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Gregor Mendel and regulation of child’s growth: genes, molecules, and paediatric clinical routine


Authors: Toni Ledjona *;  Plachý Lukáš *;  Amaratunga Anne Shenali *;  Dušátková Petra;  Kodytková Aneta;  Koloušková Stanislava;  Průhová Štěpánka;  Lebl Jan
Authors‘ workplace: Pediatrická klinika 2. lékařské fakulty UK a Fakultní nemocnice v Motole, Praha
Published in: Čes-slov Pediat 2022; 77 (4): 206-213.
Category: Comprehensive Report
doi: https://doi.org/10.55095/CSPediatrie2022/033

Overview

Determination of human growth is mostly genetic (80%) and only partially environmental (20%). The key genes regulating growth include genes encoding proteohormones a related molecules (growth hormone, IGF-1, IGF-2, acid-lable subunit ALS), hormonal receptors (receptors for growth hormone, IGF and pituitary releasing hormones – GHRH and ghrelin), with a limited role of enzymes (PAPPA 2). Genes encoding transcription factors regulate pituitary morphogenesis (sonic hedgehog cascade and others) and differentiation (PROP1, POU1F1) and also chondrocytes (SHOX). Structural molecules include components of cartilagineous extracellular matrix (gens encoding aggrecan, collagens, matrillin, fibrillin and others). The spectrum of genes responsible for both severe growth failure and minor variability of height includes genes for paracrine chondrocyte signalisation (FGFR3/NPR2 system), for intracellular signalisation (Ras-MAPK cascade, JAK-STAT signalling pathway) and for fundamental intracellular processes – regulation of DNA epigenetic modifications and control of DNA integrity. Genetic testing offers dual benefits: Immediate, as it bears an important information for the patient and his/her family about the disease nature, its future outcome and its inheritance – and a long-term – each testing contributes to understanding of disease mechanisms and to proposing novel therapies.

Keywords:

genes – Mendel – regulation of longitudinal growth – pituitary – chondrocyte


Sources

1. Mendel G. Versuche über Pflanzenhybriden. Verhandlungen des naturforschenden Vereines in Brünn, Bd. IV für das Jahr 1865: 3–47.

2. Garrod AE. The incidence of alkaptonuria: a study in clinical individuality. Lancet 1902; 2(4137): 1616–1620.

3. Nirenberg M. Historical review: Deciphering the genetic code – a personal account. Trends Biochem Sci 2004; 29: 46–54.

4. Green ED, Watson JD, Collins FS. Human Genome Project: Twenty-five years of big biology. Nature 2015; 526: 29–31.

5. Mullis PE. Genetics of growth hormone deficiency. Endocrinol Metab Clin North Am 2007; 36: 17–36.

6. Phillips JA 3rd, Hjelle BL, Seeburg PH, Zachmann M. Molecular basis for familial isolated growth hormone deficiency. Proc Natl Acad Sci USA 1981; 78: 6372–6375.

7. Woods KA, Camacho-Hübner C, Savage MO, Clark AJL. 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.

8. Toni L, Pádrová K, Plachý L, et al. Význam acidolabilní podjednotky (ALS) v etiologii a v diagnostice malého vzrůstu. Ces-Slov Pediat 2021; 75: 214–218.

9. Begemann M, Zirn B, Santen G, et al. Paternally Inherited IGF2 mutation and growth restriction. N Engl J Med 2015; 373: 349–56.

10. Dauber A, Rosenfeld RG, Hirschhorn JN. Genetic evaluation of short stature. J Clin Endocrinol Metab 2014; 99: 3080–92.

11. Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone--a new inborn error of metabolism? Isr J Med Sci 1966; 2: 152–155.

12. Amselem S, Duquesnoy P, Attree O, et al. Laron dwarfism and mutations of the growth hormone-receptor gene. N Engl J Med 1989; 321: 989–995.

13. Eshet R, Laron Z, Pertzelan A, et al. Defect of human growth hormone receptors in the liver of two patients with Laron-type dwarfism. Isr J Med Sci 1984; 20: 8–11.

14. Amaratunga SA, Tayeb TH, Dusatkova P, et al. Invaluable role of consanguinity in providing insight into paediatric endocrine conditions: Lessons learnt from congenital hyperinsulinism, monogenic diabetes, and short stature. Horm Res Paediatr 2022; 95: 1–11.

15. Wajnrajch MP, Gertner JM, Harbison MD, et al. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet 1996; 12: 88– 90.

