Abstract
Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by Albright’s hereditary osteodistrophy (AHO) and resistance to hormones that act via the α subunit of the Gs protein (Gsα) protein, ie PTH, TSH, FSH/LH, and, as recently described in limited series, GHRH. However, the current lack of data on GHRH secretion, obesity and short stature included in the AHO phenotype hampers interpretation of GH secretory status and its effects on these subjects. We evaluated GH secretion after GHRH plus arginine (Arg) stimulus, IGF-I levels and anthropometric features in an exclusively pediatric population of 10 PHP-Ia subjects. Of our PHP-Ia children, 5 out of 10 (50%) showed impaired GH responsiveness to the provocative test, with a lower prevalence than the 75–100% previously reported. A negative correlation (p=0.024) was found between GH secretion and body mass index (BMI), whereas no correlation emerged between GH and IGF-I values (p=0.948). Height and growth velocity did not significantly differ between GH-deficient and GH-sufficient subjects. In the 5 GH-deficient patients, GHRH resistance could arguably be responsible for hormonal impairment; however, 3 of them were obese, showing normal stature and IGF-I levels: the increased BMI in these subjects could influence GH secretion and its effects. In conclusion, GH deficiency is frequent among PHP-Ia children and its prevalence is variable, two factors indicating that GH secretory testing should be part of the routine management of this patient group. It could be argued that GHRH resistance is the pathogenetic mechanism in most patients, but further studies on GHRH secretion are needed to define which values can be considered as raised. Lastly, because BMI has been indicated as a major determinant of evoked adult GH response to provocative testing, GH levels related to increased BMI also in childhood could be helpful in defining GH assessment in obese or overweight PHP-Ia children.
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References
Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism — an example of “Seabright Banatam syndrome”. Endocrinology 1942, 30: 922–32.
Weinstein LS. Albright hereditary osteodystrophy, pseudohypoparathyroidism, and Gs deficiency. In: Spiegel AM ed. G proteins, receptors, and disease. Totowa, NJ: Humana Press Totowa. 1998, 23–56.
Levine MA. Pseudohypoparathyroidism. In: Bilezikian JP, Raisz LG, Rodan GA eds. Principles of bone biology. San Diego: Academic Press. 2002, 1137–63.
Shima M, Nose O, Shimizu K, Seino Y, Yabuuchi H, Saito T. Multiple associated endocrine abnormalities in a patient with pseudohypoparathyroidism type 1a. Eur J Pediatr 1988, 147: 536–8.
Levine MA, Ahn TG, Klupt SF, Kaufman KD, et al. Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein G(s) as the molecular basis for Albright hereditary osteodystrophy. Proc Nat Acad Sci USA 1988, 85: 617–21.
Aldred MA, Trembath RC. Activating and inactivating mutations in the human GNAS1 gene. Hum Mutat 2000, 16: 183–9.
Nakamoto JM, Sandstrom AT, Brickman AS, Christenson RA, Van Dop C. Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsalpha gene mutation. Am J Med Genet 1998, 77: 261–7.
Weinstein LS. The stimulatory G protein a-subunit gene: mutations and imprinting lead to complex phenotypes. J Clin Endocr Metab 2001, 86: 4622–6.
Hayward B, Kamiya M, Strain L, et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 1998, 95: 10038–45.
Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005, 63: 65–74.
Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The Gsa gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 2002, 87: 4736–40.
Scott DC, Hung W. Pseudohypoparathyroidism Ia and growth hormone deficiency in two siblings. J Pediatr Endocrinol Metab 1995, 8: 205–7.
Kaji M, Umeda K, Ashida M, Tajima T. A case of pseudohypoparathyroidism type Ia complicated with growth hormone deficiency: recovery of growth hormone secretion after vitamin D therapy. Eur J Pediatr 2001, 160: 679–81.
Faull CM, Welbury RR, Paul B, Kendall-Taylor P. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. QJM 1991, 78: 251–64.
Mantovani G, Maghnie M, Weber G, et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003, 88: 4070–4.
Germain-Lee EL, Groman J, Crane JL, Jan de Beur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003, 88: 4059–69.
Sassolas G. Growth hormone-realising hormone: past and present. Horm Res 2000, 53: 88–92.
