GROWTH AND GROWTH AND GROWTH DISORDERSGROWTH DISORDERS

dr. H. Hakimi, Sp.AKdr. H. Charles Darwin Siregar, Sp.A

dr. Melda Deliana, Sp.AKd Si k M i L bi S A

Pediatric Endocrinology Division

dr. Siska Mayasari Lubis, Sp.A

11

Pediatric Endocrinology DivisionH.Adam Malik Hospital/Medical School

University of Sumatera Utara

Physiology of HormonesPhysiology of HormonesPhysiology of Hormones Physiology of Hormones

22

CONTROL OF GROWTHCONTROL OF GROWTH

33

GROWTH EVALUATIONGROWTH EVALUATIONGROWTH EVALUATIONGROWTH EVALUATIONAverage growth velocity at different phases :Average growth velocity at different phases :g g y pg g y p1. Prenatal growth1. Prenatal growth 1,2 to 1,5 cm/wk1,2 to 1,5 cm/wk2. Infancy2. Infancy 23 to 28 cm/yr23 to 28 cm/yryy yy3. Childhood3. Childhood 5 to 6,5 cm/yr5 to 6,5 cm/yr4. Puberty4. Puberty 8,3 cm/yr (girls)8,3 cm/yr (girls)

9,5 cm/yr (boys)9,5 cm/yr (boys)

44

GROWTH CHARTGROWTH CHARTGROWTH CHARTGROWTH CHARTA chart that reflects the height and weight A chart that reflects the height and weight g gg gof a certain population which is specific of a certain population which is specific for race, age, and sexfor race, age, and sexggGrowth charts fall into several categories : Growth charts fall into several categories : distance charts, velocity, crossdistance charts, velocity, cross--sectionalsectionaldistance charts, velocity, crossdistance charts, velocity, cross sectional sectional charts and longitudinal chartscharts and longitudinal chartsThere are charts available for certainThere are charts available for certainThere are charts available for certain There are charts available for certain genetic syndromes including Turner genetic syndromes including Turner syndromesyndrome

55

syndromesyndrome

PARENTAL TARGET HEIGHTPARENTAL TARGET HEIGHTPARENTAL TARGET HEIGHTPARENTAL TARGET HEIGHT

Potential genetic heightPotential genetic height:: The range ofThe range ofPotential genetic heightPotential genetic height:: The range of The range of adult height that adult height that shouldshould be achieved the be achieved the child regarding to the biological parentschild regarding to the biological parentschild regarding to the biological parents child regarding to the biological parents final height final height

•Boys = (Fh + 13) + Mh ± 8.5 cm

2 2 •Girls = (Fh - 13) + Mh ± 8.5 cm

662

GROWTH VELOCITYGROWTH VELOCITYGROWTH VELOCITYGROWTH VELOCITYGrowth velocityGrowth velocity is calculated using a minimum of is calculated using a minimum of t t bt i d ti ith tht t bt i d ti ith thtwo measurements, obtained across time, with the two measurements, obtained across time, with the plotted data point representing the mean growth plotted data point representing the mean growth velocity during the interval as opposed to the velocity during the interval as opposed to the y g ppy g ppmeasurable increment between the two time pointsmeasurable increment between the two time points

Ch l i lCh l i l di bi h ddi bi h dChronological ageChronological age according to birth dateaccording to birth date

Height ageHeight age is the appropriate age for the heightis the appropriate age for the heightHeight ageHeight age is the appropriate age for the height is the appropriate age for the height observed. Obtained by drawing a horizontal line from the observed. Obtained by drawing a horizontal line from the observed height to cross the 50observed height to cross the 50thth percentile of the growth percentile of the growth

77

chartchart

SKELETAL MATURATION AND SKELETAL MATURATION AND PREDICTING OF ADULT HEIGHTPREDICTING OF ADULT HEIGHTPREDICTING OF ADULT HEIGHTPREDICTING OF ADULT HEIGHTB AB A t i d ft i d fBone Age:Bone Age: represents an index of represents an index of maturation that relates more closely maturation that relates more closely than chronological age to growth.The than chronological age to growth.The

th t ti l i t b l bth t ti l i t b l bgrowth potential in tubuler bones can growth potential in tubuler bones can be assesed by evaluation of the be assesed by evaluation of the progression of ossification within the progression of ossification within the

i hi hepiphysesepiphyses

Useful in predicting final height (ifUseful in predicting final height (ifUseful in predicting final height (if Useful in predicting final height (if bone age >6 years old)bone age >6 years old)

