Copyright© AE&M all rights reserved. 608 GHR isSTAT5B. stimulatesthesynthesis Thisprotein STAT signalingof implicatedinthegrowth-promoting activators oftranscription(STATs). Themostimportant which mayinvolveafamily ofsignaltransducersand thegene transcription, orregulating metabolic effects intracellularpathways, leading todirect of different leadstoactivation with GHR.JAK2phosphorylation kinaseassociated ofJAK2, atyrosine phosphorylation indimerizationoftheGHR and GH bindingresults superfamily. belongingtothecitokinereceptor receptor (GHR),ahomo-dimerictransmembrane to itsreceptor GH actsbybinding actiononGHsecretion. inhibitory hasan , anotherhypothalamichormone, bythegastriccells. (GHS), whichisalsosecreted inthehypothalamus,andghrelin (GHRH), produced hormone-releasing stimulation ofgrowth gland,inapulsatilemanner, under the anteriorpituitary of bysomatotropes axis.GHissecreted somatotropic the key componentsofthe factor 1(IGF-1)are andinsulin-like growth also knownassomatotropin, T INTRODUCTION ;shortstature;IGF;somatotropicaxis Keywords 2019;63(6):608-17 on thedescriptionofGH-IGFaxisgeneticdefectsreported inthelastdecade. large heterogeneousgroupofconditionsassociatedwithgrowthretardation.Inthisreview, wefocus affect fromthesecretionof GHtothebioavailabilityandactionofIGF-1. Affected patientspresenta than forty geneswereassociated withanimpairmentofthesomatotropicaxis. These defects can several othercandidategenesthatcouldaffect theGH-IGF1- pathway. To date,defectsinmore enhancement oflarge-scalesequencingtechniques hasexpandedthespectrumofknowngenesand promote orimpairhormonesproductionandactionhasbeengrowingover thelastdecade. The axis. This axishasbeenstudiedforalongtimeandtheknowledgeof how somemoleculescould growthfactor1(IGF-1)as somatotropin,andinsulin-like componentsofthesomatotropic arethekey The somatotropicaxisisthemainhormonalregulatorofgrowth.Growthhormone(GH),alsoknown ABSTRACT https://orcid.org/0000-0003-2567-7360 Alexander A. L. Jorge https://orcid.org/0000-0003-2107-9494 Fernanda A.Correa https://orcid.org/0000-0002-1628-7881 Nathalia L. M. Andrade https://orcid.org/0000-0002-6455-8682 A. Gabriela Vasques axis geneticdefects Update onnew GH-IGF review regulator of growth. Growth hormone (GH), hormone Growth ofgrowth. regulator axisisthemainhormonal he somatotropic 2 1,2 1,2 1,2 associated with growth retardation (4).Studies in retardation associated with growth of conditions group axis lead to alarge heterogeneous (1,3). andproliferation cell growth signaling, asthePI3K/AKT pathway, for important called IGF1R. This binding activates intracellular kinasereceptor tyrosine by bindingtothecellsurface in intrauterine development. IGF-1and IGF-2 act role period,IGF-1andIGF-2haveessential In theprenatal factorinpostnatalgrowth. IGF-1 isthemaingrowth 1). half-life(Figure the tissues,extendingitsserum IGF-1to theavailabilityoffree essential todecrease molecule ofacid-labilesubunit(ALS).Thiscomplexis type3 (IGFBP-3) and one of IGF binding protein consisting ofonemoleculeIGF-1, complex, byaternary IGF-1iscarried of circulating autocrine manner, plate.Most asoccursinthegrowth IGF-1thatactsin aparacrine/ tissues canproduce bytheliver. produced IGF-1 ispredominantly Other Circulating IGF-1production. mainly through 1)(1,2). bioavailability (Figure IGF-1 of IGF-1andothermoleculesthatincrease Defects in many related to the somatotropic to thesomatotropic Defects in many genes related occurs growth ofpromoting The GHeffect Arch Endocrinol Metab. Arch Metab. Endocrinol 2019;63/6 Universidade deSãoPaulo Faculdade deMedicina, Celular eMolecular(LIM25), Laboratório deEndocrinologia Alexander A. L.Jorge Correspondence to: Paulo, SãoPaulo, SP, Brasil Medicina, Universidade deSão das Clínicas,Faculdade de Molecular (LIM42),Hospital de HormônioseGenética Desenvolvimento, Laboratório 2 