Abstract
Objectives
We performed a cross-sectional study on anthropometric and laboratory characteristics of inhabitants of Rampasasa (Flores, Indonesia). Adults were categorised according to ancestry into three groups: pygmoid (P/P, offspring of pygmoid parents, n=8), mixed pygmoid (P/N, offspring of pygmoid and non-pygmoid parents, n=12) and non-pygmoid (N/N, n=10). Children (n=28) were P/N.
Methods
Measurements included height, weight, sitting height, arm span, head circumference, haematological analysis and serum albumin, calcium, vitamin D, insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3). Pubertal stage and bone age was assessed in children. Anthropometric data were expressed as standard deviation score (SDS) for age. IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio were expressed as SDS for age, bone age and pubertal stage.
Results
Mean height SDS showed a gradient from P/P (−4.0) via P/N (−3.2) to N/N (−2.3) (−3.4, −3.1 and −2.2 adjusted for age-associated shrinking). Sitting height and head circumference showed similar gradients. Serum IGF-I SDS was similar among groups (approximately −1 SDS). IGFBP-3 SDS tended toward a gradient from P/P (−1.9) via P/N (−1.5) to N/N (−1.1), but IGF-I/IGFBP-3 ratio was normal in all groups. In P/P and P/N, mean head circumference SDS was >2 SD greater than mean height SDS. Children showed a progressive growth failure and bone age delay, delayed female pubertal onset and an initial low serum IGF-I, normal IGFBP-3 and low IGF-I/IGFBP-3 ratio.
Conclusions
P/P showed proportionate short stature with relative macrocephaly and relatively low IGFBP-3; P/N presented an intermediate pattern. P/N children were progressively short, showed delayed skeletal maturation, delayed puberty in girls and low IGF-I and IGF-I/IGFBP-3.
Acknowledgements
The authors thank the late Prof. Teuku Jacob, who initially inspired this study and first brought the research team to Rampasasa. The authors are grateful to the late Prof. Henriette Delemarre-van de Waal, who mentored the study design from Leiden, the Netherlands. The authors acknowledge the help of Drg. D. Nababan and the management of Ruteng Regional Hospital; Mrs. Nengah and the team from Prodia Laboratories in Bali; Drs. D.L. Pramesti, S.F. Adiprabowo, L.A. Santoso, R. Purbasari, M. Yasin serving as research assistants; Dr. I.W. Bikin for help in accommodation and logistics in Bali; Dr. INA Purwana for assistance in sample collections; Prof. J.R.L. Batubara and Dr. B. Tridjaja for fruitful advice and support; Prof. W. Ramelan for discussions on genetic studies; A.W. Pulungan for help with documentation and sample transportation; and the local guides who assisted us in Rampasasa.
-
Research funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Costs for laboratory tests were partially covered by Prodia Laboratories.
-
Author contributions: AP: conception of the study, choice of methodology, literature review, data collection and analysis, preparation of first version of the manuscript, critical reviewing of subsequent versions of the manuscript. AAA: data management, statistical analysis, critical reviewing of subsequent versions of the manuscript. FS: literature review, data collection and analysis, preparation of first version of the manuscript. MRY: literature review, data collection and analysis, preparation of first version of the manuscript. CdB: advice on data analysis, critical reviewing various versions of the manuscript. AW: consultant for biomedical data, laboratory procedures and laboratory analysis. AF: general supervisor of the research design and field work. JMW: supervision of data analysis, review of the literature, writing successive versions of the manuscript. All authors reviewed the pre-final version and agreed with the submitted version of the manuscript.
-
Competing interests: All authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the authors’ institutional review board (Health Research Ethics Committee of the Faculty of Medicine, Universitas Indonesia – Cipto Mangunkusumo Hospital) or equivalent committee (Approval Letter no. 472/PT02.FK/ETIK/2012).
