Endocrinology of Growth Laura K. Bachrach, M.D. Stanford Medical School

Why Discuss Growth? Major parental/social concern

Growth makes headlines

Why Discuss Growth? Major parental/social concern Barometer of health in children Variability of normal is challenging Underscore interaction of genetic, endocrine, & non-endocrine factors

There’s more to growth than growth hormone

Goals of Growth Talk Review tempo of growth & puberty Discuss normal variants Review causes of short & tall stature

Expected Growth Rates Age Cm (inches)/yr (10) (5) (3) (2) Puberty 7.5 (3) females 10 (4) males

Growth Velocity is Key Normal growth tracks along curve “Catch up” or “catch down” growth before age 2 may be normal Crossing percentiles after 2 years suggests slow or accelerated growth

Worrisome!

Puberty & Growth Puberty modifies growth rates

Growth Hormone & Puberty Williams

Puberty & Growth Puberty modifies growth rates What’s normal? What determines variability?

Tanner Stages

Puberty in Girls Breast bud at 10 Pubic hair soon after Menarche at 12.7 Growth spurt early in puberty

Puberty in Boys Testes start to enlarge at 11.5 Pubic hair 1-2 yrs later Testes mature at 15 Growth spurt later in puberty

Puberty & Growth FemalesMales

Puberty & Growth

What Determines Timing? Secular trend?

Is Puberty Happening Earlier?

Ethnic Differences in Puberty in Girls Breasts HairMenses Blacks Hispanics Whites Wu et al. Pediatrics 2002; 110:

Earlier Puberty? Early start linked to BMI in white females African American female Age at menarche essentially unchanged in past 40 years

What Determines Timing? Secular trend? Ethnicity/race Tempo of puberty in parents Nutrition Illness

Growth Regulation Varies In Infancy & Childhood

Growth Regulation - The Fetus Maternal factors/Placenta Insulin-like growth factors Insulin Thyroid hormone - essential for brain Growth hormone - not essential

Placenta & Fetal Growth Post natal catch up 10% stay small

Insulin – A Potent Growth Factor Expect “catch down” growth

Infant of a Diabetic Mother Increased maternal glucose & amino acids Fetal hyperinsulinemia Manifestations in fetus macrosomia polycythemia delayed lung maturation neonatal hypoglycemia

Growth Regulation in Childhood Hormonal Growth hormone/IGFs Thyroid hormone Glucocorticoids - inhibitory effect Metabolic, nutritional

Growth Regulation - Puberty Hormonal Growth hormone/IGFs Thyroid hormone Sex steroids Glucocorticoids – inhibitory Metabolic, nutritional

Short Stature “Short” Population stds (<-2 SD) Family standards (<mid-parental ht) Growing too slowly – decrease ht %

Causes of Short Stature Normal variants – most common Familial (genetic) – Short parents – Nl birth and growth – Will be short as adult Constitutional Delay of Growth – Parents not short – Delayed growth & puberty (after 2) – Normal adult height

Constitutional Delay – “Late Bloomer”

Causes of Short Stature Non-endocrine skeletal abnormalities genetic/chromosomal disorders intrauterine growth retardation chronic disease

Achondroplasia & Hypoplasia

Hypochondroplasia Disproportionate short stature

Turner Syndrome

Common: 1 in 2,000 females Clinical features vary short stature100% gonadal failure 96% cardiac 55% renal anomalies 39% cubitus valgus 47% webbed neck 25%

Endocrine Short Stature Hypothyroidism Growth hormone deficiency Glucocorticoid excess

Hypothyroidism

Signs of Acquired Hypothyroidism growth failure puberty - delayed, rarely precocious constipation dry skin weight gain bradycardia fatigue feeling cold

Before & After Thyroxine

Risks of Prolonged Hypothyroidism Incomplete “catch-up” growth Pseudo tumor cerebri Altered mental status –decline in school performance –attention-deficit-like symptoms –emotional lability/psychosis

Incomplete Catch Up Growth

Endocrine Causes of Short Stature Growth hormone deficiency isolated panhypopituitarism

GH Deficiency

Endocrine Causes of Short Stature Growth hormone deficiency isolated panhypopituitarism Growth hormone resistance – rare abnormal GH receptor post-receptor signaling defect defect IGF-1 or IGF-1 receptor

GH-IGF-I Axis

GH Receptor Deficiency (Laron) Rosenbloom AL. JCEM 1994; 79: 695 Father with GHRD Sons (7, 10 yr) Daughter (5 yr)

Growth Curves – GH-IGF Axis Defects X Laron syndrome Del IGF-I Stat5b defect Hwa V. JCEM 2005; 90:

Glucocorticoid Excess

Growth Increased weight Slowed height Causes Iatrogenic Endogenous

Tall Stature

Growth rates Normal Accelerated

Tall Without Accelerated Growth Familial (genetic) tall stature Syndromes – Marfan syndrome – Klinefelter syndrome – Homocystinuria

Marfan Syndrome Autosomal dominant Tall stature Ectopia lentis Arachnodactyly Aortic abnormalities

Tall WITH Accelerated Growth Exogenous obesity Precocious puberty Congenital adrenal hyperplasia Hyperthyroidism GH excess – RARE Cerebral gigantism

Exogenous Obesity Rapid growth Weight > height %iles Tall & fat Normal adult stature

Exogenous Obesity Tall for age when young Earlier puberty Reach genetic potential

Precocious Puberty Rapid growth Signs of sex maturity Short as adult if untreated

Tall adult if untreated Gigantism – GH Excess

Investigating Growth Problems

Growth Evaluation History – Birth weight & length – Growth patterns – Illness & meds Family history – Heights – Timing of puberty Exam – height, weight, trends, puberty

Lab Studies Endocrine T4, TSH IGF-1 & IGF binding protein 3 Sex steroids (if appropriate) Rarely cortisol Non-endocrine CBC, ESR celiac screen renal, hepatic function karyotype

Questions ?