Endocrine Aspects of 11qIs there a role for GH?

…no issue

Thomas G. Kelly, MD, FAAPPediatric 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 GrowthWhat 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

OK135S057

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).

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.

What’s normal ?

Normal Growth Rates During Childhood

National Center for Health Statistics

AgeAge Growth (cm/year)Growth (cm/year)

Birth to 1 yearBirth to 1 year 1717– 26– 26

1 to 2 years1 to 2 years 1010–13–13

2 years to puberty2 years to puberty 55–7–7

PubertyPuberty

GirlsGirls 77–12–12

BoysBoys 88–13–13

Normal Growth Rates During Childhood

Gro

wth

ra

te (

cm/y

)

Age (y)2 193 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

0

13

12

11

10

9

8

7

6

5

4

3

2

1

National Center for Health Statistics.Tanner JM, et al. J Pediatr. 1985.

Girls: solid linesBoys: dashed lines

Girls’ peak growth rate: 11.5 yearsBoys’ peak growth rate: 13.5 years

Boys: dashed lines

Boys’ peak growth rate: 13.5 years

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 Height-An 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 = 61Divided by 2(61+61)/2 = 61”MPH for a boy =

Dad’s Ht + Mom’s Ht +52

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

BA

MPH

Factors Affecting Growth

GrowthEnvironmental Influences

EconomicFactors

Genes

NutritionBiological Factors

GenesAlthough 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 Problemsthat 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.

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.

Nutritional/Biologic Factors and Growth

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 catch-up growth at puberty

Pubertal Delay

• Growth Velocity: prepubertal

• BA<CA

• May intervene to initiate puberty

What Can Go Wrong?

GrowthEnvironmental stressors

EconomicStressors

Genetic/Chromosomal Abnormalities

MalnutritionAnd Disease

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 growthKnown or suspected Chromosomal disorders.History of IUGR/SGAGenetic Syndrome

• Conditions that have the potential to alter growth.

Metabolic Disorders RenalEndocrine Disorders CardiacGastrointestinal InfectiousHematologic PsychosocialImmune 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 %

Idiopathic GHD 10,106 72.8 9190 81.7

Organic GHD 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*

Levy RA, et al. J Pediatr Endocrinol Metab. 2003.* Percentage of organic GHD cases

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 Abnormalitiesin 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 >-2SDOne had IUGRFour had low IGF-1 levels

• 4/9 males had cryptorchidism (failure of testes to descend).

Endocrine Abnormalitiesin 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