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Clinica Pediatrica di Novara Università del Piemonte Orientale “A. Avogadro” OLD AND NEW INDICATIONS OF TREATMENT WITH GROWTH HORMONE Gianni Bona, Giulia.

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Presentation on theme: "Clinica Pediatrica di Novara Università del Piemonte Orientale “A. Avogadro” OLD AND NEW INDICATIONS OF TREATMENT WITH GROWTH HORMONE Gianni Bona, Giulia."— Presentation transcript:

1 Clinica Pediatrica di Novara Università del Piemonte Orientale “A. Avogadro” OLD AND NEW INDICATIONS OF TREATMENT WITH GROWTH HORMONE Gianni Bona, Giulia Genoni

2 OLD: GH Deficiency Turner Syndrome Prader-Willi Syndrome Chronic Renal Failure NEW: Small for Gestational Age ISS,Noonan Syndrome, SHOX

3 J.M. Wit. Horm Res. 2007 Causes of short stature according to the ESPE classification

4  The short stature continuum ranges from GHD through ISS to severe primary IGFD  As GH secretion diminishes, GHD becomes more severe.  As GH sensitivity decreases, the degree of severe primary IGFD increases. Adapted from Savage MO et al. Clin Endocrinol (Oxf). 2010 Extreme GHD CONTINUUM OF GH-IGF-I AXIS DEFECTS

5 a)Stature < -3SD or stature < -2DS plus groth rate/yr < -1SD for age and gender in two different evaluations at a time distance of 6 months; Nota 39 (16.10.09) Clinical and auxological parameters: GH DEFICIENCY (GHD)

6 b) Growth rate/yr < -2SD or < -1,5 SD after 2 consecutive years, also without short stature; c) Pituitary or hypotalamic malformations/lesions with a neuroradiological demonstration or multiple pituitary deficiencies with GHD (CPHD); GHD

7 LABORATORY AND HORMONAL EVALUATION 2 different provocative tests with GH peak <10 µg/L GH peak <20 µg/L if one of the provocative tests used is GHRH + Arginine or GHRH + Pyridostigmine Nocturnal GH profile OR GHD Nota 39 (16.10.09)

8 TURNER SYNDROME (TS)  TS affects one in 2500 live-born females.  The diagnosis requires the presence of characteristic physical features in phenotypic females coupled with complete or partial absence of the second sex chromosome, with or without cell line mosaicism. CLINICAL FEATURES M.L. Davenport. J Clin Endocrinol Metab. 2010

9 SHORT STATURE Short stature is the most common clinical feature of TS. The deficit in height is caused by haploinsufficiency of the short- stature homeobox-containig gene (SHOX). It results in an average adult stature 20 cm shorter than their target height: 142-147 cm. Growth pattern:  Mild intrauterine growth retardation;  Slow growth during infancy;  Delayed onset of the chidhood component of growth;  Absence of the pubertal growth spurt. C.A. Bondy. J Clin Endocrinol Metab. 2010 Turner Syndrome

10 GROWTH HORMONE TREATMENT Goals of growth-promoting therapies:  to attein a normal height for age as early as possible;  to reach the progress through puberty at a normal age;  to attain a normal adult height;  to improve quality of life. Since 1996 Food and Drug administration approved GH therapy in Turner Syndrome Dose: 0.375 mg/Kg/week Turner Syndrome

11 rhGH increases final adulte stature in TS. The age at initiation and the duration of rhGH therapy are the major factors in determinig the magnitude of its effect. M.L. Davenport. Growth Horm IGF Res. 2006

12 PRADER-WILLY SYNDROME (PWS) PWS is a genetic disorder usually caused by a microdeletion of a part of the paternal chromosome 15q11-13 (70-75%) or uniparental maternal disomy of the same region (22%). Growth pattern:  Fetal size is generally normal;  The poor suck and lethargy result in a failure to thrive;  Short stature is almost always present during the second decade and lack of pubertal growth spurts results in an average untreated height of 155 cm for males and 148 cm for females. The estimated prevalence is 1:10.000 to 1.30.000.

