...ושמו שאול.....אין איש מבני ישראל טוב ממנו משכמו ומעלה...
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Transcript of ...ושמו שאול.....אין איש מבני ישראל טוב ממנו משכמו ומעלה...
...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