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Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment
YGHIR-01094; No of Pages 4 Growth Hormone & IGF Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment Zvi Laron ⁎, Rivka Kauli Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
a r t i c l e
i n f o
Article history: Received 4 June 2015 Received in revised form 27 July 2015 Accepted 3 August 2015 Available online xxxx Keywords: Laron syndrome GH insensitivity IGF-I IGF-I treatment Dwarfism Obesity
a b s t r a c t Clinical and laboratory investigations of dwarfed children newly Jewish immigrants from Yemen and Middle East and who resembled patients with isolated growth hormone deficiency were started by our group in 1958. In 1963 when we found that they have high serum levels of hGH, we knew that we had discovered a new disease of primary GH insensitivity. It was subsequently coined Laron Syndrome (LS, OMIM #262500). The etiopathogenesis was disclosed by 2 liver biopsies demonstrating a defect in the GH receptor. Subsequent investigations demonstrated deletions or mutations in the GHR gene. The defect lead to an inability of IGF-I generation, resulting in severe dwarfism, obesity, and other morphologic and biochemical pathologies due to IGF-I deficiency. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Following closely our cohort of 69 patients with LS enabled us to study its features in untreated and IGF-I treated patients. This syndrome proved to be a unique model to investigate the effects of IGF-I dissociated from GH stimulation. In recent studies we found that homozygous patients for the GHR mutations are protected lifelong from developing malignancies, opening new directions of research. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction In 1958, at a time when no assay for human growth hormone (hGH) was available three children aged a few days, 1.5 and 3.5 years (2 males and 1 female) with marked growth retardation were referred to our clinic [1]. They belonged to a consanguineous Jewish family recently immigrated from Yemen. Older siblings were of normal height. Within one year we were able to collect a total of 22 children with the same features all belonging to consanguineous families coming from the Middle East or Arabian Peninsula [2]. Their characteristics were dwarfism, obesity, small genitalia in the boys and severe hypoglycemia. They had a typical head configuration, a small face, and a protruding forehead resulting in a saddle nose. Their voice was high pitched and they had sparse hair. Phenotypically they resembled what was known as GH deficiency, at the time that they were diagnosed with dwarfism and insulin induced hypoglycemia non-responsiveness due to insulin sensitivity [3]. When radioimmunoassays for hGH became available in 1963 [4], we were surprised to find that these children had markedly elevated serum
⁎ Corresponding author at: Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, 14 Kaplan Street, Petah Tikva 29202, Israel. E-mail address: [email protected] (Z. Laron).
hGH levels [1,2]. We recognized that we had discovered a new disease. We were confronted with 2 possible explanations: a) An abnormal structure of the GH b) Resistance to GH of normal structure. Technological limitation delayed the final answer for 20 years. Immunological studies comparing the patients' serum hGH by radioimmuno and radio-receptor assays for hGH showed identical behavior with serum from healthy controls indicating a normal structure of the GH in the LS patients [5,6]. This was confirmed subsequently by hGH gene analysis [7]. Proof of insensitivity to GH was shown by the lack of response to exogenous hGH administration and the absence of rise of serum somatomedin (IGF-I) [8]. So the “IGF-I generation test” was born. The name Laron Dwarfism (later changed to Laron Syndrome (LS)) was coined by Elders et al. [9]. Definite evidence for GH resistance was found by liver biopsy in 2 LS patients, showing that I125hGH did not bind to the liver membranes of these patients, in contrast to membranes from controls (taken during renal transplants) [10]. Cloning of the GH receptor in 1987 [11] enabled the identification of partial gene deletion in the GH receptor gene in 2 of our patients [12]. The discovery of the PCR technique enabled the identification of many mutations in the GHR also in our patients [12-14]. With time our cohort of patients increased in size and comprises at present 69 patients, belonging to different ethnic groups.
http://dx.doi.org/10.1016/j.ghir.2015.08.004 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004
2
Z. Laron, R. Kauli / Growth Hormone & IGF Research xxx (2015) xxx–xxx
Table 1 Laron Syndrome — the Israeli cohort. Ethnic origin.
