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GROWTH:GROWTH:A ClinicalA Clinical

PerspectivePerspectiveSharon E. Oberfield, M.D.Sharon E. Oberfield, M.D.

Professor of PediatricsProfessor of PediatricsColumbia University Medical CenterColumbia University Medical Center

February 12, 2007February 12, 2007

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Normal Growth and DevelopmentNormal Growth and Development

Expected Growth Rate Per YearExpected Growth Rate Per Year

Annually5-62-2.53 years to puberty

* More frequently if growth abnormality is suspected

7.5-103-424 to 36 months

3 to 4 times/year*10-134-512 to 24 months

18-259-11Birth to 12 months

Frequency ofEvaluation

Cm/YearInches/ YearAge

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What is Short Stature?What is Short Stature?

DefinitionDefinition Height SDS < -2 for age and sexHeight SDS < -2 for age and sex Approximately 3% of all childrenApproximately 3% of all children

Figure 2. Differential diagnosis of short stature. IUGR = intrauterine growth retardation. Figure 2. Differential diagnosis of short stature. IUGR = intrauterine growth retardation. (Modified from (Modified from RimoinRimoinDL, DL, BorochowitzBorochowitz Z, Horton WA. West J Med 144:710,1986, with permission) Z, Horton WA. West J Med 144:710,1986, with permission)

Short StatureShort Stature

Normal VariantsNormal Variants PathologicPathologicFamilial short statureFamilial short statureConstitutional delayConstitutional delay

ProportionateProportionate DisproportionateDisproportionateSkeletal Skeletal dysplasiadysplasiaRicketsRickets

PrenatalPrenatal PostnatalPostnatalIUGRIUGR Endocrine disordersEndocrine disorders

Placental DiseasesPlacental Diseases Psychosocial disordersPsychosocial disordersInfectionsInfections MalnutritionMalnutritionTeratogensTeratogens Gastrointestinal diseasesGastrointestinal diseases

DysmorphicDysmorphic syndromes syndromes Cardiopulmonary diseasesCardiopulmonary diseasesChromosomal disordersChromosomal disorders Chronic anemiaChronic anemia

Renal disordersRenal disorders

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Assessment of Suspected GrowthAssessment of Suspected Growth AbnormalitiesAbnormalities

AuxologicAuxologic Data Data

Abnormally slow growth rateAbnormally slow growth rate Ages 3 to 12 years: Less than 2 inches/year (5Ages 3 to 12 years: Less than 2 inches/year (5

cm/year)cm/year)

Downwardly crossing Downwardly crossing centilecentile channels on channels ongrowth chart after the age of 18 monthsgrowth chart after the age of 18 months

Height below third percentile (-2 SD)Height below third percentile (-2 SD) Height significantly below genetic potential (-Height significantly below genetic potential (-

2 SD below 2 SD below midparentalmidparental height) height)

History and PhysicalHistory and PhysicalExaminationExamination

Birth History Birth History –– Small for Gestational Age, Small for Gestational Age,Intrauterine Growth RetardationIntrauterine Growth Retardation

General History General History –– Chronic Illness Chronic Illness Family History Family History –– Genetic, Psychosocial Genetic, Psychosocial Physical Examination Physical Examination –– Proportions, Proportions,

AbnormalitiesAbnormalities Growth Chart Growth Chart –– Growth Velocity, Age of Growth Velocity, Age of

Onset, Change in Growth PatternOnset, Change in Growth Pattern

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Blood TestsBlood Tests

Complete Blood CountComplete Blood Count Erythrocyte Sedimentation RateErythrocyte Sedimentation Rate Serum Electrolytes and ChemistriesSerum Electrolytes and Chemistries Thyroid Hormone LevelsThyroid Hormone Levels Exercise-Induced GH LevelExercise-Induced GH Level IGF-1 Level IGF-1 Level Chromosomal Analysis (Karyotype) Chromosomal Analysis (Karyotype) ♀♀

Tissue Tissue TransglutaminaseTransglutaminase Antibody Antibody GliadinGliadin Antibodies (IGG, IGA) Antibodies (IGG, IGA)

Additional Measurements inAdditional Measurements inAssessing Short StatureAssessing Short Stature

Head SizeHead Size Body ProportionsBody Proportions Sexual MaturationSexual Maturation Skeletal MaturationSkeletal Maturation

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Calculating Calculating MidparentalMidparental and Target Heights and Target HeightsMidparentMidparent Height (in inches) Height (in inches)

Target HeightMidparental Height ± 2 SD

(1 SD = 2 inches)

(Mother’s height + 5 inches) + (Father’sheight)

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Midparentalheight for boys

(Father’s height – 5 inches ) + (Mother’sheight)

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Midparentalheight for girls

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Differential Diagnosis of Growth AbnormalitiesDifferential Diagnosis of Growth Abnormalities