References
1. Cavalli Sforza, LL. African pygmies. Orlando: Academic Press; 1986.Search in Google Scholar
2. Migliano, AB, Vinicius, L, Lahr, MM. Life history trade-offs explain the evolution of human pygmies. Proc Natl Acad Sci U S A 2007;104:20216–9. https://doi.org/10.1073/pnas.0708024105.Search in Google Scholar
3. Cavalli-Sforza, LL, Menozzi, P, Piazza, A. The history and geography of human genes. Princeton, NJ: Princeton University Press; 1994.Search in Google Scholar
4. Jarvis, JP, Scheinfeldt, LB, Soi, S, Lambert, C, Omberg, L, Ferwerda, B, et al.. Patterns of ancestry, signatures of natural selection, and genetic association with stature in Western African pygmies. PLoS Genet 2012;8:e1002641. https://doi.org/10.1371/journal.pgen.1002641.Search in Google Scholar
5. Tommaseo-Ponzetta, M, Mona, S, Calabrese, F, Konrad, G, Vacca, E, Attimonelli, M. Mountain pygmies of Western New Guinea: a morphological and molecular approach. Hum Biol 2013;85:285–308. https://doi.org/10.3378/027.085.0314.Search in Google Scholar
6. Rozzi, FV, Koudou, Y, Froment, A, Le Bouc, Y, Botton, J. Growth pattern from birth to adulthood in African pygmies of known age. Nat Commun 2015;6:7672. https://doi.org/10.1038/ncomms8672.Search in Google Scholar
7. Jinam, TA, Phipps, ME, Saitou, N. Admixture patterns and genetic differentiation in negrito groups from West Malaysia estimated from genome-wide SNP data. Hum Biol 2013;85:173–88. https://doi.org/10.3378/027.085.0308.Search in Google Scholar
8. Migliano, AB, Romero, IG, Metspalu, M, Leavesley, M, Pagani, L, Antao, T, et al.. Evolution of the pygmy phenotype: evidence of positive selection from genome-wide scans in African, Asian, and Melanesian pygmies. Hum Biol 2013;85:251–84. https://doi.org/10.3378/027.085.0313.Search in Google Scholar
9. Perry, GH, Foll, M, Grenier, JC, Patin, E, Nedelec, Y, Pacis, A, et al.. Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers. Proc Natl Acad Sci U S A 2014;111:E3596–603. https://doi.org/10.1073/pnas.1402875111.Search in Google Scholar
10. Sjostrand, AE, Sjodin, P, Jakobsson, M. Private haplotypes can reveal local adaptation. BMC Genet 2014;15:61. https://doi.org/10.1186/1471-2156-15-61.Search in Google Scholar
11. Perry, GH, Dominy, NJ. Evolution of the human pygmy phenotype. Trends Ecol Evol 2009;24:218–25. https://doi.org/10.1016/j.tree.2008.11.008.Search in Google Scholar
12. Becker, NS, Verdu, P, Georges, M, Duquesnoy, P, Froment, A, Amselem, S, et al.. The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature. Eur J Hum Genet 2013;21:653–8. https://doi.org/10.1038/ejhg.2012.223.Search in Google Scholar
13. Le Bouc, Y. Have we finally solved the enigma of the small size of Pygmies? Ann Endocrinol 2017;78:83–7. https://doi.org/10.1016/j.ando.2017.04.022.Search in Google Scholar
14. Scheffler, C, Hermanussen, M, Bogin, B, Liana, DS, Taolin, F, Cempaka, P, et al.. Stunting is not a synonym of malnutrition. Eur J Clin Nutr 2020;74:377–86. https://doi.org/10.1038/s41430-019-0439-4.Search in Google Scholar
15. Meazza, C, Pagani, S, Bozzola, M. The pygmy short stature enigma. Pediatr Endocrinol Rev 2011;8:394–9.Search in Google Scholar
16. Rimoin, DL, Merimee, TJ, Rabinowitz, D, Cavalli-Sforza, LL, McKusick, VA. Peripheral subresponsiveness to human growth hormone in the African pygmies. N Engl J Med 1969;281:1383–8. https://doi.org/10.1056/nejm196912182812502.Search in Google Scholar
17. Merimee, TJ, Rimoin, DL, Cavalli-Sforza, LL. Metabolic studies in the African pygmy. J Clin Invest 1972;51:395–401. https://doi.org/10.1172/jci106825.Search in Google Scholar
18. Merimee, TJ, Zapf, J, Froesch, ER. Dwarfism in the pygmy. An isolated deficiency of insulin-like growth factor I. N Engl J Med 1981;305:965–8. https://doi.org/10.1056/nejm198110223051701.Search in Google Scholar
19. Merimee, TJ, Zapf, J, Hewlett, B, Cavalli Sforza, LL. Insulin-like growth factors in pygmies. The role of puberty in determining final stature. N Engl J Med 1987;316:906–11. https://doi.org/10.1056/nejm198704093161503.Search in Google Scholar
20. Baumann, G, Shaw, MA, Merimee, TJ. Low levels of high-affinity growth hormone-binding protein in African pygmies. N Engl J Med 1989;320:1705–9. https://doi.org/10.1056/nejm198906293202601.Search in Google Scholar