13  Neonatal and infantile central hypotonia with poor suck;  Feeding problems and/or failure to thrive in infancy;  Onset of rapid weight gain between ages 12 months and six years, causing central obesity;  Hyperphagia;  Characteristic facial features: narrow bifrontal diameter, almond-shaped palpebral fissures, down-turned mouth;  Hypogonadism manifest as: genital hypoplasia, incoplete and delayed puberty, infertility;  Developmental delay/ mild to moderate intellectual disability/ multiple learning disabilities. Major Criteria Minor Criteria  Decreased fetal movement and infantile lethargy, improving with age;  Typical behavior problems (temper tantrums, obsessive-compulsive behavior…);  Sleep disturbance/ Sleep apnea;  Short stature;  Hypopigmentation;  Hands and feet that are small for height age;  Narrow hands with straight ulnar border;  Esotropia, myopia;  Thick, viscous saliva;  Speech articulation defects;  Skin picking. Prader-Willi Syndrome CLINICAL DIAGNOSIS Major Criteria weight one point each; Minor Criteria weight one-half point each. < 3 yr: 5 points are required for diagnosis, 4 of which must be major criteria > 3 yr: 8 points are required, 5 of which must be major critera. M. Gunay-Aygun. Pediatrics. 2001

14 Prader-Willi Syndrome Reduced growth hormone secretion in PWS. GH deficiency is also seen in adults with PWS. GROWTH HORMONE SECRETION P. Burman. Endocr Rev. 2001 G. Grugni. Clin Endocrinol. 2006

15 Prader-Willi Syndrome GROWTH HORMONE TREATMENT GH treatment:  normalizes height;  increases lean body mass, increases muscle mass, decreases fat mass increases mobility;  improves respiratory function. Since 2000 Food and Drug administration approved GH therapy in Prader-Willi Syndrome  Increase in language and cognitive skills in treated infants and an improvement in mental speed, flexibility and motor performance in adults;  A review of the results of 1 to 2 yr of GH treatment among 328 children indicates an improvement of growth velocity, particularly in prepubertal children, but no change in BMI. Dose: 0.24 mg/kg/week S.E. Myers. Am J Med Genet A. 2007 M.E. Craig. Clin Endocrinol. 2006

16 Prader-Willi Syndrome Angulo et al. 2007. The objective of the study was to compare adult height (AH) attained in PWS subjects with and without GH treatment. Data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects. Marzullo et al. 2007. A 12-month GH therapy decreased cardiovascular risk; reduced total body fat and abdominal visceral fat and increased lean mass. GH therapy increased left ventricular mass devoid of diastolic consequences. Harriette et al. 2008. GH improves body composition, normalizes T3, and is well tolerated without glucose impairment in PWS LONG TERM EFFECTS

17 GH therapy increases height velocity of PWS patients but does not necessarily develop scoliosis, and early start of the therapy may not be an exacerbating factor of scoliosis. Prader-Willi Syndrome SAFETY No difference in frequency or severity of scoliosis in children treated with GH compared to children not treated. T. Nagai. Am J Genet Med A. 2006

18 Prader-Willi Syndrome Risk factors of SED  severe obesity;  history of upper airway obstruction or unidentified respiratory infections;  male gender. SUDDEN UNEXPETED DEATH (SED) The cause of SED is not different between PWS patients with and without GH treatment. Attention when using GH in PWS patients with careful determination of the dose of GH and careful monitoring of patient's respiratory conditions, especially in male obese patients with respiratory problems. T. Nagai. Am J Med Genet A. 2005 G. Grugni. J Endocrinol Invest. 2005

