The Intellectual Capacity of Patients with Laron Syndrome (LS) Differs with Various Molecular Defects of the Growth Hormone Receptor Gene. Correlation with CNS Abnormalities

Abstract

The correlation between the molecular defects of the GH receptor (R), psychosocial development and brain abnormalities were evaluated in 10 patients with Laron syndrome (LS), in whom all data were available. The findings revealed that the intelligence quotient (IQ) and abnormalities in the brain of the patients with LS differ with various molecular defects of the GH-receptor. The most severe mental deficits and brain pathology occurred in patients with 3, 5, 6 exon deletion. Patients with point mutations in exons 2, 4 and 7 presented various degrees of medium to mild CNS abnormalities that correlated with the IQ. Notably, the patient with the E180 splice mutation in exon 6 had a normal IQ, which fits the report on normal IQ in a large Ecuadorian cohort with the same mutation. This is the first report to support a correlation between IQ, brain abnormalities and localization of the molecular defects in the GH-R gene. As all patients with LS are IGF-I-deficient, it must be assumed that other as yet unknown factors related to the molecular defects in the GH-R are the major cause of the differences in intellect and brain abnormalities.

IGF-I deficiency · laron syndrome · primary growth hormone insensitivity · intelligence quotient · brain MRI · brain abnormalities

