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Flashcards in Evaluation of Worrisome Growth Deck (51):

Why Do We Care?

a. Poor growth may be the first and only sign of an underlying health problem

b. Consequences of delayed or missed diagnoses include potential permanent height deficits
i. limited time to possibly regain loss height (likely to be permenent)


Comparison of WHO and CDC growth charts for girls

a. Comparing the length and weight variables with a specific age
i. *The WHO growth chart is better than the CDC chart

b. AAP 2000 Recommendations:
i. Children’s height and weight should be measured at least at birth, age two to four days,1, 2, 4, 6, 9, 12, 15, 18, and 24 months, and every year thereafter through age 21
ii. Height and weight then plotted on growth charts


Worrisome Growth - Definitions

a. Growth can be worrisome along two variables: height
and growth velocity

b. Height
i. Short stature: height below -2 SD (3% is – 1.9 SD)
for age and gender OR height more than 3.5 inches
below the midparental target height


Midparental Target

For boys:
(Mother’s height + 13 cm (5 in) + (Father’s height) / 2

For girls:
(Father’s height - 13 cm (5 in) + (Mother’s height) / 2

*Notice that 13 cm = 5 inches

*97% of children will fall within 3.5 inches of target


Worrisome Growth - Definitions

Growth Velocity:
a. Abnormally slow linear growth velocity or dropping
across two major centile lines on the growth chart

b. Rule of 5’s


Abnormal growth Velocity
and Short Stature

*Important slide

a. Abnormal growth velocity shows a slowing of growth on the chart
i. will see "de-accelerating" of the growth
ii. this is clinically WORRISOME= something pathological

b. Short stature--> will have consistent lower growth compared to rest of population
i. short stature is less worrisome


Skeletal Maturation

a. There is a direct correlation between the degree of skeletal maturation and the time of epiphyseal closure

b. The greater the bone age delay, the longer the time
before epiphyseal fusion ceases growth

c. Assessed by most using standards of Greulich-Pyle
(US children living in Cleveland)


Predictions with Skeletal Maturation

a. Height predictions can be made using child’s height and bone age

b. Predictions not accurate in children with growth disorders

c. Predictions may also be inaccurate because cannot predict pubertal tempo

d. May help in differentiating causes of short stature


Causes of Short Stature/Abnormal

*Familial short stature
*Constitutional short stature
Zinc, iron deficiency
IBD, celiac disease, CF
Growth hormone deficiency

Turner syndrome
Down syndrome
Prader-Willi syndrome
Skeletal Dysplasias
Small for gestational age
Chronic Diseases
Psychosocial deprivation


Familial Short Stature

a. Children who have normal growth velocity and height that are within normal limits for parents’ heights

b. Initially will have decrease in growth rate between 6 and 18 months of age

c. *Some families with short stature may have an underlying pathologic cause (eg, skeletal dysplasias, Noonan syndrome)


Constitutional Growth Delay

a. Characterized by growth deceleration during first 2 years of life followed by normal growth paralleling lower percentile curve throughout prepubertal years
i. *Will see normal growth velocity after the first 2 years

b. Skeletal maturation is delayed

c. Catch-up growth achieved by late puberty and delayed fusion of growth plates

d. Generally end up along lower end of normal height range for families

e. Appear to be polygenic trait; positive family in about 60-80% if patients

 Genetic defects causing CGD unclear


Constitutional Growth Delay

a. Reassurance of normal growth pattern

b. Can treat boys with testosterone if bone age ≥11-1/2 years to avoid compromising final height

c. Can treat girls with estrogen (not as common)


Failure To Thrive

a. Infants or toddlers (< 2 years of age) with:
i. Deceleration of weight gain to a point <3% or
ii. Fall in weight across 2 or more major percentiles

b. Non-organic causes most common – poor nutrition and psychosocial factors

c. May look like constitutional growth delay


Nutritional Growth Retardation

a. Linear growth stunting from poor weight gain in children over 2 years of age

b. May be secondary to systemic illnesses such as celiac disease, inflammatory bowel disease

c. Stimulant medications

d. Sometimes hard to distinguish from constitutional growth delay and constitutional thinness


Hormonal Causes of Worrisome

Generally, weight is spared ---> They will not become underweight
i. will be normal or overweight with hormonal cause

