caused by mutations in the gene encoding the G6Pase alpha (G6Pasea), and GSD1b, caused by mutations in the gene encoding the G6P translocase (G6PT), which transports G6P from cytoplasm to microsomes. 2,3 G6Pasea is expressed in the liver, kidney, and intestine, whereas G6PT is ubiquitous. Both glycogen accumulation and a G6Pase system, composed of G6PT and a different G6Pase, named G6Paseb, have been detected in the pituitary gland. 4,5 The clinical and biochemical phe- notype of GSD1 include hepatomegaly, lactic acidemia, hypertriglyceridemia, and hyperuricemia; patients with GSD1b also show neutropenia and neutrophil dysfunction with consequent susceptibility to recurrent infections. 1 GSD1 is associated with endocrine dysfunctions, including thyroid autoimmune disease. 6 In the past, short stature, often associated with delayed puberty, was frequently reported. 7,8 The introduction of specific dietary treatment has improved growth pattern. 9,10 However, there is still a considerable variability in the final stature achieved by patients with GSD1. 11 Earlier studies evaluating the growth From the Department of Pediatrics (D.M., G.P., R.D.C., M.S., F.B., P.P., G.A.) and Department of Molecular and Clinical Endocrinology and Oncology (R.P., C.D.S., A.C.), Federico II University, Naples, Italy The authors declare no conflicts of interest 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.10.032 AHA Anti-hypothalamus antibodies ALS Acid labile subunit APA Anti-pituitary antibodies BMI Body mass index G6Pase Microsomal glucose-6- phosphatase G6Pasea G6Pase alpha G6PT G6P translocase GH Growth hormone GSD1 Glycogen storage disease type 1 ICR1 Imprinting Center Region 1 IG Immunoglobulin IGF Insulin-like growth factor IGFBP IGF binding proteins SNP Single nucleotide polymorphism 663