IL DEFICIT DI GH IN ETÀ PEDIATRICA - AccMed · Il ruolo del GH e dell’IGF-I nella crescita pre e...

© 2014 - Ospedale Pediatrico Bambino Gesù e Accademia Nazionale di Medicina Lezione “Il deficit di GH in età pediatrica”

Corso FAD: Approccio alle Malattie Rare

IL DEFICIT DI GH IN ETÀ PEDIATRICA Stefano Cianfarani

Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Roma U.O.C. Endocrinologia Molecolare, Ospedale Pediatrico Bambino Gesù, Roma


Il processo di accrescimento


Cartilagine di accrescimento


Il controllo endocrino nell’accrescimento


Il ruolo del GH e dell’IGF-I nella crescita pre e post-natale

IGF-I is involved in prenatal and postnatal growth

GH is involved in only postnatal growth

Age (years)

Cro

wn

–hee

l len

gth

ve

loci

ty (

cm/4

wee

ks) 10

8

6

4

2

0 10 20 30

Postmenstrual age (weeks)

2 6 10 14 18 4 8 2 16 0

4

8

12

16

20

Heigh

t velocity

(cm/year)

Birth

No GH

No IGF

50th percentile normal GH

No GH or no IGF-I

Direct sex steroid effect 40

Rosenfeld RG.N Engl J Med 2003; 349: 2184-2186

http://www.ncbi.nlm.nih.gov/pubmed/?term=14657423







Cause genetiche e acquisite di deficit di GH (GHD)

GHD

Genetic causes GH1 gene deletion

POU1F1, PROP1, LHX3, LHX4, HESX1 mutations

GHRH receptor defects

Idiopathic GHD

Acquired causes Hypothalamic–pituitary tumours

(e.g. germinoma) Cranial tumours

Cranial irradiation Traumatic brain injury

Hypothalamus

Pituitary

Wales JK. In: Brook C et al. Brook’s Clinical Pediatric Endocrinology (6th edn). Wiley-Blackwell, Oxford, UK, 2009, pp 124–54 Fujieda K, Tanaka T. In: Ranke MB et al. Growth Hormone Therapy in Pediatrics – 20 Years of KIGS. Basel, Karger, 2007, pp 16–22


Eziologia del deficit di GH (GHD)


Valutazione del bambino con bassa statura

Physical examination

Initial investigations

Genetic analysis

Consideration of therapy

History

Diagnosis

Endocrine investigations

Height, sitting height, weight, body mass index, height velocity

Parental heights Birth weight/length Nutritional assessment Evaluate for presence/absence of dysmorphic features

Screening tests to exclude systemic disease Start endocrine screen (including IGF-I, free serum

thyroxine (T4) and thyroid-stimulating hormone)

Repeat IGF-I measurements GH stimulation testing Other endocrine evaluations

Mod. da: Savage MO,et al. Clin Endocrinol (Oxf) 2010; 72: 721-728 Cohen P. et al. J Clin Endocrinol Metab 2008; 93: 4210-4217
















Anamnesi ed esame obiettivo

Patient history should assess(1,2)

Birth length, weight, head circumference, gestational age at birth (SGA/AGA)

Parental consanguinity, and height of parents and siblings

History of systemic symptoms

Intellectual retardation, emotional or psychological abnormality

Timing of pubertal onset

Previous height measurements (allow the creation of growth curves)

Physical examination should be performed by evaluating(1,2)

Length or height, sitting height, head circumference, weight, BMI

Pubertal stage

Growth velocity

Facial or body dysmorphic features

1. Growth Hormone Research Society. J Clin Endocrinol Metab 2000; 85:3990-3993 2. Cohen P. et al. J Clin Endocrinol Metab 2008; 93: 4210-4217

http://press.endocrine.org/doi/full/10.1210/jcem.85.11.6984














“Gold standard” per la diagnosi del deficit di GH (GHD)

Peak GH responses < 10 µg/L (IS 80/505) < 7 µg/L (IS 98/574) to two different provocative tests

Pitfalls:

GH stimulation tests are:

Invasive

Nonphysiological

Hazardous

The threshold level used to define a normal GH response is defined arbitrarily


Risposta alla terapia con GH nel deficit di GH


Statura finale nei pazienti con deficit di GH dopo terapia sostitutiva con GH

Median initial GH dose: 0.20 mg/kg/week (equivalent to 0.03 mg/kg/day)

