Die Genetik häufiger Wachstumsstörungen

Zusammenfassung

Die Ätiologie der unterschiedlichen Wachstumsstörungen wurde während der letzen 20 Jahre in vielen Fällen geklärt, wobei gezeigt werden konnte, dass ganz unterschiedliche genetische Defekte, meist Einzelgendefekte, für den Kleinwuchs verantwortlich sind. In dieser Übersichtsarbeit haben wir uns auf zwei Gruppen von Wachstumsstörungen, die allerdings sehr komplex sind, beschränkt und zwar auf den Kleinwuchs nach intrauteriner Mangelgeburt bzw. den idiopathischen Kleinwuchs. Beide Phänotypen werden häufig in der kinderendokrinologischen Sprechstunde vorgestellt. Erst kürzlich konnte gezeigt werden, dass bei einem kleinen Prozentsatz von Patienten mit einem idiopathischen Kleinwuchs eine SHOX-Mutation ursächlich ist. Anhand eines Fallbeispiels aus unserer endokrinologischen Sprechstunde möchten wir diesen Zusammenhang erläutern.

Summary

Our understanding of growth disorders has steadily improved over the last twenty years. Today many genetic defects are understood to contribute to poor growth, the majority of these being single gene disorders. In this overview we focus on SGA-related short stature and idiopathic short stature (ISS). These disorders are seen commonly in the paediatric endocrine clinic and are likely to have a more complex multifactorial aetiology. More recently SHOX mutations have been able to account for a small proportion of the ISS cases, and an illustrative example from our clinical experience is described.

Schlüsselwörter

Kleinwuchs - intrauterine Wachstumsretardierung (SGA) - idiopathischer Kleinwuchs (ISS)

Keywords

Short stature - small for gestational age (SGA) - idiopathic short stature (ISS)

• Literatur

• 1 Abuzzahab MJ, Schneider A. et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349 (23) 2211-2222.
• 2 Baker J, Liu JP. et al. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993; 75 (01) 73-82.
• 3 Barker DJ, Gluckman PD. et al. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993; 341 8850 938-941.
• 4 Belin V, Cusin V. et al. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet 1998; 19 (01) 67-69.
• 5 Binder G, Ranke MB. et al. Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in school-age children with unexplained short stature. J Clin Endocrinol Metab 2003; 88 (10) 4891-4896.
• 6 Blum WF, Cao D. et al. Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009; 71 (03) 167-172.
• 7 Blum WF, Crowe BJ. et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab 2007; 92 (01) 219-228.
• 8 Bonapace G, Concolino D. et al. A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Genet 2003; 40 (12) 913-917.
• 9 Cicognani A, Alessandroni R. et al. Low birth weight for gestational age and subsequent male gonadal function. J Pediatr 2002; 141 (03) 376-379.
• 10 Clayton PE, Cianfarani S. et al. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007; 92 (03) 804-810.
• 11 Clement-Jones M, Schiller S. et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet 2000; 9 (05) 695-702.
• 12 Dattani MT. Growth hormone deficiency and combined pituitary hormone deficiency: does the genotype matter?. Clin Endocrinol (Oxf) 2005; 63 (02) 121-130.
• 13 Eggermann T, Schonherr N. et al. Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. J Med Genet 2006; 43 (07) 615-616.
• 14 Ellison JW, Wardak Z. et al. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 1997; 6 (08) 1341-1347.
• 15 Ester WA, van Duyvenvoorde HA. et al. Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype. J Clin Endocrinol Metab 2009; 94 (12) 4717-4727.
• 16 Falcinelli C, Lughetti L. et al. SHOX point mutations and deletions in Leri-Weill dyschondrosteosis. J Med Genet 2002; 39 (06) E33.
• 17 Gicquel C, Rossignol S. et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 2005; 37 (09) 1003-1007.
• 18 Giudice LC, de Zegher F. et al. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 1995; 80 (05) 1548-1555.
• 19 Hokken-Koelega AC, de Ridder MA. et al. Children born small for gestational age: do they catch up?. Pediatr Res 1995; 38 (02) 267-271.
• 20 Huber C, Rosilio M. et al. High incidence of SHOX anomalies in individuals with short stature. J Med Genet 2006; 43 (09) 735-739.
• 21 Inagaki K, Tiulpakov A. et al. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab 2007; 92 (04) 1542-1548.
• 22 Jorge AA, Arnhold IJ. Anthropometric evaluation of children with SHOX mutations can be used as indication for genetic studies in children of short stature. J Med Genet 2007; 44 (10) e90 author reply e91.
• 23 Karlberg J, Albertsson-Wikland K. Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 1995; 38 (05) 733-739.
• 24 Kruis T, Klammt J. et al. Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 2010; 95 (03) 1137-1142.
• 25 Larroque B, Bertrais S. et al. School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study. Pediatrics 2001; 108 (01) 111-115.
• 26 Leger J, Levy-Marchal C. et al. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 1997; 315 7104 341-347.
• 27 Liu JP, Baker J. et al. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993; 75 (01) 59-72.
• 28 Magnus P. Further evidence for a significant effect of fetal genes on variation in birth weight. Clin Genet 1984; 26 (04) 289-296.
• 29 Magnus P. Causes of variation in birth weight: a study of offspring of twins. Clin Genet 1984; 25 (01) 15-24.
• 30 Netchine I, Azzi S. et al. Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab 2009; 94 (10) 3913-3921.
• 31 Netchine I, Rossignol S. et al. 11p 15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 2007; 92 (08) 3148-3154.
• 32 Rao E, Weiss B. et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997; 16 (01) 54-63.
• 33 Rappold G, Blum WF. et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007; 44 (05) 306-313.
• 34 Savage MO, Attie KM. et al. Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat Clin Pract Endocrinol Metab 2006; 2 (07) 395-407.
• 35 Walenkamp MJ, Karperien M. et al. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 2005; 90 (05) 2855-2864.
• 36 Wallborn T, Wuller S. et al. A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 2010; 95 (05) 2316-2324.
• 37 Weedon MN, Frayling TM. Reaching new heights: insights into the genetics of human stature. Trends Genet 2008; 24 (12) 595-603.
• 38 Wit JM, Ranke MB, Kelnar CJH. ESPE Classification of Paediatric Endocrine Diagnoses. Hormone Research 2007; 68 (Suppl. 02) 1-120.
• 39 Wollmann HA. Intrauterine growth restriction: definition and etiology. Horm Res 1998; 49 (Suppl. 02) 1-6.
• 40 Woods KA, Camacho-Hubner C. et al. Intrauterine growth retardation and postnatal groth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996; 335 (18) 1363-1367.