Paulo, SãoPaulo, SP, Brasil Medicina, Universidade deSão das Clínicas,Faculdade de Molecular (LIM25),Hospital Endocrinologia Celulare Genética, Laboratóriode 1 DOI: 10.20945/2359-3997000000191 Accepted onNov/19/2019 Received onSept/3/2019 [email protected] 01246-903 –SãoPaulo, SP, Brasil 5º andar, sala5.340 Av. Dr. Arnaldo, 455, UnidadedeEndocrinologiado UnidadedeEndocrinologia Arch Metab. Endocrinol 2019;63/6 Figure 2. the proteolyticcleavageofIGFBPsbyPAPPA2 deficiency;8)bioinactiveIGF-1; and 9)IGFinsensitivitycausedby GH; 3)GHinsensitivityby Figure 1. mice(8).Two yearslater,spontaneous dwarf an formally specific positivetranscription factor1 ( for thehypopituitarismphenotype,namedpituitary- complete insensitivitytoGH(7).Acandidategene with stature short established ascauseofsevere were mutationsin in 1989,autosomalrecessive its first monogeniccause in 1981 (6). Subsequently, deficiency, deletions in offamilialcasesisolatedGH many reports developmentandfunction(5).After for pituitary hypothesized thatsomegeneswouldberesponsible long-standingand,in1929,researchers are this area 1981 GH1 Historical timeline with genespreviouslyassociated GH-IGF-1axisdefects until2009. Schematic representationoftheGH-IGFaxisindicatingmaindisorders inthissystem: 1)growthhormonedeficiency(GHD);2)bioinactive PIT1 ... 1989 GHR ) was reported in1990basedona ) wasreported GHR defects;4)GHinsensitivityby GH1 PO1F1 1992 were recognized as recognized genewere POU1F1, GHRHR STAT5B 1996 IGF1 GHR 1997 GLI3 defects;5)IGF-1deficiency;6)acid-labilesubunit(ALS)7) defectsin

PROP1 HSX1 1998 depicted in a historical timeline (Figure 2). depicted inahistoricaltimeline(Figure 2009are associated withGH-IGF-1axisdefectsbefore (11).Genesthatwere failure postnatalgrowth severe microcephaly, intellectualdevelopment,and retarded retardation, in achildwithintrauterinegrowth of-function mutationsin deficiency (10).Inthesameperiod,homozygousloss- with , with or without gonadotropic alsodescribedinindividuals were pattern recessive factor ofPOU1F1gene( Also in90s,inactivatingmutationsofthetranscription in patients with GH,PRL and TSHdeficiency(9). mutationin autosomal recessive LHX3 2000 LHX 2001 STAT5B IGF1R 2003 GLI2 IGFALS IGF1R 2004 IGF-1 PROP1) defects. POU1F1 gene were reported reported genewere SOX2 2006 New GH-IGFaxisdefects inanautosomal wasidentified RB28 OTX2 2008 609

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 610 SOD =septoopticdysplasia, HPE=holoprosencephaly, KS= IGHD: Isolatedgrowthhormonedeficiency;CPHD: hormone deficiencies; HH: combined pituitary hypogonadotropichypogonadism; A: aplastic;NL: normal; Table 1. describedinthe thesubtlemidlinemalformation from (12).Apart and hypoplasiaoftheanteriorpituitary usually associatedwithanectopicposteriorpituitary stalk, orabsentpituitary deficiencies, athin,interrupted characterized byhormone a distinctclinicalpicture (PSIS)hasbeenclassifiedas syndrome interruption stalk Thepituitary region. the hypothalamic-pituitary changes of or a wide range of structural abnormalities withno itcan present neuroimaging, and, regarding deficiencies (CPHD).Itcanbecongenitaloracquired (IGHD) orcombinedwithotherpituitary deficiencycanbeeitherisolated hormone Growth DEFICIENCY NEW GENETICDEFECTSASSOCIATED WITHGH defects associatedwithGH-IGFsaxis”. associated withGHdeficiency”and“newgenetic intwo main topics: “new genetic defects this review in thelasttenyears.Fordidacticpurpose,wedivided we describetheGH-IGFaxisgeneticdefectsreported the bioavailabilityandactionofIGF-1.Inthisreview, ofGHto thesecretion from These defectscanaffect axis. ofthesomatotropic associated withanimpairment New GH-IGFaxisdefects PAX6 FGFR1 FGF8 GLI2 Gene PROK2 TCF7L1 TGIF1 PROKR2 IGSF1 GPR161 CDON ARNT2 GLI3 To genes were thanforty date,defectsinmore New genesassociatedwithgrowthhormonedeficiencyeitherisolated(IGHD) orcombined(CPHD)andtheirclinicalfeatures