Jews Oriental (Iran, Iraq, Lebanon, Syria, Morocco, Yemen, Afghanistan) Muslims Druse Christians Total
Table 3 Laron Syndrome — the Israeli cohort. Current age. Females
Males
Total
Age — years
Females
Males
Total
20
13
33
3 1 11 35
13
16 1 19 69
b10 10–20 20–30 30–40 40–50 50–60 N60 Total
4 6 5 2 5 8 5 35
2 9 7 4 4 5 3 34
6 15 12 6 9 13 8 69
8 34
The total number of LS patients worldwide is not known as many are probably undiagnosed. The number of known and/or published LS patients is around 350. 1.1. Subjects The number of LS patients in the Israeli cohort and their ethnic origin are shown in Table 1. All families originate from the Middle East or Mediterranean area. Many belong to consanguineous families and in several families more than one child is affected. Table 2 presents their age at referral. It is seen that 33 were referred below age 4, enabling treatment in those referred after the year 1987. Table 3 shows their present age including the age at death of 5 of our patients. 2. Methods During the growth periods the patients were followed every 3–4 months, on which occasion they underwent body measurements, complete physical examinations and laboratory investigations. Our close follow-up of all the patients by the same team enabled us to study the clinical characteristics and the physio-pathology of hGH and IGF-I deficiency to late adult age in the untreated LS patients, and to study the pharmacology and effects of IGF-I in the treated children and adults. Our overall findings have been summarized in two major publications [15,16]. Following are the most striking findings in our cohort of LS patients. 2.1. Clinical characteristics of Laron Syndrome As young children they have a special facial phenotype, a small face, a protruding forehead, sparse hair and a below normal head circumference [17]. Dwarfism is already evident by short birth length which if untreated deviates more and more from the lower centiles reaching sizes of −4 to − 8 height SDS [18]. From the typical growth pattern we designed specific growth charts [19], which fit any congenital IGF-I deficiencies [20], except the acid-labile subunit (ALS) syndrome [21]. Puberty and full sexual development are delayed mainly in boys [22]. Table 2 Laron Syndrome — the Israeli cohort. Age at referral. Age
Females
Males
Total
4 days–6 m 1 y–3 y 11 m 4 y–9 y 11 m 10 y–16 y 9 m 34 y–51 y Total
2 15 12 4 2 35
5 11 12 4 2 34
7 26 24 8 4 69
Part of the referrals were before IGF-I was available.
Final heights range from 116–142 cm (males) and 108–136 (females) with an increased upper/lower body ratio, denoting short limbs [18]. One of the major complications is marked obesity, lipidemia and fatty liver [23–25]. The obesity, reaching 60% of body composition in females and 40% in males, is not due to overeating or low energy expenditure [26] but to a metabolic dysfunction, one of its characteristics being high serum adiponectin [27]. LS patients also have pathologies in the carbohydrate metabolism. In infancy they suffer from hypoglycemia (sometimes severe); subsequently during progressing obesity they develop glucose intolerance and even Type 2 diabetes (Table 4). Ten patients developed cardiovascular disease (Table 5). Psychological tests revealed a below normal IQ in part of the patients with improvement of the verbal IQ with time [28]. MRI of the skull showed overt pathological findings in the CNS in some of the patients [29,30]. Noteworthy is the underdevelopment of the sinuses. LS patients have a tendency for auditory defects [31] as do also patients with other disorders causing congenital IGF-I deficiency. 2.2. Treatment Twenty one children (11 girls, 10 boys) were or are still treated by recombinant IGF-I (Fujisawa (Astellas) or TERCICA–IPSEN); in doses ranging from 150–220 μg/kg once daily [32,33]. Their height, brain and organ growth respond rapidly to the IGF-I administration but to a slightly lesser degree than GH deficient children to hGH. Mean growth velocity in the 1st year of treatment was 8 cm/y. Linear growth catchup and changes in the U/L ratio showed a change in Ht SDS from − 6.1 ± 1.2SDS to − 4.6 ± 1.2SDS (p b 0.001) without change in the U/L ratio. IGF-I increased the mean (± SD) head circumference from − 3.3 ± 0.9 to + 0/87 ± 1.8. Injecting the IGF-I only with the main meal, resulted in less adverse effects than reported with twice daily injections, yielding the same results [34]. After a short decrease in adiposity and lipidemia, both increases again progressively resulting in marked obesity at the end of puberty [35]. Treatment of 5 adult LS patients by IGF-I in doses of 50–150 μg/kg once daily for one year resulted in beneficial metabolic effects [36]. Table 4 Laron Syndrome patients with diabetes mellitus (NIDDM). Patient
Sex
Age at referral (y/m)
Age range of (abnormal) OGTT onlya
Age at Dg DMb
Age at (April 2015)
1 2 3
M M M
36 y 10 m 1y 5m
39 y 4 m 7 y 10 m–28 y 9 m 12 y 2 m–26 y
39 y 4 m 37 y 3 m 39 y 8 m
4 5 6 7
M M F M
6m 3y1m 3 y 7.5 m 7y9m
14 y 2 m–16 y 7 m 16 y–39 y 4 m 14 y 8 m–36 y 4 m 15 y 6 m–26 y 4 m
37 y 60 y 58 y 58–59 y?
