1. Advances in diagnosis and treatment of growth disorders 10 May 2014 - Istanb ul,Turkey

2. Interactive workshops with clinical case presentations Valentina Pampanini Management and GH treatment in Small for Gestational Age patients

3. Disclosure statement: No conflict of interest to be declared 2014-05-10Valentina Pampanini 1

4. Male, 9 years and 8/12 months old referred to our Center of Pediatric Endocrinology for severe short stature  Maternal Pregnancy normal  Caesarean section at 38 weeks gestational age (prenatal diagnosis of interventricular septal defect (VSD)  Birth weight 1.900 Kg (-2.38 SDS)  Birth length 45 cm ( -3.2 SDS) 2014-05-10Valentina Pampanini 2 Case History (1)

5. What is the correct definition of SGA  a. Weight and/or length at birth < the 10th percentile  b. Weight and/or length at birth < the 5th percentile  c. Weight and/or length at birth < the 3rd percentile  d. Weight and/or length at birth < – 2 SDS 2014-05-10Valentina Pampanini 2

6. Small for Gestational Age (SGA) - Definition 2014-05-10Valentina Pampanini 10 Weight and/or length at birth less than 2 SD from the mean It requires 1)accurate knowledge of gestational age (ideally based on first trimester ultrasound exam) 2)accurate measurements at birth of weight, length, and head circumference, and 3)a cutoff against reference data from a relevant population Approximately 10% of infants born SGA remain short throughout childhood and adolescence and are at risk for short adult height P. E. Clayton, S. Cianfarani, P. Czernichow, G. Johannsson, R. Rapaport, and A. Rogol. CONSENSUS STATEMENT: 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. JCEM, March 2007, 92(3):804–810.

7. Small for Gestational Age (SGA) - Mechanisms Maternal Vascular disease Environmental factors Infection Nutrition Placental Insufficiency Abruption Infarction Vascular abnormalities 2014-05-10Valentina Pampanini 10 Fetal Genetic abnormalities Congenital malformations Metabolic problems Multiple gestations Demographic Maternal age and height Father’s size Obstetric history Race

8. 152 cm Dysmorphic featu res T2D MT2D M 164 cm 2014-05-10Valentina Pampanini 10 172 cm 164 cm Menarche 16 yr T2D MT2D M Case History (2)

9.  Surgery for bilateral inguinal hernia at 4 months  Surgery for VSD at 9 months  Developmental delay  Audiometry: bilateral trasmissive hypoacusia 2014-05-10Valentina Pampanini 10 Case History (3)

10.  Physical examination at 9 yr and 8/12 months  Anthropometry Height 95 cm (-7.26 SDS) Weight 13.3 Kg (-3.92 SDS), BMI 14.74 Kg/m² (-1.31 SDS) OFC 45 cm (< 3 ° ct) Normal body proportions  Severe dysmorphic features  Testicular volume 2 ml, hypospadia, pubarche I according to Tanner stages  Normal thyroid  Mental retardation 2014-05-10Valentina Pampanini 10 Case History (4)

11.  Special investigations 2014-05-10Valentina Pampanini 10  Biochemical screening for short stature: normal  Basal GH 9.27 ng/mL, GH peak under arginine test: 15.96 ng/mL (nr > 10 ng/mL)  IGF1 level: -0.53 SDS (224 ng/mL)  IGFBP3 level: 4 µg/mL (nr 2.4-4.8 µg/mL)  Hand X-ray: bone age between 7-8 yrs. Middle phalanx hypoplasia of fifth finger

12. What is your hypothesis  a. Genetic disease  b. Growth hormone / IGF-I axis abnormalities  c. Short stature after being born SGA  d. All of above 2014-05-10Valentina Pampanini 10

13.  a. Other iinnvveessttiiggaattiioonnss??  b. Follow-up ?  c. GH therapy ? How would you manage this patient 2014-05-10Valentina Pampanini 10