Inheritance Dominant or Recessive Recessive Recessive Dominant Dominant Dominant Dominant Dominant Dominant Dominant Dominant recessive X-linked IGHD orCPHD IGHD orCPHD IGHD orCPHD IGHD orCPHD deficiencies HH orCPHD HH, IGHDor HH, IGHDor Hormonal CPHD CPHD CPHD CPHD CPHD CPHD CPHD IGHD pituitary Anterior NL or ↑ NL or A or orNL NL NL ↓ ↓ ↓ ↓ ↓ ↓ A ↓ ↓ ↓ Topic orEctopic Topic orEctopic Ectopic or TopicEctopic Ectopic/NV Posterior pituitary Ectopic Ectopic Ectopic Topic Topic Topic Topic Topic NV SOD, midlinecraniofacialmalformations, corpuscallosumabnormalities Brain, eye, tractabnormalities, kidneyandurinary corpuscallosum Midline craniofacialmalformations, ophthalmologicabnormalities GLI2 some ofwhichwillbediscussedbelow. listofthesenewgeneticdefects,and comprehensive pathogenesis ofthesephenotypes(14).Table 1hasa of each mutation or its synergy individual role in the However, neededtoexplain the studiesare more to adigenicoroligogeniccauseofGHdeficiency. whichpoints thanonegeneaffected, could havemore advocatedthatsomepatients It hasalsobeenrecently subset ofpatientswithcomplexphenotypesorPSIS. congenital hypopituitarism,mostof them in a small deficiency, manyother geneshavebeenassociatedwith geneticdefectsassociatedwithGH most frequent disability (13).Afterthedescriptionofclassicand dysplasia (SOD)anddevelopmentaldelay/intellectual septo-optic complexcraniofacialmalformations, are: othercomplexphenotypes.Themostcommon present PSIS, it posterior pituitary lobeformation posterior pituitary forhypothalamus,infundibulumand It isimportant duringembryogenesis. implicated incellularproliferation the Sonic Hedgehog (Shh) signaling pathway, which is forbindingtoDNAandisinvolved in responsible region GLI2 isatranscriptionfactorthatcontainszinc-finger HPE, maternalethanolexposureworsens thephenotype –agenefrequentlyinvolvedinGHdeficiency Polydactyly, HPE, craniofacialmalformations HPE, midlinecraniofacialmalformations Macroorchidism, undetectable is notunusualthatpatientswithgeneticdefects SOD, HPE, KS, Moebiussyndrome SOD, Hirschsprungdisease Pallister-Hall syndrome Other features abnormalities Digenic SOD Arch Metab. Endocrinol 2019;63/6 ↓ (15). : small; ↑ : large;NV: non-visualized; Reference (18) (16) (14) (62) (61) (17) (21) (60) (22) (20) (59) (58) (17)

Arch Metab. Endocrinol 2019;63/6 (OMIM children clinical manifestations insixaffected in afamilywithanunusualand distinctcombinationof mutation inanautosomalmode ofinheritancewasfound hypothalamic development. Using exome sequencing, a for HLH-PAS tobeimportant subfamilyproven ARNT2 isatranscriptionfactor memberofthebasic phenotypes ARNT2 (17-19). syndrome associated withSOD,HPE,PSISandMoebius deficiencies hormonal combinations ofpituitary different are described,there the clinicalpictures inheritance withincompletepenetrance.Among with autosomal dominant or recessive heterogeneity genetic isagreat without complexphenotypes.There also beenassociatedwithIGHDorCPHD hypogonadismhave associated withhypogonadotropic phenotypes (17).Untilnow, manygenespreviously for both could be responsible of these structures defectsingenesinvolvedthedevelopment Therefore, placodes. the adenohypophyseal,lens,andolfactory givesriseto calledpreplacodal structure embryogenic was madebasedontheknowledgethatan could also lead to hypopituitarism Kallmann syndrome The hypothesesthatmutationsingenesunderling between GHdeficiency andhypogonadotropic FGF8 the pathogenicityofallthem(15,16). found inthesepatients,althoughonecannotconfirm geneticdefect variants makingitthemostfrequent either loss-of-function or non-synonymous wassequenced,15patients(5%)had coding region deficiency, among 284 patientsinwhomthecomplete of role oftheimportant review inthephenotype.Inarecent factors mayplayarole it ispossiblethatothergeneticand/orenvironmental autosomal