30 A.L. RosenbloomThis characteristic permits assaying circulat-ing GHBP as a measure of cellular-boundGHR, which usually correlates with GHR func-tion .The GH molecule binds to a molecule of cellsurface GHR, which then dimerizes with anotherGHR molecule in the extracellular domain, sothat a single GH molecule is enveloped by twoGHR molecules . The intact receptor lackstyrosine kinase activity but is closely associatedwith JAK2, a member of the Janus kinase family.JAK2 is activated by binding of GH with theGHR dimer, which results in self-phosphoryla-tion of the JAK2 and a cascade of phosphoryla-tion of cellular proteins. Included in this cascadeare signal transducers and activators of transcrip-tion (STATs), which couple ligand binding to theactivation of gene expression, and mitogen-activated protein kinases (MAPK). STAT5b is themost important of these activator proteins. This isa mechanism typical of the growth hormone/prolactin/cytokine receptor family that includesreceptors for erythropoietin, interleukins, andother growth factors .The effect of GH on growth is indirect, viastimulation of IGF-I production in the liver andgrowing tissues, particularly bone and muscle. Hepatic (endocrine) IGF-I circulates almostexclusively bound to IGFBPs, less than 1%being unbound. The IGFBPs are a family of sixstructurally related proteins with a high afﬁnityfor binding IGF. At least four other related pro-teins with lower afﬁnity for IGF peptides havebeen identiﬁed and are referred to as IGFBP-related proteins [5, 6]. IGFBP3 is the most abun-dant IGFBP, binding 75–90% of circulatingIGF-I in a large (150–200 kDa) complex whichconsists of IGFBP-3, an acid-labile subunit(ALS), and the IGF molecule. Both ALS andIGFBP3 are produced in the liver as a directeffect of GH. The ALS stabilizes the IGF–IGFBP3 complex, reduces the passage of IGF-Ito the extravascular compartment, and extendsits half-life. The remainder of bound IGF is in a50-kDa complex with mostly IGFBP-1 andIGFBP-2.IGFBP-1 production is highly variable, withthe highest concentrations in the fasting, hypoin-sulinemic state. The circulating concentration ofIGFBP-2 is less ﬂuctuant and is partly under thecontrol of IGF-I; levels are increased in GHR-deﬁcient states but increase further with IGF-IHypothalamusGHRHRGHRH(stimulation)SS(inhibition)GHPituitaryBonesignal transductionMusclesignal transductionALS/IGFBP3/IGF-I(ternary complex)GrowthIGF-IRIGF-IRALSLiverIGF-IIGFBP3STAT5BGHRFig. 2.1 Simpliﬁed diagram of the hypothalamic-pituitary-GH/IGF-I axis, showing mutational targets resulting in GHinsensitivity indicated in bold
312 Growth Hormone Insensitivitytherapy of such patients . The IGFBPs modu-late IGF action by controlling storage and releaseof IGF-I in the circulation, by inﬂuencing thebinding of IGF-I to its receptor, by facilitatingstorage of IGFs in extracellular matrices, and byindependent actions .Autocrine and paracrine production of IGF-Ioccurs in tissues other than the liver. In growingbone, GH stimulates differentiation of pre-chon-drocytes into chondrocytes able to secrete IGF-I,which stimulates clonal expansion and matura-tion of the chondrocytes, with growth. It is esti-mated that at least 20% of GH-stimulated growthresults from this autocrine/paracrine IGF-I mech-anism .IGF binding involves three types of receptors:the structurally homologous insulin receptor andtype 1 IGF receptor and the distinctive type 2IGF-II/mannose-6-phosphate receptor. Althoughthe insulin receptor has a low afﬁnity for IGF-I,IGF-I is present in the circulation at molar con-centrations that are 1,000 times those of insulin.Thus, even a small insulin-like effect of IGF-Icould be more important than that of insulinitself, were it not for the IGFBPs that control theavailability and activity of IGF-I. In fact, intravenousinfusion of recombinant human IGF-I (rhIGF-I)can induce hypoglycemia, especially in theIGFBP3-deﬁcient state .GH InsensitivityGH insensitivity (GHI) or resistance is deﬁned asthe absence of an appropriate growth and meta-bolic response to endogenous GH or to GHadministered at physiologic replacement dosage. Table 2.1 lists the known conditions associ-ated with GH resistance and their clinical andbiochemical features. The genetic disorders thatinterfere with the response to GH include muta-tions affecting the GH receptor (GHR), STAT5b,ALS, IGF-I, and IGF-I receptor (Fig. 2.1).The conditions that have been associated withacquired GHI may not demonstrate low levels ofIGF-I, or even consistent growth failure. AcquiredGH resistance occurs in some patients with GHgene deletion for whom injections of recombi-nant human GH stimulate the production ofGH-inhibiting antibodies . Growth failureassociated with chronic renal disease is thoughtto be related to increased concentrations ofIGFBPs with normal or elevated GH and usuallynormal total IGF-I levels .Table 2.1 Conditions characterized by unresponsiveness to endogenous or exogenous growth hormone: clinicaland biochemical characteristicsCondition Growth failure GH GH-binding protein IGF-I IGFBP3GeneticGHR def recessiveformsSevere Elevated Absent–lowaVery low Very lowGHR def dom negformsMild–moderate Elevated Increased Very low Low normalSTAT5b mutation Severe Elevated Normal Very low Very lowALS mutation None–moderate Normal Normal Very low Very lowIGF-I gene mutation Severe Elevated Normal Absent/highbLow/normalIGF-I receptormutationMild–moderate Normal–elevatedNormal Normal–elevated Normal–elevatedAcquiredGH inhib antibodies Severe Absent Normal Very low LowMalnutrition None to severe Elevated Decreased Variable VariableDiabetes mellitus None to mild Elevated Decreased Decreased IncreasedRenal disease Mild to severe Normal Decreased Normal IncreasedHepatic disease Mild to severe Elevated Normal–increased Decreased NormalaIncreased in mutations of or near the transmembrane domain of the GH receptorbAbsent with partial IGF-I gene deletion; very high with abnormal IGF-I
32 A.L. RosenbloomThe Molecular Basis of GHIGHR Gene MutationsThe GHR gene (Fig. 2.2) is on the proximal shortarm of chromosome 5, spanning 86 kilobasepairs. The 5¢ untranslated region (UTR) is fol-lowed by 9 coding exons. Exon 2 encodes thelast 11 base pairs of the 5¢-UTR sequence, an 18amino acid signal sequence, and the initial 5amino acids of the extracellular hormone-bindingdomain. Exons 3–7 encode the extracellular hor-mone-binding domain, except for the terminal 3amino acids of this domain, which are encodedby exon 8. Exon 8 further encodes the 24 aminoacid hydrophobic transmembrane domain andthe initial 4 amino acids of the intracellulardomain. Exons 9 and 10 encode the large intrac-ellular domain. Exon 10 also encodes the 2 kb3¢-UTR .More than 50 mutations in the GHR have beendescribed in the approximately 250 knownpatients with GHR deﬁciency (Laron syndrome),which result in a clinical picture identical to thatof severe GH deﬁciency, but with elevated serumGH concentrations. The report of the character-ization of the complete GHR gene included theﬁrst description of a genetic defect of the GHR, adeletion of exons 3, 5, and 6 ; recognition thatthe exon 3 deletion represented an alternativelyspliced variant without functional signiﬁcanceresolved the dilemma of explaining deletion ofnonconsecutive exons. In addition to the originalexon 5 and 6 deletion, another deletion of exon 5has been described, along with numerous non-sense mutations, missense mutations, frameshiftmutations, splice mutations, and a unique intronicmutation resulting in insertion of a pseudo-exon.A number of other mutations have been describedthat are either polymorphisms or have notoccurred in the homozygous or compoundheterozygous state .All but a few of the defects result in absent orextremely low levels of GH-binding protein(GHBP). Noteworthy is the D152H missensemutation that affects the dimerization site, thuspermitting the production of the extracellulardomain in normal quantities but failure ofdimerization at the cell surface, which is neces-sary for signal transduction and IGF-I produc-tion. Two defects that are close to (G223G) orwithin (R274T) the transmembrane domain resultin extremely high levels of GHBP. These defectsinterfere with the normal splicing of exon 8,which encodes the transmembrane domain, withthe mature GHR transcript being translated into atruncated protein that retains GH-binding activitybut cannot be anchored to the cell surface.All these homozygous and compoundheterozygous defects, whether involving theextracellular domain or the transmembranedomain and whether associated with very low orunmeasurable GHBP, or with the more rare trans-membrane defects that can be associated withelevated GHBP levels, result in a typical pheno-type of severe GH deﬁciency (Table 2.2). In con-trast, the intronic mutation present in theheterozygous state in a mother and daughter with2 3 4 5 6 7 8 9 10intracellulardomainand 3 UTRTrans-membranedomainExtracellularbinding domainSignalsequence5 UTRFig. 2.2 Representation of the GHR gene. The blackhorizontal line represents intron sequence; breaks in linesindicate uncloned portions of the intron and the boxes rep-resent exons, which are enlarged for clarity. UTR refers tountranslated regions of the transcripts. Translated regionsare exons 2–10
