GH excess; GPR101; X-LAG; acromegaly; gigantism; neurofibromatosis type 1; optic pathway glioma; overgrowth; pituitary tumor; Medicine (all); General Medicine
Abstract :
[en] Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Hannah-Shmouni, Fady ; Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA
Trivellin, Giampaolo ; Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA ; Laboratory of Cellular and Molecular Endocrinology, Humanitas Research Hospital-IRCCS, 20089 Rozzano, Italy
Beckers, Pablo ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA
Karaviti, Lefkothea P; Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA
Lodish, Maya; Department of Pediatrics, University of California, San Francisco, CA 94143, USA
Tatsi, Christina ; Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA
Adesina, Adekunle M; Immunology and Pediatrics-Hematology/Oncology, Neuropathology and Molecular Neuropathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA
Adamidou, Fotini; Department of Endocrinology, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece
Mintziori, Gesthimani; Department of Endocrinology, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece
Josefson, Jami L; Division of Endocrinology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Quezado, Martha; Laboratory of Pathology, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA
Stratakis, Constantine A; Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA ; Human Genetics & Precision Medicine, Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research & Technology Hellas, 70013 Heraklion, Greece ; Experimental-Research Center ELPEN, 19009 Athens, Greece
Language :
English
Title :
Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess.
Funding: This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (project number Z1A HD008920).Conflicts of Interest: C.A.S. holds patents on the PRKAR1A, PDE11A and GPR101 genes and/or their function and his laboratory has received research funding from Pfizer Inc. Trivellin holds a patent on the GPR101 gene and its function (US Patent No. 10,350,273, Treatment of Hormonal Disorders of Growth). The authors declare that they have no conflicts of interest that may interfere with the contents of this article.
Friedman, J.M. Neurofibromatosis 1. In GeneReviews®; Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., Bird, T.D., Ledbetter, N., Mefford, H.C., Smith, R.J.H., et al., Eds.; University of Washington: Seattle, WA, USA, 1993–2022. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1109/(accessed on 20 February 2022).
Stewart, D.R.; Korf, B.R.; Nathanson, K.L.; Stevenson, D.A.; Yohay, K. Care of adults with neurofibromatosis type 1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 2018, 20, 671–682. [CrossRef] [PubMed]
Lammert, M.; Friedman, J.M.; Kluwe, L.; Mautner, V.F. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch. Dermatol. 2005, 141, 71–74. [CrossRef] [PubMed]
Griffiths, S.; Thompson, P.; Frayling, I.; Upadhyaya, M. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam. Cancer 2007, 6, 21–34. [CrossRef] [PubMed]
Bruzzi, P.; Sani, I.; Albanese, A. Reversible Growth Hormone Excess in Two Girls with Neurofibromatosis Type 1 and Optic Pathway Glioma. Horm. Res. Paediatr. 2015, 84, 414–422. [CrossRef]
Hozumi, K.; Fukuoka, H.; Odake, Y.; Takeuchi, T.; Uehara, T.; Sato, T.; Inoshita, N.; Yoshida, K.; Matsumoto, R.; Bando, H.; et al. Acromegaly caused by a somatotroph adenoma in patient with neurofibromatosis type 1. Endocr. J. 2019, 66, 853–857. [CrossRef]
Adeloye, A. Coexistence of acromegaly and neurofibromatosis in a Nigerian. East Afr. Med. J. 1979, 56, 38–39.
Barberis, M.; Gambacorta, M.; Versari, P.; Filizzolo, F. About a case of Recklinghausen’s disease associated with pituitary adenoma (author’s transl). Pathologica 1979, 71, 265–272.