16. Baumann G, Maheshwari H. The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Paediatr Suppl 1997; 423: 33–38.

17. Chanoine JP, De Waele K, Walia P. Ghrelin and the growth hormone secretagogue receptor in growth and development. Int. J. Obes 2009; 33(S1): S48–S52.

18. Klammt J, Kiess W, Pfäffle R. IGF1R mutations as cause of SGA. Best Pract Res Clin Endocrinol Metab 2011; 25: 191–206.

19. Dauber A, Muñoz-Calvo MT, Barrios V, et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGFI availability. EMBO Mol Med 2016; 8: 363–74.

20. Riedl S, Vosahlo J, Battelino T, et al. Refining clinical phenotypes in septo- -optic dysplasia based on MRI findings. Eur J Pediatr 2008; 167: 1269–76.

21. Gregory LC, Dattani MT. The molecular basis of congenital hypopituitarism and related disorders. J Clin Endocrinol Metab 2020; 105: dgz184.

22. Lebl J, Vosáhlo J, Pfaeffle RW, et al. Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. Eur J Endocrinol 2005; 153: 389–96.

 23. Navardauskaite R, Dusatkova P, Obermannova B, et al. High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency. J Clin Endocrinol Metab 2014; 99: 299–306.

24. Dusatkova P, Pfäffle R, Brown MR, et al. Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations. Eur J Hum Genet 2016; 24: 415–20.

25. Tatsumi K, Miyai K, Notomi T, et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1992; 1: 56–58.

26. Jee YH, Andrade AC, Baron J, Nilsson O. Genetics of Short Stature. Endocrinol Metab Clin North Am 2017; 46: 259–281.

27. Shears DJ, Vassal HJ, Goodman FR, et al. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 1998; 19: 70–73.

28. Gkourogianni A, Andrew M, Tyzinski L, et al. Clinical characterization of patients with autosomal dominant short stature due to Aggrecan mutations. J Clin Endocrinol Metab 2017; 102: 460–469.

29. Plachy L, Dusatkova P, Maratova K, et al. Familial Short Stature - a novel phenotype of growth plate collagenopathies. J Clin Endocrinol Metab 2021; 106: 1742–1749.

30. Plachy L, Strakova V, Elblova L, et al. High prevalence of growth plate gene variants in children with familial short stature treated with growth hormone. J Clin Endocrinol Metab 2019; 104: 4273–4281.

31. Borochowitz ZU, Scheffer D, Adir V, et al. Spondylo-epi-metaphyseal dysplasia (SEMD) matrilin 3 type: homozygote matrilin 3 mutation in a novel form of SEMD. J Med Genet 2004; 41: 366–372.

32. Toni L, Dušátková P, Novotná D, et al. Short stature in a boy with atypical progeria syndrome due to LMNA c.433G>A.(p.(Glu145Lys)]: apparent growth hormone deficiency but poor response to growth hormone therapy. J Pediatr Endocrinol Metab 2019; 32: 775–779.

33. Kronenberg HM. Developmental regulation of the growth plate. Nature 2003; 423(6937): 332–6.

34. Bartels CF, Bükülmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004; 75: 27–34.

35. Plachy L, Dusatkova P, Maratova K, et al. NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone. J Clin Endocrinol Metab 2020; 105: dgaa037.

36. Miura K, Namba N, Fujiwara M, et al. An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS One 2012; 7: e42180.

37. Lebl J, Kolouskova S, Toni L, et al. Syndrom Noonanové a další RASopatie: Etiologie, diagnostika a terapie. Ces-Slov Pediat 2020; 75: 219– 226.

38. Klammt J, Neumann D, Gevers EF, et al. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun 2018; 9: 2105.

39. Sediva H, Dusatkova P, Kanderova V, et al. Short stature in a boy with multiple early-onset autoimmune conditions due to a STAT3 activating mutation: Could intracellular growth hormone signalling be compromised? Horm Res Paediatr 2017; 88: 160–166.

40. Wang YR, Xu NX, Wang J, Wang XM. Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms. World J Pediatr 2019; 15: 528–535.

41. Boniel S, Szymańska K, Śmigiel R, Szczałuba K. Kabuki syndrome – clinical review with molecular aspects. Genes (Basel) 2021; 12: 468.

42. Rauch A, Thiel CT, Schindler D, et al. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 2008; 319(5864): 816–819.

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