M th dM th d G li h & P lG li h & P l TW IITW II88

Methods Methods Greulich & PyleGreulich & Pyle, , TW IITW II, , RWTRWT

AnthropometricsAnthropometricsAnthropometricsAnthropometrics

GeneralGeneralHeightHeightHeightHeightWeightWeightHead circumferenceHead circumferenceHead circumferenceHead circumference

Body proportionBody proportionSitting heightSitting heightSitting heightSitting heightArm spanArm span

99

GROWTH FAILUREGROWTH FAILUREGROWTH FAILUREGROWTH FAILUREDefinitionsDefinitions ::-- Height below 3Height below 3rdrd percentile (percentile (--2 SDs for age and 2 SDs for age and gender)gender)H i ht i ifi tl b l ti t ti l (H i ht i ifi tl b l ti t ti l ( 22-- Height significantly below genetic potential ( Height significantly below genetic potential ( --2 2 SDs below midSDs below mid--parental target)parental target)

-- Abnormally slow growth velocity (<2 inchies orAbnormally slow growth velocity (<2 inchies orAbnormally slow growth velocity ( 2 inchies or Abnormally slow growth velocity ( 2 inchies or 5 cm/yr from age 3 years to puberty)5 cm/yr from age 3 years to puberty)

-- Downwardly crossing percentile channels on Downwardly crossing percentile channels on growth chart (after age of 18 months)growth chart (after age of 18 months)

1010

DIFFERENTIAL DIAGNOSED OF SHORT DIFFERENTIAL DIAGNOSED OF SHORT STATURE/GROWTH FAILURESTATURE/GROWTH FAILURESTATURE/GROWTH FAILURESTATURE/GROWTH FAILURE

11 Healthy but short childrenHealthy but short children1. 1. Healthy but short childrenHealthy but short children-- Familial short statureFamilial short stature-- Constitutional growth delayConstitutional growth delay

2. 2. Non organic etiologiesNon organic etiologies-- Psychosocial deprivationPsychosocial deprivation

Nutritional dwarfingNutritional dwarfing-- Nutritional dwarfingNutritional dwarfing~ ~ Gross deficienciesGross deficiencies : kwashiorkor, anorexia : kwashiorkor, anorexia

nervosanervosa~ ~ Subtle macronutriens deficienciesSubtle macronutriens deficiencies : non : non

organic failure to thrive (NOFTT), picky eater, fear organic failure to thrive (NOFTT), picky eater, fear of obesity fear of hypercholesterolemiaof obesity fear of hypercholesterolemia

1111

of obesity, fear of hypercholesterolemiaof obesity, fear of hypercholesterolemia~ Micronutrient deficiencies : iron, zinc~ Micronutrient deficiencies : iron, zinc

DIFFERENTIAL DIAGNOSED OF SHORT DIFFERENTIAL DIAGNOSED OF SHORT STATURE/GROWTH FAILURESTATURE/GROWTH FAILURESTATURE/GROWTH FAILURESTATURE/GROWTH FAILURE

3. Intrinsic short stature3. Intrinsic short statureS ll f i lS ll f i l-- Small for gestational ageSmall for gestational age

-- Genetic syndromeGenetic syndrome~ ~ Down syndromeDown syndrome~~ Turner syndromeTurner syndrome~ ~ Turner syndromeTurner syndrome~ ~ PraderPrader--Willi syndromeWilli syndrome

-- Achondroplasia/HypochondroplasiaAchondroplasia/Hypochondroplasia4 Systemic diseases4 Systemic diseases4. Systemic diseases4. Systemic diseases

-- Infectious : HIV,TBCInfectious : HIV,TBC-- CardiacCardiac-- Renal : Acute tubular acidosis, Chronic Renal : Acute tubular acidosis, Chronic ,,renal insufficiencyrenal insufficiency-- GIT: Cystic fibrosis, inflammatory GIT: Cystic fibrosis, inflammatory bowel disease, Celiac diseasebowel disease, Celiac disease

