Sergio Bernasconi pdf

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IL DEFICIT DI ORMONE DELLA CRESCITA E’

UNA CONDIZIONE RARA

S. Bernasconi,

Dipartimento dell’età evolutiva

Università di Parma

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IL DEFICIT DI ORMONE DELLA CRESCITA E’ UNA CONDIZIONE RARA

The frequency of GHD is reported to be about one in 3000 to one in 4000…..

M Dattani, M. Preece

Lancet 2004

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Causes of GH deficiency

Congenital

Genetic

Associated with structural defects of the brain Agenesis of the corpus callosum

Septo-optic dysplasia Holoprosencephaly Encephalocele

Hydrocephalus

Associated with midline facial defects Cleft lip or palate

Single central incisor

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Acquired

Trauma

Perinatal trauma Postnatal trauma Infection

Meningitis or encephalitis CNS tumours

Craniopharyngioma Pituitary germinoma Pituitary adenoma Optic glioma

Langerhans cell histiocytosis Postcranial irradiation

Postchemotherapy Pituitary infarction

Neurosecretory dysfunction Psychosocial deprivation Hypothyroidism

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In oltre l’80% dei casi il GHD isolato dipende da una compromissione funzionale della cellule GH secernenti, non legata a patologie espansive o infiammatorie a carico della regione ipotalamo-ipofisaria e apparentemente

idiopatica.

Juul A. et al. Horm Res 1999. 51:284-99

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Grazie alla disponibilità di indagini radiologiche ad alta risoluzione, negli ultimi anni le conoscenze sulla fisiologia del GHD “idiopatico” sono molto migliorate : più del 70%

dei GHD idiopatici dipendono da una patologia

disembriogenetica ipotalamo-ipofisaria per lo più isolata (interruzione del peduncolo ipofisario) o più raramente associata ad una sindrome malformativa della linea mediana.

Arrigo T. et al Eur J Endocrinol 1998. 139:84-88

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Si pensa che un 5-30% dei casi di GHD isolato possa infine avere una origine familiare, geneticamente

determinata oppure essere associata a mutazioni de novo a carico dei geni coinvolti nella secrezione del GH o dei suoi recettori o fattori di trascrizione.

Mullis PE et al. J Clin Endocrinol Metab 2005

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e 8.5

Shh

Shh BMP4

WNT5 FGF8

WNT4 BMP2 Lhx3

DI

OE

e 9.0

HesX1 Lhx3,Lhx4 Pax6, PTX1, PTX2

SIX3, SIX6 DI

OE

Expression of Lhx3 and Lhx4 in an early stage of Rathke‘s pouch

Interaction between the Oral Ectoderm (OE) and the ventral Diencephalon (DI) via several transcription factors

Embryonic Development Of The

Mouse Pituitary I

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Embryonic Development Of The Mouse Pituitary II

e 10

HesX1 Prop1 pri

RT _Lhx3

Lhx4

Lhx3 Lhx4

Prop1

e 12.5

Expression in precursor cells of the pituitary

Formation of Rathke‘s pouch

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e 12.5

T

S

L

G C

Lhx3/4 Prop1

Prop1 PTX2

PTX1 SF1

Prop1 Pit1

S/L

TPit NeuroD1

GATA2

e 13 e 13.5 e 14 e 14.5 e 15 e 15.5 e 16 e 16.5

Mouse

Human ^{We 4} ^{We 5} ^{We 9} ^{We 8 We 10} ^{We 12}

Zn16 Prop1OTX1

Pit1

ER

Embryonic Development Of The

Mouse Pituitary III

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Idiopathic GHD is the indication for treatment in 50% of children receiving GH, as reported for

100000 children worldwide in 1999

J Pediatr 1999

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J.CLIN.ENDOCRINOL METAB 79:1663-1669,1994

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Cacciari et al, JCEM 79:1663-1669,1994

normalizzazione

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Tauber, M. et al. J Clin Endocrinol Metab 1997;82:352-356

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Carel, J.-C. et al. BMJ 2002;325:70

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The frequency of GHD is reported to be about one in 3000 to one in 4000, althought this is probably an overstimate in view of the reversibility of this deficiency in 25-75% of patients

M Dattani, M. Preece

Lancet 2004

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Deficit di GH transitorio o falso deficit ?

