Endocrine Aspects of 11q
Is there a role for GH?
…no
issue
Thomas G. Kelly, MD, FAAP
Pediatric Endocrinology
UC San Diego / Rady Children’s Hospital San Diego
Short Stature Can Be a Stigma
Goals
• Review the process of growth
• Promote an understanding of factors that are
critical to this process.
• Discuss examples of growth failure and
discuss how they are treated.
• Discuss 11q syndrome and what is known
about growth and growth hormone.
Overview
• Introduction with Basic Growth
Vocabulary
• How Do We Grow?
• What can go wrong?
• How do we fix it?
Understanding Your Child’s Growth
What you need to know
• Height and Height %
- an assessment of stature and its comparison to the general
population
• Growth Velocity
- an assessment of the rate of growth
• Mid parental height
- a calculation of predicted height based on parental heights
• Bone age
- An assessment of the degree of growth plate closure
Assessing Stature
• Current Height
• Growth Velocity
• Predicted Height
Height
• Evaluation of height must
be done in the context of
normal standards
• Charts compare child’s
height with the 3rd-97th%
of normal American kids
• Plotting height and weight
provides a useful and
objective assessment of
the adequacy of growth.
• SDS score (Ht-mean
HT/SD) describes the
location of those whose
Ht is >97th +2SD
and<3rd % (-2SD).
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OK135S057
What creates error in measurement
Good Technique = Good Data
– Method of
measurement
– Staff with different
techniques
– Standing vs lying
– The “birthday
plot”
Incorrect Height Measuring Techniques
• Line of sight not at eye
level
• Using floppy arm
device
• Child’s back not
against board
• Child’s hairpiece not
removed
• Child’s socks still on
Scoliosis
Rickets
Height Velocity
• Invaluable in assessing
a child with growth
abnormalities.
• Kids grow with
remarkable fidelity
relative to the growth
curves from 2yrs to
puberty.
• Any crossing of Ht %’s is
a concern.
• Velocity should be
calculated over at least a
6 month period.
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What’s normal ?
Normal Growth Rates
During Childhood
Age
Growth (cm/year)
Birth to 1 year
17– 26
1 to 2 years
10–13
2 years to puberty
5–7
Puberty
Girls
7–12
Boys
8–13
National Center for Health Statistics
Normal Growth Rates During
Childhood
13
12
Growth rate (cm/y)
11
10
9
8
7
6
5
4
3
2
Girls: solid lines
Boys: dashed lines
1
0
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
Age (y)
Girls’ peak growth rate: 11.5 years
Boys’ peak growth rate: 13.5 years
National Center for Health Statistics.
Tanner JM, et al. J Pediatr. 1985.
How tall will
I be when I
grow up?
Height Prediction
• Midparental height
– Boys: [(M+F) + 5 inches]/2
– Girls: [(M+F) – 5 inches]/2
• Bone Age
Mid-Parental HeightAn Assessment of Genetic Potential
• The “mid-parental height” or MPH is a
calculation based on parental heights of
the expected final height of the child.
• A useful tool in the assessment of
whether a child’s current height
percentile is appropriate.
• MPH is adjusted ± 5 inches to account
for the difference between the male and
female heights on the growth curve. .
Examples of Mid-Parental Height
• Dad = 66”;
• Mom = 61”
• MPH for a girl =
Dad’s ht -5 or 66-5= 61”
+
Mom’s ht = 61
Divided by 2
(61+61)/2 = 61”
MPH for a boy =
Dad’s Ht + Mom’s Ht +5
2
66”
61”
61”
A bone age demonstrates growth
potential
Phalanges
(Finger Bones)
Epiphysis
(Growth Plate)
Metacarpal
(Hand Bones)
Carpal
(Wrist Bones)
Epiphysis
(Growth Plate)
Male, 8 years
Male, 14 years
MPH
BA
Factors Affecting Growth
Genes
Environmental
Influences
Growth
Nutrition
Biological
Factors
Economic
Factors
Genes
Although length and
weight at birth
depend on the
intrauterine
environment the
final height achieved
by a child is largely
dependent on their
genetic endowment.