332 Growth Hormone Insensitivityrelatively mild growth failure (both with standarddeviation score [SDS] for height −3.6), andresulting in a dominant negative effect on GHRformation, is not associated with other phenotypicfeatures of GH deﬁciency . This splice muta-tion preceding exon 9 results in an extensivelyattenuated, virtually absent intracellular domain.Japanese siblings and their mother have a similarheterozygous point mutation of the donor splicesite in intron 9, also resulting in mild growth fail-ure compared to GHR deﬁciency but with deﬁnite,although mild, phenotypic features of GHdeﬁciency . GHBP levels in the Caucasianpatients were at the upper limit of normal with aradiolabeled GH-binding assay and in Japanesepatients twice the upper limit of normal, using aligand immunofunction assay. These heterozy-gous GHR mutants transfected into permanentcell lines have demonstrated increased afﬁnityfor GH compared to the wild-type full-lengthGHR, with markedly increased production ofGHBP. When co-transfected with full-lengthGHR, a dominant negative effect results fromoverexpression of the mutant GHR and inhibitionof GH-induced tyrosine phosphorylation andtranscription activation . Naturally occurringtruncated isoforms have also shown this domi-nant negative effect in vitro .A novel intronic point mutation was discov-ered in a highly consanguineous family with twopairs of affected cousins with GHBP-positive GHinsensitivity and severe short stature, but withoutthe facial features of severe GH deﬁciency orinsensitivity. This mutation resulted in a 108-bpinsertion of a pseudo-exon between exons 6 and7, predicting an in-frame, 36-residue amino acidsequence, in a region critically involved in recep-tor dimerization .Genetic Disorders Affecting GH-GHRSignal Transduction and TranscriptionSTAT5bThere are seven members of the STAT family ofproteins activated by multiple growth factorsand cytokines, participating in a wide range ofbiological activities, particularly relating togrowth and immunocompetence. While GHactivates four members of this family, STAT5bhas emerged as the one that is crucial for growth. The GH-activated GHR recruits theSTAT5b which docks to speciﬁc phosphoty-rosine residues on the receptor, undergoingtyrosine phosphorylation by the receptor-asso-ciated JAK2. The phosphorylated STAT dissoci-ates rapidly from the receptor, forms a dimer,Table 2.2 Clinical features of severe IGF-I deﬁciencydue to GH deﬁciency or GH receptor deﬁciency orSTAT5b mutationGrowthBirth weight—normal; birth length—usually normal•Growth failure, from birth, with velocity ½ normal•Height deviation correlates with (low) serum levels•of IGF-I, IGF-II, and IGFBP-3Delayed bone age but advanced for height age•Small hands or feet•Craniofacial characteristicsSparse hair before age 7; frontotemporal hairline•recession all agesProminent forehead•Head size more normal than stature with impression•of large head“Setting sun sign” (sclera visible above iris at rest)•25% <10 years of ageHypoplastic nasal bridge, shallow orbits•Decreased vertical dimension of face•Blue scleras•Prolonged retention of primary dentition with decay;•normal permanent teeth may be crowded; absent 3rdmolarsSculpted chin•Unilateral ptosis, facial asymmetry (15%)•Musculoskeletal/body compositionHypomuscularity with delay in walking•Avascular necrosis of femoral head (25%)•High-pitched voices in all children, most adults•Thin, prematurely aged skin•Limited elbow extensibility after 5 years of age•Children underweight to normal for height, most adults•overweight for height; markedly decreased ratio oflean mass to fat mass, compared to normal, at all agesOsteopenia indicated by DEXA•MetabolicHypoglycemia (fasting)•Increased cholesterol and LDL-C•Decreased sweating•Sexual developmentSmall penis in childhood; normal growth with•adolescenceDelayed puberty•Normal reproduction•
34 A.L. Rosenbloomand translocates to the nucleus, binding to DNA,interacts with other nuclear factors, and initiatestranscription.Ten patients have been described with sevenautosomal recessively transmitted mutations ofSTAT5b . Similar to children with severeGH deﬁciency and GHR deﬁciency, but unlikethose with IGF-I gene or IGF-I receptor muta-tions (below), birth size is normal, indicatingGH-independent IGF-I production in utero. Alsosimilar to GH and GHR deﬁciency, postnatalgrowth shows rapid decline in SDS ranging from−9.9 to −5.6 at diagnosis, which was from 2.1 to31 years of age. Serum concentrations of IGF-I,IGFBP-3, and ALS were markedly low; basaland stimulated GH concentrations were eithernormal or elevated. The features (growth pat-terns, facial disproportion, and biochemistry withthe exception of GH-binding protein) have beenidentical to those of patients with severe GHRdeﬁciency.As might be expected because STAT5b isinvolvedinintracellularsignalingforothercytokinereceptors besides the GHR, immunodeﬁciencywith serious complications has been described inall but one of the reported patients with STAT5bmutation. Reported abnormalities include T cellfunctional defects, low numbers of NK and gdT-cells, and IL-2 signaling defects.PTPN11Fifty percent of children with Noonan syn-drome, which is characterized by short stature,cardiac defects, skeletal abnormalities, andfacial dysmorphism, have been found to carry again of function mutation of PTPN11. This geneencodes a non-receptor-type tyrosine phos-phatase (SHP-2) involved in intracellular sig-naling for a variety of growth factors andcytokines. Activated SHP-2 is thought to serveas a negative regulator of GH signaling. Childrenwith Noonan syndrome who have this mutationhave more severe statural deﬁcit than thosewithout the mutation. They also have lowerserum concentrations of IGF-I and IGFBP-3 withhigher GH concentrations and less robust growthresponse to rhGH treatment, all suggesting mildGH insensitivity .Mutations of the IGF-I GeneFailure of IGF-I synthesis due to a gene deletionwas described in a patient with a homozygouspartial deletion of the IGF-I gene . His pro-found intrauterine growth failure (IUGR) per-sisted into adolescence and he had sensorineuraldeafness with severe mental retardation andmicrognathia. Subsequently, a second patient wasdescribed with the same clinical phenotype but adifferent mutation also resulting in near absenceof circulating IGF-I . A third similarlyaffected patient had a defect in IGF-I synthesisresulting in production of a nonfunctioning IGF-Imolecule circulating in high concentration .The absence of the craniofacial phenotype ofsevere GH or GHR deﬁciency and the presence ofnormal IGFBP-3 in these patients, despite absentIGF-I function, indicate that the craniofacial fea-tures and low IGFBP-3 of GH and GHR deﬁciencyare related to an absence of the direct effects ofGH that do not act through the medium of IGF-Isynthesis. It is also noteworthy that profoundIUGR and mental retardation are not characteris-tic of GH or GHR deﬁciency, but IGF-I knockoutmice have defective neurological development aswell as growth failure. Thus, IGF-I production inutero does not appear to be GH-GHR dependent.A milder molecular defect in IGF-I synthesisdue to a homozygous missense mutation of theIGF-I gene has been described, resulting in IUGRand postnatal growth failure, undetectable IGF-Iby highly speciﬁc monoclonal assay but elevatedlevels with a polyclonal assay, microcephaly, andmild intellectual impairment, but with normalhearing .Mutations of the Acid-LabileSubunit GeneALS is an 85-kDa glycoprotein that modulatesIGF-I bioavailability by stabilizing the binarycomplex of IGF-I and IGFBP-3. It is a member ofa family of leucine-rich repeat (LRR) proteinsthat are able to participate in protein–proteininteractions; ~75% of the mature protein corre-sponds to the consensus motif for the LRR super-
