Short Stature

Jackson Smith M.D.

Division of Endocrinology

University of Kentucky

Objectives

Review growth charts

Discuss initial evaluation

• Mid-parental height

• Bone age

• Laboratory studies

Identify patients eligible for GH therapy

Who are Candidates for GH

GH deficient

Turner syndrome

SGA

• No catch-up growth by age 2

Idiopathic short stature

• < 2.25 SD below mean for age

Chronic renal failure

• Pre-transplant

Prader-Willi syndrome

Noonan syndrome

Short stature homeobox (SHOX) gene mutation

Growth Charts

www.cdc.gov/growthcharts

Clinical growth charts

3rd to 97th %http://www.cdc.gov/growthcharts/clinical_charts.h

tm#Set2

2.25th to 97th %http://www.humatrope.com/Documents/pdf/growth_chart_b

oth.pdf

OK135S067

http://www.humatrope.com/Documents/pdf/growth_chart_both.pdf

Definitions

Short stature:

• Height more than 2 SD below the population mean (or less than the 3rd %).

Growth failure:

Short Stature: Initial Evaluation

History• Birth length and weight• Parent (family) heights and growth history• Chronic illnesses and/or medications• Nutrition• Thorough review of systems

Examination Calculate target height Consider obtaining a “bone age”

Height Distribution of Patients

- 4 - 2 0 2 4

0.0

0.2

0.4

0.6

0.8

1.0

Height SDS

Average adult height

General Population

M: 5' 9”F: 5' 4”

Average adult height (US general population*)

*From Kuczmarski RJ et al. 2000 NCHS

Target Height(Mid-parental Height)

Target height for males (inches) =

father’s height + (mother’s height + 5 inches) 2

Target height for females (inches) = mother’s height + (father’s height - 5 inches) 2

Height may vary by +/- 4 inches (2 SD) from target height

“Bone Age”

AP view of left hand Result: age in years (and months) Congruent with age

• Genetic short stature• Primary growth abnormality

“Delayed” = < 2SD for age• Nonspecific:

– Many secondary causes (hypothyroid, GH deficiency)– Seen with some primary growth abnormalities

• Constitutional delay in growth

Predicted Height

Baley-Pinneau

• Most commonly used method.

• May be requested with bone age report:– Patients height needed to calculate.

– If available from radiologist!

• Assumes a normal growth velocity.

Greatest source of inaccuracy: inaccurate bone age interpretation.

Short Stature: Differential Diagnosis

Conditions evident by age 3. Genetic short stature Constitutional delay of growth Primary growth abnormalities

• Small for gestational age (SGA)• Abnormalities in bone formation:

– Is the child dysmorphic?– Does the child have:

• Turner syndrome• Prader-Willi syndrome• Noonan syndrome

Secondary Growth Disorders Chronic disease (chronic renal insufficiency)

Malnutrition Endocrine

• Hypothyroidism• Growth hormone deficiency

– Isolated– Hypopituitarism

• Cushing syndrome• Calcium and mineralization disorders

– Rickets– Calcium, phosphorus abnormalities

MM

M

--- M 6.5”M 5”11”

5’2”

Genetic Short Stature Other names: familial or intrinsic short stature

Height compatible with mid-parental height.

Child is:

• Otherwise healthy

• Proportional and non-dysmorphic

Bone age = chronological age.

Follow-up: height maintains same %

Constitutional Delay in Growth

Diagnosis of exclusion.

History and physical exam normal.

Family history: delayed growth and/or puberty (not always present).

Bone age delayed.

Predicted height consistent with parental heights.

Growth rate normal.

Normal laboratory evaluation: if needed?

Laboratory Evaluation

Chronic disease and calcium disorders:• CBC, sedimentation rate, electolytes,

CO2, creatinine, calcium, UA Hypothyroidism:

• TSH (primary) and Free T4 (central) Growth hormone deficiency:

• IGF-I

Laboratory Evaluation

If associated with delayed puberty

• FSH

Others based on history and physical

• Celiac disease testing– Tissue transglutaminase antibody

• Karyotype

Constitutional Delay in Growth

Normal growth velocity

Typically have a delay in onset of puberty.

• Abnormal delay:– Girls: no breast development by 13 years.

– Boys: no testicular enlargment by 14 years.

Height may drop further below the 3rd % when peers enter puberty.

Requires follow-up of linear growth and pubertal development in ~6 months (longer in most cases).

SGA

90% will achieve “catch-up” growth by age 2 (height > 2.3%).

10% will remain < 2SD below average.

Adult height• SGA patients: height < 3% at age 2

– 95% will be short adultsPediatric Research 1995;38:733-9

July 2001 FDA approves use of GH for “SGA children who do not achieve catch-up growth by 2 years of age”.

Turner Syndrome

Incidence: 1:2500 newborn girls

Short stature evident by 3 years old (older if mosiac karyotype)

Karyotype:

• Classic: 45,X

• Many other mosiac forms

Dysmorphic features may be few or absent in mosiac varieties

Turner Syndrome: Classic Features

Short stature 100%

Gonadal failure 94%

Abnormal upper-to

-lower segment ratio 90%

Otitis media 75%

Characteristic facies

with micrognathia 60%

Cubitus valgus 45%

Low posterior hairline 40%

High arched palate 35%

Short metacarpals 35%

Genu valgum 30%

Multiple nevi 25%

Webbed neck 23%

Strabismus 17%

Scoliosis 12%

Nail dysplasia 12%

SHOX Mutation

Short stature homeobox (SHOX) gene mutation

Laboratory Evaluation

Chronic disease and calcium disorders:• CBC, sedimentation rate, electolytes,

CO2, creatinine, calcium, UA Hypothyroidism:

• TSH (primary) and Free T4 (central) Growth hormone deficiency:

• IGF-I

Laboratory Evaluation

If associated with delayed puberty

• FSH

Others based on history and physical

• Celiac disease testing– Tissue transglutaminase antibody

• Karyotype

Height -2.25 SDS (1.2 percentile)

No distinguishing phenotypic features

Likely heterogeneous etiology, such as:

• Familial/genetic factors

• Abnormalities of GH/IGF axis

• Abnormalities of growth plate

IGF-I may be normal or low

Height velocity may be normal or low

Idiopathic Short Stature (ISS)

http://www.humatrope.com/Documents/pdf/growth_chart_both.pdf

GH Treatment of ISS

ISS is a diagnosis of exclusion• May include patients with:

– Genetic short stature– Constitutional delay in growth

Criteria for possible treatment with GH• Predicted adult height (based on BA)

– Less than 5 feet 3 inches: males– Less than 4 feet 11 inches: females

GH therapy is not approved to treat less severe short stature!

GH Treatment

Risks• Slipped capital femoral epiphysis

• Pseudotumor cerebri

• Pancreatitis

• Increased long term mortality?

– Increased death due to bone tumors or cerebral hemorrhage

– Duration or follow-up from start of GH to time of census or death ~ 17 years

– Greater risk seen in those on higher dosages

– J Clin Endocrinol Metab 97: 416–425, 2012

GH Treatment

Cost

• About $50 per mg– 4 year old (15 kg) = $12,000/year

– 16 year old (60 kg) = $48,000/year

• Estimated cost in ISS: $50,000 per inch!

(based on 2006 calculation)

FDA Approved Indications for GH Therapy

GH deficient

Turner syndrome

Prader-Willi syndrome

SGA or IUGR

• Lack of “catch up” growth by age 2

Idiopathic short stature

• < 2.25 SDS or

• < (1.2 percentile) or

• Predicted height– < 5’3” boys

– < 4’11” girls

Chronic renal failure

• Pre-transplant