14.  a. KKaarryyoottyyppee  bb.. EExxoommee sseeqquueenncciinngg  c. ArrayCGH  d. IGFI generation test  ee.. SSkkeelleettaall xx--rraayy 2014-05-10Valentina Pampanini 10 What other investigations would you ask

15.  Other investigations  Karyotype 46 XY/45 XY and a ring chromosome 15 in 47/50 cells  ArrayCGH “…q26.2q26.3 (7.2 Mb) deletion of cr.15…” 2014-05-10Valentina Pampanini 11

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17. WWhhaatt iiss yyoouurr hhyyppootthheessiiss  a. Genetic disease  b. Growth hormone / IGF-I axis abnormalities   c. Short stature after being born SGA  d. Genetic disease involving GH/IGF-I axis and responsible for small size for gestational age and short stature 2014-05-10Valentina Pampanini 13

18.  a. Other investigations?  b. Follow-up ?  c. GH therapy ?  d. IGF-1 therapy ? How would you manage this patient 2014-05-10Valentina Pampanini 14

19. Small for Gestational Age (SGA) – Indications for rhGH P. E. Clayton et al, JCEM, March 2007, 92(3):804–810 Early intervention with GH for those with severe growth retardation (height SDS score < -2.5; age, 2-4 yrs) should be considered at a dose of 35-70 μg/kg*day 2014-05-10Valentina Pampanini 15

20. Auxological Parameters at 10 yrs and 1/12 months Height 95.8 cm (-7.28 SDS) Weight 13.500 Kg (-3.87 SDS), BSA 0.59 m² Growth velocity 2.11 cm/yr (-4.03 SDS) 2014-05-10Valentina Pampanini 16 START GH THERAPY: 30 μg/Kg*d  c. GH therapy ?

21. Response to Treatment S DS HeightHeight Gain Growth Velocity -7,28 -4,03 -7,28 0 -2,41 -7,08 0,2 -1,44 -6,77 0,5 -2,1 -8 -7 -6 -5 -4 -3 -2 0 1 0-3-6-12 months rhGH 2014-05-10Valentina Pampanini 17 IGF-I + 1.3 SDS (548.5 ng/ml) CA Δ IGF-I: 1.8 SDS IGF-I + 3.1 SDS (548.5 ng/ml) BA

22. rhGH Target Height 2014-05-10Valentina Pampanini 18

23. Small for Gestational Age (SGA) – Response to rhGH 2014-05-10Valentina Pampanini 19 There should be a positive response to GH treatment (height velocity SDS more than 0.5 in the first year of treatment). If there is an inadequate response, reevaluation is indicated, including consideration of compliance, GH dose, diagnosis, and the decision to discontinue treatment. P. E. Clayton et al, JCEM, March 2007, 92(3):804–810

24. Definitions of a response to rhGH therapy 2014-05-10Valentina Pampanini 20 ¹Bang P. et al. Clin Endocrinol 2012; 76: 1-13 ²Ranke M. B. et al. J Clin Endocrinol Metab 2010; 95: 1229-1237 □ Increase in height SDS > 0.5 in year 1 of therapy¹ □ Increase in height velocity > 3 cm/year in year 1 of therapy (age- dependent)¹ □ Increase in height velocity > +1 SDS compared with healthy children in year 1 of therapy²

25. Response to Treatment S DS HeightHeight Gain Growth Velocity -7,28 -4,03 -7,28 0 -2,41 -7,08 0,2 -1,44 -6,77 0,5 -2,1 -8 -7 -6 -5 -4 -3 -2 0 1 0-3-6-12 months rhGH + 0.5 SDS - 2.1 SDS IGF-I + 1.3 SDS (548.5 ng/ml) CA 2014-05-10Valentina Pampanini 21 Δ IGF-I: 1.8 SDS IGF-I + 3.1 SDS (548.5 ng/ml) BA

