A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency

in European Journal of Endocrinology

Correspondence should be addressed to J M Wit; Email: j.m.wit@lumc.nl
Keywords:

The recent article by Keselman et al. published in this journal (1) describes the clinical, laboratory, genetic and functional data of a patient with well-documented complete IGF-I deficiency (MIM #608747; International Classification of Paediatric Endocrine Diagnoses (ICPED) code 1B.4e) (2) caused by a homozygous non-functional mutation of the gene (IGF1) encoding insulin-like growth factor-I (originally abbreviated as IGF-I). An IGF1 mutation is one of the causes of a spectrum of disorders of the growth hormone (GH)–-IGF1 axis, usually called GH insensitivity syndrome (GHIS), which further includes loss-of-function mutations of genes encoding the GH receptor (GHR) (Laron syndrome), STAT5B (STAT5B) and acid-labile subunit (IGFALS), and activating mutations of STAT3, as well as conditions characterized by increased serum IGF1 concentrations such as IGF1R and PAPPA2 defects (3).

The phenotype of this young child carrying a homozygous IGF1 mutation (p.Tyr108His) is strikingly similar to that of two previously reported patients: one with a homozygous deletion of exons 4 and 5 (4) and another with a non-functional mutation (p.Val92Met) (5). The main clinical features include severe prenatal and postnatal growth failure, severe microcephaly, retrognathia, sensorineural deafness and severe global developmental delay. When the auxological data of these three patients are combined, birth length SDS varies between −4.3 and −6.3, much shorter than in patients with complete GH deficiency or insensitivity. Height SDS tends to decrease by age (−6.2, −6.9 and −8.5 at 3, 16 and 55 years) and a similar decrease may be seen in head circumference SDS (−6.1, −4.9 and −8.0). The deceased brother of the patient described by our group (5) had a similar phenotype. Thus, in contrast to the suggestion aroused by the title of the paper by Keselman et al. (1), their observations have not really broadened the clinical phenotype, but rather confirmed it. The clinical features of this condition have confirmed the findings in Igf1-knockout mice (6, 7) that IGF1 is a key factor in intrauterine growth and brain and inner ear development and provided the insight that IGFI secretion is independent of GH in utero.

About the evolution of the clinical phenotype with age, only the 55-year-old patient carrying the Val92Met mutation can provide information. In this patient, additional observations included increased abdominal fat mass, facial dysmorphic features (including deep-set eyes, flat occiput, a columella extending beyond the alae nasi), broad end phalanges, convex nails, hypermobility of the interphalangeal joints, restricted mobility of both elbows, hypertension, small testicular volume, micropenis, cataracts of both eyes and osteoporosis (5).

There still exists an enigmatic report on a patient with similarly severe clinical features (8) that were thought to be caused by a novel homozygous transversion T->A in the 3′ untranslated region of exon 6 of IGF1. This variant resides on the consensus sequence AATATA of the polyadenylation site and was shown in vitro to lead to a deregulated IGF1 mRNA maturation, altering the E domain of the IGF1 precursor. However, in a later paper by other investigators the same allelic variant was also observed in homozygous and heterozygous states in normal height controls, corresponding to 4% of studied alleles (9). The three most frequently identified allelic variants of IGF1 3′ UTR showed no effect on height SDS of adult controls nor on birth characteristics in SGA children (9). The authors suggested that a non-screened mutation in the intronic or in the promoter region of IGF1 might be responsible for the phenotype observed in the patient reported by Bonapace et al. (8), but as far as we know such additional studies have not been reported.

A less severe pre- and post-natal growth failure, mild intellectual deficit and normal hearing was observed in a French patient carrying a homozygous IGF1 mutation (p.Arg84Gln), which is transcribed into a mutated IGF1 protein with some remaining function (10). A patient from Saudi Arabia carrying a homozygous variant (p.Arg98Trp), now identified as a variant of unknown significance (1), showed a similarly relatively mild phenotype (11), but the lack of studies on segregation and in vitro functionality makes it impossible to be certain about the pathogenicity of this variant.

In contrast to the similarity in the phenotype of homozygous carriers of loss-of-function IGF1 mutations, there is a striking variation in ‘chemotype’ with regard to serum IGF1 concentration, the serum GH response to stimulation tests and insulin sensitivity. As expected, in the patient with the deletion of exons 4 and 5 serum IGF1 was undetectable (4), but the case with the p.Val92Met mutation showed an extremely high IGF1 concentration as measured by radioimmunoassay (5). In the French patient with partial IGF1 deficiency serum IGF1 concentrations varied between assays (10), while in the Argentinian case IGF1 concentrations showed unexplained variations using the same assay (1).