21. Bozzola, M, Travaglino, P, Marziliano, N, Meazza, C, Pagani, S, Grasso, M, et al.. The shortness of Pygmies is associated with severe under-expression of the growth hormone receptor. Mol Genet Metabol 2009;98:310–3. https://doi.org/10.1016/j.ymgme.2009.05.009.Search in Google Scholar
22. Clavano-Harding, AB, Ambler, GR, Cowell, CT, Garnett, SP, Al-Toumah, B, Coakley, JC, et al.. Initial characterization of the GH-IGF axis and nutritional status of the Ati Negritos of the Philippines. Clin Endocrinol 1999;51:741–7. https://doi.org/10.1046/j.1365-2265.1999.00877.x.Search in Google Scholar
23. Davila, N, Shea, BT, Omoto, K, Mercado, M, Misawa, S, Baumann, G. Growth hormone binding protein, insulin-like growth factor-I and short stature in two pygmy populations from the Philippines. J Pediatr Endocrinol Metab 2002;15:269–76. https://doi.org/10.1515/jpem.2002.15.3.269.Search in Google Scholar
24. Ishida, T, Suzuki, J, Duangchan, P, Settheetham-Ishida, W. Preliminary report on the short stature of Southeast Asian forest dwellers, the Manni, in southern Thailand: lack of an adolescent spurt in plasma IGF-I concentration. Southeast Asian J Trop Med Publ Health 1998;29:62–5.Search in Google Scholar
25. Schwartz, J, Brumbaugh, RC, Chiu, M. Short stature, growth hormone, insulin-like growth factors, and serum proteins in the Mountain Ok people of Papua New Guinea. J Clin Endocrinol Metab 1987;65:901–5. https://doi.org/10.1210/jcem-65-5-901.Search in Google Scholar
26. Dulloo, AG, Shahkhalili, Y, Atchou, G, Mensi, N, Jacquet, J, Girardier, L. Dissociation of systemic GH-IGF-I axis from a genetic basis for short stature in African Pygmies. Eur J Clin Nutr 1996;50:371–80.Search in Google Scholar
27. Brown, P, Sutikna, T, Morwood, MJ, Soejono, RP, Jatmiko, Saptomo, EW, et al.. A new small-bodied hominin from the Late Pleistocene of Flores, Indonesia. Nature 2004;431:1055–61. https://doi.org/10.1038/nature02999.Search in Google Scholar
28. Jacob, T, Indriati, E, Soejono, RP, Hsu, K, Frayer, DW, Eckhardt, RB, et al.. Pygmoid Australomelanesian Homo sapiens skeletal remains from Liang Bua, Flores: population affinities and pathological abnormalities. Proc Natl Acad Sci USA 2006;103:13421–6. https://doi.org/10.1073/pnas.0605563103.Search in Google Scholar
29. Tucci, S, Vohr, SH, McCoy, RC, Vernot, B, Robinson, MR, Barbieri, C, et al.. Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia. Science 2018;361:511–6. https://doi.org/10.1126/science.aar8486.Search in Google Scholar
30. Kuczmarski, RJ, Ogden, CL, Grummer-Strawn, LM, Flegal, KM, Guo, SS, Wei, R, et al.. CDC growth charts: United States. Adv Data 2000;314:1–27.Search in Google Scholar
31. Pulungan, AB, Julia, M, Batubara, JRL, Hermanussen, M. Indonesian national synthetic growth charts. Acta Sci Paediatr 2018;1:20–34.Search in Google Scholar
32. Bundak, R, Bas, F, Furman, A, Gunoz, H, Darendeliler, F, Saka, N, et al.. Sitting height and sitting height/height ratio references for Turkish children. Eur J Pediatr 2014;173:861–9. https://doi.org/10.1007/s00431-013-2212-3.Search in Google Scholar
33. Gerver, WJM, Gkourogianni, A, Dauber, A, Nilsson, O, Wit, JM. Arm span and its relation to height in a 2- to 17-year-old reference population and heterozygous carriers of ACAN variants. Horm Res Paediatr 2020;93:164–72. https://doi.org/10.1159/000508500.Search in Google Scholar
34. Quanjer, PH, Capderou, A, Mazicioglu, MM, Aggarwal, AN, Banik, SD, Popovic, S, et al.. All-age relationship between arm span and height in different ethnic groups. Eur Respir J 2014;44:905–12. https://doi.org/10.1183/09031936.00054014.Search in Google Scholar
35. Nellhaus, G. Head circumference from birth to eighteen years. Pediatrics 1968;41:106–14.10.1542/peds.41.1.106Search in Google Scholar
36. Greulich, WW, Pyle, SJ. Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. California: Stanford University Press; 1959.10.1097/00000441-195909000-00030Search in Google Scholar
37. Zhu, H, Xu, Y, Gong, F, Shan, G, Yang, H, Xu, K, et al.. Reference ranges for serum insulin-like growth factor I (IGF-I) in healthy Chinese adults. PLoS One 2017;12:e0185561. https://doi.org/10.1371/journal.pone.0185561.Search in Google Scholar