Checa Garrido, A.; del Pozo Pico, C. Acromegaly and type 1 neurofibromatosis. Is association of both conditions due to chance? Endocrinol. Nutr. 2013, 60, 144–145. [CrossRef]
Fuqua, J.S.; Berkovitz, G.D. Growth hormone excess in a child with neurofibromatosis type 1 and optic pathway tumor: A patient report. Clin. Pediatr. 1998, 37, 749–752. [CrossRef]
Josefson, J.; Listernick, R.; Fangusaro, J.R.; Charrow, J.; Habiby, R. Growth hormone excess in children with neurofibromatosis type 1-associated and sporadic optic pathway tumors. J. Pediatr. 2011, 158, 433–436. [CrossRef] [PubMed]
Hannah-Shmouni, F.; Demidowich, A.P.; Rowell, J.; Lodish, M.; Stratakis, C.A. Large pituitary gland with an expanding lesion in the context of neurofibromatosis 1. BMJ Case Rep. 2017, 2017, bcr-2017. [CrossRef] [PubMed]
Cambiaso, P.; Galassi, S.; Palmiero, M.; Mastronuzzi, A.; Del Bufalo, F.; Capolino, R.; Cacchione, A.; Buonuomo, P.S.; Gonfiantini, M.V.; Bartuli, A.; et al. Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. Am. J. Med. Genet. A 2017, 173, 2353–2358. [CrossRef] [PubMed]
Bizzarri, C.; Bottaro, G. Endocrine implications of neurofibromatosis 1 in childhood. Horm. Res. Paediatr. 2015, 83, 232–241. [CrossRef] [PubMed]
Sani, I.; Albanese, A. Endocrine Long-Term Follow-Up of Children with Neurofibromatosis Type 1 and Optic Pathway Glioma. Horm. Res. Paediatr. 2017, 87, 179–188. [CrossRef] [PubMed]
Kurozumi, K.; Tabuchi, A.; Ono, Y.; Tamiya, T.; Ohmoto, T.; Furuta, T.; Hamasaki, S. Pituitary adenoma associated with neurofibromatosis type 1: Case report. No Shinkei Geka 2002, 30, 741–745. [PubMed]
Nakajima, M.; Nakasu, Y.; Nakasu, S.; Matsuda, M.; Handa, J. Pituitary adenoma associated with neurofibromatosis: Case report. Nihon Geka Hokan 1990, 59, 278–282.
Pei, L.; Melmed, S. The neurofibromatosis gene in human pituitary adenomas. Endocr. Pathol. 1994, 5, 229–232. [CrossRef]
Manski, T.J.; Haworth, C.S.; Duval-Arnould, B.J.; Rushing, E.J. Optic pathway glioma infiltrating into somatostatinergic pathways in a young boy with gigantism. Case report. J. Neurosurg. 1994, 81, 595–600. [CrossRef] [PubMed]
Duchowny, M.S.; Katz, R.; Bejar, R.L. Hypothalamic mass and gigantism in neurofibromatosis: Treatment with bromocriptine. Ann. Neurol. 1984, 15, 302–304. [CrossRef]
Josefson, J.L.; Listernick, R.; Charrow, J.; Habiby, R.L. Growth Hormone Excess in Children with Optic Pathway Tumors Is a Transient Phenomenon. Horm. Res. Paediatr. 2016, 86, 35–38. [CrossRef] [PubMed]
Trivellin, G.; Daly, A.F.; Faucz, F.R.; Yuan, B.; Rostomyan, L.; Larco, D.O.; Schernthaner-Reiter, M.H.; Szarek, E.; Leal, L.F.; Caberg, J.H.; et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N. Engl. J. Med. 2014, 371, 2363–2374. [CrossRef]
Beckers, A.; Lodish, M.B.; Trivellin, G.; Rostomyan, L.; Lee, M.; Faucz, F.R.; Yuan, B.; Choong, C.S.; Caberg, J.H.; Verrua, E.; et al. X-linked acrogigantism syndrome: Clinical profile and therapeutic responses. Endocr. Relat. Cancer 2015, 22, 353–367. [CrossRef]
Trivellin, G.; Bjelobaba, I.; Daly, A.F.; Larco, D.O.; Palmeira, L.; Faucz, F.R.; Thiry, A.; Leal, L.F.; Rostomyan, L.; Quezado, M.; et al. Characterization of GPR101 transcript structure and expression patterns. J. Mol. Endocrinol. 2016, 57, 97–111. [CrossRef]
Drimmie, F.M.; MacLennan, A.C.; Nicoll, J.A.; Simpson, E.; McNeill, E.; Donaldson, M.D. Gigantism due to growth hormone excess in a boy with optic glioma. Clin. Endocrinol. 2000, 53, 535–538. [CrossRef]
National Institutes of Health. National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Bethesda, Md., USA, July 13–15, 1987. Neurofibromatosis 1988, 1, 172–178.