Also the results of GH stimulation tests are confusing. Due to disruption of the negative feedback in patients with loss-of-function mutations of IGF1 one would expect an increased baseline GH and high GH peak in response to a stimulation test, and this was indeed noticed in the first reported patient (4). In the second patient the GH peak was high in childhood and in the upper half of the reference range in adulthood (5) and the patient described in this issue (1) had baseline GH levels between 0.2 and 29 ng/mL, suggesting an increased spontaneous GH secretion.

With respect to insulin sensitivity, a severe insulin resistance was observed in the first reported patient (4). In contrast, the adult with the Val92Met mutation just had a mild glucose intolerance (fasting glucose 6.2 mmol/L, insulin 13 mU/L, HbA1c 5.7%), though functional studies showed that binding or activation of both insulin receptor isoforms was not detectable even at micromolar concentrations (12). The patient described by Keselman et al. (1) and the patient carrying the Arg84Gln mutation did not show insulin resistance (10).

Moving further away from the extreme end of the phenotypic spectrum, there is relatively strong evidence that heterozygosity for a pathogenic mutation can cause short stature (13, 14, 15). For the two siblings described by our group, we showed that there was no dominant negative effect of the truncated protein (16). Further, relatives of a patient with a homozygous IGF1 mutation who are heterozygous carriers of the mutation are relatively short (1, 4), which was statistically confirmed in the large pedigree studied by our group, in which mutation carriers had a mean height SDS of −1.0 vs −0.4 in carriers of the wild-type gene (P = 0.04) (5). In addition, the heterozygous IGF1 splicing variant described by Fuqua et al. segregated in a large pedigree with short stature (14). These observations suggest that haploinsufficiency of IGF1 may be one of the genetic causes of children presenting with moderate short stature who may be initially registered as idiopathic short stature (ISS) or as small for gestational age (SGA) with failure to catch-up growth. Such gene-dose effect has also been documented for IGFALS and STAT5B mutations (17, 18).

There is also evidence suggestive of an effect of polymorphisms in the IGF1 gene promoter region and serum IGFI concentration on intra-uterine and postnatal growth in the general population (19, 20, 21, 22, 23, 24, 25, 26). So far, activating IGF1 variants or duplications have not been discovered, but one would expect tall stature in individuals with such variants, in line with the observations of overgrowth in patients with duplications or activating mutations of IGF1R (27, 28, 29).

A critical clinician may wonder why it would be important to report a paper on a patient with an apparently very rare disorder. We would respond that for each monogenic disorder, it is relevant to collect information about the phenotype, which can then be used as a reference when in future patients a variant of unknown (uncertain) significance is found, either with a candidate gene approach or through hypothesis-free whole exome sequencing (WES). When a sufficient number of patients has been collected, one can prepare a clinical score that can be used to guide the decision to perform genetic testing, such as reported for SHOX haploinsufficiency, Silver-Russell syndrome and heterozygous IGF1R defects (30, 31, 32). The extreme rarity of IGF1 deficiency will make this not feasible. A second reason is that clinical observations in rare patients contribute to the understanding of the physiological role of the protein encoded by the gene. For example, the clinical features of the cases with homozygous IGF1 mutations, in comparison with patients with complete GH deficiency or insensitivity, have provided important information about GH-independent versus GH-dependent effects of IGF1. A third reason is that at the present time, when WES is not yet universally available in the diagnosis of the short child, the candidate gene approach is still useful, as illustrated by the report of Keselman et al. (1) and previous observations. Fourthly, collecting information on such patients will generate hypotheses and document observations about potential therapeutic options.

To date, there is little and contradictory information on therapeutic options for patients with IGF1 deficiency. The homozygous carrier of the exon 4 and 5 deletion was treated with recombinant human IGF1 for 1 year, which increased height velocity and bone size and improved body composition and insulin sensitivity (33). The patient with partial IGF1 deficiency was treated with recombinant human GH (rhGH) resulting in an insufficient growth response (10). The growth response to rhGH treatment in the two siblings carrying a pathogenic heterozygous IGF1 mutation (13) was considered sufficient to continue treatment up to adult height.

Some years ago a group of pediatric endocrinologists considered that a registry of cases with mutations in genes associated with the GH-IGF1 axis would be useful, and in fact such registry was available on line for a number of years (34). Unfortunately, the decreasing number of visitors of the website led the curator to close the registry (von Stein, personal communication).