1212

DIFFERENTIAL DIAGNOSED OF SHORT DIFFERENTIAL DIAGNOSED OF SHORT STATURE/GROWTH FAILURESTATURE/GROWTH FAILURE

5 Endocrinopathies5 Endocrinopathies5. Endocrinopathies5. Endocrinopathies-- Early pubertyEarly puberty-- Cortisol excess : endogenous & iatrogenicCortisol excess : endogenous & iatrogenicCortisol excess : endogenous & iatrogenicCortisol excess : endogenous & iatrogenic-- HypothyroidismHypothyroidism-- Poorly controlled DMPoorly controlled DMyy-- Inadequate growth hormone actionInadequate growth hormone action

~ GH deficiency : isolated vs ~ GH deficiency : isolated vs yypanhypopituitarism, congenital vs panhypopituitarism, congenital vs aqcuiredaqcuired

1313~ GH insensitivity : ~ GH insensitivity : Laron Laron types 1 & 2types 1 & 2

DIFFERENTIAL DIAGNOSIS OFDIFFERENTIAL DIAGNOSIS OFDIFFERENTIAL DIAGNOSIS OF DIFFERENTIAL DIAGNOSIS OF CONGENITAL GH DEFICIENCYCONGENITAL GH DEFICIENCY

1 Idi i ( h f )1 Idi i ( h f )1. Idiopatic (the most common from)1. Idiopatic (the most common from)2. Identified malformations2. Identified malformations

Congenital absence of pituitaryCongenital absence of pituitary-- Congenital absence of pituitaryCongenital absence of pituitary-- Associations (Holoprosencephaly, Associations (Holoprosencephaly, SeptoSepto--opticoptic--dysplasia, Midline defectsdysplasia, Midline defectsSeptoSepto opticoptic dysplasia, Midline defects dysplasia, Midline defects (cleft lip, cleft palate))(cleft lip, cleft palate))

3. Identified genetic mutations3. Identified genetic mutations (Familial (Familial lti l t i it it hlti l t i it it hmultiple anterior pituitary hormone multiple anterior pituitary hormone

deficiency & Familial isolated GH deficiency & Familial isolated GH deficiency deficiency GH gene mutations)GH gene mutations)

14144. Trauma4. Trauma : birth trauma/perinatal insult: birth trauma/perinatal insult

DIFFERENTIAL DIAGNOSIS OF DIFFERENTIAL DIAGNOSIS OF ACQUIRED GH DEFICIENCYACQUIRED GH DEFICIENCYACQUIRED GH DEFICIENCYACQUIRED GH DEFICIENCY

1. Idiopathic1. Idiopathic (the most common)(the most common)pp ( )( )2. Infection :2. Infection : viral, bacterial, fungal & TBCviral, bacterial, fungal & TBC3. Vascular :3. Vascular : pituitary infection or aneurysmpituitary infection or aneurysmp y yp y y4. Infiltration affecting pituitary gland or sella 4. Infiltration affecting pituitary gland or sella

turcica :turcica : Histiocytosis, SarcoidosisHistiocytosis, Sarcoidosis5. Trauma :5. Trauma : child abuse or other closed head child abuse or other closed head

injury, surgical damage of the pituitary injury, surgical damage of the pituitary gland/stalkgland/stalkgland/stalkgland/stalk

6. Tumors :6. Tumors : Craniopharyngioma, Craniopharyngioma, Medulloblastoma, Glioma, PinealomaMedulloblastoma, Glioma, Pinealoma

1515

, ,, ,7. Pituitary or hypothalamic irradiation7. Pituitary or hypothalamic irradiation8. Chemotherapy8. Chemotherapy

KEY ELEMENTS IN HISTORY GATHERING FOR KEY ELEMENTS IN HISTORY GATHERING FOR THE EVALUATION OF GROWTH FAILURETHE EVALUATION OF GROWTH FAILURE