Deceased at 75.8 51 y 9 m Deceased at 49 y 6 m 38 y 3 m 60 y 59 y 4 m 61 y
a Fasting glucose levels were normal until DM was diagnosed. There were no symptoms suggestive for DM. b Glucose intolerance and/or hyperinsulinism.
Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004
Z. Laron, R. Kauli / Growth Hormone & IGF Research xxx (2015) xxx–xxx
3. Conclusions
Table 5 Laron Syndrome — the Israeli cohort. Cardiovascular disease. Females Congenital Patent ductus arteriosus Acquired Rheumatic heart disease Hypertension Coronary heart disease Peripheral vascular disease
Males
2
Total
2
2
1 2 1 6
2 1 4 1 10
1
3
We consider obesity as the most frequent adverse effect of IGF-I treatment, and acknowledge that no fat reducing treatment has succeeded so far.
2.3. Adverse effects (AEs) The majority of AEs are due to over dosage or administration of rIGFI without an adequate meal. The results are hypoglycemia, not only in infancy. Other AEs are headache, intracranial hypertension, swelling of the lymphoid tissues, and hyperandrogenism [32,34].
2.4. Social aspects The occupation of the adult LS patients is shown in Table 6. All but one female have sexual activity. Ten (5 males and 5 females) are married to unaffected partners and have children of normal size.
2.5. Mortality Among our 69 patients we registered 5 deaths. One 9 month old girl, sister of one of our patients, died long ago of suspected encephalitis (the possibility of undiagnosed hypoglycemia cannot be ruled out); 2 patients (one male and one female) died at ages 50 and 54 due to neglected cardio-vascular disease and one 76 year old male died in a car accident. In the Ecuadorian cohort 30 deaths have been reported since 1988 [37], nine were over age 9 (8 died due to cardiac disease and one of stroke).
2.6. Laron Syndrome and cancer In two epidemiological studies comprising 169 [38] and 230 [39] patients with Laron Syndrome we observed that homozygous patients for this disease were protected lifelong from developing cancer. Their 752 heterozygote first degree family members including 274 siblings were not protected. The same was reported for the large Ecuadorian cohort of Laron Syndrome patients [39]. In collaboration with Prof Haim Werner and Lena Lapkina PhD of the Department of Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, we are trying to decipher the protecting mechanism [40].
Table 6 Laron Syndrome — the Israel cohort. Occupation of adult patients.