1 ^*deceased

References

• 1 Laron Z, Pertzelan A, Karp M. Pituitary dwarfism with high serum levels of growth hormone.  Isr J Med Sci. 1968;  4 883-894
• 2 Eshet R, Laron Z, Pertzelan A, Dintzman M. Defect of human growth hormone receptors in the liver of two patients with Laron type dwarfism.  Isr J Med Sci. 1984;  20 8-11
• 3 Godowski P J, Leung D W, Meacham L, Galgagni J P, Hellmiss R, Keret R, Rotwein P S, Parks J S, Laron Z, Wood W I. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron type dwarfism.  Proc Natl Acad Sci USA. 1989;  86 8083-8088
• 4 Amselem S, Duquesnoy P, Attree O, Novelli G, Bousnina S, Postel-Vinay M C, Goosens M. Laron dwarfism and mutations of the growth hormone receptor gene.  N Engl J Med. 1989;  321 989-995
• 5 Laron Z, Klinger B, Eshet R, Kaneti H, Karasik A, Silbergeld A. Laron syndrome due to a post-receptor defect: response to IGF-I treatment.  Isr J Med Sci. 1993;  29 757-763
• 6 Kofoed E M, Hwa V, Little B, Woods K A, Buckway C K, Tsubaki J, Pratt K L, Bezrodnik L, Jasper H, Tepper A, Heinrich J J, Rosenfeld R G. Growth hormone insensitivity associated with a STAT5b mutation.  N Engl J Med. 2003;  349 1139-1147
• 7 Laron Z, Pertzelan A, Karp M, Kowaldo-Silbergeld A, Daughaday W H. Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone. Measurement of sulfation factor, metabolic and linear growth responses.  J Clin Endocrinol Metab. 1971;  33 332-342
• 8 Laron Z. Natural history of the classical form of primary growth hormone (GH) resistance (Laron Syndrome).  J Pediatr Endocrinol Metab. 1999;  12 231-249
• 9 Laron Z. Laron Syndrome (primary GH resistance or insensitivity). The personal experience 1958 - 2003.  J Clin Endocrinol Metab. 2004;  89 1031-1044
• 10 Laron Z. Laron Type Dwarfism (Hereditary Somatomedin Deficiency): A Review. In: Frick P, Von Harnack GA, Kochsiek K, Martini GA, Prader A (eds) Advances in Internal Medicine and Pediatrics. Berlin-Heidelberg; Springer-Verlag 1984: 117-150
• 11 Laron Z. Final height and psychosocial outcome of patients with Laron syndrome (primary GH resistance): a model of genetic IGF-I deficiency. Chapter 23. In: Gilli G, Schell L, Benso L (eds) Human Growth from Conception to Maturity. London; Smith-Gordon Publ. 2002: 215-225
• 12 Kornreich L, Horev G, Schwarz M, Karmazyn B, Laron Z. Craniofacial and brain abnormalities in Laron syndrome (primary growth hormone insensitivity).  Eur J Endocrinol. 2002;  146 499-503
• 13 Shevah O, Rubinstein M, Laron Z. Molecular defects of the growth hormone receptor gene, including a new mutation, in Laron syndrome patients in Israel: relationship between defects and ethnic groups.  Isr Med Assoc J. 2004;  6 630-633
• 14 Wechsler D. The Wechsler intelligence scale for children - revised. New York Psychological Corporation 1974
• 15 Wechsler D. The Wechsler adult intelligence scale - revised. New York Psychological Corporation 1981
• 16 Terman L M, Merrill M A. Revised Stanford-Binet Scales (in Hebrew). Boston; Houghton-Miffin Co 1965
• 17 Anlar B, Sullivan K A, Feldman E L. Insulin-like growth factor-I and central nervous system development.  Horm Metab Res. 1999;  31 120-125
• 18 Laron Z. Growth Hormone and Insulin-Like Growth Factor-I: Effects on the Brain. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones, Brain and Behavior ch 85. San Diego-Amsterdam; Academic Press (Elsevier Science) 2002: 75-96
• 19 Coculescu M. Blood-brain barrier for human growth hormone and insulin-like growth factor.  J Pediatr Endocrinol Metab. 1999;  12 113-124
• 20 Reinhardt R R, Bondy C A. Insulin-like growth factors cross the blood-brain barrier.  Endocrinology. 1999;  135 1753-1761
• 21 Nyberg F, Burman P. Growth hormone and its receptors in the central nervous system - localization and functional significance.  Horm Res. 1996;  45 18-22
• 22 Meyer-Bahlburg H FL, Feinman J A, MacGillivray M H, Aceto T. Growth hormone deficiency, brain development, and intelligence.  Am J Dis Child. 1978;  132 565-572
• 23 Laron Z, Galatzer A. Growth hormone, somatomedin and prolactin - relationship to brain function.  Brain Develop. 1985;  7 559-567
• 24 Brown K, Rodgers J, Johnstone H, Adams W, Clarke M, Gibson M, Cheetham T. Abnormal cognitive function in treated congenital hypopituitarism.  Arch Dis Child. 2004;  89 827-830
• 25 Laron Z, Galatzer A. Effect of hGH on head circumference and IQ in isolated growth hormone deficiency.  Early Hum Develop. 1981;  5 211-214
• 26 Almqvist O, Thoren M, Saaf M, Eriksson O. Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency: a pilot study.  Psychoneuroendocrinology. 1986;  11 347-352
• 27 Deijen J B, de Boer H, Blok G J, van der Veen E A. Cognitive impairments and mood disturbances in growth hormone deficient men.  Psychoneuroendocrinology. 1996;  21 313-322
• 28 Frankel J J, Laron Z. Psychological aspects of pituitary insufficiency in children and adolescents with special reference to growth hormone.  Isr J Med Sci. 1968;  4 953-961
• 29 Galatzer A, Aran O, Nagelberg N, Rubitzek J, Laron Z. Cognitive and psychosocial functioning of young adults with Laron syndrome.  Pediatr Adolesc Endocrinol. 1993;  24 53-60
• 30 Woods K A, Dastot F, Preece M A, Clark A JL, Postel-Vinay M-C, Chatelain P G, Ranke M B, Rosenfeld R G, Amselem S, Savage M O. Phenotype: Genotype relationships in growth hormone insensitivity syndrome.  J Clin Endocrinol Metab. 1997;  82 3529-3535
• 31 Kranzler J H, Rosenbloom A L, Martinez V, Aguirre J. Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: A controlled study in genetically homogeneous population.  J Clin Endocrinol Metab. 1998;  83 1953-1958
• 32 Murakami Y, Yamashita Y, Matsuishi T, Utsunomiya H, Okudera T, Hashimoto T. Cranial MRI of neurologically impaired children suffering from neonatal hypoglycaemia.  Pediatr Radiol. 1999;  29 23-27
• 33 Woods K A, Camacho-Hubner C, Savage M O, Clark A JL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene.  N Engl J Med. 1996;  335 1363-1367
• 34 Abuzzahab M J, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith R J, Chernausek S D. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation.  N Engl J Med. 2003;  349 2211-2222
• 35 Coschigano K T, Holland A N, Riders M E, List E O, Flyvbjerg A, Kopchick J J. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span.  Endocrinology. 2003;  144 3799-3810
• 36 Ransome M I, Goldshmit Y, Bartlett P F, Waters M J, Turnley A M. Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness.  Eur J Neurosci. 2004;  19 2069-2079
• 37 Turnley A M, Faux C H, Rietze R L, Coonan J R, Bartlett P F. Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling.  Nature Neurosci. 2002;  5 1155-1162
• 38 Galli-Tsinopoulos A, Nousia-Arvanitakis S, Tsinopoulos I, Bechlivanides C, Shevah O, Laron Z. Laron syndrome. First report from Greece.  Hormones. 2003;  2 120-124