1.1. Familial history :Familial history : parents height, parents age ofparents height, parents age of1.1. Familial history :Familial history : parents height, parents age of parents height, parents age of puberty, familial history of short stature, familial puberty, familial history of short stature, familial history of delayed growth or puberty, familial history of delayed growth or puberty, familial history of endocrinopathies or systemichistory of endocrinopathies or systemichistory of endocrinopathies or systemic history of endocrinopathies or systemic illnessesillnesses

2.2. Child’s history :Child’s history : when did growth failure begin? when did growth failure begin? H h i ll di t d i th hildH h i ll di t d i th hildHow psychosocially distressed is the child How psychosocially distressed is the child about his or her growth? Perinatal history, about his or her growth? Perinatal history, history of systemic illnesses, any signs of history of systemic illnesses, any signs of

b t d t hi h th db t d t hi h th dpuberty and age at which they commencedpuberty and age at which they commenced3.3. Medication historyMedication history (non prescription drugs & (non prescription drugs &

health food supplements)health food supplements)1616

health food supplements)health food supplements)4.4. Dentition historyDentition history5.5. Psychosocial historyPsychosocial history

INITIAL SCREENING EVALUATION INITIAL SCREENING EVALUATION OF GROWTH FAILUREOF GROWTH FAILUREOF GROWTH FAILUREOF GROWTH FAILURE

1. General tests1. General testsCh i t (kid d li f tiCh i t (kid d li f ti-- Chemistry (kidney and liver function Chemistry (kidney and liver function tests)tests)

-- Complete blood cell count with differentialComplete blood cell count with differentialComplete blood cell count with differentialComplete blood cell count with differential-- Sedimentation rateSedimentation rate-- UrinalysisUrinalysis

2. Genetic tests :2. Genetic tests : chromosome in every femalechromosome in every female3. Endocrine tests 3. Endocrine tests

-- Thyroid function testsThyroid function tests-- Thyroid function testsThyroid function tests-- Growth factors : IGFGrowth factors : IGF--I and IGFBPI and IGFBP--33

4. Imaging studies :4. Imaging studies : bone age (anteroposterior radiograph of bone age (anteroposterior radiograph of

1717

left hand and wrist)left hand and wrist)

CURRENT FOOD AND DRUG ADMINISTRATIONCURRENT FOOD AND DRUG ADMINISTRATION--APPROVED INDICATIONS FOR RECOMBINANT HUMAN APPROVED INDICATIONS FOR RECOMBINANT HUMAN

GH THERAPYGH THERAPY

1. Linear growth1. Linear growthgg-- Pediatric growth hormone Pediatric growth hormone deficiencydeficiency

Chronic renal insufficiencyChronic renal insufficiency-- Chronic renal insufficiencyChronic renal insufficiency-- Turner syndromeTurner syndrome-- Small for gestational ageSmall for gestational age-- Idiopathic short statureIdiopathic short stature

2. Metabolic effects2. Metabolic effectsAdult GH deficiencyAdult GH deficiency-- Adult GH deficiencyAdult GH deficiency

-- AIDS cachexiaAIDS cachexia-- PraderPrader--Willi syndromeWilli syndrome

1818

yy

OVERGROWTHOVERGROWTHOVERGROWTHOVERGROWTHThe child whose height is greater than The child whose height is greater than g gg g+2 SD is less likely to be the subject of +2 SD is less likely to be the subject of evaluation than the one whose height is evaluation than the one whose height is

SSless than less than --2 SD2 SDA child with advanced skeletal A child with advanced skeletal maturation and progressive deviation > maturation and progressive deviation > 9797thth percentile should be evaluated for percentile should be evaluated for precocious pubertal developmentprecocious pubertal developmentprecocious pubertal development. precocious pubertal development. Screening for excessive GH secretion Screening for excessive GH secretion should be initiated with random IGFshould be initiated with random IGF--II

1919

should be initiated with random IGFshould be initiated with random IGF--I I levellevel

DIFFERENTIAL DIAGNOSIS OF DIFFERENTIAL DIAGNOSIS OF OVERGROWTHOVERGROWTHOVERGROWTHOVERGROWTH

1 Prenatal onset1 Prenatal onset1. Prenatal onset1. Prenatal onset-- Maternal diabetesMaternal diabetes-- Sotos syndromeSotos syndrome-- Weaver syndromeWeaver syndrome