352 Growth Hormone Insensitivityfamily. ALS is a donut-shaped molecule thatbinds readily to the binary complex of IGF-I andIGFBP-3, but does not interact directly with freeIGF-I and has low afﬁnity for IGFBP-3 that is notbound to IGF-I. Functional mutation of the ALSgene was ﬁrst reported in 2004 and by 2010included 21 individuals from 16 families, with 16discrete homozygous or compound heterozygousmutations noted [23–29]. ALS is undetectableand serum IGF-I and IGFBP-3 concentrations areextremely low. Nonetheless, statural impairmentis generally modest, with near adult or adultheight, available for 11 of the patients, being bet-ter than target height in one patient, less than 1SD below mean in an adopted child with unknowntarget height, and within 1.5 SD of target heightin 6 others. The modest, at worst, effect on growthdespite circulating concentrations of IGF-I thatare similar to those of severe GH insensitivity ordeﬁciency emphasizes the compensatory capabil-ity of local IGF-I production .Mutations of the IGF-I ReceptorMouse studies demonstrated that deletion of theIGF-I receptor resulted in intrauterine growthretardation and perinatal death. Thus, it is notsurprising that only heterozygous mutations inthe IGF-I receptor gene (IGF-IR) have beendescribed. The initial report of IGF-IR mutationfollowed systematic examination in two groupsof children with intrauterine growth retardation(IUGR) who remained greater than 2 SD belownormal for length after 18 months of age. Thispopulation was selected for study because IGF-Ireceptor knockout mice have more severe IUGRthan do IGF-I knockout mice. Among 42 US sub-jects who did not have low IGF-I and IGFBP3concentrations, a single patient was identiﬁedwith compound heterozygosity for mutations ofthe IGF-I receptor resulting in amino acid substi-tutions. She had severe IUGR (birth weight1,420 g at 38 weeks), poor postnatal growth, andelevated concentrations of IGF-I and integratedGH concentration when prepubertal, consistentwith IGF-I resistance. The location of the muta-tions was within a putative ligand-binding domainand the heterozygous parents were subnormal instature and also had low birth weight. In the samestudy, a European group of 50 IUGR subjectswas selected who had elevated circulating IGF-Iconcentrations and a second subject identiﬁed,who had a heterozygous nonsense mutationreducing the number of IGF-I receptors onﬁbroblasts; two other affected ﬁrst-degree rela-tives were identiﬁed . In all, 17 cases in 7families, each family with a unique mutation, hadbeendescribedby2010,withinvitroconﬁrmationof failure of IGF-I binding and function [31–36].There is wide phenotypic variability amongthese individuals, with height SDS ranging from−1.6 to −5.7, substantial delay in osseous matura-tion to normal bone ages for chronologic age andnormal timing of puberty, and normal to mark-edly increased serum concentrations of IGF-I andIGFBP3. The effect of IGF-I gene mutations onintrauterine growth, however, is uniformly repli-cated in this less severe circumstance.EpidemiologyRace/NationalityAmong the approximately 250 affected individ-uals identiﬁed worldwide with growth failuredue to GHR mutations, about two-thirds areSemitic and half of the rest are of Mediterraneanor South Asian origin. The Semitic groupincludes Arabs, Oriental, or Middle EasternJews, and the largest group, the geneticallyhomogeneous 90+ conversos in Ecuador (Jewswho converted to Christianity during theInquisition). The identiﬁcation of an Israelipatient of Moroccan origin with the E180 splicemutation found in the Ecuadorian patients indi-cated the Iberian provenance of this mutation,which readily recombined in the isolated com-munities of these sixteenth-century immigrantsestablished in the southern Ecuadorian Andes.Recently, additional patients with the E180splice mutation on the same genetic backgroundhave been identiﬁed in Chile and Brazil, likelyof the same origin. Among those who are not ofSemitic, South Asian, or Mediterranean origin,
36 A.L. Rosenbloomthere is wide ethnic representation, includingNorthern European, Eurasian, East Asian,African, and Anglo-Saxon (Bahamas) .The individuals with STAT5b mutation includeKuwaiti siblings, two unrelated Argentinians,siblings from Brazil, one patient from Turkey,and one patient from the Caribbean .ALS mutations were reported in three Kurdishbrothers, three unrelated and two sibling Spanishpatients, three Norwegian/German siblings, twounrelated Swedish patients, and individualpatients of Turkish, Argentinian, AshkenaziJewish, Pakistani, mixed European, and Mayanorigin. Families with heterozygous mutations ofthe IGF-I receptor were of Dagestani, European,and Japanese origin [23–29].IGF-I receptor mutations have been reportedfrom the USA, Germany, Russia, Korea, Japan,and the Netherlands [31–36].GenderAmong patients observed since the originaldescription of the GHR deﬁciency syndrome byLaron, Pertzelan, and Mannheimer in 1966 until 1990, a normal sex ratio was noted. The ini-tial report of 20 cases from a single province inEcuador included only one male , but subse-quent observations from an adjacent provinceindicated a normal sex ratio, and a few moremales were subsequently identiﬁed in the initialprovince . The abnormal sex ratio for thatlocus remains unexplained. All but 3 of the 21individuals with IGFALS mutations are male, butthis may reﬂect ascertainment bias because of therelatively modest effects on stature being of lessconcern in girls than in boys.Morbidity and MortalityThe only available report of the effect of GHRdeﬁciencyonmortalitycomesfromtheEcuadorianpopulation . Because families in the relativelysmall area from which the Ecuadorian patientsoriginate had intensive experience with this con-dition, lay diagnosis was considered reliable. Of79 affected individuals for whom informationcould be obtained, 15 (19%) died under 7 years ofage, as opposed to 21 out of 216 of their unaf-fected siblings (9.7%, p<0.05). The kinds of ill-nesses resulting in death, such as pneumonia,diarrhea, and meningitis, were no different foraffected than for unaffected siblings.The complete lifespan included in theEcuadorian cohort provided an opportunity tolook at adult mortality risk factors. Twenty-threeadults with GHD had elevated cholesterol levels,normal HDL-cholesterol levels, elevated LDL-cholesterol levels, and normal triglyceride con-centrations compared to relatives and nonrelatedcommunity controls. It was postulated that theeffect of IGF-I deﬁciency due to GHRD was todecrease hepatic clearance of LDL-C, becausethe triglyceride and HDL-C levels were unaf-fected. This effect was independent of obesity orof IGFBP-1 levels, which were used as a surro-gate for insulinemia. The key pathogenic factorwas thought to be the absence of GH inductionof LDL receptors in the liver . Preliminarydata suggest an increased cardiovascular mortal-ity in the Ecuadorian GHR-deﬁcient adult sub-jects. In contrast, there has been no deathrecorded from cancer, despite a high cancer mor-tality in relatives .Clinical Findings (Table 2.2)GrowthIndividuals with GHI due to GHR deﬁciencyusually have normal intrauterine growth .Nonetheless, IGF-I is required for normal intra-uterine growth as demonstrated by patients withIUGR with a proven IGF-I gene defect or IGFreceptor mutation. Thus, this intrauterine IGF-Isynthesis does not appear to be GH dependent.SDS for length declines rapidly after birth inGHR deﬁciency (Fig. 2.3) indicating the GHdependency of extrauterine growth. Growthvelocity with severe GH deﬁciency or GHRdeﬁciencyisapproximatelyhalfnormal(Fig.2.4).Occasional periods of normal growth velocitymay be related to improved nutrition.
372 Growth Hormone InsensitivityDespite normal sexual maturation, the puber-tal growth spurt is minimal or absent in GHRdeﬁciency, as documented in the most extensiveavailable data, from Israel and Ecuador [42, 43].The adolescent growth spurt is GH dependent,reﬂected in signiﬁcantly elevated circulating lev-els of GH and IGF-I compared to preadolescenceand adulthood .Adult stature in GHR deﬁciency varies from−12 to −5.3 SDS in Ecuadorian patients and −9to −3.8 SDS in others in the literature, using theUS standards . This is a height range of0–2–4–6–8–1–3–5–7–90 0.5 1.0 1.5 2.0 2.5 3.0Age in Years–10LengthStandardDeviationScoreFig. 2.3 Length standard deviation scores of nine girlsfrom Ecuador (open circles, solid lines) and two brothersfrom southern Russia (solid circles, dashed lines) withknown birth lengths, followed over the ﬁrst 2–3 years oflife [Adapted from Trends Endocrinol Metab, vol 5, #7,Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG,Pollock BH. Growth in growth hormone insensitivity, pp296–303, Copyright 1994, with permission from Elsevier]8410624 6 9 12 15 183 8 11 14 172 5 7 10 13 16 19Age (yrs)0HeightVelocity(cm/yr)Boys8410620Girls50th percentile3rd percentileFig. 2.4 Growth velocities of 30 Ecuadorian patients (10males) with GH receptor deﬁciency; repeated measureswere at least 6 months apart. Third and 50th percentilesare from Tanner JM, Davies PSW: Clinical longitudinalstandards for height and height velocity for NorthAmerican children. J Pediatr 1985; 107:317–329 [Adaptedfrom Trends Endocrinol Metab, vol 5, #7, RosenbloomAL, Guevara-Aguirre J, Rosenfeld RG, Pollock BH.Growth in growth hormone insensitivity, pp 296–303,Copyright 1994, with permission from Elsevier]
38 A.L. Rosenbloom95 cm to 124 cm for women and 106–141 cmfor men in the Ecuadorian population. Thiswide variation in the effect of GHR deﬁciencyon stature was not only seen within the popula-tion but also within affected families; suchintrafamilial variability has also been describedwith severe GH deﬁciency due to GH genedeletion .Some patients with GHR deﬁciency may havean appetite problem in addition to their IGF-Ideﬁciency. Crosnier et al.  studied a childaged 3½ years with GHR deﬁciency who hadsevere anorexia. With his usual intake of approxi-mately 500 kcal/day, he grew at a rate of 2 cm/year. With moderate hyperalimentation to approx-imately 1,300 kcal/day, growth rate increased to9 cm/year without signiﬁcant change in plasmaIGF-I level. The hyperalimentation period wasassociated with an increase in the IGFBP-3 bandson Western ligand blots, from total absence in theanorexic period to levels comparable to thoseseen in GH deﬁciency. The catch-up growthnoted could not be explained by hyperinsulinism,which has provided the explanation for acceler-ated or normal growth in children with GHdeﬁciency and obesity following removal of acraniopharyngioma. There was no appreciableincrease in circulating basal or stimulated insulinduring the hyperalimentation. In this patient,there was speculation that a nutrition-dependentautocrine/paracrine increase in IGF-I concentra-tion at the cartilage growth plate might haveoccurred, independent of the GHR. The impor-tance of adequate nutrition for catch-up growthwas emphasized by this study, which also rein-forced the notion that normal periods of growthin patients with GHR deﬁciency without IGF-Ireplacement therapy, as noted in Fig. 2.4, mightbe explained by periods of improved nutritionalone.Craniofacial CharacteristicsChildren with GHR deﬁciency are recognizedby knowledgeable family members at birthbecause of craniofacial characteristics of fron-tal prominence, depressed nasal bridge, andsparse hair, as well as small hands or feet andhypoplastic ﬁngernails. Decreased verticaldimension of the face is demonstrable by com-puter analysis of the relationships betweenfacial landmarks and is present in all patientswhen compared with their relatives includingthose without obviously abnormal facies .Blue scleras, the result of decreased thicknessof the scleral connective tissue, permitting visu-alization of the underlying choroid, were origi-nally described in the Ecuadorian populationand subsequently recognized in other popula-tions with GHR deﬁciency as well as in severeGH deﬁciency [38, 47]. Unilateral ptosis andfacial asymmetry may reﬂect positional defor-mity due to decreased muscular activity inutero, although mothers do not recognizedecreased fetal movement in pregnancies withaffected infants .As noted above, individuals with STAT5bmutations have growth impairment and facialdysmorphism indistinguishable from those withhomozygous or compound heterozygous GHRmutation. IGF-I mutations result in micrognathiaand microcephaly but no craniofacial abnormali-ties similar to those with GHR or STAT5bmutations.Musculoskeletal and Body CompositionHypomuscularity is apparent in radiographs ofinfants with GHR deﬁciency and is thought tobe responsible for delayed walking, despitenormal intelligence and timing of speech onset. Radiographs of the children also suggestosteopenia; dual-photon absorptiometry anddual-energy X-ray absorptiometry in childrenand adults conﬁrm this. A study of dynamicbone histomorphometry in adults with GHRdeﬁciency, however, demonstrated normal bonevolume and formation rate, with the only abnor-mality being reduction in trabecular connectiv-ity. This study suggested that some of thedensitometry ﬁndings were artifactual, due tothe small bone size .Limited elbow extensibility seen in mostpatients over 5 years of age in the Ecuadorian
392 Growth Hormone Insensitivitypopulation is an acquired characteristic, absentin younger children and increasing in severitywith age [38, 48]. That this feature is not pecu-liar to the Ecuadorian population or to IGF-Ideﬁciency due to GHR deﬁciency has beenconﬁrmed by ﬁnding a Brazilian patient having adifferent GHR mutation with limited elbowextension  and observing this ﬁnding in allbut the youngest patient in a family with eightindividuals affected by multiple pituitarydeﬁciencies . The cause of this elbow con-tracture is unknown.Although children appear overweight, theyare actually underweight to normal weight forheight, while most adults, especially females, areoverweight with markedly decreased lean to fatratios .ReproductionGHR deﬁciency is associated with small penissize with normal penile growth at adolescence orwith testosterone treatment in childhood.Although puberty may be delayed 3–7 years insome 50% of individuals, there is normal adultsexual function with documented reproductionby males and females . Females requireC-section delivery.Intellectual and Social DevelopmentGHR DeﬁciencyIntellectual impairment was originally consid-ered a feature of the Laron syndrome on thebasis of uncontrolled observations . Among18 affected children and adolescents tested withthe Wechsler Intelligence Scale for Children,only 3 had IQs within the average range [90–110]; of the remaining 15 subjects, 3 were in thelow average range [80–89], 3 in the borderlinerange [70–79], and 9 in the intellectually dis-abled range [<70]. These studies were donewithout family controls, so that the possibilityof other factors related to consanguinity thatmight affect intellectual development and theappropriateness of the testing materials in thisMiddle Eastern population could not beaddressed. In a follow-up study 25 years later,the investigators reexamined 8 of the original 18patients and 4 new patients with GHR deﬁciency,excluding 5 patients with mental disabilitieswho were in the original study . This grouphad mean verbal and performance IQs of 86 and92 on the Wechsler scale without evidence ofvisual motor integration difﬁculties that hadbeen noted in the earlier group, but there was asuggestion of deﬁcient short-term memory andattention. The investigators hypothesized thatearly and prolonged IGF deﬁciency mightimpair normal development of the central ner-vous system or that hypoglycemia common inyounger patients may have had a deleteriouseffect.Sporadic anecdotal reports of patients withGHR deﬁciency suggested a normal range ofintelligence. The collective data from theEuropean IGF-I treatment study group, whichincludes a wider range of clinical abnormalitythan either the Ecuadorian or Israeli population,notes a mental retardation rate of 13.5% among82 patients, but formal testing was not carriedout . Here again, the high rate of consan-guinity was proposed as a possible explanation;hypoglycemia could not be correlated with theseﬁndings.In the Ecuadorian population, exceptionalschool performance was reported among 51affected individuals of school age or older whohad attended school, with 44 typically in the top3 places in their classes and most thought to be asbright or brighter than the smartest of their unaf-fected siblings .The ﬁrst controlled documentation of intel-lectual function in a population with GHRdeﬁciency was in the Ecuadorian patients, astudy of school-age individuals compared totheir close relatives and to community controls.No signiﬁcant differences in intellectual abilitycould be detected among these groups, usingnonverbal tests with minimal cultural limita-tions. It was hypothesized that the exceptionalschool performance in this population mighthave been related to the lack of social opportuni-ties due to extreme short stature, permitting