In general, the fast development of genetic diagnostic tools, particularly next-generation sequencing, has considerably changed the guidelines for the diagnostic approach of the child with growth failure (short stature and/or growth faltering). The consensus statement on ISS in 2008 only contained one paragraph on genetic tests: ‘In situations where a specific genetic diagnosis associated with short stature is expected (such as Noonan syndrome or GH insensitivity syndrome) the genes of interest should be examined (…). Although routine analysis of SHOX should not be undertaken in all children with ISS, SHOX gene analysis should be considered for any patient with clinical findings compatible with SHOX haploinsufficiency’ (35). In the meantime genetic analyses of short children have shown that the diagnostic yield of genetic testing is considerable (36, 37), and this has led to various reviews and guidelines emphasizing the advantages of the use of WES-based specific growth-related gene panels, CGH- or SNP-arrays, and full trio-based WES, if clinical features are suggestive for a monogenetic defect (38, 39, 40, 41, 42, 43, 44, 45, 46, 47). In recent guidelines (44, 45, 46) extensive information on the application of genetic testing for the evaluation of a child with short stature is included, describing genetic techniques, reasons why it is important to identify a genetic cause and a recommendation on which children should be identified for genetic testing. The novel case with an IGF1 mutation in this journal (1) would have fulfilled these criteria because of severe prenatal and postnatal growth retardation in combination with microcephaly, dysmorphic features and deafness.

The availability of these novel genetic techniques have made it essential to develop and use a uniform classification of genetic variants, which was recently published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (48, 49). This classification describes criteria for pathogenic and likely pathogenic variants, variant of unknown significance, and likely benign and benign variants, based on population prevalence data, segregation analysis, in silico prediction analysis and functional data. In the description of cases in the literature the criteria according to the AMCG/AMP guideline should always be included, and the clinician ordering genetic techniques in the work-up of short stature should be aware of the interpretation of variants according to this classification.

Before performing genetic tests the clinician should counsel the patient and the parents about the possible results and manage expectations regarding causes and treatment of a growth disorder. This should include mentioning the possibility of finding a variant of unknown significance that may lead to many questions and uncertainty. Especially in case of such variants of unknown significance there may be a need for further investigations in family members, literature search or contacting colleagues in order to arrive at a correct interpretation of the genetic findings. This process of counselling and interpretation of genetic findings requires the expertise of an experienced and dedicated team consisting of pediatric endocrinologists, clinical geneticists and molecular geneticists.

Genetic investigations in children with short stature should certainly not be limited to defects in the GH-IGF1 axis, since these only represent a small percentage of the genetic causes (39). Heterozygous mutations in several genes encoding proteins associated with growth plate function, such as SHOX, NPR2, ACAN, IHH and NPPC, can be found in 1–2% of short children (36, 37, 44).

In conclusion, the paper by Keselman et al. (1) adds useful and mainly confirmatory information to the existing body of evidence on the phenotype and laboratory data of patients carrying homozygous IGF1 mutations, which can guide clinicians to perform genetic testing in similar cases. The rapidly expanding use of hypothesis-free genetic testing in children with short stature will probably lead to the detection of more cases and a wider range of phenotypic variation.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this commentary.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    KeselmanACMartinAScagliaPASanguinetiNArmandoRGutierrezMBraslavskyDBalleriniMGRopelatoMGRamirezL et al. A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency. European Journal of Endocrinology 2019 181 K43–K53. (https://doi.org/10.1530/EJE-19-0563)

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    QuigleyCAR. M.B. International classification of pediatric endocrine diagnoses, www.icped.org. Rotterdam: Growth Analyser, 2016.

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    StorrHLChatterjeeSMetherellLAFoleyCRosenfeldRGBackeljauwPFDauberASavageMOHwaV. Non-classical growth hormone insensitivity (GHI): characterization of mild abnormalities of GH action. Endocrine Reviews 2018 476–505. (https://doi.org/10.1210/er.2018-00146)

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    WalenkampMJKarperienMPereiraAMHilhorst-HofsteeYvan DoornJChenJWMohanSDenleyAForbesBvan DuyvenvoordeHA Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. Journal of Clinical Endocrinology and Metabolism 2005 2855–2864. (https://doi.org/10.1210/jc.2004-1254)

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    LupuFTerwilligerJDLeeKSegreGVEfstratiadisA. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Developmental Biology 2001 141–162. (https://doi.org/10.1006/dbio.2000.9975)

