...ושמו שאול.....אין איש מבני משכמו ומעלה טוב ממנוישראל

מכל העם"גבוה1-2שמואל א' פרק ט' , פס'

עובדה

מערכות הבחירות 20/25ב- האחרונות לנשיאות ארה"ב

זכה המועמד הגבוה יותרמבין שני המובילים

ומה אצלנו ?

““Heightism””

הצלחה אקדמית

חברתית

קריירה ציבורית

אבחון

טיפול

קומה נמוכה, מחלה ?

The Growing YearsThe Growing YearsFrom Birth to 2 YearsFrom Birth to 2 Years

Full-term babies are between 48 - 53 cm long at birthFull-term babies are between 48 - 53 cm long at birth The average birth weight is between 3.0 and 3.4 kgThe average birth weight is between 3.0 and 3.4 kg Infants triple their birth weight and grow between 20 - Infants triple their birth weight and grow between 20 -

25.5 cm by the125.5 cm by the1stst y. y. 2 y weigh about four times what they weighed at birth 2 y weigh about four times what they weighed at birth

and have grown between 10 -12.5 cm in the 2and have grown between 10 -12.5 cm in the 2ndndyearyear Most babies who are small at birth may "catch-up" by Most babies who are small at birth may "catch-up" by

growing at a faster-than-average rate during infancygrowing at a faster-than-average rate during infancy For a rough estimate of adult height, double a boy's For a rough estimate of adult height, double a boy's

height at 24-27 months and a girl's height at 18-20 height at 24-27 months and a girl's height at 18-20 months. months.

The Growing YearsThe Growing Years From 2 Years to PubertyFrom 2 Years to Puberty

After age 2, most After age 2, most children gain children gain about 2.2 kg. per about 2.2 kg. per year year

At 3-4 y the At 3-4 y the growth rate is 6-8 growth rate is 6-8 cm and then 4.8 cm and then 4.8 –– 6 cm per year 6 cm per year until puberty until puberty

The Growing Years The Growing Years PubertyPuberty

Puberty take place over 3 to 4 years for Puberty take place over 3 to 4 years for most teenagers. most teenagers.

The peak growth spurt occurs at Tanner The peak growth spurt occurs at Tanner III-IV in girls; and at Tanner IV in boys. III-IV in girls; and at Tanner IV in boys.

Girls grow 6.5 -11.5 cm/y during growth Girls grow 6.5 -11.5 cm/y during growth spurt. Boys grow 7.5-12.5.spurt. Boys grow 7.5-12.5.

After their first menstrual period After their first menstrual period followed by regular ones most girls will followed by regular ones most girls will grow less then 4 cm grow less then 4 cm

Working Working Diagnosis of Diagnosis of Short StatureShort Stature

History and clinical criteriaHistory and clinical criteria Auxological criteriaAuxological criteria Radiological evaluationRadiological evaluation Evaluation of genetic disordersEvaluation of genetic disorders Biochemical assessment of GH Biochemical assessment of GH

deficiencydeficiency

Prenatal historyPrenatal history Birth weight and neonatal historyBirth weight and neonatal history History of chronic illness(CV, GI, Renal History of chronic illness(CV, GI, Renal

and Pul)and Pul) Growth dataGrowth data Pituitary symptomsPituitary symptoms Parents height and Family history of short Parents height and Family history of short

stature or delayed pubertystature or delayed puberty Diet history Diet history Drug history Drug history

History and clinical criteriaHistory and clinical criteria - I- I

History and clinical criteriaHistory and clinical criteria - - IIII

In the neonate: hypoglycemia, prolonged In the neonate: hypoglycemia, prolonged jaundice, microphallus or traumatic deliveryjaundice, microphallus or traumatic delivery