1. Hypothyroidism
2. Growth hormone/IGF-1 abnormalities
3. Cushing syndrome
4. Rickets



a. Can result in profound growth failure

b. Many clinical features that are seen in hypothyroid adults are lacking in children


Primary and Central Hypothyroidism

a. Primary hypothyroidism is straightforward - increased TSH, low T4

b. Central hypothyroidism – low T4, normal TSH


Thyroid and TSH levels in example patient

T4 4.9 (5 -12)
FT4 0.5 (0.8 – 1.8)
TSH 3.2 (0.5-5.0)

Based on these values, the patient has central hypothyroidism
(Low T4 and FT4, normal TSH)


Growth Hormone

a. Anterior pituitary hormone

b. Main function is to promote linear growth

c. Also effects body composition – increases lean body mass and decreases fat


Growth Hormone Deficiency –

Hypothalamic-pituitary malformations:
1. Holoprosencephaly/Schizencephaly

2. Isolated Cleft lip or palate

3. Septo-Optic-Dysplasia – 50% have hypopituitarism
i. congenital malformation syndrome featuring underdevelopment of the optic nerve, pituitary gland dysfunction, and absence of the septum pellucidum (a midline part of the brain)

4. Optic nerve hypoplasia

5. Empty sella syndrome


Growth Hormone Deficiency

a. Absent or inadequate production of growth hormone

b. GHD is a continuum - a range of GH levels are seen

c. GHD may be associated with deficiencies in other pituitary hormones


Growth Hormone Deficiency - Acquired

1. Trauma

2. CNS infection

3. Hypophysitis

4. CNS tumors – craniopharyngioma, germinoma

5. Cranial irradiation


Growth Hormone Deficiency

Abnormal growth velocity with exclusion of other causes


Growth Hormone Deficiency

1. Decreased muscle build

2. Increased subcutaneous fat, especially around trunk

3. Face immature for age

4. Prominent forehead, depressed midface

5. In males, small phallus

6. Other midline facial defects

7. May have history of prolonged jaundice and/or hypoglycemia in newborn period


Growth Hormone Deficiency

a. Bone age

b. Random, single GH value not useful

c. IGF-1
i. May be reduced in malnutrition regardless of GH status
ii. IGFBP-3 is less affected by nutrition and may be a better test in young children

d. Stimulation testing – clonidine, arginine, glucagon, L- dopa (r/o with any value >10 ng/ml)



Growth Hormone deficiency

FT4 - 1.47
TSH - 1.76

IGF-1 - 46 (56-144)
IGF BP-3 - <0.1 ( 0.7-3.6)

GH stimulation test:
i. Clonidine - 0.5, 0.18, .28,0.32
ii. Arginine- 0.23, 0.33, 0.25


Lab Evaluation

a. TSH 3.971,FT4 1.0,T4 6.4  IGF-1 31 (52-297)

b. IGF-BP3 1.7 (1.3 – 5.6)


Syndromic Short Stature (chromosomal)

1. Skeletal Dysplasias and other genetic syndromes

2. Turner syndrome – Haploinsufficiency of SHOX genes

3. Prader-Willi syndrome – GH deficient

4. Noonan syndrome – abnormal GH post-receptor signaling


Turner Syndrome

a. Most common sex chromosome abnormality of female

b. Affects ~3% of female concepti

c. Caused by complete or partial absence of 1 of X chromosomes

d. Occurs in approximately 1/2,000 live-born females


Turner Syndrome

a. Virtually all of girls with Turner syndrome exhibit short stature
b. Final height is about 20 cm less than their target height if untreated
c. Haploinsufficiency of the SHOX genes are responsible for skeletal and growth abnormalities


Turner Syndrome TX

a. Growth hormone therapy has been shown to significantly improve growth and final adult height in these patients

b. Starting treatment early is important because it offers best potential for growth


Turner Syndrome
Clinical Findings

a. Clinical findings may be subtle so diagnosis is often delayed and some girls are never diagnosed

Skeletal Abnormalities:
•Short Stature
•Increased carrying angle •Short neck
•Micro or retrognathia

Lymphatic obstruction
•Low hairline
•Webbed neck

-Cardiac abnormalities- bicuspid aortic valve, coarctation
- Renal – horseshoe kidney
- Ovarian insufficiency
- Hypothyroidism/celiac disease
- Otitis media
- Hearing loss
- Non-verbal learning disability