Office work, in business Manual On social security
3
Females
Males
Total
2 9 2
3 2 6
5 11 8 24
Laron Syndrome due to deletions and mutations in the human GHreceptor enabled us to study the effects of the GH/IGF-I dissociation and deficiency, its clinical and biochemical sequelae and the pharmacology and clinical effects of IGF-I replacement treatment. Last but not least Laron Syndrome may hold the secret of preventing cancer development. References [1] Z. Laron, A. Pertzelan, S. Mannheimer, Genetic pituitary dwarfism with high serum concentration of growth hormone. A new inborn error of metabolism? Isr. J. Med. Sci. 2 (1966) 153–155. [2] Z. Laron, A. Pertzelan, M. Karp, Pituitary dwarfism with high serum levels of growth hormone, Isr. J. Med. Sci. 4 (1968) 883–894. [3] Z. Laron, Laron type dwarfism (hereditary somatomedin deficiency): a review, in: P. Frick, G.A. Von Harnack, G.A. Koschsiek, A. Prader (Eds.), Advances in Internal Medicine and Pediatrics, 51, Springer-Verlag, Berlin-Heidelberg 1984, pp. 117–150. [4] S.M. Glick, J. Roth, R.S. Yalow, S.A. Berson, Immunoassay of human growth hormone in plasma, Nature 199 (1963) 784–788. [5] R. Eshet, Z. Laron, M. Brown, R. Arnon, Immunoreactive properties of the plasma hGH from patients with the syndrome of familial dwarfism and high plasma IRhGH, J. Clin. Endocrinol. Metab. 37 (1973) 819–821. [6] R. Eshet, S. Peleg, Z. Josefsberg, C. Fuchs, R. Arnon, Z. Laron, Some properties of the plasma hGH activity in patients with Laron-type dwarfism determined by a radioreceptor assay using human liver tissue, Horm. Res. 22 (1985) 276–283. [7] R.E. Russell, J.S. Parks, M.C. McKean, G.I. Bell, R. Keret, M. Kelijman, Z. Laron, Larontype dwarfism is associated with normal growth hormone and insulin-like growth factor I gene restriction patterns, Isr. J. Med. Sci. 25 (1989) 342–344. [8] Z. Laron, A. Pertzelan, M. Karp, A. Kowadlo-Silbergeld, W.H. Daughaday, 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. 33 (1971) 332–342. [9] M.J. Elders, J.T. Garland, W.H. Daughaday, D.A. Fisher, J.E. Whitney, E.R. Hughes, Larons's dwarfism: studies on the nature of the defect, J. Pediatr. 83 (1973) 253–263. [10] R. Eshet, Z. Laron, A. Pertzelan, M. Dintzman, Defect of human growth hormone in the liver of two patients with Laron type dwarfism, Isr. J. Med. Sci. 20 (1984) 8–11. [11] D.W. Leung, S.A. Spencer, G. Cachianes, R.G. Hammonds, C. Collins, W.J. Henzel, R. Barnard, M.J. Waters, W.I. Woods, Growth hormone receptor and serum binding protein: purification, cloning and expression, Nature 330 (1987) 537–543. [12] P.J. Godowski, D.W. Leung, L.R. Meachem, J.P. Galgani, R. Hellmiss, R. Keret, P.S. Rotwein, J.S. Parks, Z. Laron, W.I. Wood, 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. U. S. A. 86 (1989) 8083–8087. [13] S. Amselem, P. Duquesnoy, O. Attre, G. Novelli, S. Bousnina, M.C. Postel-Vinay, M. Goosens, Laron dwarfism and mutations of the growth hormone-receptor gene, N. Engl. J. Med. 321 (1989) 989–995. [14] O. Shevah, Z. Laron, Genetic aspects, in: Z. Laron, J. Kopchick (Eds.), Laron Syndrome — From Man to Mouse, Springer Verlag, Berlin Heidelberg 2011, pp. 29–52. [15] Z. Laron, Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958–2003, J. Clin. Endocrinol. Metab. 89 (3) (2004) 1031–1044. [16] Laron syndrome from man to mouse, in: Z. Laron, J.J. Kopchick (Eds.), Genetics, Pathophysiology Aspects, Treatment and Experimental, 1st ed.Springer Verlag, Berlin Heidelberg 2011, p. 531. [17] Z. Laron, M. Iluz, R. Kauli, Head circumference in untreated and IGF-I treated patients with Laron syndrome. Comparison with untreated and hGH-treated children with isolated growth hormone deficiency, Growth Hormon. IGF Res. 22 (2012) 49–52. [18] Z. Laron, R. Kauli, Linear growth pattern of untreated Laron syndrome patients, in: Z. Laron, J. Kopchick (Eds.), Laron Syndrome — From Man to Mouse, Springer Verlag, Berlin Heidelberg 2011, pp. 63–89. [19] Z. Laron, P. Lilos, B. Klinger, Growth curves for Laron syndrome, Arch. Dis. Child. 