Near-final height SDS: −0.8 for isolated GHD (IGHD) and −0.7 for MPHD

No marked difference between patients with IGHD and MPHD

Differences in responsiveness and wide range of near final height values

Caucasian males n = 505

130

140

150

160

170

180

190

200

50

60

70

80

90

100

110

120

40

0 5 10

Chronological age (years)

20 25 30 15

Hei

ght

(cm

)

Blue box plot represents medians and 25th and 75th percentiles, with whiskers at the 10th and 90th percentiles

Data from KIGS; Reiter EO, et al. J Clin Endocrinol Metab. 2006; 91: 2047-2054

Near-adult height

Starting height











La risposta alla terapia con GH è variabile

Differences can be attributed to:

Diagnosis

Age

GH dose

Parental height (Ht)

Compliance

Intercurrent illness

Other (endocrine) therapies

And still poorly defined molecular and biochemical factors that may include:

The structure and concentration of GH receptors

The robustness of the post-receptor signaling cascade

IGF-I transcriptional and translational efficiency

Epiphyseal responsiveness to GH, IGF-I


Risposta del GH ai vari test di stimolazione ipofisaria in soggetti normali

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





Asse GH-IGF-I

GH-IGF- cartilage AXIS

IGF-I + IGFBP-3 + ALS

Hypothalamus

GHRH SS

GH

Pituitary

Liver

Bone


Livelli di IGF-I nel deficit di GH (GHD) e nella bassa statura idiopatica (non-GHD) rispetto ai valori normali

Non-GHD

0 5 10 15 20

GHD

0

100

200

300

400

500

600

IGF-

I (μ

g/L

)

Age (years)

0 5 10 15 20 0

100

200

300

400

500

600

IGF-

I (μ

g/L

)

Age (years)

95th centile

50th centile

5th centile

95th centile

50th centile

5th centile

Ranke MB, et al. Horm Res 2000; 54: 60-68





-1.9 z-score

IGF-I

Cut-off (10 g/L)

GH

GH tests: Sensitivity: 100% Specificity: 57%

IGF-I: Sensitivity: 73% Specificity: 95%

GHI

ISS

Sensibilità e specificità del dosaggio dell’IGF-I nella diagnosi di GHD (1)


Sensibilità e specificità del dosaggio dell’IGF-I nella diagnosi di GHD (2)

Author Sensitivity Specificity

Cianfarani et al. 1995 75% 90%

Nunez et al. 1996 69% 76%

Juul et al. 1997 53% 98%

Tillman et al. 1997 34% 72%

Rikken et al. 1998 65% 78%

Mitchell et al. 1999 62% 47%

Weinzimer et al. 1999 73% NA

Granada et al. 2000 70% 95%

Cianfarani et al. 2002 73% 95%

Bussieres et al. 2000 72% 95%

Das et al. 2003 86% 100%

Lissett et al. 2003 86% NA

Boquete et al. 2003 68% 97%


Sensibilità e specificità della velocità di crescita nella diagnosi di GHD (3)

HV

25th centile

HV: Sensitivity: 82% Specificity: 43%

GH

Cianfarani S, et al. Clin Endocrinol (Oxf) 2002; 57: 161-167

Cut-off (10 g/L)

GHI

ISS

















Sensibilità e specificità della velocità di crescita e dell’IGF-I nella diagnosi di GHD

A B

C D

(44%) (26%)

(23%) (7%)

Cut-off (25th centile)

GHI

ISS

IGF-I

HV

-1.9 z-score

IGF-I + HV: Sensitivity: 97% Specificity: 98% Cianfarani S, et al. Clin Endocrinol (Oxf) 2002; 57: 161-167

















Conclusione

A simple assessment of Height Velocity and IGF-I may lead to

exclude or, in association with only one GH stimulation test,

make the diagnosis of GHI in more than half of patients with

short stature

High Sensitivity & Specificity of HV + IGF-I Measurements:


Caratteristiche cliniche del bambino con ipopituitarismo

Jaundice, hypoglycaemia, microphallus, undescended testes

Features of hypothyroidism

Prominent forehead, mid-facial hypoplasia

Delayed dentition, bone maturation

Increased subcutaneous fat, decreased muscle mass

Thin sparse hair, high-pitched voice and slow nail growth

Short stature, poor growth velocity


Risonanza magnetica cerebrale di neonato con GHD (1)

Pituitary Aplasia Normal Pituitary

Sezione sagittale


Risonanza magnetica cerebrale di neonato con GHD (2)

Pituitary Aplasia Normal Pituitary

Sezione coronale


Formazione dell’ipofisi durante lo sviluppo embrio-fetale

Kelberman D, et al. Endocr Rev 2009; 30: 790-829

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806371/




Fattori di trascrizione che intervengono nella formazione dell’ipofisi durante lo sviluppo embrio-fetale


Fenotipi associati a mutazioni di PIT1, PROP1, HESX1, LHX3 e e LHX4

Parks JS, et al. J Clin Endocrinol Metab 1999; 84: 4362-4370

Gene PIT1 PROP1 HESX1 LHX3 LHX4

GH Absent Low Low Low Low

Prl Absent Low Low/? Absent Low

TSH Low Low Low/? Absent ?