Height is highly
heritable!
Although this achievable height is
limited by genetic factors …
up to this limit height potential depends
on environmental factors
Environment
• Normal interaction
between infants and
children and their
environment is
necessary for normal
growth and
development.
• Syndrome of growth
failure and weight loss
is long recognized in
infants separated from
their mothers or
socially isolated, subject
to cruelty, neglect, or
institutional upbringing.
Economics
• Socioeconomic
Deprivation -Poverty
leads to Stunting from:
– Poor nutrition
– Increased
susceptibility to
infections
– Limited access to
health care
– Recurrent and/or
chronic infections
Nutrition
• Adequate Nutrition is
essential for good linear
growth.
• Growth Failure may be
the direct result of
inadequate protein or
other essential
nutrients.
• Alternatively, biologic
influences such as
disturbances of bowel
endocrine, or metabolic
function may play a role
Examples of Feeding Problems
that can lead to impaired Nutrition
• Problems with gastroesophageal reflux (GER) can
contribute to problems with feeding. Many children with
neurodevelopmental problems have GER
• Tactile sensitivity or sensory defensiveness, common
among children with cerebral palsy, autism, and spina
bifida may cause a child to avoid putting things in his/her
mouth.
• Children with feeding problems as a result of behavioral
or emotional issues. Or, the result of complex perinatal
medical interventions that center around feeding or
around the mouth, making subsequent oral experiences,
including feeding, unpleasant.
Nutritional/Biologic Factors
and Growth
Low Birth Weight
• Intrauterine Growth Retardation (IUGR) is a fetus
with an estimated weight < 10th % for gestational
age.
• Small for gestational age (SGA) is an infant with a
birthweight <10th%.
• Depending on the timing, duration and severity of the
insult, and success of postnatal intervention, the
growth potential of IUGR/SGA children may be
permanently adversely affected.
• IUGR leading to SGA is an approved indication for
Growth Hormone if growth deficit is not overcome in
the first 3 yrs of life.
Generalizations About Growth
• Despite all the factors mentioned
–
–
–
–
Genes
Environment
Nutrition
Economics
• Children normally grow at a remarkably predictable
rate.
• The sequence of growth is usually uncomplicated and
orderly, but variations exist and individual growth patterns
may be confused with problems of hormonal regulation
Normal Growth Patterns associated
with Short Stature
Two Common Conditions
• Genetic Short Stature
• Late Bloomer (Constitutional Delay)
Familial Short Stature
• Diagnosis
– Growth chart pattern
– Family history (with
accurate family
heights)
– Normal bone age
– Normal growth
velocity
Constitutional Delay
• Late Bloomers
• Generally refers to a
delay in growth as
well as pubertal
development
• More common in
boys
• Possibly related to
nutrition
The Late Bloomer
(AKA Constitutional Delay)
• Not associated with growth failure
• Adolescents channeled to a curve that
may be short for the population and/or
family
• Family history of late puberty with catchup growth at puberty
Pubertal Delay
• Growth Velocity:
prepubertal
•
BA<CA
• May intervene to initiate
puberty
What Can Go Wrong?
Genetic/Chromosomal
Abnormalities
Environmental
stressors
Growth
Malnutrition
And Disease
Economic
Stressors
Genetic and Chromosomal
Abnormalities
• A genetic disorder is any disorder caused by
faults in inherited genetic material within a
persons cells.
• In these conditions there is the potential for
altered growth because the affected metabolic
pathways disturb energy production and/or the
building of body tissue.
Examples: Genetic abnormalities of bone, cartilage
Genetic and Chromosomal
Abnormalities
• A Chromosomal Abnormality is any change in
the normal structure or number of
chromosomes.
• It can be associated with growth patterns that
differ from those of children without
chromosomal abnormalities.
• It is assumed that these differing growth patterns
represent altered growth potential related to the
underlying chromosomal abnormality.