Assessment ofAssessment ofGrowth Hormone Growth Hormone SecetionSecetion

Provocative stimuliProvocative stimuli Arginine-insulinArginine-insulin ClonidineClonidine L-dopa L-dopa ± ± propranololpropranolol GlucagonGlucagon OthersOthersPhysiologic testsPhysiologic tests Exercise-stimulatedExercise-stimulated Serial samplingSerial sampling

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Growth Deficiency-PrenatalGrowth Deficiency-PrenatalOnsetOnset

Exogenous Causes-Secondary Growth DeficienciesExogenous Causes-Secondary Growth DeficienciesMaternal MalnutritionMaternal Malnutrition InfectionsInfectionsToxemiaToxemia RubellaRubellaHypertensionHypertension CytomegalicCytomegalic Inclusion Virus Inclusion VirusRenal or Cardiac DiseaseRenal or Cardiac Disease ToxoplasmosisToxoplasmosisNicotineNicotine SyphilisSyphilisEthanolEthanolHydantoinsHydantoins

May or may not show post-natal catch-up growthMay or may not show post-natal catch-up growth

Endogenous Causes-Primary Growth DeficienciesEndogenous Causes-Primary Growth DeficienciesChromosomal Abnormalities, e.g. TurnerChromosomal Abnormalities, e.g. Turner’’s Syndromes SyndromeOsteochondrodysplasiasOsteochondrodysplasiasMultiple Malformation SyndromesMultiple Malformation Syndromes

Do not show post-natal catch-up growthDo not show post-natal catch-up growth

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Postnatal Growth DeficiencyPostnatal Growth Deficiency

NutritionalNutritional Neglect, Neglect, MalabsorptionMalabsorption

Cardiac DefectCardiac Defect Renal DysfunctionRenal Dysfunction Growth Hormone DeficiencyGrowth Hormone Deficiency Thyroid Hormone DeficiencyThyroid Hormone Deficiency Metabolic DisordersMetabolic Disorders

HypercalcemiaHypercalcemia, Glycogen Storage Disease, Poorly, Glycogen Storage Disease, PoorlyControlled Diabetes Mellitus, Salt Wasting SyndromeControlled Diabetes Mellitus, Salt Wasting Syndrome

Specific treatment results in catch-up growthSpecific treatment results in catch-up growth

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Familial Short StatureFamilial Short Stature

Annual Growth Rate NormalAnnual Growth Rate Normal Height at or Below 3Height at or Below 3rdrd Percentile Percentile No Systemic or Endocrine DiseaseNo Systemic or Endocrine Disease Pubertal Growth Spurt at Normal AgePubertal Growth Spurt at Normal Age Skeletal Age Equal to Chronological AgeSkeletal Age Equal to Chronological Age Ancestors Relatively ShortAncestors Relatively Short

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Constitutional Growth DelayConstitutional Growth Delay

Delayed PubertyDelayed Puberty Retarded bone ageRetarded bone age Normal predicted adult height in context ofNormal predicted adult height in context of

family patternfamily pattern No organic or emotional cause for growthNo organic or emotional cause for growth

failurefailure

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Table 1. Principal Clinical Features in 13Table 1. Principal Clinical Features in 13Cases of CushingCases of Cushing’’s Syndrome in Children*s Syndrome in Children*

6Headache7Cutaneous striae7Osteoporosis

10†Hypertension10Flushed cheeks11Acne11Hirsutism11Short Stature (10th percentile or less)

13Truncal Obesity, moon face, buffalohump

No. of PatientsClinical Feature

From McArthur, R.G., Cloutier M.D., Hayles A.B., et al. Cushing’s disease in children.Mayo Clin Proc 47:318, 1972

† Diastolic pressure of 90 mm Hg or higher

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Prevalence of GHD: Utah Growth StudyPrevalence of GHD: Utah Growth Study

114,881 measurements available for evaluation in 1114,881 measurements available for evaluation in 1stst year year 1,334 children with heights > 2 SD below the mean1,334 children with heights > 2 SD below the mean 52 children referred for further evaluation of growth52 children referred for further evaluation of growth

problemsproblems 79,495 measurements available for evaluation in 279,495 measurements available for evaluation in 2ndnd year year

578 children with height < 3578 children with height < 3rdrd percentile and growth rate percentile and growth rate< 5 cm/y< 5 cm/y

503 of 578 children available for follow-up were503 of 578 children available for follow-up wereevaluated furtherevaluated further

16 new cases of GHD diagnosed16 new cases of GHD diagnosed 17 GH-treated GHD children not identified because of17 GH-treated GHD children not identified because of

normal growth ratesnormal growth rates

Estimated prevalence of GHD in the UnitedEstimated prevalence of GHD in the UnitedStates: 1:3,480States: 1:3,480