dominantwithincomplete penetration and of associateddiabetesinsipidus.Theinheritanceis and isamarkerofseverity. reports alsorare are There to of polydactyly should prompt presence incisor, havebeendescribed.The median maxillary such as cleftpalateanda craniofacial malformations, well aspolydactyly. Insomepatients,othermidline findingas isafrequent ectopic posteriorpituitary GLI2 Re , mutations may have IGHD or CPHD. An FGFR1 garding the clinical picture, patientswith theclinicalpicture, garding and IGSF1 , PROKR2 – GH deficiency with very unusual –GHdeficiency withvery and PROK2 GLI2 – the overlap –theoverlap mutationsinGH GLI2 GLI2 testing rare rare clinical characteristics of male patients are congenital clinical characteristics of male patients are gland. Mutationsin inRathke’spouchandtheanterior pituitary expressed bladder (20). and neurogenic reflux such as gastro-oesophageal with additional features, dysmorphic andpresented tolight.Allpatientswere and minimalpupilresponse palsy total body spastic cerebral examination revealed Neurological . generalized tonic-clonic/partial microcephaly, globaldevelopmentaldelayand severe developedsecondary myelination. Allsixchildren lobes, thincorpuscallosumandaglobaldelayinbrain , andtemporal hypoplasticfrontal stalk,hypoplastic posterior pituitary, thinpituitary in all patients: non-visualized of abnormalities pattern asimilar LH/FSH andGH.MRIofthebrainrevealed deficiencies:ADH,ACTH,TSH, hormone of pituitary 6159 interactions (24). Regarding CDON,asynergy interactions (24). Regarding for this phenomenon is the involving othergenes,and onemechanismproposed anomalieswithmutations other familieswithpituitary Incomplete penetrancehas beendescribedinmany cholestasis and hypotelorism (OMIM 614226) (23). association with (HPE)phenotypesin ofHoloprosencephaly spectrum a broad penetrance (22). Bae and cols. reported convergent strabismus–whichpointed toincomplete phenotype–congenital mutation withadifferent posterior pituitary. Thepatients’motherhadthesame small anteriorpituitary, absentstalk,and ectopic evaluationindicated Theneuroimaging bilirubin. delivery, conjugated neonataljaundicewithincreased cesarean presentation, perinatal complications:breech CDON activity. nonsensemutationin Aheterozygous SHH signaling that promotes binding protein sonichedgehog(SHH) CDON isacellsurface environmental enhancers CDON small stalklesion(PSIS)(21). withhypoplasiaofthecorpuscallosumand abnormal BMI. InonepatientwithGHdeficiency, MRIwas development andincreased pubertal disharmonious deficiency, andtransientGH,prolactin partial ofpatientspresented 300888). Avariableproportion (OMIM andmacroorchidism central hypothyroidism IGSF1 is a plasma membrane glycoprotein IGSF1 isaplasmamembraneglycoprotein 26) (20).Thepatientshadavariablecombination –GHdeficiency andthelinkwith wasdescribedinapatientwithPSIS CDON IGSF1 mutations, including hepatic are X-linkedandthemain are New GH-IGFaxisdefects gene-environment gene-environment 611

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 612 AD: autosomaldominant; AR: autosomalrecessive; ADp: AD withpaternaltransmission; ND: nodata. Table 2. and intellectual microcephaly stature, postnatal short with classicalGHI. thanindividuals stature short IGF-1 andlesssevere detectable levels of 604271). They usually presented (OMIM stature be initiallyclassifiedasidiopathicshort These patientshadamildGHIphenotypewhichcan recently,reported totaling seven patients to date (28). havebeen mutations withadominant-negativeeffect caused by heterozygous failure with growth patients ascausal.Three although fewhavebeenproven phenotype, stature have beenassociatedwiththeshort variants in 262500) (27). Several heterozygous and IGF-1 deficiency (OMIM dysmorphic features facial stature, short (GHI), characterizedbyextreme ( mutations in the GHR gene Autosomal-recessive