19 CHRONIC RENAL FAILURE (CRF)  GH resistance;  water-electrolyte disturbances and metabolic acidosis;  nephrogenic osteodystrophy;  malnutrition;  deteriorated tissue metabolism of some growth factors. Multifactorial growth retardation G. Johannsson. Growth Horm IGF Res. 2003 renal clearance of growth hormone: GH number of GH-Rs IGFBP-1; IGFBP-3 ALTERATIONS OF GH/IGF-I AXIS/ GH RESISTANCE R. Lanes. Treat Endocrinol. 2004

20 CRF CORRELATION BETWEEN: Short statureDuration of renal failure Renal failure stage Result of GH treatment GH treatment must be inplemented as soon as possible, without any delay if: - short stature persists > 6 months; - marked deceleration of growth velocity. G.Gorman. Pediatr Nephrol. 2005 D. Haffner. J Am Soc Nephrol. 1998 Dose: 0.35 mg/kg/week Long-term therapy results in quick catch-up and most of subjects achieve their adult height within normal limits. D. Haffner. N Engl J Med. 2000 J.M. Wit. Best Pract Res Clin Endocrinol Metab. 2002


22 SMALL FOR GESTATIONAL AGE (SGA) SGA represents a statistical grouping of infants whose birth weight and/or length is at least 2 SD below the mean (2 SD) for gestational age. The definition requires:  accurate knowledge of gestational age;  accurate measurements at birth of weight, length, and head circumference;  a cut-off against reference data from a relevant population. (New Italian Growth Charts, Bertino et Al, JPGN, 2010) Subclassification into:  SGA for weight (SGAw);  SGA for length (SGAl);  SGA for both weight and length (SGAwl). Hight incidence: 91 000 infants in the United States born SGA annually. The same cohort produce only 800 female infants with Turner syndrome and 1100 individuals with growth hormone deficiency. P.A. Lee. Pediatrics. 2003

23 SGA CAUSES FETAL FACTORS Karyotypic abnormalities (trisomy 21, trisomy 18, monosomy X, trisomy 13); Other chromosomal abnormalities (autosomal deletions, ring chromosomes); Genetic diseases (achondroplasia, Bloom syndrome); Congenital anomalies (Potter syndrome, cardiac abnormalities). MATERNAL FACTORS Medical conditions (hypertension, renal disease, diabetes mellitus, collagen vascular diseases, maternal hypoxemia); Infection (toxoplasmosis, rubella, cytomegalovirus, herpesvirus, malaria, trypanosomiasis, human immunodeficiency virus); Nutritional status (low prepregnancy weight, low pregnancy weight with poor weight gain during pregnancy); Substance use/abuse (cigarette smoking, alcohol, illicit drugs, therapeutic drugs).

24 CAUSES (2) SGA UTERINE/PLACENTAL FACTORS Gross structural placental factors (single umbilical artery, velamentous umbilical cord insertion, bilobate placenta, placental hemangiomas, infarcts, focal lesions); Insufficient uteroplacental perfusion (suboptimal implantation site); Placenta previa; Low-lying placenta; Placental abruption. DEMOGRAPHIC FACTORS Maternal age (very young age, older age); Maternal height and weight; Maternal and paternal race; Parity (nulliparity, grand multiparity); Previous delivery of SGA infants. P.A. Lee. Pediatrics. 2003

25 SGA GROWTH  The preterm SGA infant can take 4 or more years to achieve a height in the normal range. Approximately 10% of children born SGA will remain ≤ -2 SD for height throughout childhood and adolescence and into adulthood.  90% of SGA children experiences a catch-up growth during the first 24 months of life that results in a stature above -2 SD.  Catch-up is typically an early postnatal process: most of the catch-up growth occurs during the first year and is near completion by 2 years of age. In 80% of infants who are born SGA, catch-up growth occurs during the first 6 months of life. P.A. Lee. Pediatrics. 2003 P.E. Clayton. J Clin Endocrinol Metab. 2007

26 SGA CONSEQUENCES SGA Cardiovascolar disease DM2 Metabolic Syndrome Precocious puberty Short stature Hypercortisolism Low bone density Thyroid disfunctions- Attention deficit M.A. Veening. J Clin Endocrinol Metab. 2002 C. Levy-Marchal. Pediatr Daiabetes. 2004