– Turner’s Syndrome missing an X chromosome or
parts of an X.
– Down’s Syndrome has an extra chromosome.
What Can We Do?
Evaluate For:
• Conditions that alter growth
Known or suspected Chromosomal disorders.
History of IUGR/SGA
Genetic Syndrome
• Conditions that have the potential to alter
growth.
Metabolic Disorders
Endocrine Disorders
Gastrointestinal
Hematologic
Immune
Renal
Cardiac
Infectious
Psychosocial
Pulmonary
Endocrine Causes of Short Stature
• Low Thyroid Function
•
•
•
•
•
Decreased appetite
Constipation
Lethargy
Dry skin and hair
GROWTH FAILURE
• Growth Hormone Deficiency
• GROWTH FAILURE
• Decreased lean body mass, increased fat mass
• Decreased bone mineral content
Endocrine Causes of Short Stature
Growth Hormone Deficiency
• Prevalence is 1/4000-1/80000
• Diagnosis is suspected by poor growth,
history of brain irradiation or trauma
• Since growth hormone secretion is
pulsatile so random growth hormone
measures are useless.
• IGF-1 and IGFBP-3 are surrogate
markers of GH sufficiency
• Note that IGF-1 is significantly affected
by nutritional status.
GH Testing
• GH deficiency is
confirmed using
stimulatory tests
– Arginine, clonidine, L
Dopa and insulin
– Some agents (arginine
and clonidine) may act as
GHRH agonists in the
pituitary
• Stimulatory tests are not
perfect:
– May miss partially
deficient patients
Etiologies of Pediatric GHD
Early NCGS
Pediatric Registry
(1986-1994)
Later NCGS
Pediatric Registry
(1995-2002)
N
%
N
%
10,106
72.8
9190
81.7
3767
27.2
2059
18.3
Other/unknown
996
26.4*
955
46.4*
CNS irradiation
884
23.5*
317
15.4*
Other CNS tumor
799
21.2*
308
15.0*
Craniopharyngioma
600
15.9*
214
10.4*
Septo-optic dysplasia
413
11.0*
248
12.0*
Trauma
75
2.0*
17
0.8*
Idiopathic GHD
Organic GHD
* Percentage of organic GHD cases
Levy RA, et al. J Pediatr Endocrinol Metab. 2003.
Pediatric Indications For Growth
Hormone
• The FDA has approved GH for the following
pediatric conditions associated with short
stature:
– GH deficiency (defined as on the basis of the
provocative tests)
– Turner Syndrome
– Chronic renal insufficiency
– SGA or IUGR infants that fail to demonstrate
catch-up growth
– Prader-Willi Syndrome
– Idiopathic short stature (<2.5 SD below the mean
and not expected to meet a normal adult height)
Cancer and GH Therapy
• No definitive link between GH therapy
and an increased incidence of leukemia.
• Currently GH therapy is not
recommended in patients with an active
malignant condition.
Endocrine Abnormalities
in 11q- Syndrome
9 children with Jacobsen (11q-) were studied in
San Diego with the following findings:
• 8/9 had short stature (ht<5th%)
Six with >-2SD
One had IUGR
Four had low IGF-1 levels
• 4/9 males had cryptorchidism (failure of
testes to descend).
Endocrine Abnormalities
in 11q- Syndrome
Case Reports suggest an association of 11q
deletions or translocations with short stature.
6 publications with 5 single case reports plus the
small series from San Diego of 8 affected patients
One publication of central GH and TH deficiencies.
Studies suggest that genetic information encoded in
11q is important for normal growth.
Insufficient data is available to suggest a mechanism
for growth failure in these children.
Take-away Messages
• Growth Velocity correlates with
good health
• Abnormal growth velocity merits
evaluation
• A good history and exam are often
diagnostic
• Laboratory and Imaging studies
may be helpful
• Timing is everything
Resources For Patients &
Families
MAGIC Foundation:
www.magicfoundation.org
Human Growth Foundation:
www.hgfound.org