Craniofacial midline abnormalitiesCraniofacial midline abnormalities Cranial irradiationCranial irradiation Signs indicative of head trauma or central Signs indicative of head trauma or central

nervous system infectionnervous system infection Consanguinity and/or an affected family Consanguinity and/or an affected family

membermember Organic acquired GHDOrganic acquired GHD Signs of MPHDSigns of MPHD

Complete physical Complete physical examinationexamination

Measurments;Measurments;– Height, Weight, Head circumference, Arm Height, Weight, Head circumference, Arm

spanspan– Weight to Height ratio, Upper segment to Weight to Height ratio, Upper segment to

Lower segment ratioLower segment ratio Growth pattern (height velocity) Growth pattern (height velocity) Dysmorphic features including mid-line defects Dysmorphic features including mid-line defects Fundal examinationFundal examination Thyroid examinationThyroid examination Pubertal staging including penile length and Pubertal staging including penile length and

testicular sizetesticular size Maternal and paternal heights Maternal and paternal heights

Radiological Radiological evaluationevaluation Bone age evaluation: Bone age evaluation: X-ray of left wrist and hand in children over X-ray of left wrist and hand in children over

one year of age. one year of age. In infants less than one year of age, X-rays In infants less than one year of age, X-rays

of knee and ankle may be usefulof knee and ankle may be useful

CNS imaging by MRI or CT is required, if CNS imaging by MRI or CT is required, if intracranial tumors, optic nerve intracranial tumors, optic nerve hypoplasia/ septo-optic dysplasia or other hypoplasia/ septo-optic dysplasia or other structural or development anomaly is structural or development anomaly is known or suspectedknown or suspected

Bone Age X-RayBone Age X-Ray

Laboratory evaluationLaboratory evaluation

CBC, ESR & ChemistryCBC, ESR & Chemistry Urinalysis urine and stool cultureUrinalysis urine and stool culture Celiac antibodiesCeliac antibodies If growth deceleration is documented -, If growth deceleration is documented -,

FT4, TSH, IGF1, IGFBP3FT4, TSH, IGF1, IGFBP3 Karyotype in females and if the patient Karyotype in females and if the patient

has dystrophic features - chromosomal has dystrophic features - chromosomal analysis and genetic counselinganalysis and genetic counseling

If the patient has documented growth If the patient has documented growth retardation and decreased IGF1 plan for retardation and decreased IGF1 plan for provocative growth hormone stimulation provocative growth hormone stimulation tests tests

Short stature, Short stature, Normal growth rateNormal growth rate Late onset of pubertyLate onset of puberty Slow growth rate at infancySlow growth rate at infancy Normal growth spurt and normal Normal growth spurt and normal sexual sexual Paternal history more in boysPaternal history more in boys Delayed bone ageDelayed bone ageNormal GH and IGF levelsNormal GH and IGF levels

Constitutional growth Constitutional growth delaydelay

Secondary EtiologiesSecondary Etiologies

GastrointestinalGastrointestinal– Inflammatory bowel Inflammatory bowel

diseasedisease– Celiac diseaseCeliac disease– Mal-absorptionMal-absorption

Endocrine-Endocrine-– HypothyroidismHypothyroidism– Cushing syndromeCushing syndrome– GH deficiencyGH deficiency– Multiple Pituitary Multiple Pituitary

Syn.Syn. SurgicalSurgical

Chromosomal Chromosomal abnorm.abnorm.– TurnerTurner– Down syndromesDown syndromes

IUGRIUGR MetabolicMetabolic

– Storage diseasesStorage diseases– RicketsRickets

Chronic illnessesChronic illnesses– RenalRenal– CardiacCardiac– RespiratoryRespiratory

Drugs: Steroid, etcDrugs: Steroid, etc Psychological Psychological Bone dysplasiasBone dysplasias

OsteochondrodysplasiaOsteochondrodysplasiass

Intrinsic abnormalities of cartilage Intrinsic abnormalities of cartilage and/or boneand/or bone– Genetic transmissionGenetic transmission– Abnormalities in size and/or shape of bones Abnormalities in size and/or shape of bones

of the limbs, spine or skullof the limbs, spine or skull– Radiologic abnormalites of bonesRadiologic abnormalites of bones