40 A.L. Rosenbloomgreater devotion to studies and superior achieve-ment in school for IQ level .STAT5b Gene MutationConsistent with other evidence that the IGF-Idependence for intrauterine brain development isindependent of the need for an intact GH activa-tion pathway, individuals with STAT5b mutationsdo not have impaired brain development.IGF-I Gene MutationThere was marked intellectual impairment in thepatients with severe IGF-I deﬁciency due tomutation of the IGF-I gene, indicative of thedependence of intrauterine brain development, aswell as intrauterine growth, on IGF-I. That thisintrauterine IGF-I production is not dependent onGH is suggested by the intellectual normalitywith severe GH and GHR deﬁciency, consistentwith gene disruption studies in mice. The IGF-I-deleted mouse is neurologically impaired, whilethe GHR-deﬁcient mouse is behaviorally normal[56, 57]. Thus, GH-dependent IGF-I productionis not necessary for normal brain developmentand function.IGF-I Receptor MutationThe effect of heterozygous IGF-I receptor muta-tion on head growth and brain development isless impressive than with IGF-I gene defects.Small head size was recorded frequently, includ-ing in a proband with above-average IQ and herdaughter with slight motor delay at 1½ years ofage. Except for one individual with a reported IQof 60, intellectual development of the otherprobands ranged from normal to mild retardation[31–36].IGFALS MutationNormal neurological development with IGFALSmutation would be expected, consistent with nor-mal brain development in children with severeGH or GHR deﬁciency who would not be stimu-lating intrauterine synthesis of ALS. This wouldimply that the GH-independent IGF-I productionnecessary for normal intrauterine somatic andbrain growth is local (paracrine/autocrine) ratherthan endocrine.Biochemical FeaturesGrowth HormoneAffected children with GHR deﬁciency have ran-dom GH levels that are greater than 10 ng/ml andmay be as high as 200 ng/ml, with enhancedresponsiveness to stimulation and paradoxicalelevations following oral and intravenous glu-cose, as is seen in acromegaly . The GH lev-els show normal diurnal ﬂuctuation .Twenty-four-hour proﬁles demonstrate markedGH variability among adult patients with sup-pression by exogenous recombinant human IGF-I. Thus, the normal sensitivity of the GH secre-tion is preserved, despite lifelong elevated GHlevels and lack of feedback suppression fromIGF-I.Postpubertal patients with GHR deﬁciencymay have normal or elevated basal levels of GHbut invariably demonstrate hyperresponsivenessto stimulation, which is all the more impressiveconsidering their obesity, which suppresses GHresponsesinnormalindividuals.IntheEcuadorianpopulation, mean basal GH level in adults wassigniﬁcantly lower than that in children(11+11 ng/ml versus 32+22 ng/ml, p<0.0001).This is thought to be related to the greater, thoughstill markedly abnormal, IGF-I levels in theadults, resulting in some feedback inhibition ofGH secretion [7, 48].ALS mutations are associated with normalGH levels, despite very low circulating IGF-Iconcentrations. IGF-I receptor deﬁciency, whichisanIGF-I-resistantstate,ratherthanGH-resistantstate, can also be associated with normal GHlevels.Growth Hormone-Binding ProteinAbsence of GHBP in the circulation was initiallyconsidered a requirement for the diagnosis ofGHR deﬁciency, along with the clinical pheno-type, very low concentrations of IGF-I andIGFBP-3, and elevated (in children) or normal toelevated (in adults) GH levels. Chromatographic
412 Growth Hormone Insensitivityanalysis for serum GHBP, however, showedmeasurable though reduced levels in a number ofpatients. The ligand-mediated immunofunctionassay (LIFA) used to measure GHBP serum lev-els since 1990 uses an anti-GH monoclonal anti-body to measure the amount of GH bound toGHBP. As a largely functional assay, this shouldnot detect structurally abnormal though expressedGHBP.As noted above, certain genetic defects in theGHR, those affecting dimerization or anchoringof the GHBP to the cell membrane and dominantnegative mutations of the cytoplasmic domain,can result in normal or markedly elevated GHBPlevels. In the Ecuadorian population, despitein vitro evidence for failure of production of nor-mally spliced receptor, 4 children and 4 adultsout of 49 patients had serum GHBP levels higherthan 40% of the sex-speciﬁc lower limit for con-trols, and one adult male had a level in the lowerportion of the normal adult male range. The pres-ence or amount of GHBP measured did not relateto stature . There were no age-dependentchanges, indicating that the difference in IGF val-ues between children and adults was not relatedto the GHBP levels and the GHBP levels did notcorrelate with stature or with serum IGF-I levels.Although ﬁnding of extremely low or undetect-able levels of GHBP serves as an important diag-nostic feature, it is not a sine qua non for thediagnosis of GHR deﬁciency.Insulin-Like Growth FactorsThe lowest serum levels of IGF-I are seen insevere congenital defects in GH synthesis (GHgene deletion, GHRH-R deﬁciency), with dele-tion of the IGF-I gene and with GHR deﬁciency.IGF-II is not as severely suppressed, its reductionlikely related to diminution of GHBP-3 ratherthan to decreased synthesis. In chronic diseasestates associated with acquired GHI, IGF-I levelsare more likely to be reduced than are concentra-tions of IGF-II and IGFBP-3.Among 50 Ecuadorian patients homozygousfor the E180 splice-site mutation, IGF-I levelswere signiﬁcantly greater in adults 16–67 yearsof age (n=31, 25+19 mcg/L) than in the 19subjects under 16 years of age (3+2 mcg/L,p<0.0001), although still markedly below thenormal range of 96–270 mcg/L. The children’slevels were too low to correlate with stature, butin the adults, IGF-I levels correlated inverselywith statural SDS with a coefﬁcient of 0.64(p<0.001). IGF-II levels in adults were alsosigniﬁcantly greater than in children(151+75 mcg/L versus 70+42 mcg/L, normal388–792 mcg/L, p<0.0001). The correlationbetween serum IGF-I and IGF-II levels washighly signiﬁcant, r=0.53, p<0.001. With noindication of age difference in GHBP levels, theincreased levels of IGF-I and IGF-II with adult-hood suggests effects on synthesis of these growthfactors which are not mediated through the GHRand initially thought to be under the inﬂuence ofsex steroids. This hypothesis was challenged byﬁndings in patients with GHRH resistance due tomutation of the GHRH receptor. Sexually matureindividuals with GHRH receptor mutation andaffected children have comparably very lowIGF-I (and IGFBP-3) serum concentrations .The correlation of IGF-I levels with stature inadults with GHR deﬁciency indicates that, despitethe markedly low levels, the inﬂuence of IGF-Ion stature remains important in these subjects.IGF-Binding ProteinsIn IGF deﬁciency states that are the result ofGH or GHR deﬁciency, IGFBP-3 is reduced,and as noted above, in children and adults withGHR deﬁciency, this reduction correlates withstatural impairment . In renal disease, ele-vated IGFBP-3 and IGFBP-1 and IGFBP-2 arethought to impair the delivery of normal levelsof IGF-I .Short-term and extended treatment of GHIwith IGF-I has failed to result in increases inIGFBP-3 [7, 60–64], whereas treatment of GHDwith recombinant human GH restores levels tonormal. This indicates that IGFBP-3 productionis under the direct inﬂuence of GH.IGFBP-1iselevatedinGHandGHRdeﬁciency;in GHR deﬁciency, it is the most abundant IGFBP
42 A.L. Rosenbloomand is strongly inversely related to insulinemia.IGFBP-2 is present at a mean 300% of controlconcentrations in children with GHR deﬁciencyand 175% of control in affected adults, asigniﬁcant difference. The IGFBP-3 levels inadults with GHR deﬁciency are signiﬁcantlygreater than those in affected children .Diagnostic Issues in GH InsensitivityGHI due to deﬁciency is readily diagnosed in itstypical and complete form because of severegrowth failure, the somatic phenotype of severeGH deﬁciency, elevated serum GH levels, andmarked reduction in IGF-I, IGF-II, and IGFBP-3concentrations, with increased concentrations ofIGFBP-1 and IGFBP-2. Most such individualswill also have absent to very low concentrationsof GHBP, although the less common GHBP-positive forms make absence of GHBP an impor-tant but not essential criterion. As noted inTable 2.1, some of the biochemical features ofGHR deﬁciency may be shared by conditionsassociated with acquired GH insensitivity, suchas malnutrition and liver disease.The demonstration of a homozygous muta-tion or a compound heterozygous mutationaffecting the GHR usually provides deﬁnitivediagnosis. Thirty-one of the 82 patients reportedby Woods et al.  had a genetic study of theGHR, of whom 27 had abnormalities affectingboth alleles of the GHR gene, in associationwith clinically and biochemically unequivocalGHR deﬁciency. Identiﬁcation of heterozygousmutations, however, is not necessarily helpfulbecause, as noted earlier, polymorphisms havebeen described which appear to have no pheno-typic consequences.Partial GH ResistanceGH resistance might be expected to occur in anincomplete form, analogous to insulin resistance,androgen insensitivity, or thyroid hormone resis-tance. Affected children might have growth fail-ure with normal or slightly increased GHsecretion, variable but usually decreased GHBPlevels, and decreased IGF-I concentrations, butnot as severely reduced as in GH or GHRdeﬁciency, and might respond to supraphysio-logic doses of GH. It might also be expected,given the need for dimerization of the GHR forsignal transduction, that certain mutations couldhave a dominant negative effect in the heterozy-gous state.Credibility for a heterozygous defect as acause of short stature requires the demonstrationof functional signiﬁcance, not only by transfec-tion of the mutant allele, but by cotransfectionwith wild-type GHR gene, to approximate thecircumstance in vivo. Goddard et al. identiﬁed six mutations in eight children withshort stature (SDS for height −5.1 to −2.0) andnormal or increased stimulated GH levels. Onepatient had compound heterozygosity involving anovel mutation in exon 4 (E44K) and a mutationin exon 6 previously associated with GHRdeﬁciency in the homozygous state (R161C).Two other patients were heterozygous for thismutation. The other ﬁve patients included twowho were heterozygous for the same novel muta-tion in exon 7 (R211H) and one each with novelmutations of exon 5 (C122X), exons 7 (E224D),and exon 10 (A478T). Expression in vitro ofthese four novel mutations involving the extracel-lular domain has shown functional effects,although cotransfection studies have not beenreported. The defect involving exon 10 has notbeen expressed in vitro. Other defects withoutdemonstrable signiﬁcance have been describedinvolving exon 10. None of these putative partialGHI patients had the clinical phenotype of GHdeﬁciency. Five of the eight patients were treatedwith GH with variable improvement in growthvelocity, from slight to dramatic, in the ﬁrst year.This variable response is typical of that seen withrecombinant GH treatment of idiopathic shortstature (ISS).The subjects studied by Goddard et al. were selected from the large Genentech NationalCooperative Growth Study database in pursuit ofthe question raised by the observation that GHBPconcentrations are low in children with ISS, thatis, short children without a recognizable syndrome