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Established Genetic Defects Causing IGF Deficiency (1)Established Genetic Defects Causing IGF Deficiency (1)

Type II form of IGHDAD

Type III form of IGHD.Hypogammaglobulinemiac

X-linked

Type 1B form of IGHDAR

Gh (spontaneous dwarfrat)

Type 1A form of IGHDAR GH1

IGHD

Ghrhr (little mouse)IGHDAR GHRHR

Pit1/Ghf1 (Snellmouse, Jacksonmouse)

GH and PRL deficiencies.Variable degree of TSHdeficiency

AR, AD POU1F1

Rieg/Pitx2Reiger’s syndrome. IGHDAD RIEG1

Bioinactive GH moleculeAD

Prop1 (Ames mouse)GH, PRL, TSH, LH and FSHdeficiencies. Variable degreeof ACTH deficiency

AR PROP1

Hesx1/RpxSepto-optic dysplasia. Variableinvolvement of pituitaryhormones

AR HESX1

Developmental abnormalities

GHD owing to hypothalamic-pituitary dysfunction

Murine HomologPhenotypeInheritanceMutant gene

C The genetic defect for this syndrome is unknown Lopez-Bermejo A, Buckway CK, Rosenfeld RG, TEM 11:39-49, 2000

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Established Genetic Defects Causing IGF DeficiencyEstablished Genetic Defects Causing IGF Deficiency(2)(2)

Primary defects of IGF synthesisIgf1IGF deficiencyARIGF1

IGF deficiency. Increased ornormal GHBP

AD Intracellular domain

Stat5b knockoutIGF deficiency. Normal GHBPAR Intracellular domain (cytoplasm)

IGF deficiency. IncreasedGHBP

AR Transmembrane domain

IGF deficiency. Decreased ornormal GHBP

AR Extracellular domain

GhrGHR

GHIMurine HomologPhenotypeInheritanceMutant gene

Lopez-Bermejo A, Buckway CK, Rosenfeld RG, TEM 11:39-49, 2000

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Eugster, E. A. et. al. N Engl J Med 2003;349:1110-1112

Growth Hormone-Activated Intracellular Signaling

Eugster, E. A. et. al. N Engl J Med 2003;349:1110-1112

IGF-I receptor mutations:IGF-I Receptor Mutations: Pre and Postnatal Growth Retardation

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••IGF-I receptor mutations:IGF-I receptor mutations:IGF-I Receptor Mutations: Pre and Postnatal Growth RetardationIGF-I Receptor Mutations: Pre and Postnatal Growth Retardation

Patient 1Patient 1

Patient 1 Patient 1 –– nonconsanguinousnonconsanguinous, 1.4 kg, 38 week pregnancy, normal serum, 1.4 kg, 38 week pregnancy, normal serumIGF-I, normal GH to provocation.IGF-I, normal GH to provocation.

Patient was a compound heterozygous for mutations in exon 2Patient was a compound heterozygous for mutations in exon 2 of theof theIGF-IR gene IGF-IR gene →→ ↓↓ binding of IGF-I to IGF-I receptor. binding of IGF-I to IGF-I receptor.

Abuzzahab M et al. N Engl J Med 2003;349:2211-2222

• Patient 2- At birth, weight of 2000 grams, length of 40 cm, andmicrocephaly. Normal GH and IGF-I high for age.

Abuzzahab M et al. N Engl J Med 2003;349:2211-2222

IGF-I receptor mutations:IGF-I receptor mutations:IGF-I Receptor Mutations: Pre and Postnatal Growth RetardationIGF-I Receptor Mutations: Pre and Postnatal Growth Retardation

Patient 2Patient 2

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•Heterozygous for a potential mutation in exon 2. Exon 2 is the first exonto encode a substantial portion of the mature receptor → no visiblereceptor protein was made.

Abuzzahab M et al. N Engl J Med 2003;349:2211-2222

IGF-I receptor mutations:IGF-I receptor mutations:IGF-IR Mutations: Pre and Postnatal Growth RetardationIGF-IR Mutations: Pre and Postnatal Growth Retardation

Patient 2Patient 2

Eugster, E. A. et. al. N Engl J Med 2003;349:1110-1112

Inactivating mutations of the IGF-I gene:A Novel Insulin-Like Growth Factor-I Mutation

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••Inactivating mutations of the IGF-I gene:Inactivating mutations of the IGF-I gene:A Novel Insulin-Like Growth Factor-I MutationA Novel Insulin-Like Growth Factor-I Mutation

Walenkamp, M. J. E. et al. J Clin Endocrinol Metab 2005;90:2855-2864

Walenkamp, M. J. E. et al. J Clin Endocrinol Metab 2005;90:2855-2864

••Inactivating mutations of the IGF-I gene:Inactivating mutations of the IGF-I gene:A Novel Insulin-Like Growth Factor-I MutationA Novel Insulin-Like Growth Factor-I Mutation

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This is the first report on a homozygous This is the first report on a homozygous missensemissensemutation in the human IGF-I gene resulting in anmutation in the human IGF-I gene resulting in anIGF-I protein that is hardly capable of interactingIGF-I protein that is hardly capable of interactingwith the IGF-IR but with relatively unaffectedwith the IGF-IR but with relatively unaffectedbinding capacity for binding capacity for IGFBPsIGFBPs. This leads to severe. This leads to severeeffects on growth and development effects on growth and development in utero in utero andandduring childhood.during childhood.