Achondroplasia most commonAchondroplasia most common– Autosomal dominantAutosomal dominant– Child Ratios Child Ratios – Mutation in fibroblast growth Mutation in fibroblast growth

factor receptor 3factor receptor 3

טיפול בגורם

הורמון גדילה

טיפול בקומה נמוכה

תאריכים בהורמון גדילה

1956 – בידוד הורמון גדילה –Li & Papkoff

1958 – טיפול ראשון בנער – Raben

1963 – Radio-immuno-assay

1973- 1977 – IGF-1, BP’s, SMS

1979 ביוסינתזה של – rhGH על E.Coli

1981 -ניסויים קליניים ב -rhGH

1985 – Creutzfeld-Jacob

1981-2005הבנה תאית, ומוליקולרית –

הורמון גדילה –התויות בילדיםהורמון גדילה –התויות בילדים

חסר הורמון גדילהחסר הורמון גדילה תסמונת תסמונתTurnerTurnerקומה נמוכה באי-ספיקת כליותקומה נמוכה באי-ספיקת כליות תסמונת תסמונתPrader-WilliPrader-WilliSGASGA )) )קטנים לגיל ההריון( קטנים לגיל ההריון

catch-up growthcatch-up growthללא ללא

GH is produced in somatotroph cells of anterior pituitary

Located in lateral wings

40% to 50% of cells

hGH makes up 8 to 16% of dry weight of pituitary (4-8 mg/gland)

Structure of GH

Synthesized as a larger form (proGH) then processed

191 amino acids (MW = 22,650)– About 5-10% of

GH is 20kD arising from alternate splicing

PheGlyCysSerGlyGlu

ValSer Arg Cys Gln Val Ile Arg Leu Phe

Thr

Glu

Val

LysAspMetAsp

LysArgPheCysTyrLeuLeu

GlyTyr

Asn

Lys

Leu

Leu

Ala

Asp

Asp

Asn

His

Ser

Asn

Thr

Asp

Phe

Lys

Ser

Tyr

Thr

Gln

Lys

Phe

IleGln

GlyThr

Arg Pro Ser Gly Asp GluLeu

ArgGly

MetLeu

Thr

Gln

Ile

Gly

Glu

Glu

Leu

Asp

Leu

Leu

Asp

Val

Asn

Ser

Asp

Ser

AlaGly

Val

Leu

Ser

Asn

Ala

Phe

Val

Ser

Arg

Leu

Phe

Gln

Val

Pro

Glu

Leu

SerTrp

GlnIleLeuLeuLeuSerIle

ArgLeu

Glu

Leu

Leu

Asn

Ser

Gln

Lys

Gln

Thr

Glu

Glu

Arg

Asn

Ser

Pro

Thr

Pro

IleSer

GluSer Phe Cys Leu Ser

ThrGln

Pro

Asn

Gln

Leu

Phe

Ser

Tyr

Lys

Gln

Glu

Lys

Pro

Ile

Tyr

AlaGlu

GluPheGluGlnTyrThr

AspPhe

Ala

Leu

Gln

His

Leu

Arg

His

Ala

Arg

Leu

Met

Ala

AsnAsp

Phe Leu Arg SerLeu

Pro

Ile

Pro

Phe

Thr

Tyr

Tyr

Lys

NH2

COOH190

185180 175

170165

5055

155

160

10

15

65

20

150

14570

25

35 90

115

95

110

1

14075

135 80130

3085

125

120

605

45

40

100

105

PLASMA LEVELS

24 h average plasma levels 1.8 + 1 ng/ml

Plasma half life 6 to 20 min

About 40-50% bound noncovalently– The plasma binding

protein is the extra-cellular (hormone binding) domain of the GH receptor.