28 SGA GROWTH HORMONE TREATMENT Dose: 0.24-0.48 mg/Kg/week The maintenance phase of GH treatment seems to be less dose dependent Response: Factors associated to response are: age at start height sd score (SDS) at start midparental height dose of GH Efficacy: Height gain average from 1,2 to 2 SD It is important to wait until the spontaneous catch-up phase is completed, which usually occurs by the time a child is 2 to 3 years of age Age: P.E. Clayton. J Clin Endocrinol Metab. 2007

29 The AIFA note number 39 (13/10/09) includes patients born Small for Gestational Age to be eligible for GH treatment. Birth weight in singleton ≤ –2 SD (< 3° percentile) for gestational age based on Gagliardi’s tables and less than 2500 gr. (L. Gagliardi. Riv. Ital. Pediatr. 1999 ). Stature ≤ –2.5 SD and growth velocity ‹ 50° percentile. Age ≥ 4 years. SGA IN ITALY… CRITERIA

30 SGA GROWTH HORMONE TREATMENT SAFETY After 2 years of GH therapy, glycosylated haemoglobin and basal glucose did not change significantly. Insulin sensitivity remained within the normal range. Insulin Sensitivity and Disposition Index were comparable for GH-treated and untreated SGA subjects. Fasting glucose and insulin levels increased during GH treatment but recovered after discontinuation. Body mass index, waist circumference, high-density lipoprotein cholesterol levels, and triglycerides were equivalent. No adverse events were reported more commonly in children born SGA than in those with ISS. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA. Safety of Growth Hormone Treatment in Children Born Small for Gestational Age: The US Trial and KIGS Analysis W.S. Cutfield. Horm Res. 2006 E. Bozzola. J Pediatr Endocrinol Metab. 2005 M. Van Dijk. J Clin Endocrinol Metab. 2007 Metabolic consequencesAdverse events

31 NOONAN SYNDROME (NS) Noonan Syndrome  NS affects between 1 in 1000 and 1 in 2500 live births.  It may be inherited more commonly as an autosomal dominant, rather than a recessive disorder; at least 50% of cases appear to be sporadic. CLINICAL FEATURES  Short stature (80%);  Facial features (hypertelorism, down-slanting, anti-mongoloid palpebral fissures, ptosis, low-set posteriorly rotated ears with a thickened helix);  Heart defects: pulmonary stenosis (50–62%) and hypertrophic cardiomyopathy (10–20%);  Bleeding diathesis (20%);  Mild mental retardation;  Cryptorchidism;  Other characteristics: feeding difficulties, lymphatic dysplasias, clotting disorders, hypogonadism, autoimmune thyroiditis, thoracic deformities, hearing difficulty and juvenile myelomonocytic leukemia. Phenotypic heterogeneity R. Padidela. Horm Res. 2008

32  Prenatal linear growth is normal, although edema may influence birth weight. Noonan Syndrome Short stature is reported in more than 80% of patients.  Mean adult height is 167.4 cm in males and 152.7 cm in females. Overall, mean adult height is approximately –2 SD.  During childhood, mean height in both sexes approximates the third percentile until approximately 12 years in males and 10 years in females, after which mean height decreases below the normal range due to delayed puberty and decreased pubertal growth spurt.  The secretion of growth hormone is normal. SHORT STATURE  Puberty is delayed of 2 years. R. Padidela. Horm Res. 2008 A.A. Romano. J Clin Endocrinol Metab. 2009

33 GENETIC FEATURES Noonan Syndrome  50% of NS presents PTPN11 mutations;  Most PTPN-11 mutations are missense involving a single aminoacid in exons 3, 7, or 8 of the gene;  Mutations lead to gain in function of the SHP-2 protein inducing increased phosphatase activity;  New mutations have been identified in other genes involved in RAS-MAPK cascade (KRAS,SOS1,RAF1). R. Padidela. Horm Res. 2008