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    YakarSAdamoML. Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinology and Metabolism Clinics of North America 2012 231–47, v. (https://doi.org/10.1016/j.ecl.2012.04.008)

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    BonapaceGConcolinoDFormicolaSStrisciuglioP. A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. Journal of Medical Genetics 2003 913–917. (https://doi.org/10.1136/jmg.40.12.913)

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    CoutinhoDCColettaRRCostaEMPachiPRBoguszewskiMCDamianiDMendoncaBBArnholdIJJorgeAA. Polymorphisms identified in the upstream core polyadenylation signal of IGF1 gene exon 6 do not cause pre- and postnatal growth impairment. Journal of Clinical Endocrinology and Metabolism 2007 4889–4892. (https://doi.org/10.1210/jc.2007-1661)

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    NetchineIAzziSHouangMSeurinDPerinLRicortJMDaubasCLegayCMesterJHerichR Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. Journal of Clinical Endocrinology and Metabolism 2009 3913–3921. (https://doi.org/10.1210/jc.2009-0452)

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    ShaheenRFaqeihEAnsariSAbdel-SalamGAl-HassnanZNAl-ShidiTAlomarRSogatySAlkurayaFS. Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Research 2014 291–299. (https://doi.org/10.1101/gr.160572.113)

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    DenleyAWangCCMcNeilKAWalenkampMJvan DuyvenvoordeHWitJMWallaceJCNortonRSKarperienMForbesBE. Structural and functional characteristics of the Val44Met insulin-like growth factor I missense mutation: correlation with effects on growth and development. Molecular Endocrinology 2005 711–721. (https://doi.org/10.1210/me.2004-0409)

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    van DuyvenvoordeHAvan SettenPAWalenkampMJvan DoornJKoenigJGauguinLOostdijkWRuivenkampCALosekootMWadeJD Short stature associated with a novel heterozygous mutation in the insulin-like growth factor 1 gene. Journal of Clinical Endocrinology and Metabolism 2010 E363–E367. (https://doi.org/10.1210/jc.2010-0511)

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    FuquaJSDerrMRosenfeldRGHwaV. Identification of a novel heterozygous IGF1 splicing mutation in a large kindred with familial short stature. Hormone Research in Paediatrics 2012 59–66. (https://doi.org/10.1159/000337249)

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    BateyLMoonJEYuYWuBHirschhornJNShenYDauberA. A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency. Journal of Clinical Endocrinology and Metabolism 2014 E153–E159. (https://doi.org/10.1210/jc.2013-3106)

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    van DuyvenvoordeHAvan DoornJKoenigJGauguinLOostdijkWWadeJDKarperienMRuivenkampCALosekootMvan SettenPA The severe short stature in two siblings with a heterozygous IGF1 mutation is not caused by a dominant negative effect of the putative truncated protein. Growth Hormone and IGF Research 2011 44–50. (https://doi.org/10.1016/j.ghir.2010.12.004)

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    van DuyvenvoordeHAKempersMJTwicklerTBvan DoornJGerverWJNoordamCLosekootMKarperienMWitJMHermusAR. Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. European Journal of Endocrinology 2008 113–120. (https://doi.org/10.1530/EJE-08-0081)

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    ScalcoRCHwaVDomeneHMJasperHGBelgoroskyAMarinoRPereiraAMTonelliCAWitJMRosenfeldRG STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability. European Journal of Endocrinology 2015 173 291–296. (https://doi.org/10.1530/EJE-15-0398)

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    ArendsNJohnstonLHokken-KoelegaAvan DuijnCde RidderMSavageMClarkA. Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). Journal of Clinical Endocrinology and Metabolism 2002 2720. (https://doi.org/10.1210/jcem.87.6.8673)

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    VaessenNJanssenJAHeutinkPHofmanALambertsSWOostraBAPolsHAvan DuijnCM. Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet 2002 1036–1037. (https://doi.org/10.1016/s0140-6736(02)08067-4)

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    MurphyVESmithRGilesWBCliftonVL. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocrine Reviews 2006 141–169. (https://doi.org/10.1210/er.2005-0011)

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    YangTLXiongDHGuoYReckerRRDengHW. Comprehensive association analyses of IGF1, ESR2, and CYP17 genes with adult height in Caucasians. European Journal of Human Genetics 2008 1380–1387. (https://doi.org/10.1038/ejhg.2008.113)

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    EsterWAvan MeursJBArendsNJUitterlindenAGde RidderMAHokken-KoelegaAC. Birth size, postnatal growth and growth during growth hormone treatment in small-for-gestational-age children: associations with IGF1 gene polymorphisms and haplotypes? Hormone Research 2009 15–24. (https://doi.org/10.1159/000224336)