IGF1 Update ofgenotype-phenotypecorrelations described(Tablewere 2). Additionally, ofGH newgeneticdefectsdownstream expanding thegenotype-phenotypecorrelations. recently,mutations inthesegeneshasincreased the number of described individuals with heterozygous foralongtime, disorders been associatedto growth Although defectsin GH-IGFS AXIS NEW GENETICDEFECTSASSOCIATED WITH levelofevidenceasdiseasecausing. astrong present or etiopathogenicaspect.Allthegenesdiscussedabove clinicalpicture discussed theoneswithaninteresting the lasttenyearscausingGHdeficiency(Table 1),we with observed (25).This has alsobeen leading toHPEwasreported between a New GH-IGFaxisdefects GHR) IGF2 PIK3R1 PAPPA2 STAT3 STAT5B Gene Homozygous defectsin and Regarding the new genetic defects reported in thenewgeneticdefectsreported Regarding New geneticdefectsofGH-IGFaxisandtheirclinicalfeatures cause a classical picture ofGHinsensitivity causeaclassicalpicture IGF1R AD (withdominant-negativeeffect) Cdon AD (withgainoffunction) Gli2

mutationinthemouseandethanol Inheritance +/− GHR ADp AD AR

and Shh , IGF1 +/− IGF1

mice (26). and lead to pre and and leadtopre IGF1R Normal orslightlyhigh Hormonal levelsof GH/IGF-1/IGFBP-3 High/low/low High/low/low High ND geneshave GHR

GHR GHR ,

Mild microcephaly, smallchinsandlongthinfingers;lowfreeIGF-1 Phenotype similartoSilver-Russel syndrome;lowIGF-2levels as idiopathic. The proband had a history of intrauterine ofintrauterine hadahistory as idiopathic.Theproband initiallyclassified stature identified inachildwithshort deletion in 2014, acompleteheterozygous the same mutation (30). In carried stature with short with low IGF-1 level (SDS of-2.2). Other four relatives (heightSDSof-4.0) stature a boywithpostnatalshort heterozygous IGF-1deficiency(29). Two yearslater,maternal a mother,heterozygous withacombinationoffetaland a from born becausetheywere affected more were This factraisedthehypothesisthatprobands inherited byherfather, amilderphenotype. presented thesamemutation,whichhadbeen mother whocarried intwosiblings(29).The andmicrocephaly stature frameshift mutationin (11).In2010,aheterozygous and headcircumference heterozygous of notedthatcarriers described, theresearchers (OMIM608747).Since thefirstpatient impairment point mutations.Inaddition,amongthoseindividuals patients with appeartobehigherin of theotherclinicalfeatures andtheprevalence pectus excavatum).Thedegree (triangularface,clinodactyly,and dysmorphicfeatures mental andmotordevelopmentdelay, defects cardiac include manifestations (OMIM 270450).Otherclinical and IGF-1levelsabovethemeanforagesex microcephaly retardation, andpostnatalgrowth pre defectsin patients withheterozygous pathogenic variants in probably Acco failure. with growth alsoidentified inchildren were encompassing Initially,been reported. studiesdescribeddeletions defectsinIGF1Rgene( heterozygous anddevelopmentaldelay(31). microcephaly length SDSof-1.5and-1.2,respectively. Hepresented withweightand andwasborn restriction growth Partial GHinsensitivity, mildeczemaandelevatedIgE Partial GHinsensitivityandimmunedysregulation While defectsin Complex phenotypeofSHORT syndrome rding to a recent study, toarecent rding 36different are there Clinical features IGF1 IGF1R IGF1 IGF1R splice site mutation was identified in splicesitemutationwasidentifiedin mutations had a reduced height height mutationshadareduced deletions than in those carrying deletionsthaninthosecarrying and,yearslater, pointmutations IGF1 IGF1 Arch Metab. Endocrinol 2019;63/6 was associated with short wasassociatedwithshort are quite rare, many quiterare, are IGF1R (32) IGF1R IGF1R . Classically, References IGF1 (46-48) present present (50) (44) (37) (35) ) have was was Arch Metab. Endocrinol 2019;63/6 factors, including inteleukin-6 cytokines and growth stimulatedby awidevarietyof physiological