IL DEFICIT DI GH IN ETÀ PEDIATRICA

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1 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

2 Il processo di accrescimento

3 Cartilagine di accrescimento

4 Il controllo endocrino nell accrescimento

5 Crown heel length velocity (cm/4 weeks) Il ruolo del GH e dell IGF-I nella crescita pre e post-natale No IGF Postmenstrual age (weeks) Birth 40 No GH 50th percentile normal GH IGF-I is involved in prenatal and postnatal growth GH is involved in only postnatal growth Direct sex steroid effect 4 No GH or no IGF-I Age (years) Height velocity (cm/year) Rosenfeld RG.N Engl J Med 2003; 349:

6 Cause genetiche e acquisite di deficit di GH (GHD) Hypothalamus Genetic causes GH1 gene deletion POU1F1, PROP1, LHX3, LHX4, HESX1 mutations GHRH receptor defects Idiopathic GHD GHD Pituitary Acquired causes Hypothalamic pituitary tumours (e.g. germinoma) Cranial tumours Cranial irradiation Traumatic brain injury Wales JK. In: Brook C et al. Brook s Clinical Pediatric Endocrinology (6 th edn). Wiley-Blackwell, Oxford, UK, 2009, pp Fujieda K, Tanaka T. In: Ranke MB et al. Growth Hormone Therapy in Pediatrics 20 Years of KIGS. Basel, Karger, 2007, pp 16 22

7 Eziologia del deficit di GH (GHD)

8 Valutazione del bambino con bassa statura History Physical examination Initial investigations Endocrine investigations Genetic analysis 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 (T 4 ) and thyroid-stimulating hormone) Repeat IGF-I measurements GH stimulation testing Other endocrine evaluations Diagnosis Consideration of therapy Mod. da: Savage MO,et al. Clin Endocrinol (Oxf) 2010; 72: Cohen P. et al. J Clin Endocrinol Metab 2008; 93:

9 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: Cohen P. et al. J Clin Endocrinol Metab 2008; 93:

10 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

11 Risposta alla terapia con GH nel deficit di GH

12 Height (cm) Statura finale nei pazienti con deficit di GH dopo terapia sostitutiva con GH Caucasian males n = 505 Starting height Near-adult height 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 Chronological age (years) Blue box plot represents medians and 25 th and 75 th percentiles, with whiskers at the 10 th and 90 th percentiles Data from KIGS; Reiter EO, et al. J Clin Endocrinol Metab. 2006; 91:

13 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

14 Risposta del GH ai vari test di stimolazione ipofisaria in soggetti normali Shalet SM, et al. Endocr Rev 1998; 19:

15 Asse GH-IGF-I Hypothalamus GHRH SS GH-IGFcartilage AXIS Pituitary GH Liver IGF-I + IGFBP-3 + ALS Bone

16 Livelli di IGF-I nel deficit di GH (GHD) e nella bassa statura idiopatica (non-ghd) rispetto ai valori normali IGF-I (μg/l) IGF-I (μg/l) GHD Non-GHD th centile th centile th centile th centile 200 5th centile 200 5th centile Age (years) Age (years) Ranke MB, et al. Horm Res 2000; 54: 60-68

17 Sensibilità e specificità del dosaggio dell IGF-I nella diagnosi di GHD (1) IGF-I -1.9 z-score IGF-I: Sensitivity: 73% Specificity: 95% Cut-off (10 g/l) GH tests: Sensitivity: 100% Specificity: 57% GH GHI ISS

18 Sensibilità e specificità del dosaggio dell IGF-I nella diagnosi di GHD (2) Author Sensitivity Specificity Cianfarani et al % 90% Nunez et al % 76% Juul et al % 98% Tillman et al % 72% Rikken et al % 78% Mitchell et al % 47% Weinzimer et al % NA Granada et al % 95% Cianfarani et al % 95% Bussieres et al % 95% Das et al % 100% Lissett et al % NA Boquete et al % 97%

19 Sensibilità e specificità della velocità di crescita nella diagnosi di GHD (3) HV 25th centile GHI ISS HV: Sensitivity: 82% Specificity: 43% Cut-off (10 g/l) GH Cianfarani S, et al. Clin Endocrinol (Oxf) 2002; 57:

20 Sensibilità e specificità della velocità di crescita e dell IGF-I nella diagnosi di GHD IGF-I -1.9 z-score A (44%) (26%) B GHI ISS C Cut-off (25th centile) (23%) (7%) HV IGF-I + HV: Sensitivity: 97% Specificity: 98% Cianfarani S, et al. Clin Endocrinol (Oxf) 2002; 57: D

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

22 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

23 Risonanza magnetica cerebrale di neonato con GHD (1) Pituitary Aplasia Normal Pituitary Sezione sagittale

24 Risonanza magnetica cerebrale di neonato con GHD (2) Pituitary Aplasia Normal Pituitary Sezione coronale

25 Formazione dell ipofisi durante lo sviluppo embrio-fetale Kelberman D, et al. Endocr Rev 2009; 30:

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

27 Fenotipi associati a mutazioni di PIT1, PROP1, HESX1, LHX3 e e LHX4 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 Complex Phenotype S/M NO S/M/L/XL/ XXL NO S S/XL S SOD/EPP/ PA EPP/ Chiari I Parks JS, et al. J Clin Endocrinol Metab 1999; 84:

28 Risonanza magnetica cerebrale con normale morfologia dell area ipotalamo-ipofisaria (sezione sagittale) Michael Besser M, Thorner MO. Comprehensive Clinical Endocrinology, Third Edition. Elsevier, 2010

29 Risonanza magnetica cerebrale con normale morfologia dell area ipotalamo-ipofisaria (sezione coronale) Michael Besser M, Thorner MO. Comprehensive Clinical Endocrinology, Third Edition. Elsevier, 2010

30 Caratteristiche neuroradiologiche del deficit di GH Neuroipofisi Ectopica Agenesia del Peduncolo Ipoplasia Ipofisaria Michael Besser M, Thorner MO. Comprehensive Clinical Endocrinology, Third Edition. Elsevier, 2010

31 Neuroimaging nelle mutazioni di HESX1 Control Sibling 1 Sibling 2

32 Fenotipo fetale nelle mutazioni di HESX1

33 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 Patel, et al Mean age of SOD mothers 25.1 (n=113); CPHD 29 (n=117) McNay DE, et al. J Clin Endocrinol Metab 2007; 92:

34 Mutazioni di HESX1 Engrailed homology domain Paired-like homeodomain 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

35 Grave deficit di GH in bambino di 7 anni

36 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

37 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:

38 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:

39 Mutazioni di POU1F1 (PIT1) 28 mutations in POU1F1 associated with CPHD in >60 patients GH, PRL and variable TSH deficiency Autosomal recessive/dominant

40 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

41 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: