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OLD AND NEW INDICATIONS OF TREATMENT WITH GROWTH HORMONE

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

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

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

4 CONTINUUM OF GH-IGF-I AXIS DEFECTS
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. Extreme GHD Adapted from Savage MO et al. Clin Endocrinol (Oxf). 2010 4

5 Stature < -3SD or stature < -2DS plus groth rate/yr
GH DEFICIENCY (GHD) Nota 39 ( ) Clinical and auxological parameters: 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;

6 GHD 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);

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

8 TURNER SYNDROME (TS) CLINICAL FEATURES
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 8

9 Mild intrauterine growth retardation; Slow growth during infancy;
Turner Syndrome 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). Growth pattern: Mild intrauterine growth retardation; Slow growth during infancy; Delayed onset of the chidhood component of growth; Absence of the pubertal growth spurt. It results in an average adult stature 20 cm shorter than their target height: cm. C.A. Bondy. J Clin Endocrinol Metab. 2010

10 GROWTH HORMONE TREATMENT
Turner Syndrome GROWTH HORMONE TREATMENT Since 1996 Food and Drug administration approved GH therapy in Turner Syndrome 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. Dose: 0.375 mg/Kg/week

11 rhGH increases final adulte stature in TS.
Turner Syndrome 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%). The estimated prevalence is 1: to 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.

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

15 GROWTH HORMONE TREATMENT
Prader-Willi Syndrome GROWTH HORMONE TREATMENT Since 2000 Food and Drug administration approved GH therapy in Prader-Willi Syndrome GH treatment: normalizes height; increases lean body mass, increases muscle mass, decreases fat mass increases mobility; improves respiratory function.  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. S.E. Myers. Am J Med Genet A. 2007 M.E. Craig. Clin Endocrinol. 2006 Dose: 0.24 mg/kg/week

16 Prader-Willi Syndrome
LONG TERM EFFECTS Angulo et al 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 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 GH improves body composition, normalizes T3, and is well tolerated without glucose impairment in PWS

17 Prader-Willi Syndrome
SAFETY No difference in frequency or severity of scoliosis in children treated with GH compared to children not treated. 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. T. Nagai. Am J Genet Med A. 2006

18 SUDDEN UNEXPETED DEATH (SED)
Prader-Willi Syndrome SUDDEN UNEXPETED DEATH (SED) Risk factors of SED severe obesity; history of upper airway obstruction or unidentified respiratory infections; male gender. G. Grugni. J Endocrinol Invest. 2005 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

19 CHRONIC RENAL FAILURE (CRF)
Multifactorial growth retardation GH resistance; water-electrolyte disturbances and metabolic acidosis; nephrogenic osteodystrophy; malnutrition; deteriorated tissue metabolism of some growth factors. 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 Duration of renal failure
CRF CORRELATION BETWEEN: Short stature Duration 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. 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 J.M. Wit. Best Pract Res Clin Endocrinol Metab. 2002

21 GH TREATMENT… …NEW INDICATIONS SMALL FOR GESTATIONAL AGE
NOONAN SYNDROME IDIOPATHIC SHORT STATURE SHOX GENE MUTATIONS

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: 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 UTERINE/PLACENTAL FACTORS
SGA CAUSES (2) 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  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.  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. P.A. Lee. Pediatrics. 2003 P.E. Clayton. J Clin Endocrinol Metab. 2007

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

27 GROWTH HORMONE TREATMENT
SGA GROWTH HORMONE TREATMENT

28 GROWTH HORMONE TREATMENT
SGA GROWTH HORMONE TREATMENT Dose: 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 SGA IN ITALY… The AIFA note number 39 (13/10/09) includes patients born Small for Gestational Age to be eligible for GH treatment. CRITERIA 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). Age ≥ 4 years. Stature ≤ –2.5 SD and growth velocity ‹ 50° percentile.

30 GROWTH HORMONE TREATMENT
SGA GROWTH HORMONE TREATMENT SAFETY Metabolic consequences Adverse events After 2 years of GH therapy, glycosylated haemoglobin and basal glucose did not change significantly. Insulin sensitivity remained within the normal range. Safety of Growth Hormone Treatment in Children Born Small for Gestational Age: The US Trial and KIGS Analysis E. Bozzola. J Pediatr Endocrinol Metab. 2005 No adverse events were reported more commonly in children born SGA than in those with ISS. 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. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA. M. Van Dijk. J Clin Endocrinol Metab. 2007 W.S. Cutfield. Horm Res. 2006

31 Phenotypic heterogeneity
Noonan Syndrome NOONAN SYNDROME (NS) 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 Short stature is reported in more than 80% of patients.
Noonan Syndrome SHORT STATURE Short stature is reported in more than 80% of patients.  Prenatal linear growth is normal, although edema may influence birth weight.  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.  Puberty is delayed of 2 years.  Mean adult height is cm in males and cm in females. Overall, mean adult height is approximately –2 SD.  The secretion of growth hormone is normal. R. Padidela. Horm Res. 2008 A.A. Romano. J Clin Endocrinol Metab. 2009

33 GENETIC FEATURES 50% of NS presents PTPN11 mutations;
Noonan Syndrome GENETIC FEATURES 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 Noonan Syndrome Since May 2007 Food and Drug administration approved GH therapy in Noonan Syndrome Dose: 0.66 mg/Kg/week  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 /M+ mutation of PTPN11 /M- non mutaded
GH therapy resulted in a catch-up height SDS, which was lower after 2 yr in M+ vs. M- patients. After 1 yr during GH treatment, IGF-I increased significantly (P ): 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)
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. 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). P. Cohen. J Clin Endocrinol Metab. 2008

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

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

39 Significant increase in height SDS during years of rhGH treatment
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 ISS SAFETY 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. S.F. Kemp. J Clin Endocrinol Metab. 2005

41 ISS … 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…. P. Cohen. J Clin Endocrinol Metab. 2008

42 ISS 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. 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. 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. 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. SGA – NOONAN S. – ISS - SHOX 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.


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