68 (1993) 768–770. [20] Z. Laron, A. Silbergeld, A simple diagnostic screening test for children with short stature — with emphasis on genetic defects along the GH axis, Pediatr. Endocrinol. Rev. 4 (2006) 96–98. [21] H.M. Domené, P.A. Scaglia, H.G. Jasper, Deficiency of the insulin-like growth factorbinding protein acid-labile subunit (ALS) of the circulating ternary complex in children with short stature, Pediatr. Endocrinol. Rev. 7 (2010) 339–346. [22] Z. Laron, R. Sarel, A. Pertzelan, Puberty in Laron-type dwarfism, Eur. J. Pediatr. 134 (1980) 79–83. [23] Z. Laron, B. Klinger, Body fat in Laron syndrome patients: effect of insulin-like growth factor I treatment, Horm. Res. 40 (1993) 16–22. [24] Z. Laron, S. Ginsberg, P. Lilos, M. Arbiv, N. Vaissman, Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity), Clin. Endocrinol. 65 (2006) 114–117. [25] Z. Laron, S. Ginsberg, M. Webb, Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion, Prelim. Rep. IGF Res. 18 (2008) 434–438. [26] S. Ginsberg, Z. Laron, M. Arbiv, N. Vaisman, The obesity of patients with Laron syndrome is not associated with excessive nutritional intake, Obes. Res. Clin. Pract. 3 (2009) 3–8. [27] H. Kanety, R. Hemi, S. Ginsberg, C. Pariente, E. Yissachar, E. Barchod, T. Funahashi, Z. Laron, Total and high molecular weight adiponectin are elevated in patients with Laron syndrome despite marked obesity, Eur. J. Endocrinol. 161 (2009) 837–844.
Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004
4
Z. Laron, R. Kauli / Growth Hormone & IGF Research xxx (2015) xxx–xxx
[28] Z. Laron, Psychological aspects in patients with Laron syndrome, in: Z. Laron, J. Kopchick (Eds.), Laron Syndrome — From Man to Mouse, Springer Verlag, Berlin Heidelberg 2011, pp. 325–333. [29] L. Kornreich, G. Horev, M. Schwarz, B. Karmazyn, Z. Laron, Craniofacial and brain abnormalities in Laron syndrome (primary growth hormone in sensitivity), Eur. J. Endocrinol. 146 (2002) 499–503. [30] L. Kornreich, G. Horev, M. Schwarz, B. Karmazyn, Z. Laron, Pituitary size in patients with Laron syndrome (primary GH insensitivity), Eur. J. Endocrinol. 148 (2003) 339–341. [31] J. Attias, O. Zarchi, B.I. Nageris, Z. Laron, Cochlear hearing loss in patients with Laron syndrome, Eur. Arch. Otorhinolaryngol. 269 (2012) 461–466. [32] Z. Laron, Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity), Pediatr. Endocrinol. Rev. 5 (2008) 766–771. [33] Z. Laron, Emerging treatment options for patients with Laron syndrome, Expert Opin. Orphan Drugs 7 (2014) 681–694. [34] Z. Laron, If one daily injection of IGF-I has the same growth promoting effect as 2 injections a day, why continue to give two injections? Pediatr. Endocrinol. Rev. 10 (2013) 277–279.
[35] Z. Laron, S. Ginsberg, P. Lilos, M. Arbiv, N. Vaisman, Long-term IGF-I treatment of children with Laron syndrome increases adiposity, Growth Hormon. IGF Res. 16 (2006) 61–64. [36] Z. Laron, B. Klinger, IGF-I treatment of adult patients with Laron syndrome: preliminary results, Clin. Endocrinol. (Oxf.) 41 (1994) 631–638. [37] J. Guevara-Aguirre, P. Balasubramanian, M. Guevara-Aguirre, M. Wei, F. Madia, C.-W. Cheng, D. Hwang, A. Martin-Montalvo, J. Saavedra, S. Ingles, R. de Cabo, P. Cohen, V.D. Longo, Growth hormone receptor deficiency is associated with a major reduction in pro-aging signalling, cancer and diabetes in humans, Sci. Transl. Med. 3 (70) (2011), http://dx.doi.org/10.1126/scitranslmed.3001845 (70ra13). [38] O. Shevah, Z. Laron, Patients with congenital deficiency of IGF-I seem protected from the development of malignancies. A preliminary report, Growth Hormon. IGF Res. 17 (2007) 54–57. [39] R. Steuerman, O. Shevah, Z. Laron, Congenital IGF-I deficiency tends to confer protection against postnatal development of malignancies, Eur. J. Endocrinol. 164 (2011) 485–489. [40] L. Lapkina, Z. Laron, H. Werner, Genome-wide analysis of cancer protection pathways in Laron syndrome patients, Growth Hormon. IGF Res. 22 (2012) (P01–22:S3).
Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment Zvi Laron ⁎, Rivka Kauli Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
a r t i c l e
i n f o
Article history: Received 4 June 2015 Received in revised form 27 July 2015 Accepted 3 August 2015 Available online xxxx Keywords: Laron syndrome GH insensitivity IGF-I IGF-I treatment Dwarfism Obesity
a b s t r a c t Clinical and laboratory investigations of dwarfed children newly Jewish immigrants from Yemen and Middle East and who resembled patients with isolated growth hormone deficiency were started by our group in 1958. In 1963 when we found that they have high serum levels of hGH, we knew that we had discovered a new disease of primary GH insensitivity. It was subsequently coined Laron Syndrome (LS, OMIM #262500). The etiopathogenesis was disclosed by 2 liver biopsies demonstrating a defect in the GH receptor. Subsequent investigations demonstrated deletions or mutations in the GHR gene. The defect lead to an inability of IGF-I generation, resulting in severe dwarfism, obesity, and other morphologic and biochemical pathologies due to IGF-I deficiency. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Following closely our cohort of 69 patients with LS enabled us to study its features in untreated and IGF-I treated patients. This syndrome proved to be a unique model to investigate the effects of IGF-I dissociated from GH stimulation. In recent studies we found that homozygous patients for the GHR mutations are protected lifelong from developing malignancies, opening new directions of research. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction In 1958, at a time when no assay for human growth hormone (hGH) was available three children aged a few days, 1.5 and 3.5 years (2 males and 1 female) with marked growth retardation were referred to our clinic [1]. They belonged to a consanguineous Jewish family recently immigrated from Yemen. Older siblings were of normal height. Within one year we were able to collect a total of 22 children with the same features all belonging to consanguineous families coming from the Middle East or Arabian Peninsula [2]. Their characteristics were dwarfism, obesity, small genitalia in the boys and severe hypoglycemia. They had a typical head configuration, a small face, and a protruding forehead resulting in a saddle nose. Their voice was high pitched and they had sparse hair. Phenotypically they resembled what was known as GH deficiency, at the time that they were diagnosed with dwarfism and insulin induced hypoglycemia non-responsiveness due to insulin sensitivity [3]. When radioimmunoassays for hGH became available in 1963 [4], we were surprised to find that these children had markedly elevated serum
⁎ Corresponding author at: Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, 14 Kaplan Street, Petah Tikva 29202, Israel. E-mail address: [email protected] (Z. Laron).
hGH levels [1,2]. We recognized that we had discovered a new disease. We were confronted with 2 possible explanations: a) An abnormal structure of the GH b) Resistance to GH of normal structure. Technological limitation delayed the final answer for 20 years. Immunological studies comparing the patients' serum hGH by radioimmuno and radio-receptor assays for hGH showed identical behavior with serum from healthy controls indicating a normal structure of the GH in the LS patients [5,6]. This was confirmed subsequently by hGH gene analysis [7]. Proof of insensitivity to GH was shown by the lack of response to exogenous hGH administration and the absence of rise of serum somatomedin (IGF-I) [8]. So the “IGF-I generation test” was born. The name Laron Dwarfism (later changed to Laron Syndrome (LS)) was coined by Elders et al. [9]. Definite evidence for GH resistance was found by liver biopsy in 2 LS patients, showing that I125hGH did not bind to the liver membranes of these patients, in contrast to membranes from controls (taken during renal transplants) [10]. Cloning of the GH receptor in 1987 [11] enabled the identification of partial gene deletion in the GH receptor gene in 2 of our patients [12]. The discovery of the PCR technique enabled the identification of many mutations in the GHR also in our patients [12-14]. With time our cohort of patients increased in size and comprises at present 69 patients, belonging to different ethnic groups.
http://dx.doi.org/10.1016/j.ghir.2015.08.004 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004
2
Z. Laron, R. Kauli / Growth Hormone & IGF Research xxx (2015) xxx–xxx
Table 1 Laron Syndrome — the Israeli cohort. Ethnic origin.