Turner Syndrome
Skeletal Abnormalties

Skeletal Abnormalities:
•Short Stature
•Increased carrying angle
•Short neck
•Micro or retrognathia


Turner Syndrome

Lymphatic obstruction

Lymphatic obstruction
•Low hairline
•Webbed neck


Turner Syndrome other organ system

1. Cardiac abnormalities- bicuspid aortic valve, coarctation

2. Renal – horseshoe kidney

3. Ovarian insufficiency

4. Hypothyroidism/celiac disease

5. Otitis media

6. Hearing loss

7. Non-verbal learning disability


Children Born Small for Gestational Age

a. Defined as less than - 2SD for birth weight or length Etiologies

b. Maternal – infection, nutritional deficiencies, uterine abnormalities, smoking, alcohol, drugs,

c. Placental – Previa, abruption, infarcts, structural, multiple gestation

d. Fetal – Chromosomal abnormalities, metabolic, infections, malformations


Catch-up Growth in Children and Final Height

(Small for Gestational Age)

a. Most healthy infants born SGA achieve catch-up in height by age 2 years

b. 10-15% of children born SGA remain short as adults

c. These children typically grow along a stable trajectory but have a height projection less then their genetic target

d. Final height may also be compromised by early/rapid puberty


GH treatment and SGA children

a. Growth hormone treatment is an FDA approved indication for SGA children who fail to have catch-up growth by 2 years

b. May increase final height by an average of 3 inches


Evaluation - History

(Particularly in SGA children)

a. Family history: heights and timing of puberty

b. Birth history – gestational age, birth size, complications

c. Past medical problems – ear infections, cardiovascular

d. Medications – Stimulants, steroids

e. Developmental milestones/school performance

f. Dietary recall (if weight is primarily affected)

h. ROS – GI symptoms, headaches


Evaluation – Physical Examination

a. Remeasure!

b. Is weight or height more affected?

c. A complete physical examination should be performed looking for signs of systemic illnesses and endocrinopathies, with special attention to dysmorphic features, body proportions, and pubertal staging


Evaluation of Worrisome growth

a. Bone age (left hand and wrist)-helps to determine growth potential and can help with diagnosis

b. Metabolic panel/phosphorous – RTA, rickets

c. CBC – anemia (chronic disease, skeletal dysplasia)

d. TSH and T4

e. IGF-1 or IGFBP-3

f. Karyotype in girls – Turner syndrome

g. TTG (tissue transglutaminase antibody) and IgA – Celiac disease

h. ESR – Inflammatory bowel disease


History of Growth Hormone

a. 1887 – Linked disorder of excessive growth to pituitary tumor

b. 1900- Harvey Cushing concluded “pea size” gland secreted hormone of growth

c. 1912 - Cushing theorized that lack of this hormone during childhood caused come people to be abnormally short

d. 1921 –Herbert Evans made extracts from beef pituitaries and injected into rats

e. 1940’s – injected bovine GH into rats, bulldogs, and dachshunds with effects on growth. In humans, no effect

f. 1956 – Growth hormone isolated from human pituitary glands

h. 1960 – National Pituitary Agency formed to collect donor human pituitary glands for the preparation of a federally-distributed pituitary-derived GH (pGH) for children with GH deficiency


History of Growth hormone

a. 1 human pituitary gland to produce enough growth hormone for one day’s treatment for one patient

b. Some patients developed antibodies to GH

c. Between 1963-1985 – 7700 children in US and 27,000 children worldwide given pGH


Controversy of Growth Hormone

a. Early 1980s - 3 three men died of Creutzfeld-Jacob Disease (CJD), a slow viral infection of the CNS, and were found to have been treated with the same batch of pituitary-derived GH

b. The NPA’s GH distribution program suspended in spring of 1985 (despite new GH extraction techniques developed in 1977 blocking passage of the CJD prion)

c. Fortunately, research into the production of human GH by recombinant techniques had been ongoing since 1980, and was approved for use in human by
the FDA in the fall of 1985.