•IGF1 resistance•IGF1 mRNA gene,IGF1 receptor gene

IGF1 ReceptorChondrocytes

•Growth hormoneresistance

•GHR 1GH Receptor↓J2K, Stat 5b↓IGF1, IGFBPs,ALS↓

Hepatocytes,Osteoblasts

•Pituitary tumors•Hypoplasia

•PROP 1, PIT 1, LHX3, GH 1, POU1F1

GH↓

Pituitary

•Hypothalamic(idiopathic GHdeficiency)•Hypothalamicinfiltrative disease

PTX 1, HESX 1↓

GHRH↓

Hypothalamus

Clinical/LabPresentations

GenomicOrganization

GrowthFactor

Tissue

Table: Growth Failure Resulting from Reduced GH Secretion or Action.

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AGA AGA vsvs SGA SGA AGAAGA

Birth weight and length within 2 SD of mean for gestationalBirth weight and length within 2 SD of mean for gestationalageage

SGASGA Birth weight and/or length at least 2 SD below mean forBirth weight and/or length at least 2 SD below mean for

gestational agegestational age Other definitionsOther definitions

Birth weight <2500 g, gestational age Birth weight <2500 g, gestational age ≥≥37 wk37 wk

Birth weight or length <3Birth weight or length <3rdrd, <5, <5thth, or <10, or <10thth percentile for gestational age percentile for gestational age PonderalPonderal index less than index less than ––2 SD2 SD

Albertsson-Wikland K, Karlberg J. Acta Paediatr Suppl, 1994:399:64

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Causes of Tall Stature and ExcessiveCauses of Tall Stature and ExcessiveGrowthGrowth

Normal variants: Constitutional tall statureNormal variants: Constitutional tall stature Endocrine disordersEndocrine disorders

Growth hormone excessGrowth hormone excess Disorders of sexual maturationDisorders of sexual maturation

Precocious pubertyPrecocious puberty VirilizationVirilization FeminizationFeminization HypogonadismHypogonadism

NonendocrineNonendocrine disorders disorders Cerebral Gigantism (Cerebral Gigantism (SotosSotos syndrome) syndrome) KlinefeltersKlinefelters syndrome syndrome XYY malesXYY males MarfanMarfan syndrome syndrome HomocystinuriaHomocystinuria

Frasier SD, Tall Stature and Excessive Growth Syndromes, In Pediatric Endocrinology, 4th edition, Lifshitz ed.2003

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Large Size in ChildhoodLarge Size in ChildhoodNormal VariantsNormal Variants

EarlyNormalOnset of adolescence

Early ageUsual ageFinal heightattainment

AverageTallAdult stature

AdvancedNormalFacial appearanceand bone age inchildhood

InfancyInfancyOnset of rapid growth

AverageTallParental stature

Familial RapidMaturation

Familial TallStature

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Causes of Increased Causes of Increased StaturalStaturalGrowthGrowth

Prenatal OnsetPrenatal Onset

Maternal diabetes mellitusMaternal diabetes mellitus Beckwith-Beckwith-WiedemannWiedemann

SyndromeSyndrome Cerebral GigantismCerebral Gigantism

Postnatal OnsetPostnatal Onset Exogenous obesityExogenous obesity Pituitary GH excessPituitary GH excess MarfanMarfan syndrome syndrome Sexual precocity and virilizingSexual precocity and virilizing

syndromessyndromes McCune-Albright syndromeMcCune-Albright syndrome HomocysteinuriaHomocysteinuria Total Total lipodystrophylipodystrophy KinefelterKinefelter syndrome (47, XXY) syndrome (47, XXY) XYY karyotypeXYY karyotype HyperthyroidismHyperthyroidism

Underwood, LE & Van Wyck, JJ. Williams Textbook of Endocrinology, 1992, p. 1125

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Wise nature did never put her preciousWise nature did never put her preciousjewels into a garret four stories high: andjewels into a garret four stories high: andthereforetherefore…… exceeding tall men had ever very exceeding tall men had ever veryempty heads.empty heads.

Francis BaconFrancis Bacon