Jews Oriental (Iran, Iraq, Lebanon, Syria, Morocco, Yemen, Afghanistan) Muslims Druse Christians Total
Table 3 Laron Syndrome — the Israeli cohort. Current age. Females
Males
Total
Age — years
Females
Males
Total
20
13
33
3 1 11 35
13
16 1 19 69
b10 10–20 20–30 30–40 40–50 50–60 N60 Total
4 6 5 2 5 8 5 35
2 9 7 4 4 5 3 34
6 15 12 6 9 13 8 69
8 34
The total number of LS patients worldwide is not known as many are probably undiagnosed. The number of known and/or published LS patients is around 350. 1.1. Subjects The number of LS patients in the Israeli cohort and their ethnic origin are shown in Table 1. All families originate from the Middle East or Mediterranean area. Many belong to consanguineous families and in several families more than one child is affected. Table 2 presents their age at referral. It is seen that 33 were referred below age 4, enabling treatment in those referred after the year 1987. Table 3 shows their present age including the age at death of 5 of our patients. 2. Methods During the growth periods the patients were followed every 3–4 months, on which occasion they underwent body measurements, complete physical examinations and laboratory investigations. Our close follow-up of all the patients by the same team enabled us to study the clinical characteristics and the physio-pathology of hGH and IGF-I deficiency to late adult age in the untreated LS patients, and to study the pharmacology and effects of IGF-I in the treated children and adults. Our overall findings have been summarized in two major publications [15,16]. Following are the most striking findings in our cohort of LS patients. 2.1. Clinical characteristics of Laron Syndrome As young children they have a special facial phenotype, a small face, a protruding forehead, sparse hair and a below normal head circumference [17]. Dwarfism is already evident by short birth length which if untreated deviates more and more from the lower centiles reaching sizes of −4 to − 8 height SDS [18]. From the typical growth pattern we designed specific growth charts [19], which fit any congenital IGF-I deficiencies [20], except the acid-labile subunit (ALS) syndrome [21]. Puberty and full sexual development are delayed mainly in boys [22]. Table 2 Laron Syndrome — the Israeli cohort. Age at referral. Age
Females
Males
Total
4 days–6 m 1 y–3 y 11 m 4 y–9 y 11 m 10 y–16 y 9 m 34 y–51 y Total
2 15 12 4 2 35
5 11 12 4 2 34
7 26 24 8 4 69
Part of the referrals were before IGF-I was available.