34 Dose: 0.66 mg/Kg/week Since May 2007 Food and Drug administration approved GH therapy in Noonan Syndrome Noonan Syndrome  Treatment with rhGH significantly improved height SDS in children with NS;  This increase is similar to the gain in TS patients, although significantly less than in IGHD;  Earlier initiation and longer duration of rhGH therapy are associated with improved near-adult height outcomes. A.A. Romano. J Clin Endocrinol Metab. 2009

35 Noonan Syndrome GH therapy resulted in a catch-up height SDS, which was lower after 2 yr in M+ vs. M- patients. /M+ mutation of PTPN11 /M- non mutaded After 1 yr during GH treatment, IGF-I increased significantly (P 0.001): IGF-I levels became normal. The increase in IGF-I during GH treatment in patients with and without mutations was comparable J.M. Limal J Clin Endocrinol Metab. 2006

36 IDIOPATHIC SHORT STATURE (ISS) Children with ISS have a normal birth weight and are GH sufficient. It is estimated that approximately 60-80% of all short chidren, at or below -2 SDS, fit the definition of ISS. The definition of ISS includes constitutional delay of growth and puberty (CDGP) and familial short stature (FSS). ISS is a condition in which the height of an individual is more than 2 SD score below the corresponding mean height for a given age, sex, and population group without evidence of systemic, endocrine, nutritional or chromosomal abnormalities. P. Cohen. J Clin Endocrinol Metab. 2008

37 “…To treat or not to treat: this is the question…”

38 rhGH Placebo ISS Height gain of 3.7 cm after 4.4 years of rhGH therapy at a dose of 0.22 mg/kg/wk 68 patients with ISS: 37 treated with rhGH; 31 with placebo E.W. Leschek. J Clin Endocrinol Metab. 2004

39 ISS Cohort 1: >5 years prepubertal Cohort 2: < 5 years Cohort 3: pubertal at GH start rGH: 0.30 mg/Kg/week ISS Significant increase in height SDS during years of rhGH treatment S.F. Kemp. J Clin Endocrinol Metab. 2005

40 There did not appear to be any increased incidence of adverse events in the population of children with ISS who were treated with rhGH compared with those in general population. SAFETY ISS S.F. Kemp. J Clin Endocrinol Metab. 2005

41 P. Cohen. J Clin Endocrinol Metab. 2008 … in the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 µg/kg/d) for children shorter than 2.25 SDS… Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3– 0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4–7 yr) is 3.5–7.5 cm…. GH therapy for children with ISS has a similar safety profile to other GH indications…. ISS

42 Growth hormone therapy is effective in promoting growth in children with ISS. Treated girls were approximately 7.5 cm taller than girls randomised to the control group and 6 cm taller than girls who refused consent. No evidence supports the assumption that growth hormone treatment improves health related quality of life in children with ISS. Randomised controlled trials are required that focus on clear outcomes such as final height. ONLY ONE STUDY!!! Treated individuals remain relatively short when compared with peers of normal stature, with heights near the lower bound of the normal range. J. Bryant. Cochrane Database Syst Rev. 2007

43 ISS SHOX 2-3% of children with ISS shows SHOX mutations (pseudoautosomal region of X and Y chromosomes).  Routine analysis of SHOX should not be undertaken in all chidren with ISS;  SHOX gene analysis should be considered for any patient with clinical findings compatible with SHOX haploinsufficiency. P. Cohen. J Clin Endocrinol Metab. 2008 G.A. Rappold. Trends Endocrinol Metab. 2009

44 TAKE HOME MESSAGES There are a lot of new therapeutic indications using GH in childhood. The AIFA note 39 determined some changes in old indications too.  It is necessarily to individuate the corrects criteria to select patients that can draw the major advantages from GH treatment. SGA – NOONAN S. – ISS - SHOX

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