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A Comment on Normal Intelligence in Growth Hormone Receptor Deficiency^a

Schneider Children’s Medical Center of Israel Petah Tikva 49 100, Israel

We read with interest the recent paper by Kranzler et al. (1), which describes psychological tests in 18 school-age children from Ecuador suffering from a uniform defect in the extracellular domain of the GH receptor (E 180 splice; A G at 594 in Exon 6) (2), leading to primary insulin-like glucose factor I (IGF-I) deficiency. The findings of the above authors differ from those reported by us from the Israeli cohort (3, 4).

This cohort of patients with primary IGF-I deficiency (primary GH resistance, Laron syndrome = LS) (5) is composed not only of patients with GH receptor defects (GHRD) but also of patients with post-GH receptor defects (6). As reported previously, the mean IQ of our patients was consistently lower compared with the Israeli population, but there exists a great variability. Thus two siblings (male and female) having a 3,5,6 GH-receptor gene deletion (7) have a low IQ (73 and 46 respectively), the latter being institutionalized. Another patient having the same molecular defect in exon 6 as the Ecuadorian patients (8) has an IQ of 123. Another LS patient has a Ph.D. in microbiology (IQ 106).

Presently, we are mapping all the other patients and families who are willing to cooperate for the molecular defects, and we will be able to make a complete correlation between psychological abilities and molecular defects in the near future.

We do not completely agree with Kanzler et al. that their findings prove normal intelligence in the Ecuadorian LS patients. The conclusions drawn, that the Ecuadorian children with LS have normal intelligence, do not seem to fit the data presented in their Table 2, which shows that the control group had a significantly higher scoring on both tests of intelligence performed, even though they are relatively young (scoring differs by age). Despite a uniform molecular defect of the GH receptor in the Ecuadorian population, the variability in the IQ scores as shown in Table 2 is high. In view of the above, the conclusion that all Ecuadorian patients with LS have normal intelligence is not proven.

The authors also conclude that GH-induced IGF-I production is not required for normal brain growth. In our LS patients with a receptor defect, the patients had as children a small head circumference, which is an index of brain growth (9, 10). The small head (brain) increased rapidly with IGF-I replacement treatment (11). We found the same in infants with isolated GH deficiency due to gene deletion (i.e. secondary IGF-I deficiency) (12). There is no information in Dr. Kranzler’s paper (1) or in the review by Rosenfeld et al. (13) regarding head circumference in the Ecuadorian cohort, nor information on the early motor skills in infancy, which were delayed in most LS patients of the Israeli cohort (14). Our data in LS and hGH gene deletion patients, i.e. primary or secondary IGF-I deficiency, point to an important role of IGF-I on intrauterine and postnatal brain growth and function. The role of IGF-I on the nervous system has been further documented in many recent investigations (15, 16).

Footnotes

Address correspondence to: Zvi Laron, M.D., Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tiqra 49 100, Israel.

Received August 11, 1998.

References

1. Kranzler JH, Rosenbloom AL, Martinez V, Guevara-Aguirre J. 1998 Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: A controlled study in a genetically homogenous population. J Clin Endocrinol Metab. 83:1953–1958.[Abstract/Free Full Text]
2. Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld RG, Francke U. 1992 Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome. Hum Mutation 1:124–134.
3. Frankel JJ, Laron Z. 1968 Psychological aspects of pituitary insufficiency in children and adolescents with special reference to growth hormone. Isr J Med Sci. 4:953–961.[Medline]
4. Galatzer A, Aran O, Nagelberg N, Rubitzek J, Laron Z. 1993 Cognitive and psychosocial functioning of young adults with Laron syndrome. In: Laron Z, Parks JS, eds. Lessons from Laron Syndrome (LS) 1966–1992. Basel: Karger; 53–60.
5. Laron Z, Blum W, Chatelain P, Ranke M, Rosenfeld R, Savage M, Underwood L. 1993 Classification of growth hormone insensitivity syndrome. J Pediatr. 122:241.[Medline]
6. Laron Z, Klinger B, Eshet R, Kanety H, Karasik A, Silbergeld A. 1993 Laron Syndrome due to a post-receptor defect: response to IGF-I treatment. Isr J Med Sci. 29:757–763.[Medline]
7. Godowski PJ, Leung DW, Meacham LR, et al. 1989 Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in 2 patients with Laron type dwarfism. Proc Natl Acad Sci USA. 86:8083–8087.[Abstract/Free Full Text]
8. Berg MA, Peoples R, Perez-Jurado L, et al. 1994 Receptor mutations and haplotypes in growth hormone receptor deficiency: a global survey and identification of the Ecuadorean E180 splice mutation in an oriental Jewish patient. Acta Paediatr. [Suppl]399 :112–114.
9. Laron Z. 1998 Laron syndrome—Primary growth hormone resistance. Chapter 2. In: J.L. Jameson, ed. Hormone Resistance Syndromes. Contemporary Endocrinology, Vol. 2. Totowa: Humana Press: (in press).
10. Laron Z. 1995 Prismatic cases: Laron Syndrome (primary growth hormone resistance). From patient to laboratory to patient. J Clin Endocrinol Metab. 80:1526–1573.[Abstract/Free Full Text]
11. Laron Z, Klinger B, Erster B, Anin S. 1988 Effects of acute administration of insulin like growth factor I in patients with Laron-type dwarfism. Lancet ii: 1170–1172.
12. Laron Z, Lazar L, Galatzer A, Pertzelan A. 1995 Growth hormone treatment accelerates head circumference growth in isolated GH deficiency. In: Hauspie R, Lindgren G, Falkner F, eds. Essays on Auxology. Hertfordshire, UK: Castlemead Publications; 489–495.
13. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. 1994 Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev. 15:369–390.[Abstract/Free Full Text]
14. Laron Z. 1993 Laron syndrome—a unique model of IGF-I deficiency. In: Laron Z, Parks JS, eds. Lessons from Laron Syndrome (LS) 1966–1992. Basel: Karger; 3–23.
15. Raizada MK, LeRoith DL, eds. 1993 The role of insulin-like growth factors in the nervous system. New York: Ann NY Acad Sci. 692:1–336.
16. Rosenfeld RG, Bengtsson BA. 1994 Effects of growth hormone and insulin-like growth factors on the central nervous system. Acta Paediatr Scand. [Suppl]406 :89–91.

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