Rose, S.R.; Municchi, G.; Barnes, K.M.; Cutler, G.B., Jr. Overnight growth hormone concentrations are usually normal in pubertal children with idiopathic short stature–a Clinical Research Center study. J. Clin. Endocrinol. Metab 1996, 81, 1063–1068. [CrossRef]
Takahashi, Y.; Kipnis, D.M.; Daughaday, W.H. Growth hormone secretion during sleep. J. Clin. Investig. 1968, 47, 2079–2090. [CrossRef] [PubMed]
Ho, K.Y.; Evans, W.S.; Blizzard, R.M.; Veldhuis, J.D.; Merriam, G.R.; Samojlik, E.; Furlanetto, R.; Rogol, A.D.; Kaiser, D.L.; Thorner, M.O. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: Importance of endogenous estradiol concentrations. J. Clin. Endocrinol. Metab. 1987, 64, 51–58. [CrossRef] [PubMed]
Ho, K.Y.; Weissberger, A.J. Characterization of 24-hour growth hormone secretion in acromegaly: Implications for diagnosis and therapy. Clin. Endocrinol. 1994, 41, 75–83. [CrossRef] [PubMed]
Zadik, Z.; Chalew, S.A.; McCarter, R.J., Jr.; Meistas, M.; Kowarski, A.A. The influence of age on the 24-hour integrated concentra-tion of growth hormone in normal individuals. J. Clin. Endocrinol. Metab. 1985, 60, 513–516. [CrossRef]
Quabbe, H.J.; Schilling, E.; Helge, H. Pattern of growth hormone secretion during a 24-hour fast in normal adults. J. Clin. Endocrinol. Metab. 1966, 26, 1173–1177. [CrossRef]
Riva, P.; Corrado, L.; Natacci, F.; Castorina, P.; Wu, B.L.; Schneider, G.H.; Clementi, M.; Tenconi, R.; Korf, B.R.; Larizza, L. NF1 microdeletion syndrome: Refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am. J. Hum. Genet. 2000, 66, 100–109. [CrossRef]
Cai, Y.; Fan, Z.; Liu, Q.; Li, J.; Du, J.; Shen, Y.; Wang, S. Two novel mutations of the NF1 gene in Chinese Han families with type 1 neurofibromatosis. J. Dermatol. Sci. 2005, 39, 125–127. [CrossRef]
Hannah-Shmouni, F.; Trivellin, G.; Stratakis, C.A. Genetics of gigantism and acromegaly. Growth Horm. IGF Res. 2016, 30–31, 37–41. [CrossRef]
Thorner, M.O.; Frohman, L.A.; Leong, D.A.; Thominet, J.; Downs, T.; Hellmann, P.; Chitwood, J.; Vaughan, J.M.; Vale, W. Extrahypothalamic growth-hormone-releasing factor (GRF) secretion is a rare cause of acromegaly: Plasma GRF levels in 177 acromegalic patients. J. Clin. Endocrinol. Metab. 1984, 59, 846–849. [CrossRef]
Eigler, T.; Ben-Shlomo, A. Somatostatin system: Molecular mechanisms regulating anterior pituitary hormones. J. Mol. Endocrinol. 2014, 53, R1–R19. [CrossRef]
Boudin, G.; Pepin, B.; Vernant, C.L. Multiple tumours of the nervous system in Recklinghausen’s disease. An anatomo-clinical case with chromophobe adenoma of the pituitary gland. Presse Med. 1970, 78, 1427–1430. [PubMed]
Smith, N.; Santoreneos, S. Non-functioning pituitary macroadenoma in a child with neurofibromatosis type 1. ANZ J. Surg. 2017, 87, E220–E221. [CrossRef] [PubMed]
Filopanti, M.; Verga, U.; Ermetici, F.; Natacci, F.; Lalatta, F.; Avignone, S.; Trespidi, L.; Beck-Peccoz, P.; Mantovani, G.; Lania, A.G.; et al. Double pituitary and conserved function in an adult patient with neurofibromatosis type 1. J. Clin. En-docrinol. Metab. 2011, 96, 1953–1954. [CrossRef] [PubMed]