26. How would you manage this patient  a. Dose increase?  b. Stop treatment ?  c. Other investigations? 2014-05-10Valentina Pampanini 22 STOP rhGH THERAPY and reevaluation

27.  Karyotype 46 XY/45 XY and a ring chromosome 15 in 47/50 cells  ArrayCGH “…q26.2q26.3 (7.2 Mb) deletion of cr.15…” IGFIR gene, located at 15q26.3 2014-05-10Valentina Pampanini 23

28.  Ring chromosomes usually result from two terminal breaks in both chromosome arms, followed by fusion of the broken ends leading to the loss of genetic material Ring Chromosome 2014-05-10Valentina Pampanini 24

29.  The formation of the ring chromosome is usually a sporadic event, although there are familial ring chromosomes reported (Kosztolanyi 1987; Kosztolanyi et al. 1991)  In unbalanced ring chromosomes, the clinical phenotype may vary greatly depending in part on the loss of euchromatin distal to the breakpoints (Fryns et al. 1986; Kitatani et al. 1990; Kosztolanyi 1987; Kosztolanyi et al. 1991; Tumer et al. 2004) Ring Chromosome 2014-05-10Valentina Pampanini 25

30.  Ring chromosome 15 [r(15)] is a rare disorder that was first described by Jacobsen in 1966  Ring chromosome 15 is an uncommon finding with less than 50 patients reported  It results in a variable phenotype characterized by growth deficiency, mental retardation, triangular facies, microcephaly and brachydactyly (Butler et al. 1988; Roback et al. 1991; Schinzel 2001)  Growth deficiency is a common finding in ring chromosome 15 because 15q terminal deletions involve loss of the IGF1R gene located at 15q26.3 (Harada et al.2002;Tumer et al.2004;Glass et al.2006)  Additional common features were cafe ´ -au-lait macules, abnormal ears, cardiac anomalies, developmental and language delays with intellectual disability (Butler et al. 1988; Roback et al. 1991; Schinzel 2001 ) 2014-05-10Valentina Pampanini 26 Ring Chromosome 15

31. IGF-IR haploinsufficiency 1986 IGFIR chromosome band 15q26 1991 Roback et al Am J Med Genet. 1991 Jan;38(1):74-9 2003 Abuzzahab et al N Engl J Med 2003 Dec; 349:2211-22  Heterozygous mutations or deletions in the IGFIR gene lead to a partial resistance to IGFI and to a decreased expression of IGFIR (haploinsufficiency) which contributes to IUGR and postnatal growth failure  Homozygous IGFIR mutations or deletions have never been described in humans (lethal effect in mouse KO models) 2014-05-10Valentina Pampanini 15

32. What is the rationale of rhGH therapy in IGFIR deletions/mutations? 2014-05-10Valentina Pampanini 27

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34. The levels of phosphorylated Akt/Akt were significantly lower in patients after a challenge with IGF-I (p < 0.05) Patient’s cells needed higher IGF-I concentrations to achieve levels of Tyr- phosporylated IGFIR equivalent to those of the control. 2014-05-10Valentina Pampanini 29

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36. When a defect in IGFIR should be suspected in short SGA children? 2014-05-10Valentina Pampanini 31

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39. Take Home Messages 2014-05-10Valentina Pampanini 34 Short SGA children comprise a heterogeneous group in which only few genetic causes have been identified Several heterozygous point mutations and deletions of IGFIR(haploinsufficiency) have been described and result in IUGR and postnatal growth failure associated with normal to elevated IGF1 serum levels. Additional clinical signs have been mainly observed in IGFIR deletions, and are primarily linked to IGFIR flanking genes Case reports of children with an IGFIR deletion or mutation treated with rhGH showed a beneficial effect of GH treatment, with an increase in height of 1.0 SD per year of treatment IGFIR defects should be considered in the differential diagnosis of IUGR patients with persistent short stature, particularly if some of the major or minor criteria are present

40. Advances in diagnosis and treatment of growth disorders 10 May 2014 - Istanb ul,Turkey