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Spontaneous and Drug-induced

Secretion of GH, and Assay Methods

“Despite the dramatic progress in the treatment of GHD patients, our ability to

make a definitive diagnosis of GHD is often limited and relies on testing procedures that are, generally, nonphysiological, arbitrary, invasive, risky, and subject to considerable interassay variability”

Rosenfeld R et al., JCEM 80:1532; 1995

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Patient Group Patient Group

GHD*GHD* CRI*CRI* TS**TS** SGA**SGA** ISS*ISS*

Height SDSHeight SDS

-4 - 4 -3 - 3 -2 - 2 -1 - 1 0 0

*National Cooperative Growth Study

**Kabi**KabiInternational Growth StudyInternational Growth Study

Mean

Mean ±± SDSD

Patients with ISS Have Similar Severity of

Short Stature to Other Disorders

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Scattergrams comparing the mean and distribution of 12 month

height velocities of short normal ( ≤ 3rd centile for height) and control (10th to 90th centile for height) children 5 and 6 years of age. The data from two consecutive 12 month periods (years 1 and years 2) are shown.

Voss (1998)

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Shalet, S. M. et al. Endocr Rev 1998;19:203-223

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J.Clin. Endocrinol.Metab 1996

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Growth

Growth HormoneHormone TestingTesting forfor the diagnosisthe diagnosis of of Growth

Growth HormoneHormone DeficiencyDeficiency in in Childhood:Childhood: A PopulationA Population Register-Register- BasedBased StudyStudy

β Intervallo di

confidenza 95%

P

Età al test 1973-1980 1981-1984 1985-1989 Diagnosi Radioterapia Organico Idiopatico Non-GHD

Target genetico (DS) Caratteristiche di base Altezza-DS

Peso-DS

Età ossea –DS Stadi puberali Prepuberi

Puberi

-1.86 -1.19

0

-1.11 -2.07

0 6.71 -0.28

0.47 -0.49

0.05

0 0.53

-2.82/-0.89 -1.56/-0.83

-1.61/-0.6 -2.46/-1.68

5.69/7.73 -0.44/-0.12

0.30/0.64 -0.66/-0.32 0.003/0.10

0.12/0.95

0.0001

0.007

0.0001 0.0001

0.04 0.015

Conclusioni:

• Gli stimoli farmacologici utilizzati sono estremamente eterogenei e influenzano anche il picco di GH;

• Il picco plasmatico di GH dopo stimolo è scarsamente attendibile

• Numerose altre variabili dipendenti associate al picco di GH possono influenzare la diagnosi di GHD!!

Carel JC et al. JCEM 1997;82:1217-1221

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Mitchell, H et al. Arch Dis Child 1999;80:443-447

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IGF-I in Patients with Idiopathic Short Stature

Age (yr) Age (yr) - - 4 4

- - 3 3 - - 2 2 - - 1 1 0 0 1 1 2 2

9 9 10 10 11 11 12 12 13 13 14 14 15 15

IGF IGF - - I SDS I SDS

Baseline IGF

Baseline IGF - - I SDS for I SDS for all patients enrolled in all patients enrolled in placebo

placebo - - controlled controlled study

study

n=67n=67

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Mitchell, H et al. Arch Dis Child 1999;80:443-447

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Spontaneous GH Secretion

Assessment of GH levels:

• by serial blood sampling over 24-h;

– over 12-h and 6-h in the night;

– over 12-h and 6-h in the day;

• In urine

• After physical exercise

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Spontaneous GH Secretion by Serial Blood

Sampling

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24-h Spontaneous GH Secretion Changes at Different Ages

0 400 800 1200 1600 2000

Pre-puberty Puberty Post-puberty Middle Age

24-h GH secretionrate (µg/day)

Giustina A et al., Endocr Rev 19:717; 1995

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24h, 12h Nocturnal, 12h and 6h Diurnal Spontaneous Growth Hormone Secretion