432 Growth Hormone Insensitivityor GH deﬁciency. Using a ligand-mediatedimmunofunction assay, Carlsson et al.  stud-ied a large number of short children with knowncauses of growth failure such as GH deﬁciencyand Turner syndrome, or ISS, and compared theirGHBP concentrations in serum to those of nor-mal controls. Ninety percent of the children withISS had GHBP concentrations below the controlmean and nearly 20% had concentrations thatwere 2 standard deviations or more below thenormal mean for age and sex. In a further analy-sis of the ISS group in this database, Attie et al. identiﬁed over 500 patients who had beentreated with rhGH and had normal GH stimula-tion tests, of whom, as noted above, 20% had lowGHBP concentrations. While those with the lowGHBP levels had signiﬁcantly lower IGF-I con-centrations and higher mean 12-h serum GH lev-els, the GH differences were numericallyunimpressive (2.8 mg/L+1.1 versus 2.3+1.1).Particularly relevant to the supposed GH resis-tance, there was no correlation of GHBP levelswith the growth response to exogenous GH inthese patients. The search for defects in the GHRto explain ISS in the 100 subjects with low GHBPyielded 7 heterozygous mutations, but in studiesof the families of these children, short stature didnot segregate with the heterozygous state.More recently, the Genentech database wasanalyzed for evidence of GH insensitivity among~5,000 patients entered between 1993 and 1996,with short stature (height standard deviationscore<−2) being treated with GH. Over 40%were deemed IGF-I deﬁcient, and half of these tohave the novel diagnosis of “primary IGF-Ideﬁciency,” that is, normal GH responses withlow IGF-I. The ISS group as a whole had a simi-lar growth response to GH as did GH-deﬁcientpatients during the ﬁrst year of treatment, withgrowth response correlating inversely with IGF-Ibaseline levels, exactly the opposite of the corre-lation that would be expected if they had GHinsensitivity . This evidence of GH sensitiv-ity in the presence of low IGF-I concentrations isconsistent with the observation that the growthresponse to rhGH in children with ISS who havelow levels of IGF-I is greater than in those withmore normal levels  and with the lack ofcorrelation of growth response to GH in ISS rela-tive to peak stimulated GH levels.What cannot be appreciated from such a cross-sectional analysis of data from hundreds of pedi-atric endocrinologists is the clinical context inwhich the biochemical measures were obtained.Decreased circulating IGF-I with normal or ele-vated GH levels occurs with chronic illness andundernutrition. Many of the children seen withwhat is termed ISS are poor eaters with decreasedbody mass index and may be receiving treatmentfor hyperactivity which can suppress appetite andgrowth. Even acutely, IGF-I levels decline sub-stantially with fasting, which is considered ameans of protecting against potential insulin-likeeffects on glycemia. Clinical investigations ofchildren with ISS and varying responses to GHstimulation tests or IGF-I generation tests (inwhich GH is given for several days to stimulateIGF-I synthesis) have indicated that GH insensi-tivity is, at most, an uncommon ﬁnding .Nonetheless, promotional efforts and clinicalinvestigations have been based on the hypothesesthat much, if not most, ISS was due to IGF-Ideﬁciency as the result of GH insensitivity andthat exogenous IGF-I was appropriate growth-promoting therapy . These hypotheses werenot data based and disproven by the manufactur-ers’ clinical trial data in which subjects had dubi-ous IGF-I deﬁciency, normal GH sensitivity, andresponses to rhIGF-I in relation to bone ageadvance which were no different than in controluntreated subjects [72, 73].The possibility of an effect of heterozygosityfor a mutation which causes GHR deﬁciency inthe homozygous state was explored in the uniqueEcuadorian cohort with a single mutation, per-mitting genotyping of numerous ﬁrst-degree rela-tives. There was a minor difference in staturebetween carrier and homozygous normal rela-tives, and no difference in IGF-I or IGFBP-3 con-centrations, indicating minimal, if any, inﬂuenceof heterozygosity for the E180 splice mutation ofthe GHR . A more general indication of thelack of inﬂuence of heterozygosity for GHRmutations involving the extracellular domain ongrowth comes from studies of the large multi-center European-based GHI study .
44 A.L. RosenbloomIn both the European and Ecuadorian popula-tions, the stature of parents and of unaffected sib-lings does not correlate with statural deviation ofaffected individuals, while expected high correla-tion exists between parents and unaffected off-spring. If the mutations that cause growth failurein the homozygous state also affected growth inheterozygotes, heterozygous parents and pre-dominantly heterozygous siblings would haveheight SDS values which correlated with those ofaffected family members. In the Ecuadorian fam-ilies, there was no difference in height correla-tions with parents between carriers andhomozygous normal offspring.TreatmentSoon after the cloning of the human IGF-I cDNA,human IGF-I was synthesized by recombinantDNA techniques (rhIGF-I) and physiologic stud-ies undertaken with intravenously administeredrhIGF-I . Subcutaneous preparations ofrhIGF-I became available in 1990.GHR DeﬁciencyDuring administration of rhIGF-I at a dose of40 mg/kg sc every 12 h over 7 days to 6 Ecuadorianadults with GHR deﬁciency, hypoglycemia wasavoided by having the subjects eat meals after theinjections . Elevated 24-h GH levels typical ofthe condition were rapidly suppressed, as wasclonidine-stimulated GH release. Mean peakserum IGF-I levels were 253±11 ng/ml reachedbetween 2 and 6 h after injection and mean troughlevels were 137±8 ng/ml before the next injec-tion, values not different from those of normalcontrol Ecuadorian adults. Although IGFBP-3levels did not increase, elevated baseline IGFBP-2levels (153% of control) increased 45% (p<0.01).The short-term studies demonstrated that therewas an insigniﬁcant risk of hypoglycemia despitelow levels of IGFBP-3. There remained, how-ever, concern whether the low IGFBP-3 levelswould result in more rapid clearance of IGF-I,with blunting of the therapeutic effect.The initial report of treatment for longer than10 months was in 2 children with GHR deﬁciencywho had height velocities of 4.3 and 3.8 cm/year at8.4 and 6.8 years of age. Their elevated serum GHlevels were suppressed and serum procollagen-Ilevels increased shortly after starting treatment;6-month height velocities increased to 7.8 and8.4 cm/year, but in the second 6 months of treat-ment, the velocities decreased to 6.6 and 6.3 cm/year and in the subsequent 5 months returned topretreatment values. These patients were treatedwith a dose of 40 mcg/kg subcutaneously twicedaily (bid) and the waning of their growth responseafter a year suggested that this dosage was notadequate for sustained effect .The ﬁrst IGF-I treatment report from the largeEcuadorian cohort was of growth and body com-position changes in two adolescent patientstreated with a combination of IGF-I (120 mcg/kgbid) and long-acting gonadotropin-releasing hor-mone analog to forestall puberty. A girl aged 18and boy aged 17 years, with bone ages of 13½and 13 years, experienced an approximate tri-pling of growth velocity, increased bone mineraldensity, and maturation of facial features withrhIGF-I treatment for 1 year. There was initialhair loss followed by recovery of denser and curlyhair with ﬁlling of the frontotemporal baldness,the appearance of axillary sweating, loss ofdeciduous teeth, and appearance of permanentdentition. They had coarsening of their facial fea-tures. Submaxillary gland enlargement was notedin one patient and fading of premature facialwrinkles in the other patient. Serum IGF-I levelsincreased into the normal range for age duringthe 2–8 h following IGF-I sc injection .Studies were done at doses of 40, 80, and120 mcg/kg with pharmacokinetic proﬁles sug-gesting a plateau effect between 80 and 120 mcg/kg per dose. It was considered that the carryingcapacity of the IGFBPs was saturated at thislevel. Mean serum IGF-II levels decreased con-currently with the increase in IGF-I, and serumIGFBP-3 levels did not respond to prolongedIGF-I treatment. There was no apparent changein the half-life of IGF-I during the treatmentperiod, indicating no alteration of IGF-I pharma-cokinetics induced by prolonged treatment.