0

2

4

6

8

10

12

14

16

חצות 8:00

GHרמת )נ"ג/מ"ל(

Mechanism of Action Indirect

The majority of the growth-promoting effects of GH are exerted indirectly via insulin-like growth factors (IGFs)

Direct Some target cells have GH receptors and will react directly with GH ( e.g fat cells )

Effects on Metabolism Protein

– stimulates protein anabolism / synthesis

Fat– utilization of fat /

breakdown of triglycerides

Carbohydrates– acts as anti-insulin

increases plasma glucose levels

Reduce adiposityIncrease lean body mass

Increase IGF and protein synthesis

Increase organ size

Effect on Bone

Pituitary Developmental Pituitary Developmental defectsdefects

PIT –1 def. Prop –1 def.

LEPTIN – OB mice

GH-relin

GH-relin

טיפול בהורמון גדילה

SGA בילדים שנולדו

הצגת מקרה

שנים15היום נער בן

ברקע- הריון עם מהלך תקין

תוך רחמי עדות לקיצור גפיים USב-

2800, מ.ל. 41לידה רגילה בשבוע

מהלך פרינטלי תקין

במשפחה אין מה לציין

גיל חודשיים

גר'4320משקל-

(3 ס"מ )פחות מאחוזון 53אורך-

מצח גבוה, אוזניים נמוכות

הומלץ על מעקב

חודשים 8גיל

ירידה באחוזוני גובה ומשקל

סקירת שלד- ללא עדות לדיספלזיה בשלד

תפקוד בלוטת התריס- תקין

תפקודי כלייה- תקינים

אנזימי כבד-תקינים

בדיקת שתן- תקינה

XY,46קריוטיפ-

מבחן גירוי להורמון גדילה מבחן גירוי להורמון גדילה )גלוקגון( )גלוקגון(

GHGH (ng/ml) זמן )דקות(זמן )דקות(

0 4.15 30 1.07

60 7.35 90 8.9 120 10.7

GH GH

SGA

2SDמשקל לידה או אורך מתחת ל

3משקל או אורך לידה מתחת לאחוזון

5משקל או אורך לידה מתחת לאחוזון

10משקל או אורך לידה מתחת לאחוזון

SGAסיבות ל-

אימהיות

עובריות

שלייתיות

0 1 3 6 12 18 24 MonthsAge

Catch upCatch up

MM

-1-1

-2-2

Catch up

+1,6 ± 1,3+1,6 ± 1,3

-2,1-2,1

-0,5-0,5

Height )SDS(

+1,4+1,4

Prospective study of children born SGA

44( ( 2.62.6)% )% 1717( ( 13.613.6)% )% 11( ( 0.80.8*)% *)% 1212((13.613.6*)% *)%

166.3166.3 ± ± 6.06.0

0.00.0 ± ± 1.01.0

160.7160.7 ± ± 6.26.2**

--0.90.9 ± ± 1.01.0**179.0179.0 ± ± 6.16.1

0.00.0 ± ± 1.01.0174.4174.4 ± ± 6.56.5**

--0.80.8 ± ± 1.11.1**

20.820.8 ± ± 2.12.120.520.5 ± ± 1.91.921.021.0 ± ± 1.91.921.121.1 ± ± 1.91.9

Females

ControlControl

( ( n = 121n = 121))

ControlControl

( ( n = 121n = 121))SGA SGA

(n=213)(n=213)SGA SGA

(n=213)(n=213)SGASGA

((n = 125n = 125))

SGASGA

((n = 125n = 125))

ControlControl

( ( = n = n151151))

ControlControl

( ( n = n = 151151))

Adult Adult HeightHeight

* p < 0.001* p < 0.001* p < 0.001* p < 0.001 The Haguenau Prospective Study

Males

Age (years)

Patients (%)below -2SDS

Ht. cm sds

JCEM,Feb.2004

Ped.Res.2004

SGA

קומה נמוכה

2עמידות לאינסולין וסוכרת מסוג

יתר לחץ דם

דיסליפידמיה

השמנה במבוגרים

Sas T, et al. Clinical Endocrinology, 2001

FastingBlood

Glucose

mmol/l))