0 2 4 6 8 10 12 14 16 18 20

1 2 3 1 2 3 1 2 3 1 2 3

Max Min Mean

MeanGH concentration(mg/L)

24 h Nocturnal Diurnal Mean 6h

1= GHD (n= 21); 2= GH Neurosecr. Dysf. (n= 21); 3= Controls (n= 31)

Bercu B, et al., JCEM 63:709;1986

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24-h Spontaneous GH Secretion in GH Sufficient, Unsufficient, and in ISS Children

Normal GHD ISS

N= 54 N= 23 N= 31

Rose S, et al., NEJM 319:201; 1988

57%

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“Spontaneous GH secretion should be studied in children who have a growth pattern suggestive of GHD but a normal response to provocative testing, and in who other possible causes of impaired

growth can be eliminated.”

“The evaluation of spontaneous GH secretion over

time………..can be considered when GH and IGF-I conflict, such as normal GH and low IGF-I”

Consensus Guidelines for the diagnosis and treatment of GHD in childhood and adolescence: summary statement of the GH Research Society. JCEM 85:3990;2000

Diagnosis adn treatment of growth hormone deficiency in children and adolescents: towards a consensus. Horm Res 50:320;1998

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Growth

Growth hormone hormone Deficiency Deficiency of of Childhood Childhood Onset Onset : : Reassessement

Reassessement of GH status and Evaluation of GH status and Evaluation of the of the Predictive

Predictive Criteria Criteria for for permanent permanent GHD in GHD in Young Young Adults

Adults

0 100

100 0

ATT+ITT test (%) >10 <3 0 0 100

0 0 100

71.5 28.5 0

80 18 0

Retesting GH peak (µg/L) ITT test (%) >10 <5 <3 0 0 100

0 0 100

71.5 28.5 0

54.5 27 0 ATT test (%)

>10 <5 <3

Group IV

91.6 ± 33.6 Group

III

324.0±113.5 Group

II

392.9 ± 37 Group

I

Second MRI Pituitary

Volume (mm³)

Maghnie M, et al. JCEM 1999; 84:1324-1328

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Maghnie, M. et al. J Clin Endocrinol Metab 1999;84:1324-1328

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Growth

Growth hormone hormone Deficiency Deficiency of of Childhood Childhood Onset Onset : : Reassessement

Reassessement of GH status and of GH status and Evaluation Evaluation of of the the Predictive Predictive Criteria Criteria for for Permanent Permanent GHD in GHD in

Young

Young Adults Adults

Maghnie M, et al. JCEM 1999; 84:1324-1328

I pazienti con GHD isolato e con deficit ormonali

multipli associati ad anomalie anatomiche congenite della regione ipotalamo-ipofisaria potrebbero non

necessitare di un retesting per GH

I soggetti con GHD isolato associato ad anomalie

riscontrate alla RMN cerebrale necessitano di una

periodica valutazione della funzionalità ipofisaria,

poiché potrebbero sviluppare altri deficit ormonali.

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Do All Patients with Childhood-Onset Growth Hormone Deficiency (GHD) and Ectopic Neurohypophysis Have Persistent GHD in Adulthood?

J. Léger, S. Danner, D. Simon, C. Garel and P.Czernichow J Clin Endocrinol Metab 2005

Our study demonstrated in a large group of patients with ectopic neurohypophysis

diagnosed as GHD during childhood that

39% of all patients were no longer GHD at

reassessment in adulthood, using the current

criteria for adult GHD of less than 5 µg/liter

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Spontaneous and Drug-induced

Secretion of GH, and Assay Methods

“Despite the dramatic progress in the treatment of GHD patients, our ability to

make a definitive diagnosis of GHD is often limited and relies on testing procedures that are, generally, nonphysiological, arbitrary, invasive, risky, and subject to considerable interassay variability”

Rosenfeld R et al., JCEM 80:1532; 1995

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PL Γ (DN 2/9/1992) TG cm 169.8

Att test: picco GH: 3.9 ng/dl L-Dopa test: picco GH: 4.8 ng/dl

Concentrazioni integrate GH: 2.55 ng/dl

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1) Deficit di GH transitorio o falso deficit ?

2) Deficit di GH parziale ?