452 Growth Hormone InsensitivitySeventeen prepubertal Ecuadorian patientswere entered into a randomized double-blind,placebo-controlled trial of IGF-I at 120 mcg/kgsc bid for 6 months, following which all subjectsreceived IGF-I. Such a study was considerednecessary because of the observation of sponta-neous periods of normal growth in these young-sters, the suggestion that nutritional changes thatmight accompany intervention would be an inde-pendent variable, and the need to control for sideeffects, particularly hypoglycemia, which occurin the untreated state. The nine placebo-treatedpatients had a modest but not signiﬁcant increasein height velocity from 2.8+0.3 to 4.4+0.7 cm/year, entirely attributable to three individualswith 6-month velocities of 6.6–8 cm/year.Although this response was attributed toimproved nutritional status, there was no accom-panying increase in IGFBP-3 as noted withnutrition-induced catch-up growth in the FrenchGHR-deﬁcient patient with anorexia . Forthose receiving IGF-I, the height velocityincreased from 2.9+0.6 to 8.8+0.6 cm/year andall 16 patients had accelerated velocities duringthe second 6-month period when all were receiv-ing IGF-I. No changes or differences in circulat-ing IGFBP-3 concentrations were noted. Therewas no difference in the rate of hypoglycemiaevents, nausea or vomiting, headaches, or pain atthe injection site between the placebo and IGF-I-treated groups. Initial hair loss occurred in 90%of subjects, similar to what is seen with treat-ment of hypothyroidism, reﬂecting more rapidturnover .In the 2-year treatment study comparing120 mg/kg bid dosage to 80 mg/kg bid treatmentof GHR deﬁciency in Ecuadorian patients, no dif-ferences in growth velocity or changes in heightSDS, height age, or bone age between the twodosage groups (Table 2.3). A group of six sub-jects receiving the higher dose followed for athird year continued to maintain second-yeargrowth velocities. The annual changes in heightage in both the ﬁrst and the second year of treat-ment correlated with IGF-I trough levels whichtended to be in the low normal range despite afailure of serum IGFBP3 levels to increase(Fig. 2.5). The comparable growth responses tothe two dosage levels and the similar IGF-I troughlevels conﬁrmed the plateau effect at or below80 mcg/kg body weight twice daily observed inthe ﬁrst two patients [63, 77].The Israeli report of 3 years’ treatment of ninepatients is the only one in which patients weregiven IGF-I as a single daily dosage (150–200 mg/kg) . The European study group noted heightTable 2.3 Treatment with rhIGF-I for 1–2 years of children with GH insensitivityEurope  Ecuador  Israel  International Number 26a7 15 9 56bAge (years) 3.7–19.6 3.1–15.2 4.7–17.1 0.5–14.6 1.7–17.5Dose (/kg) 40–120 mg bid 80 mg bid 120 mg bid 150–200 mg/d 60–125 mg bidHt velocity—cm/year (SD)Pre-Rx N/A 3.0 (1.8) 3.4 (1.4) 4.7 (1.3) 2.8 (1.8)Year 1 8.8 (1.9)c9.1 (2.2) 8.8 (1.1) 8.2 (0.8) 8.0 (2.2)Year 2 7 (1.4)c5.6 (2.1) 6.4 (1.1) 6.0 (1.3)d5.8 (1.5)eHeight SDS (SD)Pre-Rx −6.5 (13)c−8.0 (1.8) −8.5 (1.3) −5.6 (1.5) −6.7 (1.8)Year 1 −5.8 (1.5)c−7.2 (1.8) −7.5 (1.1) −5.2 (1.7) −5.9 (1.8)Year 2 −5.4 (1.8)c−6.7 (1.4) −7.0 (1.2) −5.8 (1.2)d−5.6 (1.8)eaIncludes 2 patients with GH-neutralizing antibodiesbIncludes 8 patients with GH-neutralizing antibodiescFor 15 subjects treated for 4 yearsdFor 6 of the 9 subjectse48 subjects
46 A.L. RosenbloomSDS improvement of 0.7 over 1 year and 1.2 over2 years , and the Ecuadorian patients had animprovement of 1 SDS over 1 year and 1.5 over 2years at the higher dose and 0.8 SDS over 1 yearand 1.3 SDS over 2 years at the dosage of 80 mcg/kg twice daily. The Israeli patients had animprovement in height SDS of only 0.4 over 1year and for the six patients with 2-year data, 0.2over 1 year and 0.4 over 2 years. The kinetic stud-ies that originally formed the rationale for twice-daily administration were supported by theseobservations.The collective experience of treating the rareconditions in which responsiveness to GH isseverely impaired includes approximately 150individuals, mostly with GHR deﬁciency, andfewer than 10% with GH inactivating antibodies(Table 2.3). The growth velocity increment in theﬁrst year was 4.3 cm in the European and mecaser-min (Genentech/Tercica) study populations and 5.6 cm in the Ecuadorian population, allgroups receiving comparable doses of rhIGF-Iadministered twice daily. In the Israeli populationgiven a single injection of a comparable total dailydose, the increment was only 3.6 cm/year. HeightSDS improvement in the ﬁrst year of treatmentparalleled these increments at 0.7, 0.8, and 0.6 forthe twice-daily rhIGF-I in the European,Ecuadorian, and International-mecasermingroups, respectively, and 0.2 for the Israeli popu-lation. The stimulatory effect on growth wanesrapidly after the ﬁrst year, with only modest con-tinued improvement. Among 76 patients treatedfor a mean 4.4 years, overall height SDS improve-ment was 1.4, almost all of which was achieved inthe ﬁrst 2 years of treatment .Comparison of the growth response of 22rhIGF-I-treated GHR deﬁciency patients and11 GH-treated GH-deﬁcient patients in thesame setting demonstrated mean growth veloc-ity increment in those with GHR deﬁciency tobe 63% of that achieved with GH treatment ofGH deﬁciency in the ﬁrst year and less than50% in the second and third years (Table 2.3).The inadequate growth response compared toGH treatment of GH deﬁciency persisted overthis extended treatment period, with a meanimprovement in height SDS of only 1.4, from−5.6 to −4.2, thus only sustaining the improve-ment of the ﬁrst 2 years of treatment, as notedin Table 2.3. The importance of GH effectsbeyond hepatic IGF-I, IGFBP-3, and ALS syn-thesis is conﬁrmed by this experience withattempted IGF-I replacement therapy in whichonly endocrine IGF-I can be replaced .Near-total deletion of the GHR in liver only inthe mouse model had no effect on total bodyor bone linear growth .Limitations of Endocrine IGF-IReplacementThe observation that growth failure due to GHinsensitivity cannot be adequately correctedwith endocrine IGF-I replacement is notexplained by concomitant IGFBP3 deﬁciency.Substantial tissue delivery is reﬂected in pro-found effects on adipose tissue, facies, and lym-phoid tissue in treated patients (see below). Thisindicates that twice-daily injection provides60050030010040020000 0.5 1.0 1.5 2.0 2.5Change in Height Age (years)IGF-I(ncg/L)1 year2 yearFig. 2.5 Correlation of annual changes in height age anddifferences between baseline and trough levels of serumIGF-I with rhIGF-I treatment in 22 children with GHRD.The dashed line represents the 1-year correlation (r=0.54,p=0.009) and the solid line represents the 2-year correla-tion (r=0.58, p=0.005) [Adapted from The Journal ofEndocrinology and Metabolism, Two year treatment ofgrowth hormone receptor deﬁciency (GHRD) with recom-binant insulin-like growth factor-I in 22 children:Comparison of two dosage levels and to GH treated GHdeﬁciency. 82 (2), February 1997, pp 629–633. Copyright1997, The Endocrine Society]
472 Growth Hormone Insensitivitymore than adequate replacement of endocrineIGF-I, despite both IGFBP-3 and ALS deﬁciencywhich are not corrected by IGF-I treatment. Themaintenance of circulating levels of IGF-Idespite severe IGFBP-3 and ALS deﬁciencymay be the result of binding to other IGFBPs;IGFBP-2 is elevated in GHR deﬁciency andincreases further with rhIGF-I therapy .If the tissue dose of IGF-I in patients with GHItreated with IGF-I is supraphysiologic, as indi-cated by increases in body fat and acromegaloidfacial changes, why then do we not see sustainedgrowth acceleration as in GH-treated GHdeﬁciency? The dual-effector hypothesis remainsthe best explanation for inadequate growthresponse . With diminished ability to stimulateprechondrocyte differentiation and local IGF-Iproduction, children with GHI can expect onlypartial recovery of normal growth with IGF-Ireplacement. Thus, IGF-I replacement therapy ofGI may need to continue longer than GH treat-ment of GH deﬁciency to achieve more normalheight. This goal will likely require suppressingadolescence in most children with GHI, usingGnRH analogs .In addition to statural attainment, goals ofreplacement therapy with IGF-I in GHI includeimprovement in body composition, normaliza-tion of facial appearance, and possible reductionof risk factors for childhood and adult mortality.All studies that have monitored body composi-tion have veriﬁed lean mass increases, includingincreased bone density. Unlike GH replacementtherapy, however, which restores normal lipoly-sis, IGF-I therapy is lipoatrophic, increasing orsustaining the high-percentage body fat.Normalization of craniofacial features has alsobeen apparent . Voice change has not beenremarked on but can be expected.The reduction of risk factors for the highermortality in infancy and childhood with GHRdeﬁciency is to be expected with IGF-I therapy,but the reason for this increased risk is unknown.Leukocytes share in the general upregulation ofIGF-I receptors in GHR deﬁciency and appear tofunction normally in this condition . In astudy of one affected infant (who died at 7 monthswith bronchitis) and ﬁve adults with GHRdeﬁciency from Ecuador, Diamond et al. demonstrated a variety of immune disturbancesin the infant and three of the adults. The patho-logic signiﬁcance of these ﬁndings remainsuncertain .Purported Partial GHIThe deﬁnition adopted by the FDA for “severeprimary IGFD” was height SDS<−3, basal IGF-ISDS<−3, and normal or elevated GH concentra-tion. Growth velocity, osseous maturation, orprojected height relative to mean parental stature,factors that are important in clinical evaluation ofshort children, were not considered. Youngerchildren may have quite low values for IGF-I thatare not diagnostically useful, and at any age, asingle measurement may vary considerably froma subsequent determination. There is also incon-sistency between laboratories, and normal rangesvary widely. In one analysis, three of four labora-tories failed to identify 15–20% of Ecuadorianpatients with molecularly proven GHRD usingthe FDA criterion for IGF-I concentration<−3SD. Values may be spuriously low as a result ofhigh susceptibility of IGF-I to post sampling pro-teolysis . Children, especially boys, withconstitutional delay in growth and maturation(CDGM), who do not have biochemical markersof undernutrition, may be hypermetabolic andhave mean IGF-I concentrations that are only40% of those of normal age-mates, which couldlead to an inappropriate diagnosis of IGFD .This interpretation may be artifactual because ofcomparison to norms for chronologic age ratherthan biologic (bone) age.Further insight into the wide variability inIGF-I concentrations in the absence of endocrinedeﬁciency comes from a study comparing Africanand Italian children of comparable height butwith the African children having signiﬁcantlylower weight and BMI and mean IGF-I andIGFBP-3 levels <1/3 those of the Italian children. Wide ﬂuctuations in IGF-I concentrationscan be seen in normal prepubertal children,including levels <2 SDS . Finally, IGF-I gen-eration tests have poor reproducibility .