MarshallMarshall Smith syndromeSmith syndrome-- MarshallMarshall--Smith syndromeSmith syndrome-- BecwithBecwith--Wiedemann syndromeWiedemann syndrome

2. Postnatal onset2. Postnatal onset-- Familial (constitutional) tall statureFamilial (constitutional) tall stature

ObesityObesity-- ObesityObesity-- Precocious pubertyPrecocious puberty-- HyperthyroidismHyperthyroidism-- Klinefelter syndrome’Klinefelter syndrome’

XYY syndromeXYY syndrome-- XYY syndromeXYY syndrome-- Marfan syndromeMarfan syndrome-- HomocysteinuriaHomocysteinuria-- Excessive GH secretionExcessive GH secretion

2020

Wudy S et al (Pediatrics 2005;116:52–57) :Wudy S et al (Pediatrics 2005;116:52 57) :Patients with Idiopathic Short Stature point to an altere eating behavior that possibly contributes to their short stature.

Zadik Z et al (Pediatrics 2005;116:68–72) :The nutritional status of GH-treated patients b f d th h t th f GHbefore and throughout the course of GH treatment should be monitored closely to improve the growth response and preventimprove the growth response and prevent nutritional deficiencies. Special emphasis should be placed on iron nurture

2121

p

2222

Growth Chart195

175

180

185

190

97

50

155

160

165

170

50

3

130

135

140

145

150

Height (cm)

110

115

120

125

130

90

95

100

105

110

232380

85

2 4 6 8 10 12 14 16 18

Age (years)

Growth Chart195

175

180

185

19097

50

155

160

165

170

3Potential Genetic HeightPotential Genetic Height

130

135

140

145

150

Height (cm)

110

115

120

125

130

90

95

100

105

110

HAHA CACA

242480

85

2 4 6 8 10 12 14 16 18

Age (years)

INFANT PERIODINFANT PERIODCanalizationCanalizationCatchCatch--downdown

INFANT PERIODINFANT PERIOD

Potential Genetic Height

yearyear2525

0 1 2 3 year year

G th V l it CG th V l it CCm/year

Growth Velocity CurveGrowth Velocity Curve

GH Sex steroid

2626Infant Childhood Puberty

2727NORMAL

2828

NORMAL

2929TURNER & DOWN SYNDROME

3030DOWN SYNDROME

3131

DOWN SYNDROME

3232

3333

3434

PRADER-WILLISYNDROME

DOWN SYNDROME

LARONSYNDROME

3535

SYNDROME SYNDROME

ACHONDROPLASIATURNER SYNDROME

3636

MARFANSYNDROME

3737

DE CORNELIA DE LANGE SYNDROME3838

DE CORNELIA DE LANGE SYNDROME

3939NOONAN SYNDROME

SECKEL SYNDROMESECKEL SYNDROME

4040

SHORT STATURESHORT STATURE

NORMAL GROWTH VELOCITY?NORMAL GROWTH VELOCITY?

YES NO

PATHOLOGICPATHOLOGICNORMAL NORMAL VARIANTVARIANT

BODY PROPORTION?BODY PROPORTION? DYSMORPHISMDYSMORPHISMBODY PROPORTION?BODY PROPORTION? DYSMORPHISMDYSMORPHISM

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W/H INDEX?W/H INDEX?

SHORT STATURESHORT STATURE

PATHOLOGICPATHOLOGIC

PROPORTIONALPROPORTIONALDYSPROPORTIONATEDYSPROPORTIONATE

W/H W/H W/H W/H

DYSPROPORTIONATEDYSPROPORTIONATE

ENDOCRINEENDOCRINE••GH DEFICIENCYGH DEFICIENCY

••MALNUTRITIONMALNUTRITION

••CHRONIC INFECTIONCHRONIC INFECTION

DYSMORPHIC DYSMORPHIC

••HYPOTHYROIDHYPOTHYROID

••CORTISOL EXCESSCORTISOL EXCESS

••PSEUDOHYPOPARATHYRPSEUDOHYPOPARATHYR

••CHRONIC DISEASE CHRONIC DISEASE (ORGANIC)(ORGANIC)