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    KimJJLeeHIParkTKimKLeeJEChoNHShinCChoYSLeeJYHanBG Identification of 15 loci influencing height in a Korean population. Journal of Human Genetics 2010 27–31. (https://doi.org/10.1038/jhg.2009.116)

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    OkadaYKamataniYTakahashiAMatsudaKHosonoNOhmiyaHDaigoYYamamotoKKuboMNakamuraY A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Human Molecular Genetics 2010 2303–2312. (https://doi.org/10.1093/hmg/ddq091)

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    FujiharaJTakeshitaHKimura-KataokaKYuasaIIidaRUekiMNagaoMKominatoYYasudaT. Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution. Legal Medicine 2012 205–208. (https://doi.org/10.1016/j.legalmed.2012.02.001)

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    OkuboYSiddleKFirthHO'RahillySWilsonLCWillattLFukushimaTTakahashiSPertyCJSaukkonenT Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. Journal of Clinical Endocrinology and Metabolism 2003 5981–5988. (https://doi.org/10.1210/jc.2002-021080)

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    KantSGKriekMWalenkampMJHanssonKBvan RhijnAClayton-SmithJWitJMBreuningMH. Tall stature and duplication of the insulin-like growth factor I receptor gene. European Journal of Medical Genetics 2007 1–10. (https://doi.org/10.1016/j.ejmg.2006.03.005)

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    LinYvan DuyvenvoordeHALiuHYangCWarsitoDYinCKantSGHaglundFWitJMLarssonO. Characterization of an activating R1353H insulin-like growth factor 1 receptor variant in a male with extreme tall height. European Journal of Endocrinology 2018 85–95. (https://doi.org/10.1530/EJE-18-0176)

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    RappoldGBlumWFShavrikovaEPCroweBJRoethRQuigleyCARossJLNieslerB. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. Journal of Medical Genetics 2007 306–313. (https://doi.org/10.1136/jmg.2006.046581)

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    WakelingELBrioudeFLokulo-SodipeOO'ConnellSMSalemJBliekJCantonAPChrzanowskaKHDaviesJHDiasRP Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nature Reviews: Endocrinology 2017 105–124. (https://doi.org/10.1038/nrendo.2016.138)

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    WalenkampMJERobersJMLWitJMZandwijkenGRJvan DuyvenvoordeHAOostdijkWHokken-KoelegaACSKantSGLosekootM. Phenotypic features and response to growth hormone treatment of patients with a molecular defect of the IGF-1 receptor. Journal of Clinical Endocrinology and Metabolism 2019 3157–3171. (https://doi.org/10.1210/jc.2018-02065)

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    WoodsKACamacho-HubnerCBergmanRNBarterDClarkAJSavageMO. Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion. Journal of Clinical Endocrinology and Metabolism 2000 1407–1411. (https://doi.org/10.1210/jcem.85.4.6495)

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    CohenPRogolADDealCLSaengerPReiterEORossJLChernausekSDSavageMOWitJM & 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. Journal of Clinical Endocrinology and Metabolism 2008 4210–4217. (https://doi.org/10.1210/jc.2008-0509)

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    HauerNNPoppBSchoellerESchuhmannSHeathKEHisado-OlivaAKlingerPKrausCTrautmannUZenkerM Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genetics in Medicine 2018 630–638. (https://doi.org/10.1038/gim.2017.159)

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    FreireBLHommaTKFunariMFALerarioAMVasquesGAMalaquiasACArnholdIJPJorgeAAL. Multigene sequencing analysis of children born small for gestational age with isolated short stature. Journal of Clinical Endocrinology and Metabolism 2019 2023–2030. (https://doi.org/10.1210/jc.2018-01971)

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    de BruinCDauberA. Insights from exome sequencing for endocrine disorders. Nature Reviews: Endocrinology 2015 455–464. (https://doi.org/10.1038/nrendo.2015.72)

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    WitJMOostdijkWLosekootMvan DuyvenvoordeHARuivenkampCAKantSG. MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature. European Journal of Endocrinology 2016 R145–R173. (https://doi.org/10.1530/EJE-15-0937)

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    WitJMKampGAOostdijkW & on behalf of the Dutch Working Group. Towards a rational and efficient diagnostic approach in children referred for growth failure to the general paediatrician. Hormone Research in Paediatrics 2019 223–240. (https://doi.org/10.1159/000499915)

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