48 A.L. RosenbloomThe off-label promotion of rhIGF-I has beenbased on two considerations which are not evidencebased: that many children with ISS have partial GHinsensitivity and that appropriate therapy for theseindividuals is recombinant IGF-I. The absence ofconvincing evidence for this hypothesis, the limitedability of endocrine IGF-I to restore normal growthin those with unequivocal GH unresponsiveness,the suppression of local GH effects on growth withIGF-I administration, the risk proﬁle, and theabsence of data on efﬁcacy in other than provensevere GH insensitivity led the Drug andTherapeutics Committee of the Lawson WilkinsPediatric Endocrine Society to conclude thatrhIGF-I use is only justiﬁed in conditions approvedby the US Food and Drug Administration (FDA)and that use for growth promotion in other childrenshould only be investigational . The manufac-turer of IGF-I “estimates that approximately 30,000children in the US are affected by primary IGFD,which is also similar to the estimated [EuropeanUnion] EU market size” . Considering thatfewer than 200 children with GH insensitivity dueto GHRD, transduction defects, or GH-inhibitingantibodies had been identiﬁed worldwide in the pre-vious 20 years, it is apparent that there was exuber-antanticipationandextensivepromotionofoff-labeluse. Indeed, current clinical trials demonstrate theloosening of criteria from those in the approval byFDA [www.clinicaltrials.gov].In January 2008, Tercica announced that theyhad begun dosing the ﬁrst patient in a phase IIclinical trial evaluating the combination of GHand IGF-I in a study that was scheduled for com-pletion at the end of 2011 to involve 100 subjectsover 5 years of age. This is a four-arm studyinvolving rhGH alone in a dose of 45 mg/kg dailyand the same dose of GH with once-daily injec-tions of either 50, 100, or 150 mg/kg IGF-I.Inclusion requires height SDS£−2 (which is lessstringent than the criterion of SDS£−2.25 forGH treatment of ISS) and IGF-I SDS £1, alongwith normal response to GH stimulation testing,and bone age £11 years for boys and £9 years forgirls. There are no growth velocity criteria. Thisstudy was likely to include a substantial numberof children, especially males, with CDGM, themost common explanation for short stature in thegrowth clinic, and other normal short children. Itis noteworthy that there was not an IGF-I mono-therapy arm and that the IGF-I was given as a sin-gledailyinjectionincontrasttothepharmacokineticstudies and clinical experience with this drug.There is no reason to expect better growthresponse with IGF-I in patients who do not haveproven insensitivity to GH than with recombinantGH, based on the absence of evidence of GHresistance as a cause of their short stature. In fact,monotherapy with IGF-I in individuals who havenormal or even somewhat reduced GH produc-tion and action should result in suppression ofendogenous GH, which occurs rapidly withrhIGF-I administration in both normal and GHRDsubjects . This GH suppression will reduceIGFBP-3 and ALS production and, most impor-tantly, decrease GH delivery to growing bone,with reduction of chondrocyte proliferation andautocrine/paracrine IGF-I production, potentiallydecreasing growth velocity.Datapresentedbythemanufacturerofmecaser-min in 2009 provided evidence that countered thenotion that “primary IGFD” due to partial GHIwas a valid diagnosis. In their clinical trial of indi-viduals carrying this supposed diagnosis, supra-physiologic doses of IGF-I were required,resulting in circulating IGF-I levels of +2 SDS, toobtain a growth effect; thus, a pharmacologicrather than physiologic replacement therapy wasrequired, which would be inconsistent withreplacement therapy for primary IGFD. Alsoinconsistent with the diagnosis of primary IGFDwere the normal baseline growth velocities inthese subjects. When these subjects underwentIGF-I generation tests (administration of GH for 5days), there was a 76.5% increase in mean IGF-Ilevel and 34% increase in mean IGFBP-3 concen-tration . Both of these are approximately 50%greater responses than in normals and indicativeof better than normal GH sensitivity.Safety Concerns with Recombinant IGF-IEpisodes of hypoglycemia which may be severeare common in infants and children with GHRdeﬁciency. In contrast to the far less common
492 Growth Hormone Insensitivityhypoglycemia of GH deﬁciency which is cor-rected by GH replacement therapy, IGF-I treat-ment increases the risk of hypoglycemia inchildren with GHR deﬁciency. Hypoglycemiahas been the most common early adverse event,reported in 49% of subjects in the largest series,including 5% with seizures . In the 6-month,placebo-controlled Ecuadorian study, hypoglyce-mia was reported in 67% of individuals receivingplacebo and 86% of those treated with rhIGF-I,an insigniﬁcant difference . Finger-stickblood glucose measurements in 23 subjects resid-ing at a research unit indicated frequent hypogly-cemia before breakfast and lunch, which did notincrease in frequency with rhIGF-I administra-tion . Five of the subjects participated in acrossover, placebo-controlled study for 6 monthswith a 3-month washout period with fasting glu-cose determinations performed three times dailyby caregivers for the entire 15-month study. Thepercentage of glucose values <50 mg/dL was2.6% with placebo and 5.5% with rhIGF-I, not asigniﬁcant difference. In practice, hypoglycemiaassociated with IGF-I treatment appears reason-ably controllable by adequate food intake.Pain at the injection site is common. Injectionsite lipohypertrophy is frequent, affecting at leastone-third of subjects; this is the result of failureto rotate injections and injection into the lumps,which can attenuate growth response. The inotro-pic effect of IGF-I results in asymptomatic tachy-cardia in all treated patients, which clears afterseveral months of continued use . Benignintracranial hypertension or papilledema has beennoted in approximately 5% of IGF-treated sub-jects. While headache is frequent, the placebo-controlled study found no difference in incidencebetween those receiving placebo injections andthose receiving IGF-I. Parotid swelling and facialnerve palsy have been described. Lymphoid tis-sue hypertrophy occurs in over 25% of patients,with hypoacusis, snoring, and tonsillar/adenoidalhypertrophy that required surgical intervention inover 10% of patients. Thymic hypertrophy wasnoted in 35% of subjects having regular chestradiographs. It is worth noting that some of theseside effects may be more frequent than reportedbecause they take time to develop; for example,snoring incidence in the ﬁrst year for the 25 lon-gest treated subjects in the mecasermin study wasonly 4% but increased to 65% for the entire studyperiod .Anti-IGF-I antibodies have developed inapproximately half of the IGF-I-treated patientsduring the ﬁrst year of treatment, but these havehad no effect on response [78, 79]. Urticaria hasbeen noted in subjects participating in the trial ofIGF-I with GH. Transient elevation of liverenzymes has also been noted .Coarsening of facial features with dispropor-tionate growth of the jaw reminiscent of acromeg-aly has been common, particularly among thoseof pubertal age . In contrast to the increase inlean body mass and decreasing percentage ofbody fat that occurs with GH treatment of GHD,both lean and fat mass increase with rhIGF-I ther-apy . Mean body mass index (BMI) increasedfrom +0.6 SDS to +1.8 SDS during 4–7 years oftreatment with rhIGF-I in the European multi-center trial, and severe obesity has occasionallyoccurred . BMI measurement may not accu-rately reﬂect the degree of obesity, which can be adoubling or tripling of body fat as demonstratedby dual-energy X-ray absorptiometry .Hyperandrogenism with oligomenorrhea or amen-orrhea, acne, and elevated serum androgens hasbeen described in prepubertal and young adultpatients given single daily injections of rhIGF-I. There have been two instances of anaphy-laxis from rhIGF-I treatment .It is not known whether there might be long-term mitogenic effects of extended therapy withrhIGF-I in growing children. The role of IGF-I incarcinogenesis, as an antiapoptotic agent favor-ing the survival of precancerous cells, togetherwith the increased cancer risk in hypersomatotro-pic states, and the evidence for aberrant tissueeffects in rhIGF-I-treated patients dictate a needfor long-term follow-up of rhIGF-I-treatedpatients .GH TherapyFive individuals with IGF-I receptor mutationshave been treated with recombinant GH with four
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