Hsieh, H.Y.; Wu, T.; Wang, C.J.; Chin, S.C.; Chen, Y.R. Neurological complications involving the central nervous system in neurofibromatosis type 1. Acta Neurol. Taiwan 2007, 16, 68–73. [PubMed]
Ueharu, H.; Yoshida, S.; Kikkawa, T.; Kanno, N.; Higuchi, M.; Kato, T.; Osumi, N.; Kato, Y. Gene tracing analysis reveals the contribution of neural crest-derived cells in pituitary development. J. Anat. 2017, 230, 373–380. [CrossRef] [PubMed]
Kovacs, K.; Horvath, E.; Thorner, M.O.; Rogol, A.D. Mammosomatotroph hyperplasia associated with acromegaly and hyperpro-lactinemia in a patient with the McCune-Albright syndrome. A histologic, immunocytologic and ultrastructural study of the surgically-removed adenohypophysis. Virchows Arch. A Pathol. Anat. Histopathol. 1984, 403, 77–86. [CrossRef]
Moran, A.; Asa, S.L.; Kovacs, K.; Horvath, E.; Singer, W.; Sagman, U.; Reubi, J.C.; Wilson, C.B.; Larson, R.; Pescovitz, O.H. Gigantism due to pituitary mammosomatotroph hyperplasia. N. Engl. J. Med. 1990, 323, 322–327. [CrossRef]
Boikos, S.A.; Stratakis, C.A. Pituitary pathology in patients with Carney Complex: Growth-hormone producing hyperplasia or tumors and their association with other abnormalities. Pituitary 2006, 9, 203–209. [CrossRef]
Pack, S.D.; Kirschner, L.S.; Pak, E.; Zhuang, Z.; Carney, J.A.; Stratakis, C.A. Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex). J. Clin. Endocrinol. Metab. 2000, 85, 3860–3865. [CrossRef]
Trouillas, J.; Labat-Moleur, F.; Sturm, N.; Kujas, M.; Heymann, M.F.; Figarella-Branger, D.; Patey, M.; Mazucca, M.; Decullier, E.; Verges, B.; et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): A case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am. J. Surg. Pathol. 2008, 32, 534–543. [CrossRef] [PubMed]
Villa, C.; Lagonigro, M.S.; Magri, F.; Koziak, M.; Jaffrain-Rea, M.L.; Brauner, R.; Bouligand, J.; Junier, M.P.; Di Rocco, F.; Sainte-Rose, C.; et al. Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation. Endocr. Relat. Cancer 2011, 18, 347–356. [CrossRef] [PubMed]
Tirosh, A.; Papadakis, G.Z.; Chittiboina, P.; Lyssikatos, C.; Belyavskaya, E.; Keil, M.; Lodish, M.B.; Stratakis, C.A. 3D Volumetric Measurements of GH Secreting Adenomas Correlate with Baseline Pituitary Function, Initial Surgery Success Rate, and Disease Control. Horm. Metab. Res. 2017, 49, 440–445. [CrossRef] [PubMed]
Segal, L.; Darvish-Zargar, M.; Dilenge, M.E.; Ortenberg, J.; Polomeno, R.C. Optic pathway gliomas in patients with neurofibro-matosis type 1: Follow-up of 44 patients. J. AAPOS 2010, 14, 155–158. [CrossRef] [PubMed]
Gan, H.W.; Phipps, K.; Aquilina, K.; Gaze, M.N.; Hayward, R.; Spoudeas, H.A. Neuroendocrine Morbidity after Pediatric Optic Gliomas: A Longitudinal Analysis of 166 Children over 30 Years. J. Clin. Endocrinol. Metab. 2015, 100, 3787–3799. [CrossRef]