processes STAT3 thatactsinmany isacytosolicprotein Gain offunctionmutations in (8 of11)(36). mildeczema(7of 11) andelevatedIgE presented individuals themajorityofaffected dysregulation, immune -5.3to-2.9.Althoughnoonehadsevere from fam had ahighvariabilityinter- stature andintra- of short negative heterozygous d familiescarried thethree individuals from and withwild-typeSTAT5B Intotal,eleven proteins. dimerswiththemselves stimulation andcanform STAT5B uponGH canbephosphorylated proteins Mutated mutations haddominant-negativeeffects. that thosethree (36). Functionalevaluationrevealed families different from children insensitivity inthree with mildGH stature ascauseofshort reported were haploinsufficiency. mutations in of incarriers observed the slightheightreduction (35).Therefore, ofthemutantprotein of expression manner showedalack mutations inheritedbyrecessive (34). Reconstitutionexperimentswithloss-of-function in 4 of 32 carriers eczema was observed impairment, range.Besidesthegrowth height withinthenormal of-0.6, difference familymembers(heightSDS than theirnon-carrier mutations in (34). Additionally, heterozygous individualswhocarry (height SDSof-1.4±0.8 thesamepopulation thanindividualsfrom shorter cases carrying of index relatives (OMIM 245590) (33). First-degree diseaseandeczema) pulmonary clinically byprogressive (represented associated withimmunedysregulation of a GHinsensitivitysyndrome aspart stature short homozygous mutationsin GH signaling.Ithasbeenknown,since2003,that STAT5B actsasakeytranscriptionactivatorof Autosomal dominantdefectsin (32). the breakpoints condition appearstobedependentonthelocationof with Recently, mutationsin heterozygous three ilial and the height SDS of the probands ranged ilial and theheight SDSof the probands IGF1R deletions,theseverityofclinical STAT5B STAT5B STAT5B p = 0.009),althoughallofthemhad could be explained by partial couldbeexplainedbypartial STAT5B were reported to be shorter tobeshorter reported were mutations were significantly mutationswere vs. STAT5B -0.4±0.8; STAT3 mutations. The degree mutations.Thedegree STAT5B cause extreme causeextreme p ominant- < 0.001) STAT5B

chronic disease. However, in 2018, Gutiérrez and disease.However, and chronic in2018,Gutiérrez inthosepatientscouldbeduesolelytotheir observed (SDS of-2.2)(40). height SDSof-2.6at5.5yearswithIGF-137µg/L in andgain-of-function(GOF)mutations dysregulation in7of13patientswithimmune was alsoobserved stature (38). and all of them had short celiac disease) (e.g. type 1 , hypothyroidism, early-onset (diagnosisat<5years)autoimmunedisease individualshad (OMIM 615952).Thefiveaffected anewmonogeniccauseofautoimmunity mutations were described that in Blymphocytes(37).In2014,Flanaganandcols. in hepatoma cells and stimulates proliferation response STAT3, underIL-6activation,inducesanacute-phase systemsshowedthat (IL-6). Studieswithcellcultures cleavage ofIGFBP-3 and-5(44). forthespecificproteolytic responsible tissue protease A2(PAPPA2),associated plasmaprotein and aserum pregnancy- This taskisdonebythemetalloproteinase complex (42,43). the ternary from must be released highest half-life.However, toactonitsreceptor, IGF-1 with the inwhichIGF-1circulates and ALS,istheform complex,composedbyIGF-1,IGFBP-3 The ternary IGF-1 canbefoundintheplasmaboundtosixIGFBPs. ( D impact intheGHsignalingpathway(41). STAT5B transcriptional activity, suggesting anegative bothGOF GH treatment, Additionally, under unstimulatedconditions and under leadingtoenhancedactivity.dephosphorylation, delayed theypresented constitutively phosphorylated, type STAT3. AlthoughmutatedSTAT3 not were of the twoSTAT3 mutantsin comparison towild- activity reporter assay showed an increased reporter evaluation usingaSTAT3-responsive dual-luciferase infections.Functional andrecurrent diarrhea chronic eczema, hypothyroidism, SDS of -5.4. Both presented of IGF-1,whiletheother, attheageof3,hadheight associatedwithundetectable levels of GHandprolactin levels SDS of-6.4at2.4yearsage,withelevatedserum GOF caused by insensitivity andimmunedysregulation GH withpartial children cols. describedtwounrelated PAPPA2 efects intheproteolyticcleavage ofIGFBPsgene STAT3 We impairment could speculate that the growth STAT3 ) (39). Inanotherstudy, aboypresented mutations (41). One patient had height mutations(41).Onepatienthadheight de novo germline activating germline STAT3 variants decreased variantsdecreased New GH-IGFaxisdefects STAT3 de novo 613

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 614 in thecomplex phenotypeofSHORT is not syndrome The mechanismofhowmutations in range. others had height in the low-normal whereas microcephaly, with relative stature, short had prenatal Someindividuals impairment. ofthe growth degree patients,includingthe variability amongtheaffected wasaphenotype patients(47-49).There unrelated in within thecontextofaCpGmotif,wasrecurrent novo of nonsense andmissensevariants),withprevalence d were joints (OMIM269880).Severalgenedefectsin of andhyperextensibility lipodystrophy depression, ocular delayed dentition, characteristic facial features, stature, disease characterized byshort arare syndrome, establishedasthemajorcauseofSHORTwere of PI3K,encodedby subunit andtheybindtotheregulatory phosphorylated kinasereceptor,activation oftyrosine substratesare totheaction of IGF-1.After pathway iscrucial The phosphatidylinositol 3 kinase (PI3K) intracellular ( subunit ofPI3Kgene Defects intheregulatory (45). in allchildren delay. age Boneagewasconsistentwithchronological development ofneuropsychomotor with nohistory microcephaly, presented children offiveaffected Three assmallchinsandlongthinfingers(45,46). observed, with age and other characteristics were prominent wasbecomingmore impairment siblings. Thegrowth rangeandsmallerthantheunaffected the lownormal within born gestational age,whiletheotherswere smallfor born were IGF-1.Two children circulating IGF-1concentrations, despite the high levels of free activity ofthePAPPA2. Fouroffivepatientshadlow that bothmutationsledtoabsenceoftheproteolytic (p.Ala1033Val) studiesshowed Invitro wasobserved. anovelmissensevariant children, affected with three in a novel homozygous frameshift mutation harbored (45). Onefamily, children, withtwoaffected markedly elevatedIGF-1 and IGFBP-3 concentrations with stature established asthecauseofshort were in whole exome sequencing, mutations evaluated through New GH-IGFaxisdefects PIK3R1 In 2013, heterozygous mutations in In2013,heterozygous families Based onthestudyoftwodifferent PAPPA2 PAPPA2 inheritance.Onemissensevariant(p.Arg649Trp), escribed (nucleotides insertion ordeletion, escribed (nucleotidesinsertion ) (p.Asp643fs25*).Intheotherfamily, in an autosomal recessive inheritance inanautosomalrecessive PIK3R1 gene(47). PIK3R1 PIK3R1 PIK3R1 result result de problems withlowbodymassindex(50). problems clinodactily,micrognathia, andfeeding bodyasymmetry macrocephaly,relative bossing,triangularface, frontal stature, onsetshort prenatal with SRSclassicallypresent 7.Children disomyofthechromosome uniparental causeofSRSisthematernal second mostfrequent inthe which leadstoadecrease 11p15.5, of theimprinteddomainonchromosome causedbythehypomethylation 60% ofthecasesSRSare patients withtheSilver-Russell (SRS).Upto syndrome the studyof the IGF-2 functionwasacknowledgedfrom of The clinical importance fetal growth. in promoting alleleintheplacentaandhasafundamentalrole paternal period, During theprenatal IGF2 several tissues(47-49). in expressed isoforms subunit ofPI3Khasdifferent completely understood.Itisknownthattheregulatory axis disruption. The group of the oldest genes ( The group axis disruption. their implicationonGH-IGF1 evidence