sign in sign up
<<
Home , Dwarfism, Laron syndrome

768 Archives ofDisease in Childhood 1993; 68: 768-770 Growth curves for Arch Dis Child: first published as 10.1136/adc.68.6.768 on 1 June 1993. Downloaded from Z Laron, P Lilos, B Klinger

Abstract and very low concentrations of insulin- Growth curves for children with Laron like growth factor-I (IGF-I).4 The pathogenesis syndrome were constructed on the basis of of this syndrome has been found to reside in the repeated measurements made throughout receptors' and is due to infancy, childhood, and in 24 (10 boys, molecular defects mostly in the extracellular 14 girls) of the 41 patients with this syndrome domain of the receptor .8 This defect leads investigated in our clinic. Growth retardation to an inability of the to synthesise the was already noted at birth, the birth length growth hormone dependent IGF-I resulting in a ranging from 42 to 46 cm in the 12/20 available marked impairment of body and organ growth. measurements. The postnatal growth curves The extreme of these patients is deviated sharply from the normal from infancy very severe and starts in utero, and their final on. Both sexes showed no clear pubertal spurt. heights are very low. Their upper to lower body Girls completed their growth between the age proportions are more than 2 SD above the of 16-19 years to a final mean (SD) height of normal mean2 denoting a lag in growth of the 119 (8.5) cm whereas the boys continued grow- lower limbs compared with the body. ing beyond the age of20 years, achieving a final We followed up a group ofpatients with Laron height of 124 (8.5) cm. At all ages the upper to syndrome from infancy to final height and we lower body segment ratio was more than 2 SD present their growth curves, growth velocity above the normal mean. These growth curves curves, and the final heights of both sexes. constitute a model not only for primary, These curves constitute a model for untreated hereditary insulin-like growth factor-I (IGF-I) hereditary/congenital deficiency of growth deficiency (Laron syndrome) but also for hormone releasing hormone, growth hormone, untreated secondary IGF-I deficiencies such or IGF-I. as growth hormone gene deletion and idio- pathic congenital isolated growth hormone deficiency. They should also be useful in the Patients and methods follow up of children with Laron syndrome Out of 41 patients with Laron syndrome who treated with biosynthetic recombinant IGF-I. were diagnosed and examined at our clinic (30 of (Arch Dis Child 1993; 68: 768-770) Jewish and 11 of Arab origin),9 24 were followed up closely from infancy into adulthood, almost http://adc.bmj.com/ all being measured once or twice a year. At each Laron syndrome is a recessively inherited visit they underwent a complete physical exami- disease' 2 that is clinically indistinguishable from nation, including anthropometric measurements growth hormone deficiency.' It is characterised (length and height), performed by the same two by high concentrations of circulating growth nurses using Harpenden stadiometers. For sit- on September 25, 2021 by guest. Protected copyright.

Institute ofPediatric and Adolescent , Children's Medical CD) 0i Center, Beilinson - Sackler -c ._ Campus, Faculty a) ofMedicine I I Z Laron B Klinger Statistical Laboratory, School of Mathematical Sciences, Tel Aviv University, P Lilos Correspondence to: Professor Z Laron, Institute of Pediatric and Adolescent Endocrinology, Children's Medical Center, Beilinson Age Age (years) Campus, Petah Tikva 49100, (years) Israel. Figure I Growth curvefor height in girls with Laron Figure 2 Growth curvefor height in boys with Laron Accepted 21 January 1993 syndromefrom birth to 20years. syndromefrom birth to 20years. Growth curvesforLaron syndrome 769

30 i| Girls 0 2 10| Girls t 200L a) 1-901 Arch Dis Child: first published as 10.1136/adc.68.6.768 on 1 June 1993. Downloaded from 25 E, 180 D 170 I -I v 11606 co 0 20 E 140s1 0 01-30 *: * **. : * 2SD 4 1 SD 220 Mean 15 CD 1.10 . Figur0.ooS.peOlwrbd emn aisi Igrswl . 0 S 1234567~8'9 1'11'3 15 1'7 10 tt~~~~~~~~ 10 12 14 16 18 I Age (years) FigureS5 Upper to lower body segment ratios in I11 girls with 5 Laron syndrome plotted on Arad/Laron charts.'0

- Figure 3 Growth velocity nu F _,I ...... curve in girls with Laron 5 10 15 20 and height curves were smoothed using the syndromefrom birth to 20 'Lowess' method.'2 The final height was estab- years. Age (years) lished when the subjects grew less than 1 cm during one year.