Recombinant Human GH (rhGH)

a. The recombinant human GH (rhGH) was identical to pGH by several physio-chemical techniques, (radiolabelled competition-inhibition assays and mass spectrometric analysis), and allowed pediatric endocrinologists to re-institute GH therapy in their GH deficient patients

b. Pathogen-free hGH

c. Unlimited Supply


Impact of rhGH

a. The criteria used to diagnose growth hormone deficiency became less stringent

b. “Cure goes in search of diseases” - the unlimited supply (and financial potential) led to studies of the use of GH in GH-deficient adults and in many “non-GH deficient” conditions in adults and children


FDA approved uses of rhGH

1985 – Growth hormone deficiency
1993 – Chronic renal insufficiency
1996 – Adult growth hormone deficiency  1997 – Turner Syndrome
2000 – Prader-Willi Syndrome
2001 – Small for gestational age
2003 – Idiopathic short stature
2006 – SHOX deficiency
2007 – Noonan syndrome


Ethical Issues

 How good is growth hormone testing?
 Deficient response seen without endocrine disease
 Variability in assays
 Intraindividual variability from day to day
 Definition of normal response is arbitrary

 Who to treat?
 Just because there is FDA approved indication?
 What if family wants to pay?
 Developmentally delayed children?
 Who makes these decisions?

 How long to treat?
 Until final height is reached, i.e.., growth plates have fused
 Until reach genetic potential (MPH)
 Until normal height – how is this defined and is this gender specific?
 Until a height that is no longer a disability


Other Ethical issues of Growth Hormone

 Who pays?
 Mean cost $20,000/year
 $35,000 – $50,000 per inch of height
 Current bottom line is often who will pay
 Should this be how we make our medical decisions......?

 Side effects
 Slipped Capital Femoral Epiphysis
 Pseudotumor Cerebri
 ? Long term risks
 Benefits beside height - Are taller people any happier or more successful?


Bone Age Summary

*Good summary

a. Bone age is the degree of maturation of a child's bones. These changes can be seen by x-ray. The "bone age" of a child is the average age at which children reach this stage of bone maturation. A child's current height and bone age can be used to predict adult height. For most people, their bone age is the same as their biological age but for some individuals, their bone age is a couple years older or younger.

b. Those with advanced bone ages typically hit a growth spurt early on but stop growing early sooner while those with delayed bone ages hit their growth spurt later than normal. Kids who are below average height do not necessarily have a delayed bone age; in fact their bone age could actually be advanced which if left untreated, will stunt their growth.

c. At birth, only the metaphyses of the "long bones" are present. The long bones are those that grow primarily by elongation at an epiphysis at one end of the growing bone. The long bones include the femurs, tibias, and fibulas of the lower limb, the humeri, radii, and ulnas of the upper limb (arm + forearm), and the phalanges of the fingers and toes. The long bones of the leg comprise nearly half of adult height. The other primary skeletal component of height is the spine and skull.

d. As a child grows the epiphyses become calcified and appear on the x-rays, as do the carpal and tarsal bones of the hands and feet, separated on the x-rays by a layer of invisible cartilage where most of the growth is occurring. As sex steroid levels rise during puberty, bone maturation accelerates.

e. As growth nears conclusion and attainment of adult height, bones begin to approach the size and shape of adult bones. The remaining cartilaginous portions of the epiphyses become thinner. As these cartilaginous zones become obliterated, the epiphyses are said to be "closed" and no further lengthening of the bones will occur. A small amount of spinal growth concludes an adolescent's growth.


Turner Syndrome Summary Points

a. Most common sex chromosome abnormality of female
i. Affects ~3% of female concepti
ii. Caused by complete or partial absence of 1 of X chromosomes
iii. Occurs in approximately 1/2,000 live-born females

b. Virtually all of girls with Turner syndrome exhibit short stature
i. Final height is about 20 cm less than their target height if untreated
ii. Haploinsufficiency of the SHOX genes are responsible for skeletal and growth abnormalities
iii. Growth hormone therapy has been shown to significantly improve growth and final adult height in these patients
iv. Starting treatment early is important because it offers best potential for growth

c. Skeletal Abnormalities:
•Short Stature
•Increased carrying angle
•Short neck
•Micro or retrognathia

d. Lymphatic obstruction
•Low hairline
•Webbed neck

e. Other Physiological Findings:
i. Cardiac abnormalities- bicuspid aortic valve, coarctation
ii. Renal – horseshoe kidney
iii. Ovarian insufficiency
iv. Hypothyroidism/celiac disease
v. Otitis media
vi. Hearing loss
vii. Non-verbal learning disability