••PSYCHOSOCIALPSYCHOSOCIAL

4242

OIDOID ••IUGRIUGR

SHORT STATURESHORT STATURE

PATHOLOGICPATHOLOGIC

DYSMORPHICDYSMORPHICDYSPROPORTIONATEDYSPROPORTIONATE

••SKELETAL DYSPLASIASKELETAL DYSPLASIA ••CHROMOSOME CHROMOSOME A/HYPO CHONDROPLASIAA/HYPO CHONDROPLASIA

••METABOLIC DISEASESMETABOLIC DISEASESRICKETSRICKETS

••TRISOMI 21TRISOMI 21TURNER SYNDROMETURNER SYNDROME

••SYNDROMES (SYNDROMES (±± IUGR)IUGR)••SPINAL DISORDERSSPINAL DISORDERS

CRANIOSPINAL IRRADIATIONCRANIOSPINAL IRRADIATIONSPONDYLODYSPLASIASPONDYLODYSPLASIA

••SYNDROMES (SYNDROMES (±± IUGR)IUGR)FETAL ALCOHOL, RUSSELLFETAL ALCOHOL, RUSSELL--

SILVER, PRADERSILVER, PRADER--WILLI, WILLI, NOONAN SECKEL de LANGENOONAN SECKEL de LANGE

4343

SPONDYLODYSPLASIASPONDYLODYSPLASIA NOONAN, SECKEL, de LANGE, NOONAN, SECKEL, de LANGE, LARON, COCKAYNE dllLARON, COCKAYNE dll

SHORT STATURESHORT STATURE

NORMAL VARIANTNORMAL VARIANT

FAMILIAL SS CONSTITUTIONAL DELAY OF GROWTH AND PUBERTY

44BA = CABA = CA44FINAL HEIGHT < 3FINAL HEIGHT < 3RDRD

44BA < CABA < CA44FINAL HEIGHT =NORMALFINAL HEIGHT =NORMAL44FINAL HEIGHT < 3FINAL HEIGHT < 3

PERCENTILEPERCENTILE44APPROPRIATE WITH APPROPRIATE WITH PGHPGH

44FINAL HEIGHT =NORMALFINAL HEIGHT =NORMAL44APPROPRIATE WITH PGHAPPROPRIATE WITH PGH44POSITIVE FAMILY HISTORY POSITIVE FAMILY HISTORY OF CDGPOF CDGP

4444

Growth ChartFamilial Short Stature

Growth Chart

180

185

190

195

Familial Short Stature

180

185

190

195Constitutional Delay of Growth & Puberty

155

160

165

170

175

155

160

165

170

175

130

135

140

145

150

Height (cm)

130

135

140

145

150

Height (cm)

105

110

115

120

125

130

105

110

115

120

125

130

85

90

95

100

105

85

90

95

100

105

4545

802 4 6 8 10 12 14 16 18

Age (years)80

2 4 6 8 10 12 14 16 18

Age (years)

Stature and GrowthStature and Growth

4646Which child needs more attention?

QuizQuizQuizQuiz

Data of a boyData of a boyData of a boyData of a boyAge 7 yrs and 4 mos : 110 cm; BA 5 yrsAge 7 yrs and 4 mos : 110 cm; BA 5 yrsAge 8 yrs : 114 cm; BA 6 yrsAge 8 yrs : 114 cm; BA 6 yrsAge 8 yrs : 114 cm; BA 6 yrsAge 8 yrs : 114 cm; BA 6 yrsAge 9 yrs 6 mos : 122 cm; BA 7 yrsAge 9 yrs 6 mos : 122 cm; BA 7 yrs

F th 172 M th 166F th 172 M th 166Father 172 cm, Mother 166 cmFather 172 cm, Mother 166 cmMenarche (mother) 15 yrsMenarche (mother) 15 yrs

WHAT IS YOUR ASSESSMENT?WHAT IS YOUR ASSESSMENT?

4747

GROWTH CHARTGROWTH CHART

STATURE STATURE STATURE STATURE

Patient 1 (Patient 1 ( ))

Patient 2 Patient 2 (( ))

GROWTHGROWTH

NORMAL (NORMAL (→))

ABNORMAL (ABNORMAL (→))ABNORMAL (ABNORMAL (→))

CATCH UP CATCH UP ((→))

4848

4949