Hormone Resistance and Hypersensitivity

Transcription

1 Endocrine Develoment 24 Hormone Resistance and Hyersensitivity From Genetics to Clinical Management Worksho, Genoa, May Bearbeitet von M. Maghnie, S. Loche, M. Caa, L. Ghizzoni, R. Lorini, P.-E. Mullis 1. Auflage Buch. VIII, 160 S. Hardcover ISBN Gewicht: 730 g Weitere Fachgebiete > Medizin > Klinische und Innere Medizin > Endokrinologie schnell und ortofrei erhältlich bei Die Online-Fachbuchhandlung beck-sho.de ist sezialisiert auf Fachbücher, insbesondere Recht, Steuern und Wirtschaft. Im Sortiment finden Sie alle Medien (Bücher, Zeitschriften, CDs, ebooks, etc.) aller Verlage. Ergänzt wird das Programm durch Services wie Neuerscheinungsdienst oder Zusammenstellungen von Büchern zu Sonderreisen. Der Sho führt mehr als 8 Millionen Produkte.

2 Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / ) Phenotyes, Investigation and Treatment of Primary IGF- 1 Deficiency Martin O. Savage Deartment of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK Abstract GH insensitivity, also known as rimary IGF- 1 deficiency (PIGFD), resents as growth failure, and in its severe form is associated with dysmorhic and metabolic abnormalities. PIGFD is caused by genetic defects in the GH- IGF- 1 axis. The field of PIGFD due to mutations affecting GH action has evolved since the original descrition of the extreme henotye related to homozygous GH recetor mutations over 40 years ago. A continuum of genetic, henotyic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. A systematic rotocol of investigation assessing Gh secretion and the IGF system will lead to a diagnosis of PIGFD. PIGFD can be effectively treated with rhigf- 1, the otimal recommended maintenance dose being 120 μg/kg twice daily by SC injection. Most theraeutic exerience is in severely affected atients with the Laron syndrome henotye, who show growth acceleration and may reach normal adult height. Further controlled studies are needed in more mildly affected subjects. Coyright 2013 S. Karger AG, Basel GH insensitivity (GHI; OMIM No and ) was first reorted by Laron [1] in 1966, with the descrition of 3 children with extreme growth failure from a consanguineous Jewish family of emenite origin who had the henotye of hyoituitarism with high serum GH concentrations. Although an abnormal GH molecule was initially susected, this disorder, for many years referred to as Laron syndrome, was shown to be caused by a defect in the GH recetor (GHR) [2]. This striking but very rare henotye, which was also untreatable at that time, became synonymous with the diagnosis of rimary IGF- 1 deficiency (PIGFD). In the late 1980s, two ivotal develoments brought imortant changes to the field. The first was the synthesis and availability of recombinant human IGF- 1 for theray [3] and the second was the advent of molecular techniques, which led to the cloning and characterization of the human GHR [4].

3 Liver GH Periheral GH Cytokines Growth factors JAK2 JAK2 JAK2 JAK2 PI3K/AKT Ras/MAPK STAT1, 3, 5a STAT5b PI3K/AKT Ras/MAPK STAT Endocrine IGF-1 IGFBP-3 ALS IGF-1 deendent Autocrine Paracrine IGF-1 indeendent IGF-1-IGFIR axis Growth Fig. 1. The GH- IGF- 1 axis in human growth. Solid arrows indicate activation rocesses, dashed arrows, translocation rocesses. P = Phoshorylated residue; = tyrosine; AKT = v- akt murine thymoma viral oncogene homolog, also known as PKB, rotein kinase B; ALS = acid labile subunit; MAPK = mitogen- activated rotein kinase; PI3K = hoshatidylinositol 3- kinase. PIGFD is not a single entity, but a broad diagnostic category comrising a range of molecular defects in the GH- IGF axis. These defects, which may involve genes coding for roteins that regulate GH binding or signal transduction and IGF- 1 synthesis, transort or action, are associated with an equally varied range of henotyes and biochemical abnormalities. This chater will describe the range of henotyes and the investigation of ossible PIGFD and summarise its treatment with rhigf- 1. Physiology of GH and the IGF- 1 System in Relation to Linear Growth The actions of GH are mediated by a combination of comonents of the IGF system, including IGF- 1, IGF- binding roteins (IGFBPs), the IGF- 1 recetor (IGFIR), and IGF- indeendent effects through direct GH action. A diagram of the GH- IGF axis Management of Primary IGF- 1 Deficiency 139 Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / )

4 is shown in figure 1. Following the original somatomedin hyothesis [5], in 1985 Green et al. [6] roosed the dual effector hyothesis suggesting that GH regulates the exression of locally roduced IGF- 1, which then acts in an autocrine/aracrine manner. Exression of the IGF1 gene was found in multile tissues throughout embryonic and ostnatal develoment. In addition, injection of GH into hyohysectomised rats increased IGF1 mrna in numerous non- heatic tissues. Direct injection of GH into the cartilage growth late of hyohysectomised rats also resulted in significantly increased longitudinal bone growth [7]. Hence, GH has local effects, indeendent of those mediated by circulating IGF- 1. Nilsson et al. [8] demonstrated that GH stimulated differentiation of readiocytes and chondrocytes in the growth late, while IGF- 1 stimulated their clonal exansion. Le Roith et al. [9] took account of gene deletion exeriments in mice to question the role of liver- derived IGF- 1 in controlling ostnatal growth and develoment. Liver- secific Igf1 knockout mice grow normally desite reduction in circulating IGF- 1, indicating that locally roduced IGF- 1 was an imortant growth mediator [9]. Some 75% of serum IGF- 1 is liver derived, while the remainder originates from non- heatic tissues. In addition, serum levels of the acid- labile subunit (ALS) and IGFBP- 3 are imortant in maintaining circulating IGF- 1 [10]. The imortance of ALS was clearly shown in the Igfals knockout mouse model and by Domené et al. [11] who reorted the first homozygous mutation in human IGFALS causing severe IGF- 1 deficiency. Mechanisms of GH and IGF- 1 Actions Pituitary- derived GH exerts its growth effects rimarily by regulating the exression of IGF- 1 (fig. 1). GH regulates IGF- 1 roduction through the STAT (signal transducer and activator of transcrition)- 5b signalling system. The binding of GH to the cell surface homodimeric GHR recruits and induces signal transduction through the cytosolic Janus kinase 2 (JAK2). Initiation of signal transduction through the STAT5b athway requires STAT5b to associate with one of several JAK2 hoshorylated tyrosines located on the intracellular domain of GHR. STAT5b, recruited to GH- activated GHR, is subsequently hoshorylated by JAK2, whereuon the tyrosyl- hoshorlated- STAT5b forms a homodimer and translocates to the nucleus. The dimeric hoshorylated STAT5b binds to chromosomal GH resonsive elements and drives transcritional regulations of STAT5b- deendent genes [12]. IGF- 1 roduced in the liver circulates in a ternary comlex with liver- derived IGFBP- 3 and ALS, and is delivered to IGF- 1- resonsive cells and tissues. The mitogenic and metabolic effects of IGF- 1 are mediated through the tye I IGFIR, a cellsurface tyrosine kinase recetor encoded by IGF1R. The binding of IGF- 1 to IGFIR leads to recetor autohoshorylation, resulting in recruitment of cytolasmic 140 Savage Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / )

5 Table 1. Classification of GHI and PIGFD disorders with short stature Defects of the GH- IGF- 1 axis 1. GHR defects a. Extracellular mutations b. Transmembrane mutations c. Intracellular mutations 2. GH signal transduction defects (STAT5b) 3. Mutations of SHP- 2 (encoded by PTPN11), K-RAS, H-RAS 4. IGF1 gene mutations or deletions a. Defects causing IGF- 1 deficiency b. Bio-inactive IGF-1 5. ALS defects 6. IGFIR gene mutations 7. GH- neutralizing antibodies in atients with GH gene deletion PTPN11 = Protein tyrosine hoshatase, nonrecetor tye 11; SHP- 2 = Src homology region 2-domain hoshatase-2. comonents of downstream signalling athways, including the PI3K/Akt and MAPK/Erk athways, ultimately leading to cell roliferation and other metabolic effects [12]. Phenotyes of Primary IGF- 1 Deficiency Caused by Human GH- IGF Axis Mutations Normal GH secretion and the functional integrity of the IGF system are essential for normal linear growth. Defects that have been identified to cause imaired growth are shown in table 1. A summary of henotyic and biochemical features in the range of GH- IGF- 1 axis defects is given in table 2. Human renatal growth is regulated rincially by nutritional sulies, which influence fetal IGF- 1 [13]. The imortance of normal IGF- 1 roduction in humans was confirmed by the renatal growth failure reorted in atients with IGF1 mutations [14, 15]. IGF- 1 action is also essential as demonstrated by humans with mutations of IGF1R [12]. Postnatal growth may be disruted by mutations that disturb the functional integrity of the cascade of GH- GHR interaction, GH signal transduction, and IGF- 1 roduction, transort and action [12]. The Continuum of Phenotyic Features The concet of genotye:henotye relationshis in endocrinology can be alied to defects of the GH- IGF axis causing PIGFD. Since oulations of children with PIGFD were first reorted, a range of henotyes has been described. This was Management of Primary IGF- 1 Deficiency 141 Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / )

6 Table 2. Summary of henotyic and biochemical features in the range of GH- IGF- 1 axis defects. Phenotye Gene defect GHR STAT5b PTPN11 IGF-1 IGFALS IGFIR Bio-inactive GH Severe growth failure +/ Mild growth failure / Mid-face hyolasia +/ +/ + Other facial dysmorhism Deafness + Microcehaly + + Intellectual delay /+ + +/ Puberty delay +/ +/ +/ + Immune deficiency + Hyoglycaemia + /+ Hyerinsulinaemia IGF-1 deficiency + + /+ +/ IGFBP-3 deficiency + + / ALS deficiency + + / GH excess + + +/ + GHBP deficiency +/ GH1 with anti- GH antibodies Homozygous or comound heterozygous mutations /+ + Heterozygous mutations + + +/ _ + = Positive; = negative; +/ = redominantly ositive; /+ = redominantly negative; GHBP = growth hormone- binding rotein. noticeable in the series of 82 atients, mainly of Euroean origin, who were identified in the early 1990s for rhigf- 1 theray [16]. There was a gradation of severity of short stature, with height standard deviation score (SDS) ranging from 2.2 to 10.4 and a strong ositive correlation (r 2 = 0.45, 0.001) between height SDS and IGFBP- 3 SDS. A further variable in the same oulation related to henotye was the serum GHBP level which when very low or absent was associated with more severe short stature (height SDS 6.45) whilst normal GHBP values were associated with milder short stature (height SDS 4.89) [16]. A study of 142 Savage Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / )

7 craniofacial henotye in the same grou of subjects identified that those with normal facial aearance had milder short stature and could resent as idioathic short stature [12]. However in this series of GH- resistant atients, there was no clear relationshi between GHR mutation and henotye [16]. In atients from Ecuador with the homozygous E180 slice GHR mutation, heterogeneity of statural henotye was also seen with height SDS values ranging from 5.3 to 11.5 and height SDS correlated ositively ( < 0.01) with both IGF- 1 SDS and IGFBP- 3 SDS values [12]. GHR Mutations Thirty- eight atients with PIGFD were studied in the Centre for Endocrinology at Barts and the London School of Medicine and Dentistry, London, and identified to have homozygous, comound heterozygous or heterozygous dominant negative GHR mutations [12]. In order to erform an assessment of height SDS and tye of GHR mutation, these 38 subjects were analysed together with 32 subjects, also fulfilling the same PIGFD criteria, who were added from the literature. Relationshis between GHR mutation tye and height SDS are shown in figure 2. For the first time, dominant negative GHR mutations [17] and GHR intronic seudoexon mutations [18] were associated with significantly less severe growth henotyes ( < 0.05) than GHR missense and non- sense mutations. STAT5B and IGFALS Mutations Patients with homozygous STAT5B mutations have a range of henotyic characteristics [12]. Height SDS values ranged from 5.6 to 9.9. The majority of these atients had serious immunological abnormalities, which almost certainly contributed to their growth failure. In a recent review of 17 cases with homozygous IGFALS mutations, height SDS values in reubertal subjects (n = 15) ranged from 1.1 to 3.9 (mean 2.6), in adolescent subjects (n = 10) from 1.0 to 4.4 (mean 2.8) and in adult subjects (n = 8) from 0.5 to 4.4 (mean 2.2) [19]. IGF1 Mutations The key feature of IGF1 defects is their association with imaired fetal growth. Key additional henotyic features of IGF1 defects are microcehaly, deafness, and some degree of intellectual retardation [14, 15]. However, as more cases are diagnosed, the henotye is likely to evolve. Management of Primary IGF- 1 Deficiency 143 Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / )

8 < 0.05 < 0.05 < < 0.05 < Height SDS Non-sense Missense Slice Pseudoexon Dom. neg. GHR defects Fig. 2. Height SDS values in 70 children with PIGFD and GHR mutations divided according to the tye of mutation [12]. Each boxlot deicts the median, 25th and 75th ercentiles. Whiskers deict minimum and maximum observed values. Statistical analyses were erformed using R version (R Develoment Core Team, 2008, R Foundation for Statistical Comuting, Vienna, Austria). Numerical variables were exressed as median (range). Comarison between continuous variables was erformed using the Student s t test. A two- sided value <0.05 was considered indicative of statistical significance. Bonferroni adjustment was erformed to reduce the likelihood of tye I error. The Continuum of Biochemical Changes The cardinal features of PIGFD states are deficiency of IGF- 1 and normal or increased GH secretion. In GHR mutations, IGF- 1, IGFBP- 3, and ALS levels are usually severely decreased, although the degree is variable [12]. Most homozygous GHR mutations cause extreme deficiency of all GH- deendent etides with increase in basal and stimulated GH secretion [16]. However, a range of IGF- 1 and IGFBP- 3 deficiencies was resent articularly in some of the less homogeneous oulations where a range of IGFBP- 3 values was noticeable. A range of IGF- 1 deficiency was also resent in atients from Ecuador [12]. Patients with dominant negative, slice site and the seudoexon 6Ψ GHR mutations have a less severe IGF- 1 deficiency comared to PIGFD subjects with non- sense and GHR missense mutations [12]. 144 Savage Maghnie M, Loche S, Caa M, Ghizzoni L, Lorini R (eds): Hormone Resistance and Hyersensitivity. From Genetics to Clinical Management. Endocr Dev. Basel, Karger, 2013, vol 24, (DOI: / )