ting height an anthropometer was used, the Results length of the lower segment being calculated by Twenty newborn infants had birth length subtracting sitting height from total height. measured9 and in 12 it ranged from 42 to 46 cm They were compared with charts designed for and was 2 SD or more below the normal length healthy Israeli children." The 24 patients (10 for sex and ethnic origin.'3 In eight the birth boys, 14 girls) were found to have sufficient length was within normal limits. Figures 1 and 2 measurements to allow their inclusion in the represent the smoothed height growth curves as calculations ofgrowth charts. mean (2 SD) for girls and boys with Laron At first the growth increments over periods of syndrome. From the two charts it is seen that the 1-3 years were calculated for each sex separately. spread ofthe mean (2 SD) is wider in boys than in These increments enabled us to plot the growth girls. The girls reached their final height between velocity curve. ages 16-19 years whereas the boys continued to http://adc.bmj.com/ The height curves were constructed using the grow beyond age 20. The mean (SD) final height Tanner-Gupta method" as follows: the mean of the girls was 119-5 (8-5) cm and that of the height was calculated for boys at age 10 and for boys (reached around age 24 years and not shown girls at age 8 years. From these points the mean on the graphs) was 124- 1 (8-5) cm. Figures 3 and calculated yearly growth increments were added 4 illustrate the growth velocity curves ofthe girls or subtracted going backwards to birth (age 0) or and boys with Laron syndrome. It is evident that to 20. Both the forward up age growth velocity both sexes lack the typical pubertal growth on September 25, 2021 by guest. Protected copyright. spurt. The mean age at onset of puberty in girls was 10-7 (0-7) years and in boys 15-6 (2-6) years. Figures 5 and 6 show the upper to lower body segment ratio. 30 ' Boys

25 I .o 2-10 . Boys -C II 2-00 a) c 190 20 Eco E 1.80 CD)m 170 * clD 0 > 160 * 0 15

- S 0a0 0. 15000 10 1-0. I 0 09

OL 1 23578 1 3151 5 * . 12 3 4 5 6 7 8 9 11 13 1 5 17 10 12 14 16 18 Figure 4 Growth velocity uII _- -_---4--- Age (years) curve in boys with Laron 0 5 10 15 20 syndromefrom birth to 20 Figure 6 Upper to lower body segment ratios in 10 boys with years. Age (years) Laron syndrome plotted on Arad/Laron charts. '0 770 Laron, Lilos, Klinger

Discussion deletion type IA patients25 with biosynthetic The use of a reference growth chart is routine IGF-I. in nowadays any paediatric clinic. Height and Arch Dis Child: first published as 10.1136/adc.68.6.768 on 1 June 1993. Downloaded from The authors wish to acknowledge the criticism and advice of growth are plotted on one of the several growth Professor J M Tanner in the preparation ofthis article. charts developed for normal children based on We also thank Dr M Lapidot and Mrs 0 Gordon for help at various stages of this study, and special thanks are due to the Tanner-Whitehouse charts.'4 For children Ms Dahlia Peled, RN, without whose exact measurements with certain diseases characterised by marked throughout the years this study would not have been possible. Z Laron is Incumbent ofthe Irene and Nicholas Marsh Chair of growth retardation and a typical growth pattern, Endocrinology and Juvenile , Tel Aviv University. special growth charts have been established,' thus there is a growth curve for ,'6 1 Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary for girls with Turner's and for with high serum concentration of growth syndrome,'7 hormone. A new inborn error of metabolism? IsrJ Med Sci Noonan's syndrome.'8 1966; 2: 152-5. Children with Laron at a 2 Laron Z. Laron type dwarfism (hereditary somatomedin syndrome'2 grow deficiency): a review. In: Frick P, von Harnack GA, subnormal rate because of their inability to Kochseik K, Martini GA, Prader A, eds. Advances in internal which is caused medicine and pediatrics. Berlin-Heidelberg: Springer Verlag, generate endogenous IGF-I,4 by 1984: 117-50. a molecular defect in the growth hormone 3 Laron Z. Deficiencies of growth hormone and somatomedins and this results in a hormone in man. In: Cohen MP, Foa PP, eds. Special topics in receptors,5 growth endocrinology andmetabolism. Vol 5. New York: Alan R Liss, resistant state. These patients present a uniform 1983: 149-99. type of growth retardation. The we 4 Laron Z, Pertzelan A, Karp M, Kowadlo-Silbergeld A, opportunity Daughaday WH. Administration of growth hormone to had to follow up a large group of patients patients with familial dwarfism with high plasma immuno- throughout and childhood into adult- reactive growth hormone. Measurement of sulfation factor, infancy metabolic and linear growth response. J Clin Endocrinol hood enabled us to construct growth curves for Metab 1971; 33: 332-42. the patients with Laron and to learn 5 Eshet R, Laron Z, Pertzelan A, Dintzman M. Defect ofhuman syndrome growth hormone receptors in the liver of two patients with about the role of growth hormone and IGF-I on Laron type dwarfism. IsrJ Med Sci 1984; 20: 8-11. body growth. 6 Godowski PJ, Leung DW, Meacham LR, et al. Characteriza- tion of the human growth gene and the The fact that some ofthese patients are shorter demonstration of a partial gene deletion in 2 patients with than normal at birth to Laron type dwarfism. Proc NatlAcad Sci USA 1989; 86: suggests that, contrary 8033-8. previous beliefs, IGF-I also influences intra- 7 Amselem S, Duquesnoy P, Attree 0, et al. Laron dwarfism uterine to some the and mutations ofthe gene. N Engl growth degree. Postnatally JMed 1989; 321: 989-95. growth velocity slows, and after age 3 years 8 Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld maintains a velocity of 4-5 in and RG, Francke U. Laron syndrome in : point cm/year girls mutation in the growth hormone receptor gene causes 3-4 cm in boys. This difference in velocity makes deletion of 8 amino acids from the extracellular domain. In: the mean of the than that of Laron Z, Parks JS, eds. Lessonsfrom Laron syndrome (1966- height girls greater 1992). Pediatric and adolescent endocrinology. Vol 24. Basel: the boys between ages 5-15 years but always S Karger, 1993: 160-6. much below the normal curves. the fact 9 Laron Z. Laron syndrome - from description to therapy. Despite Endocrinologist 1993; 3: 21-8. that patients with Laron syndrome have full 10 Arad J, Laron Z. Standards for upper/lower body segment sexual development'9they do not have a pubertal ratio sitting height - subichial leg length, from birth to 18 years in girls and boys. Proceedings of 1st International http://adc.bmj.com/ growth spurt. They grow slowly and have a Congress of Auxology. Rome, April 1977. Milan: Centro delayed and slow that is more accentu- Auxologia Italiano di Piancavallo, 1979: 159-64. puberty 11 Tanner JM. Some notes on the reporting of growth data. ated in the boys.20 These facts explain why boys Hum Biol 1951; 23: 93-159. continue to grow even after an at 12 Cleveland WS. Robust locally weighted regression and age 20, age smoothing scatterplots. Journal of the American Statistical which the girls have already reached final height. Association 1979; 74: 829-36. Our that 13 Zaizov R, Laron Z. Body length and weight at birth and one findings prove postnatal growth year of age in different communities in Israel. Acta Paediatr proceeds even in the absence of circulating Scand 1966; 55: 52408. IGF-I, but the and deficit can 14 Tanner JM, Whitehouse RH. Clinical longitudinal standards on September 25, 2021 by guest. Protected copyright. prenatal perinatal for height, weight, height velocity, weight velocity and never be made up. In the absence of IGF-I stages ofpuberty. Arch Dis Child 1976; 51: 170-9. is and and this 15 Hulse JA. Special growth charts. Arch Dis Child 1988; 63: puberty delayed prolonged pre- 1179-80. vents the pubertal growth spurt. The signific- 16 Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. than normal to lower Standard growth curves for achondroplasia. J Pediatr 1978; antly higher upper body 93: 435-8. segment ratio denotes that the deficient height is 17 Lyon AJ, Preece MA, Grant DB. Growth curve for girls with more in than it is in . Arch Dis Child 1985; 60: 932-5. proportionately leg growth 18 Witt DR,Keen BA, Hall JG, Allanson JE. Growth curves for sitting height. height in . Clin Genet 1986; 30: 150-3. We have described that skull size as 19 Laron Z, Pertzelan A, Karp M. Pituitary dwarfism with high previously serum levels ofgrowth hormone. Isrj Med Sci 1968; 4: 883- measured by head circumference is smaller than 94. the normal in with Laron 20 Laron Z, Sarel R, Pertzelan A. Puberty in Laron type patients syndrome.2 21 dwarfism. EurJPediatr 1980; 134: 79-83. Acromicria - small chin, hands, and feet - is also 21 Laron Z, Galatzer A. Aspects ofbrain development in children of this The above and adolescents with pituitary hormone deficiency. In: de typical syndrome.'2I9 findings Wied D, van Keep PA, eds. and the . document the important role that IGF-I, the Lancaster: MTP Press, 1980: 293-302. effector hormone of 22 Illig R, Prader A, Ferrandez A, Zachmann M. Hereditary pituitary growth hormone, prenatal growth hormone deficiency with increased has on total body and segmental growth. tendency to growth hormone antibody formation, A-type of The linear and curves isolated growth hormone deficiency. Acta Paediatr Scand growth growth velocity 1971; 60 (suppl): 607. presented for boys and girls with Laron syn- 23 Laron Z, Keliiman M, Pertzelan A, Keret R, Schoffner JM, drome constitute a model not for Parks JS. Human growth hormone gene deletion without only primary antibody formation or growth arrest during treatment -a IGF-I deficiency and growth hormone resistance new disease entity? Isr3'Med Sci1985; 21:9991006. but also for 24 Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. Effects of syndromes, perinatal growth insulin-like growth factor on linear growth, head circumfer- hormone/IGF-I deficiency and untreated growth ence and body fat in patients with Laron type dwarfism. hormone deletion.2223 These charts should Lancet 1992; 339: 1258-61. gene 25 Nishi Y, Okada S, Tajiri H, et al. Effect of IGF-I on isolated also be of use when following the recently GH deficiency type IA and Laron type dwarfism. In: Laron introduced treatment of those Z, Parks JS, eds. Lessonsfrom Laron syndrome (1966-1992). regimen with Pediatric and adolescent endocrinology. Vol 24. Basel: Laron syndrome24 and growth hormone gene S Karger, 1993: 244-53.