Low dose GH High dose GH

GH treatment (years)

JCEM, Feb.2005

BMI standard deviation score

mean

Years of GH treatment

JCEM, Feb 2005

Cholesterol

Yrs. of GH therapy

Total

LDL

HDL

mmol/l

לסיכום

טיפול בהורמון גדילה: SGAבילדים שנולדו משפר גדילהלא מזיק למטבוליזם הסוכר

יתכנו השפעות נוספות על:לחץ דם

BMI

רמת השומנים בדם

ETHICAL ISSUES RELATED ETHICAL ISSUES RELATED TO THE TREATMENT OF TO THE TREATMENT OF SHORT STATURESHORT STATURE

Growth Hormone: Who should be treated?

Should short stature be Should short stature be considered a disease or considered a disease or

disabilitydisability ? ?

The major ethical focal point

In the disease model, the emphasis is placed on the pathologic process causing short stature.

The underlying assumption is that if there is a pathologic process, it should be treated.

Short stature - disease Short stature - disease modelmodel

Disease model

Advantage– Easily defined criteria

Disadvantage- Inherently discriminatory

Does it make a difference if she Does it make a difference if she has low GH levels or was SGAhas low GH levels or was SGA??

The problem is stature and its incumbent disabilities - not disease

Short stature as a physical Short stature as a physical disabilitydisability

– Extreme short stature associated with significant daily life obstacles Driving Reaching up to kitchen cabinets Public transportation

– Impact on quality of life

Is society obligated to improve the Is society obligated to improve the quality of life of short citizensquality of life of short citizens??

The answer depends upon several The answer depends upon several variables:variables:– Can society afford the costs?Can society afford the costs?– Will the distribution of GH be equitable Will the distribution of GH be equitable

and just?and just?– Will the overall QOL of the entire Will the overall QOL of the entire

population be improved?population be improved?

Growth hormone costs Growth hormone costs approximately IS 30,000/y for a 30 approximately IS 30,000/y for a 30

kg childkg child

Growth Hormone is not cheap

Idiopathic short stature Idiopathic short stature –– Should it be treatedShould it be treated??

FDA approved the use of humatrope FDA approved the use of humatrope (Lilly) for the treatment of idiopathic (Lilly) for the treatment of idiopathic short stature for the lowest 1.2% of short stature for the lowest 1.2% of the population the population

Does size matter

HEIGHT

%

subjects

1.2% 1.2%

Height as a relative value

Treating ISS will only cause a redistribution, but not a total reduction of short stature

Treatment with RHGH to improve Quality Treatment with RHGH to improve Quality of lifeof life

BackgroundBackground

– Wild rams have a hierarchical Wild rams have a hierarchical society based on horn sizesociety based on horn size

– Male rams with larger horns Male rams with larger horns have a higher number of have a higher number of couplingscouplings

– Male rams with small horns Male rams with small horns have a miserable QOL because have a miserable QOL because all they do is watchall they do is watch

Well-meaning veterinarians want Well-meaning veterinarians want to treat rams with small horns to treat rams with small horns with RHGH (Ram Horn Growth with RHGH (Ram Horn Growth Hormone) Hormone)

Will treatment with RHGH increase the overall QOL of the herd?

Coltman, et al. Proc R Soc Lond B Biol Sci. 2002; 269:165-72

Tom Thumb

Charles Sherwood Stratton born 1838, Conn .

“sexual ateliotic dwarfism” (M/P Isolated GH deficiency)

At 5 mts. – 53.3 cm.Final Ht. 101.4 cm.

EmploymentP.T. Barnum Circus 1842-1882

Tom Thumb

Presented to Queen Victoria

Kissed 1,000,000 women inEngland alone

Married Levinia Warrenhad one child

Probably missed 40-70 cm. by missing GH