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Tauber, M. et al. J Clin Endocrinol Metab 1997;82:352-356

(48)

Partial

Partial GHD:more GHD:more similarities similarities to to idiopathic

idiopathic short stature short stature than than to to severe GHD severe GHD

“Smyczynska J et al. ESPE Lyon 2005”

sGHD

(GH peak

< 5 ng/dl)

pGHD

(GH peak 5-10 ng/dl)

ISS

(GH peak

>10 ng/dl)

Height SDS

-2.5 ± 0.89^a,b -2,10 ± 0,63^a -2,13 ± 0,61^b

IGF-I SDS -0,49 ± 1,60^c,d 0,02 ± 1,11^c 0,27 ± 1,39^d PAH SDS -1,49 ± 1,27^e,f -1,00 ± 1,05^e,g -1,26 ± 0,96^f,g

Valutati 540 soggetti di età media di 11,7 ± 3,2 anni, con altezza <-1,88 DS per età e sesso, sottoposti a test

di stimolo per GH e dosaggio della IGF-I.

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Shalet, S. M. et al. Endocr Rev 1998;19:203-223

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J Clin Endocrinol Metab 2003

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Conclusioni

La diagnosi di GHD è complessa, si deve basare sulla coesistenza di vari parametri clinico-auxoligici e di laboratorio e deve essere rivalutata nel follow up

La diagnosi di GHD viene in genere utilizzata

per una serie molto eterogenea di situazioni

che dovremmo cercare di tenere distinte e di

sottoclassificare

(52)

Grazie per l’attenzione

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Leger J, et al. JCEM 2005; 90:650-656

Normal Normal Hypoplastic Normal Normal Normal Hypoplastic Hypoplastic Hypoplastic Hypoplastic Normal Normal Normal Normal Normal Hypoplastic Normal Hypoplastic

Aspect

Median eminence 4,4

Thin TSH,ACTH, LH-FSH

46

<0,2 18

Proximal stalk 3,7

Thin No

175 3,3

17

Median eminence 3,2

Absent TSH,ACTH, LH-FSH

32 0,2

16

Median eminence 3,5

Thin TSH

318 4,7

15

Median eminence 5

Thin TSH,ACTH, LH-FSH

81

<0,2 14

Median eminence 5,5

Absent TSH, ACTH

60 2,2

13

Median eminence 3

Absent TSH, ACTH

2,2 12

Median eminence Absent

<0,2 11

Median eminence 2,5

Absent TSH

402 0,8

10

Median eminence 1

50

<0,2 9

Median eminence 4,4

135

<0,3 8

Group III

Proximal stalk 4,5

Thin No

212 8,7

7

Proximal stalk 4,5

Thin ACTH, FSH-LH

121 7,3

6

Proximal stalk 4,5

Thin No

433 9,0

5 Group II

Proximal stalk 3,9

Thin No

245 19,5

4

Proximal stalk 2,5

Thin No

227 19,1

3

Proximal stalk 6

Normal No

290 14,9

2

Median eminence 2,4

Thin No

221 11,7

1 Group I

Localizzation of EPPHS Pituitary

height (mm) Pituitary

stalk Associated pituitary

deficiency IGF-I

(µg/L) GH peack

(µg/L) ATT+ITT

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Diagnosis 1 Retesting

A B C A B C D

All subjects=184

122 67 (54,9%) 22 (18%) 15 (12,3%) 18 (14,8%)

30 12 (40%) 7 (23,3%) 3 (10,0%) 8 (26,7%)

32 19 (59,4%) 2 (6,2%) 3 (9,4%) 8 (25%)

Total 66,3% 16,3% 17,4% 53,3% 16,8% 11,4% 18,5%

Prepubertal subjects

100 45 12 11 4

16 6 3 1

24 12 2 1 4

Total 71,4% 11,4% 17,2% 62,4% 13,9% 14,8% 8,9%

Patients n=140 Patients n=101

Already pubertal subjets n=44

22 10 5 7

14 3 5 6

8 5 3

Total 50,0% 31,8% 18,2% 40,9% 22,7% 36,4%

Cacciari et al, JCEM 79:1663-1669,1994