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New Genetic Markers of Severe Primary IGF Deficiency

New Genetic Markers of Severe Primary IGF Deficiency

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New Genetic Markers of Severe Primary IGF Deficiency

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  1. New Genetic Markers of SeverePrimary IGF Deficiency Marie-José Walenkamp, MD, PhD VU University Medical Center Amsterdam

  2. Secondary IGF-I deficiency GH

  3. GH nl or Primary IGF-I deficiency GH signal transduction GH receptor ALS production IGF-I production

  4. Growthhormone receptor GHBP ------------------------------------ normal GHBP • Decreased binding • Defective dimerization • Defective anchoring • Defective signaling

  5. Growth hormone receptor defect 8.2 years -8.3 SDS 6.1 years -9.4 SDS Laron JCEM

  6. Homozygous GHR defects (>200 pts, >60 defects) Rosenfeld et al, Trends Endocrinol Metab. 2007

  7. GH signal transduction

  8. Homozygous STAT5b mutations SH2 TAD ND L CCD DBD 5’ 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 A630P R152X 1191insG 1680delG 1103insC F646S Rosenfeld, Hwa (in press)

  9. STAT5b defect: postnatal growth Kofoed et al NEJM 2003 Hwa et al, JCEM 2005 Walenkamp et al, EJE 2007

  10. STAT5b: immune dysfunction Pulmonary infections Intersitial pneumonia Pulmonary fibrosis Arthritis Hwa et al, JCEM 2005

  11. Homozygous STAT5B defects (5F, 1M) Rosenfeld et al.Trends Endocrinol Metab. 2007

  12. Acid –labile Subunit Janosi et al, J of Biol Chem 1999

  13. ALS mutations Leucine Rich Repeats (LRR) Cys-rich C-terminus Signal NH2 1 2 D440N 583_591dup9 C540R E35fsX120 Q320X 1308_1316dup9 L244F C60S L134Q N276S 1490dupT P73L L241P

  14. ALS mutations Domene , NEJM, 2007

  15. ALS mutation: postnatalgrowth Domene , NEJM, 2007 Heath, JCEM, 2008

  16. Homozygous or compound heterozygous ALS defects (15M, 2F)

  17. IGF-I deletion Woods NEJM 1996

  18. IGF-I deletion: postnatal growth Woods 1996

  19. IGF-I mutation: postnatal growth 9 yrs 11 yrs 117.8 cm 55 years van Gemund 1969 Walenkamp 2005

  20. IGF-I deletion and mutation

  21. Diagnostic approach Patient with proportionate short stature of unknown origin Height < -2.5 SDS SGA ? BW or length < -2 SDS No Yes

  22. Short stature and normal birth size IGF-I < -2 SDS and GH stimulation < 7 ng/ml other pituitary deficiencies ? no yes Positive family history ? yes no GHRHR Idiopathic GH

  23. Short stature and normal birth size IGF-I < -2 SDS and GH stimulation > 25 ng/ml IGF-I generation test: 0.7 mg/m2 GH IGF-I 1.4 mg/m2 GH IGF-I 2.8 mg/m2 GH IGF-I no IGF-I GHR STAT5b ALS GHR GH

  24. Short stature and SGA Head circumference ? Deafness ? IGF-I undetectable IGF-I < -2SDS IGF-I > 0 SDS IGF-I IGF-I IGF-I IGF1R

  25. Conclusions Genetic markers of severe primary IGF-I deficiency: - GH receptor defects - STAT5b defects - ALS defects - IGF-I defect Birth size and head circumference are essential for differentiating between GH receptor or GH signaling vs. IGF-I.

  26. Conclusions STAT5B deficiency does not always include immunodeficiency, but is associated with hyperprolactinemia. ALS deficiency causes moderate postnatal growth retardation, suggesting an important role for local IGF-I. Homozygous IGF-I defects are characterized by intrauterine and postnatal growth retardation, microcephaly and deafness.