Cnossen, M.H.; Stam, E.N.; Cooiman, L.C.; Simonsz, H.J.; Stroink, H.; Oranje, A.P.; Halley, D.J.; de Goede-Bolder, A.; Niermeijer, M.F.; de Muinck Keizer-Schrama, S.M. Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1. Pediatrics 1997, 100, 667–670. [CrossRef]
Collet-Solberg, P.F.; Sernyak, H.; Satin-Smith, M.; Katz, L.L.; Sutton, L.; Molloy, P.; Moshang, T., Jr. Endocrine outcome in long-term survivors of low-grade hypothalamic/chiasmatic glioma. Clin. Endocrinol. 1997, 47, 79–85. [CrossRef]
Habiby, R.; Silverman, B.; Listernick, R.; Charrow, J. Precocious puberty in children with neurofibromatosis type 1. J. Pediatr. 1995, 126, 364–367. [CrossRef]
Vassilopoulou-Sellin, R.; Klein, M.J.; Slopis, J.K. Growth hormone deficiency in children with neurofibromatosis type 1 without suprasellar lesions. Pediatr. Neurol. 2000, 22, 355–358. [CrossRef]
Parsa, C.F.; Hoyt, C.S.; Lesser, R.L.; Weinstein, J.M.; Strother, C.M.; Muci-Mendoza, R.; Ramella, M.; Manor, R.S.; Fletcher, W.A.; Repka, M.X.; et al. Spontaneous regression of optic gliomas: Thirteen cases documented by serial neuroimaging. Arch. Ophthalmol. 2001, 119, 516–529. [CrossRef]
Iacovazzo, D.; Caswell, R.; Bunce, B.; Jose, S.; Yuan, B.; Hernandez-Ramirez, L.C.; Kapur, S.; Caimari, F.; Evanson, J.; Ferrau, F.; et al. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: A clinico-pathological and genetic study. Acta Neuropathol. Commun. 2016, 4, 56. [CrossRef]
Franke, M.; Daly, A.F.; Palmeira, L.; Tirosh, A.; Stigliano, A.; Trifan, E.; Faucz, F.R.; Abboud, D.; Petrossians, P.; Tena, J.J.; et al. Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism. Am. J. Hum. Genet. 2022, 109, 553–570. [CrossRef] [PubMed]
Nilaweera, K.N.; Wilson, D.; Bell, L.; Mercer, J.G.; Morgan, P.J.; Barrett, P. G protein-coupled receptor 101 mRNA expression in supraoptic and paraventricular nuclei in rat hypothalamus is altered by pregnancy and lactation. Brain Res. 2008, 1193, 76–83. [CrossRef] [PubMed]
Trivellin, G.; Faucz, F.R.; Daly, A.F.; Beckers, A.; Stratakis, C.A. GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis. Endocr. Relat. Cancer 2020, 27, T87–T97. [CrossRef]
Daly, A.F.; Lysy, P.A.; Desfilles, C.; Rostomyan, L.; Mohamed, A.; Caberg, J.H.; Raverot, V.; Castermans, E.; Marbaix, E.; Maiter, D.; et al. GHRH excess and blockade in X-LAG syndrome. Endocr. Relat. Cancer 2016, 23, 161–170. [CrossRef]
Nunley, K.S.; Gao, F.; Albers, A.C.; Bayliss, S.J.; Gutmann, D.H. Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch. Dermatol 2009, 145, 883–887. [CrossRef]
DeBella, K.; Poskitt, K.; Szudek, J.; Friedman, J.M. Use of “unidentified bright objects” on MRI for diagnosis of neurofibromatosis 1 in children. Neurology 2000, 54, 1646–1651. [CrossRef]
DeBella, K.; Szudek, J.; Friedman, J.M. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000, 105, 608–614. [CrossRef]
Carmi, D.; Shohat, M.; Metzker, A.; Dickerman, Z. Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis type 1: A longitudinal study. Pediatrics 1999, 103, 1257–1262. [CrossRef] [PubMed]