regarding of regulators IGF2 pathway and act as positive upstream patients. Bothgenesbelong totheHMGA2–PLAG1– and described newloss-of-functionmutations in (51-53,56). alsoreported were andambiguousgenitalia transposition, ashypospadia,penoscrotal Male genitalabnormalities, andatrialorventricularseptaldefects. ductus arteriosus abnormalities, cardiac presented developmentaldelay.neuropsychomotor Fiveprobands and offeedingproblems degrees They hadvarying -3.3to-6.2). age(heightSDSrangedfrom preschool at stature andshort macrocephaly length, hadrelative weightand smallforgestationalageregarding born IGF2 (3 frameshift,2nonsenseand1splice-site)inthe now, one missense and six loss-of-function variants allelecausingSRS-like(52-56).Upto the paternal other fivestudiesidentifiedvariantsin report, fathers (OMIM616489)(51).Afterthisfirst theirhealthy mutation inallpatients,inheritedfrom analysis, theauthorsidentifiedan exome molecularcause.Through without arecognized thesame family with SRS phenotype individuals from IGF2 All genesdescribedabove haveagoodlevelof In additiontomutationsin In 2015,Begemannandcols defects PLAG1 gene were reported. All affected children were were children Allaffected reported. genewere (54). genes in a cohort ofsuspectedSRS genesinacohort Arch Metab. Endocrinol 2019;63/6 IGF2 IGF2 IGF2 is expressed by the bythe isexpressed . including patent , Habibandcols. describedfour expression. The The expression. IGF2 IGF2 nonsense geneon HMGA2 GHR ,

Arch Metab. Endocrinol 2019;63/6 inthisarea. continuous research and GH-IGF1 axisdefects.This willdemandcareful associatedto impact ofvariantsingenesnot previously will continuebeingachallenge toevaluatetheclinical amultisystem phenotype.Also,webelieveit present and would individuals would be rare tissues, affected pathwaysindifferent to different important are Asthesemolecules stature. molecules couldcauseshort in othergeneswhichencodedintracellularsignaling (ClinGen)(57). Resource level ofeviden the newgeneticdefectsregarding on themostrelevant biodisponibility andaction.Inthisreview, wefocused toIGF-1 theGHproduction from responsible are These genes stature. this pathway could lead to short itisinsightfulthatdefectsatanystepof of growth, clinical useofthegeneticknowledge. to known genes, boosting the related correlations theexpansionofgenotype-phenotype permitted identification ofnewgeneticdefects,thisinnovation Besidesthe candidategeneapproach. than theprevious time defects simultaneouslyatlowcostandinashorter sequencing), whichallowedtheanalysisofmanygenetic scale parallelsequencingtechniques(targeted orexome was mainly due to the development of large-increment overthelast decade.This in newgeneshasincreased of defects 2010, the discovery described before were genetic defects many decadesandthemostfrequent for havebeenrecognized GH-IGF1 axisdisruption Although many phenotypes associated withthe CONCLUSION thegene-diseaserelationship. reinforcing of isaprevalence and there complex individualsare axis. Thephenotypeofaffected genes that impair the somatotropic clinically relevant evaluation. Finally, to phenotypeandhadaconvincingfunctional families, respectively, according thevariantssegregated and twodifferent inonlythree reported genes were gene-disease clinicalvalidity. Althoughdefectsinthese and homozygous mutations in mutations in families.Heterozygous different individuals from ofaffected manyreports are level ofevidence,asthere IGF1 As a future perspective,wespeculatethatdefects As afuture Since theGH-IGF1axisismainregulator and IGF1R STAT5B ce recommended bytheClinicalGenome ce recommended ) inadditionto STAT3 with a dominant-negative effect withadominant-negativeeffect and PAPPA2 IGF2 the novo PIK3R1 havethehighest also present a also present inheritance, are also are 4. 3. 2. 1. 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