Final heights range from 116–142 cm (males) and 108–136 (females) with an increased upper/lower body ratio, denoting short limbs [18]. One of the major complications is marked obesity, lipidemia and fatty liver [23–25]. The obesity, reaching 60% of body composition in females and 40% in males, is not due to overeating or low energy expenditure [26] but to a metabolic dysfunction, one of its characteristics being high serum adiponectin [27]. LS patients also have pathologies in the carbohydrate metabolism. In infancy they suffer from hypoglycemia (sometimes severe); subsequently during progressing obesity they develop glucose intolerance and even Type 2 diabetes (Table 4). Ten patients developed cardiovascular disease (Table 5). Psychological tests revealed a below normal IQ in part of the patients with improvement of the verbal IQ with time [28]. MRI of the skull showed overt pathological findings in the CNS in some of the patients [29,30]. Noteworthy is the underdevelopment of the sinuses. LS patients have a tendency for auditory defects [31] as do also patients with other disorders causing congenital IGF-I deficiency. 2.2. Treatment Twenty one children (11 girls, 10 boys) were or are still treated by recombinant IGF-I (Fujisawa (Astellas) or TERCICA–IPSEN); in doses ranging from 150–220 μg/kg once daily [32,33]. Their height, brain and organ growth respond rapidly to the IGF-I administration but to a slightly lesser degree than GH deficient children to hGH. Mean growth velocity in the 1st year of treatment was 8 cm/y. Linear growth catchup and changes in the U/L ratio showed a change in Ht SDS from − 6.1 ± 1.2SDS to − 4.6 ± 1.2SDS (p b 0.001) without change in the U/L ratio. IGF-I increased the mean (± SD) head circumference from − 3.3 ± 0.9 to + 0/87 ± 1.8. Injecting the IGF-I only with the main meal, resulted in less adverse effects than reported with twice daily injections, yielding the same results [34]. After a short decrease in adiposity and lipidemia, both increases again progressively resulting in marked obesity at the end of puberty [35]. Treatment of 5 adult LS patients by IGF-I in doses of 50–150 μg/kg once daily for one year resulted in beneficial metabolic effects [36]. Table 4 Laron Syndrome patients with diabetes mellitus (NIDDM). Patient
Sex
Age at referral (y/m)
Age range of (abnormal) OGTT onlya
Age at Dg DMb
Age at (April 2015)
1 2 3
M M M
36 y 10 m 1y 5m
39 y 4 m 7 y 10 m–28 y 9 m 12 y 2 m–26 y
39 y 4 m 37 y 3 m 39 y 8 m
4 5 6 7
M M F M
6m 3y1m 3 y 7.5 m 7y9m
14 y 2 m–16 y 7 m 16 y–39 y 4 m 14 y 8 m–36 y 4 m 15 y 6 m–26 y 4 m
37 y 60 y 58 y 58–59 y?
Deceased at 75.8 51 y 9 m Deceased at 49 y 6 m 38 y 3 m 60 y 59 y 4 m 61 y
a Fasting glucose levels were normal until DM was diagnosed. There were no symptoms suggestive for DM. b Glucose intolerance and/or hyperinsulinism.
Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004
Z. Laron, R. Kauli / Growth Hormone & IGF Research xxx (2015) xxx–xxx
3. Conclusions
Table 5 Laron Syndrome — the Israeli cohort. Cardiovascular disease. Females Congenital Patent ductus arteriosus Acquired Rheumatic heart disease Hypertension Coronary heart disease Peripheral vascular disease
Males
2
Total
2
2
1 2 1 6
2 1 4 1 10
1
3
We consider obesity as the most frequent adverse effect of IGF-I treatment, and acknowledge that no fat reducing treatment has succeeded so far.
2.3. Adverse effects (AEs) The majority of AEs are due to over dosage or administration of rIGFI without an adequate meal. The results are hypoglycemia, not only in infancy. Other AEs are headache, intracranial hypertension, swelling of the lymphoid tissues, and hyperandrogenism [32,34].
2.4. Social aspects The occupation of the adult LS patients is shown in Table 6. All but one female have sexual activity. Ten (5 males and 5 females) are married to unaffected partners and have children of normal size.
2.5. Mortality Among our 69 patients we registered 5 deaths. One 9 month old girl, sister of one of our patients, died long ago of suspected encephalitis (the possibility of undiagnosed hypoglycemia cannot be ruled out); 2 patients (one male and one female) died at ages 50 and 54 due to neglected cardio-vascular disease and one 76 year old male died in a car accident. In the Ecuadorian cohort 30 deaths have been reported since 1988 [37], nine were over age 9 (8 died due to cardiac disease and one of stroke).
2.6. Laron Syndrome and cancer In two epidemiological studies comprising 169 [38] and 230 [39] patients with Laron Syndrome we observed that homozygous patients for this disease were protected lifelong from developing cancer. Their 752 heterozygote first degree family members including 274 siblings were not protected. The same was reported for the large Ecuadorian cohort of Laron Syndrome patients [39]. In collaboration with Prof Haim Werner and Lena Lapkina PhD of the Department of Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, we are trying to decipher the protecting mechanism [40].
Table 6 Laron Syndrome — the Israel cohort. Occupation of adult patients.
Office work, in business Manual On social security
3
Females
Males
Total
2 9 2
3 2 6
5 11 8 24
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Please cite this article as: Z. Laron, R. Kauli, Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.08.004