Transcript Diapositiva 1 - www.sasia.org.ar

OLD AND NEW INDICATIONS OF
TREATMENT WITH GROWTH HORMONE
Gianni Bona, Giulia Genoni
Clinica Pediatrica di Novara
Università del Piemonte Orientale
“A. Avogadro”
GH Deficiency
OLD:
Turner Syndrome
Prader-Willi Syndrome
Chronic Renal Failure
NEW:
Small for Gestational Age
ISS,Noonan Syndrome, SHOX
Causes of short stature according to the ESPE classification
J.M. Wit. Horm Res. 2007
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.
Extreme
GHD
 As GH sensitivity decreases,
the degree of severe primary
IGFD increases.
Adapted from Savage MO et al. Clin Endocrinol (Oxf). 2010
GH DEFICIENCY (GHD)
Nota 39 (16.10.09)
Clinical and auxological parameters:
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;
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);
GHD
LABORATORY AND HORMONAL
EVALUATION
Nota 39 (16.10.09)
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
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
Turner Syndrome
SHORT STATURE
Short stature is the most common clinical feature of TS.
The deficit in height is caused by haploinsufficiency of the shortstature 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: 142-147 cm.
C.A. Bondy. J Clin Endocrinol Metab. 2010
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
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
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 1:10.000 to 1.30.000.
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.
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
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
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;
S.E. Myers. Am J Med Genet A. 2007
 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
M.E. Craig. Clin Endocrinol. 2006
LONG TERM EFFECTS
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
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
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
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
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.
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
GH TREATMENT…
…NEW INDICATIONS
 SMALL FOR GESTATIONAL AGE
 NOONAN SYNDROME
 IDIOPATHIC SHORT STATURE
SHOX GENE MUTATIONS
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
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).
SGA
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
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
SGA
CONSEQUENCES
Low bone
density
Precocious
puberty
Thyroid
disfunctionsAttention deficit
Short
stature
Metabolic
Syndrome
SGA
DM2
Hypercortisolism
Cardiovascolar
disease
M.A. Veening. J Clin Endocrinol Metab. 2002
C. Levy-Marchal. Pediatr Daiabetes. 2004
SGA
GROWTH HORMONE TREATMENT
GROWTH HORMONE TREATMENT
Age:
Dose:
SGA
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
0.24-0.48 mg/Kg/week
The maintenance phase of GH treatment seems to be less
dose dependent
Efficacy:
Height gain average from 1,2 to 2 SD
Response:
Factors associated to response are:
• age at start
• height sd score (SDS) at start
• midparental height
• dose of GH
P.E. Clayton. J Clin Endocrinol Metab. 2007
IN ITALY…
SGA
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.
GROWTH HORMONE TREATMENT
SGA
SAFETY
Metabolic consequences
After 2 years of GH therapy,
glycosylated haemoglobin and basal
glucose did not change significantly.
Insulin sensitivity remained within the
normal range.
E. Bozzola. J Pediatr Endocrinol Metab. 2005
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.
M. Van Dijk. J Clin Endocrinol Metab. 2007
Adverse events
Safety of Growth Hormone
Treatment in Children Born Small for
Gestational Age: The US Trial and
KIGS Analysis
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.
W.S. Cutfield. Horm Res. 2006
Noonan Syndrome
NOONAN SYNDROME (NS)
 NS affects between 1 in 1000 and 1 in 2500 live births.
 Short stature (80%);
CLINICAL FEATURES
 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
 It may be inherited more commonly as an autosomal dominant, rather
than a recessive disorder; at least 50% of cases appear to be sporadic.
R. Padidela. Horm Res. 2008
SHORT STATURE
Noonan Syndrome
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 167.4 cm in males and 152.7 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
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
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
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 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
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
“…To treat or
not to treat:
this is
the question…”
ISS
68 patients with ISS: 37 treated with rhGH; 31 with placebo
rhGH
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
ISS
rGH: 0.30 mg/Kg/week
ISS
Cohort 1: >5 years prepubertal
Cohort 2: < 5 years
Cohort 3: pubertal at GH start
Significant increase in height SDS during years of rhGH treatment
S.F. Kemp. J Clin Endocrinol Metab. 2005
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
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
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
SHOX
ISS
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
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.