38. Elmlinger, MW, Kuhnel, W, Weber, MM, Ranke, MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med 2004;42:654–64. https://doi.org/10.1515/cclm.2004.112.Search in Google Scholar
39. Niewenweg, R, Smit, ML, Walenkamp, MJ, Wit, JM. Adult height corrected for shrinking and secular trend. Ann Hum Biol 2003;30:563–9. https://doi.org/10.1080/0301446032000112661.Search in Google Scholar
40. Pulungan, AB, Nugraheni, RP, Advani, N, Akib, AAP, Devaera, Y, Sjakti, HA, et al.. Age at menarche and body fat in adolescent girls. Paediatr Indones 2020;60:269–76. https://doi.org/10.14238/pi60.5.2020.269-76.Search in Google Scholar
41. Fredriks, AM, Van Buuren, S, van Heel, WJ, Dijkman-Neerincx, RH, Verloove-Vanhorick, SP, Wit, JM. Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 2005;90:807–12. https://doi.org/10.1136/adc.2004.050799.Search in Google Scholar
42. Meazza, C, Travaglino, P, Pagani, S, Laarej, K, Duse, M, Bozzola, M. Hyperimmunoglobulinaemia in Babinga Pygmies is present from infancy. Int J Immunopathol Pharmacol 2009;22:1117–20. https://doi.org/10.1177/039463200902200428.Search in Google Scholar
43. Hagino, I, Hayashi, K, Kawamura, K, Sato, H, Yamauchi, T. Adolescent growth spurt and growth pattern factors related to the short stature of Pygmy hunter-gatherers of Southeast Cameroon. Ann Hum Biol 2013;40:9–14. https://doi.org/10.3109/03014460.2012.720711.Search in Google Scholar
44. van Gool, SA, Kamp, GA, Visser-van Balen, H, Mul, D, Waelkens, JJ, Jansen, M, et al.. Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty. J Clin Endocrinol Metab 2007;92:1402–8. https://doi.org/10.1210/jc.2006-2272.Search in Google Scholar
45. Becker, NS, Verdu, P, Froment, A, Le Bomin, S, Pagezy, H, Bahuchet, S, et al.. Indirect evidence for the genetic determination of short stature in African Pygmies. Am J Phys Anthropol 2011;145:390–401. https://doi.org/10.1002/ajpa.21512.Search in Google Scholar
46. Hardouin, S, Gourmelen, M, Noguiez, P, Seurin, D, Roghani, M, Le Bouc, Y, et al.. Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance. J Clin Endocrinol Metab 1989;69:1291–301. https://doi.org/10.1210/jcem-69-6-1291.Search in Google Scholar
47. Vincent, M, Jans, C, Ghesquiere, J. The new-born pigmy and his mother. Am J Phys Anthropol 1962;20:237–47. https://doi.org/10.1002/ajpa.1330200308.Search in Google Scholar
48. Bailey, RC. The comparative growth of Efe pygmies and African farmers from birth to age 5 years. Ann Hum Biol 1991;18:113–20. https://doi.org/10.1080/03014469100001452.Search in Google Scholar
49. Van de Koppel, JM, Hewlett, BS. Growth of Aka pygmies and Bangandus of the Central African Republic. In: Cavalli-Sforza, LL, editor. African pygmies. Orlando: Academic Press; 1986:95–102 pp.Search in Google Scholar
50. Lachance, J, Vernot, B, Elbers, CC, Ferwerda, B, Froment, A, Bodo, JM, et al.. Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. Cell 2012;150:457–69. https://doi.org/10.1016/j.cell.2012.07.009.Search in Google Scholar
51. Hsieh, P, Woerner, AE, Wall, JD, Lachance, J, Tishkoff, SA, Gutenkunst, RN, et al.. Model-based analyses of whole-genome data reveal a complex evolutionary history involving archaic introgression in Central African Pygmies. Genome Res 2016;26:291–300. https://doi.org/10.1101/gr.196634.115.Search in Google Scholar
52. Consortium HP-AS, Abdulla, MA, Ahmed, I, Assawamakin, A, Bhak, J, Brahmachari, SK, et al.. Mapping human genetic diversity in Asia. Science 2009;326:1541–5. https://doi.org/10.1126/science.1177074.Search in Google Scholar
53. Poh, BK, Rojroongwasinkul, N, Nguyen, BK, Sandjaja, Ruzita, AT, Yamborisut, U, et al.. 25-hydroxy-vitamin D demography and the risk of vitamin D insufficiency in the South East Asian Nutrition Surveys (SEANUTS). Asia Pac J Clin Nutr 2016;25:538–48. https://doi.org/10.6133/apjcn.092015.02.Search in Google Scholar
54. Verdu, P, Becker, NS, Froment, A, Georges, M, Grugni, V, Quintana-Murci, L, et al.. Sociocultural behavior, sex-biased admixture, and effective population sizes in Central African Pygmies and non-Pygmies. Mol Biol Evol 2013;30:918–37. https://doi.org/10.1093/molbev/mss328.Search in Google Scholar
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0526).
© 2021 Walter de Gruyter GmbH, Berlin/Boston