Guillemin R. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J Endocrinol 2005, 184: 11–28.
Abdenur JE, Solans CV, Smith MM, Carman C, Pughliese MT, Lifshitz F. Body composition and spontaneous growth hormone secretion in normal short stature children. J Clin Endocrinol Metab 1994, 78: 277–82.
Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab 1991, 73: 1081–8.
Ballerini MG, Ropelato MG, Domenè HM, Pennisi P, Heinrich JJ, Jasper HG. Differential impact of simple childhood obesity on the components of the growth hormone-insulinlike growth factor (IGF)-IGF binding proteins axis. J Pediatr Endocrinol Metab 2004, 17: 749–57.
Loche S, Pintor C, Cappa M, Ghigo E, Ruggini R, Muller EE. Pyridostigmine counteracts the blunted GH response to GHRH of obese children. Acta Endocrinol (Copenh) 1989, 120: 624–8.
de Wijn EM, Steendijk R. Growth and maturation in pseudohypoparathyroidism: a longitudinal study in 5 patients. Acta Endocrinol (Copenh) 1982, 101: 223–6.
Marguet C, Mallet E, Basuyau JP, Martin D, Leroy M, Brunelle P. Clinical and biological heterogeneity in pseudohypoparathyroidism syndrome. Results from a multicenter study. Horm Res 1997, 48: 120–30.
Nagant de Deuxchaisnes C, Krane SM. Hypoparathyroidism. In: Avioli LV, Krane SM eds. Metabolic bone disease. Vol. 2. New York: Academic Press. 1978, 217–445.
Butler MG, Meaney FJ, Kaler SG. Metacarpophalangeal pattern profile analysis in clinical genetics: an applied anthropometric method. Am J Phys Anthropol 1986, 70: 195–201.
de Sanctis L, Vai S, Andreo MR, Romagnolo D, Silvestro L, de Sanctis C. Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients. J Clin Endocrinol Metab 2004, 89: 1650–5.
de Sanctis L, Romagnolo D, Olivero M, et al. Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism. Pediatr Res 2003, 53: 749–55.
Luciano A, Bressan F, Zoppi G. Body mass index reference curves for children aged 3–19 years from Verona, Italy. Eur J Clin Nutr 1997, 51: 6–10.
Ghigo E, Bellone J, Aimaretti G, et al. Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endocrinol Metab 1996, 81: 3323–7.
Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. Stanford, CA: Stanford University Press. 1993.
Valetto RM, Bellone J, Baffoni C, et al. Reproducibility of the growth hormone response to stimulation with growth hormone-releasing hormone plus arginine during lifespan. Eur J Endocrinol 1996, 135: 568–72.
Weisman Y, Golancer A, Spirer Z, Farfel Z. Pseudohypoparathyroidism type Ia presenting as congenital hypothyroidism. J Pediatr 1985, 107: 413–5.
Riepe FG, Ahrens W, Krone N, et al. Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene. Eur J Endocrinol 2005, 152: 515–9.
Hayward BE, Barlier A, Korbonits M, et al. Imprinting of the Gas gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 2001, 107: R31–6.
Tiulpakov AN, Mazerkina NA, Brook CGD, Hindmarsh PC, Peterkova VA, Gorelyshev SK. Growth in children with craniopharyngioma following surgery. Clin Endocrinol (Oxf) 1998, 49: 733–8.
Pinto G, Bussieres L, Recasens C, Souberbielle, Zerah M, Brauner R. Pinto G. Hormonal factors influencing weight and growth pattern in craniopharyngioma. Horm Res 2000, 53: 163–9.
Bastepe M, Weinstein LS, Ogata N, et al. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci USA 2004, 101: 14794–9.
Bonert VS, Elashoff JD, Barnett P, Melmed S. Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency. J Clin Endocrinol Metab 2004, 89: 3397–401.
Corneli G, Di Somma C, Baldelli R, et al. The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol 2005, 153: 257–64.
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de Sanctis, L., Bellone, J., Salerno, M. et al. GH secretion in a cohort of children with pseudohypoparathyroidism type Ia. J Endocrinol Invest 30, 97–103 (2007). https://doi.org/10.1007/BF03347406
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DOI: https://doi.org/10.1007/BF03347406