LH, FSH Normal Absent Low/? Absent ?

ACTH Normal Low in 1/3 ? Normal Low

ADH Normal Normal N/Low Normal Normal

Pituitary S/M S/M/L/XL/

XXL S S/XL S

Complex Phenotype

NO NO SOD/EPP/

PA EPP/

Chiari I





Risonanza magnetica cerebrale con normale morfologia dell’area ipotalamo-ipofisaria (sezione sagittale)

Michael Besser M, Thorner MO. Comprehensive Clinical Endocrinology, Third Edition. Elsevier, 2010


Risonanza magnetica cerebrale con normale morfologia dell’area ipotalamo-ipofisaria (sezione coronale)



Neuroipofisi Ectopica

Agenesia del Peduncolo

Ipoplasia Ipofisaria

Caratteristiche neuroradiologiche del deficit di GH



Neuroimaging nelle mutazioni di HESX1

Control Sibling 1 Sibling 2


Fenotipo fetale nelle mutazioni di HESX1


Displasia setto-ottica (SOD)

Variable combination of midline forebrain abnormalities, eye abnormalities and hypothalamo-pituitary abnormalities

Rare: reported incidence 1/50,000; probably commoner:

2/3 features to make the diagnosis

Commoner in younger mothers: controversial

Mean age of SOD mothers 25.1 (n=113); CPHD 29 (n=117)

McNay DE, et al. J Clin Endocrinol Metab 2007; 92: 691-697

Patel, et al. 2006

















Mutazioni di HESX1

HESX1 mutations rare: overall incidence in hypopituitarism and SOD <1% (n=861) (McNay et al., 2006)

Variable inheritance: dominant, recessive

Variable phenotypes: SOD, CPHD, IGHD

Posterior pituitary may be eutopic or ectopic/undescended

Anterior pituitary may be hypoplastic or aplastic

Engrailed homology domain

Paired-like homeodomain


Grave deficit di GH in bambino di 7 anni


Mutazioni di PROP1

Commonest gene implicated in familial CPHD (50%)

22 mutations identified in >160 patients

Autosomal recessive

Phenotype: GH, TSH, PRL, FSH and LH deficiency

Variable cortisol deficiency

Variability of phenotype between mutations and with same mutation


Massa ipofisaria associata a mutazione di PROP1

PROP1 A301, G302 DELETION

Enlarged pituitary at age 8.8 years (upper panels)

Reduced pituitary size at age of 15 years

Mendonca BB, et al. J Clin Endocrinol Metab 1999; 84: 942-945

















Meccanismo della massa?

Prop1 allows for the differentiation and ventral migration of progenitors from the proliferative zone of Rathke’s pouch into the developing anterior lobe

With Prop1 mutations, there is a failure of precursor cells to migrate from RP

Trapped cells give rise to a large pituitary

Subsequent apoptosis leads to hypoplasia

Ward RD, et al. Mol Endocrinol 2005; 19: 698-710








Mutazioni di POU1F1 (PIT1)

28 mutations in POU1F1 associated with CPHD in >60 patients

GH, PRL and variable TSH deficiency

Autosomal recessive/dominant


Considerazioni conclusive

Establishing the genotype can aid the management of individual patients with hypopituitarism

For example, in a patient with an identified PROP1 mutation careful monitoring of the anterior pituitary is indicated. The identification of a mutation within POU1F1 predicts that cortisol and gonadotrophin secretion will remain normal in the patient

Identification of the genotype can also aid in genetic counselling and early diagnosis, particularly in autosomal dominant POU1F1 mutations


Raccomandazioni finali

Children with suspected endocrine-related growth failure should be referred to a paediatric endocrinologist for assessment of defects in the GH–IGF axis

Within the GH–IGF axis continuum, both GHD and severe primary IGFD should be considered as causes of short stature

Savage MO, et al. Clin Endocrinol (Oxf) 2010; 72: 721-728









IL DEFICIT DI GH IN ETÀ PEDIATRICA - AccMed · Il ruolo del GH e dell’IGF-I nella crescita pre e...

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