Therapy with recombinant human IGF-1 for children with primary insulin-like growth factor-I deficiency

Journal Pre-proof Therapy with recombinant human IGF-1 for children with primary insulin-like growth factor-I deficiency

Philippe Backeljauw PII:

S1096-6374(20)30001-0

DOI:

https://doi.org/10.1016/j.ghir.2020.01.001

Reference:

YGHIR 1306

To appear in:

Growth Hormone & IGF Research

Received date:

30 July 2019

Revised date:

16 December 2019

Accepted date:

6 January 2020

Please cite this article as: P. Backeljauw, Therapy with recombinant human IGF-1 for children with primary insulin-like growth factor-I deficiency, Growth Hormone & IGF Research (2019), https://doi.org/10.1016/j.ghir.2020.01.001

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2019 Published by Elsevier.

Journal Pre-proof

Therapy with recombinant human IGF-1 for children with primary insulin-like growth factor-I deficiency. Philippe Backeljauw, M.D. Division of Pediatric Endocrinology Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine

-p

[email protected]

ro

Corresponding author: Philippe Backeljauw, M.D.

of

Cincinnati, Ohio 45229, USA

re

Abstract

Jo

ur

na

lP

The efficacy and safety of IGF-1 therapy in patients with severe primary IGF-I deficiency has been evaluated for more than two decades. Most of the therapeutic experience comes from treating the more severe IGF-I deficient patients, who usually present with a phenotype characteristic of growth hormone receptor deficiency or Laron syndrome. Although most of these patients do not experience enough catchup growth to bring their height into normal range, many individuals achieve an adult height significantly greater than what would have been predicted in the absence of IGF-1 therapy. In the last couple of years a few reports on the benefit of IGF-1 therapy for patients with milder types of IGF-I deficiency have also been published, with variable height outcomes. More short children with prior diagnosis of idiopathic short stature are now being diagnosed with specific molecular defects of the growth hormone/IGF-I axis. Because of this, the clinical spectrum of primary IGF-I deficiency is widening to include many patients with such a milder phenotype, creating a need for well-designed long-term clinical studies evaluating the growth response to growth promoting agents such as rhIGF-1 in these individuals.

Keywords growth hormone, growth hormone insensitivity, growth hormone receptor, insulin-like growth factor-I, growth hormone resistance, primary IGF-I deficiency, recombinant human IGF-1

Introduction The existence of individuals with severe short stature likely due to a deficiency of the growth hormone (GH) receptor was already documented in medieval art, as exemplified by a painting from Andrea

Journal Pre-proof

-p

ro

of

Mantegna dated 1454. [1] Of course, the history of GH receptor deficiency associated with features of Laron syndrome goes much farther back in time as demonstrated by finding characteristic features on skeletal remains. We had to wait until 1966 for Zvi Laron to first describe a pituitary dwarfism-like syndrome associated with high GH concentrations. [2] Nearly twenty years later, 1986 became an especially fertile year for insulin-like growth factor-I (IGF-I) research, as more than 200 papers were published in that year alone - all related to somatomedin-C or IGF-I biosynthesis. Zhou and Kopchick generated a suitable mouse model of human Laron syndrome, helpful for the elucidation of many aspects of GH receptor and GH binding protein (GHBP) function. [3] Rosenbloom and colleagues further provided us with very detailed phenotyping of patients with severe primary IGF-I deficiency (IGFD) due to a single homozygous splice site mutation of the GH receptor (E180 splice), resulting in a clinical picture resembling Laron-type dwarfism. [4] The first administration of IGF-I as a drug to humans occurred in 1989. Finally, long-term trials with recombinant human (rh) IGF-1 began in 1991. This paper provides a brief overview of rhIGF-1 therapy for children with severe and milder forms of primary IGF-I deficiency. In doing so, it will provide some background on the limitations of rhIGF-1 therapy related to its efficacy potential and safety.

Case presentation

Jo

ur

na

lP

re

A 5-year-old boy has severe proportionate short stature. He was born after a normal pregnancy, with a weight at birth of 3 000 g and birth length of 47.8 cm. He developed severe postnatal growth failure (Figure 1). Around 5 years of age his height was -5.6 SDS and his weight was -3.5 SDS. Bone age was delayed by approximately 3 years. On examination, frontal bossing, sparse and thin scalp hair, micrognathia, acromicria, and increased weight/height ratio were noted. Laboratory investigations included an IGF-I of 3.0 ng/mL (< -3 SDS), IGFBP-3 of 0.2 mg/L (normal range 1.2 to 5.2), and GHBP of 40 pmol/L (normal range 320 to 3 820). His basal GH concentrations were 29 to 51 ng/mL, and peak stimulated GH was > 100 ng/mL. An IGF-I generation test (0.1 mg GH subcutaneously daily for 4 days) did not result in a significant change in the IGF-I concentration (3.0 to 5.6 ng/mL, retrospectively before and after GH). The child further underwent GH receptor sequencing, which showed he was homozygous for a previously reported mutation of the GH receptor (c.723 C>T (exon 7)). [5]

Anabolic-metabolic evaluation, and growth promotion in patients with severe primary IGFD During the last 25 years many reports of treatment with rhIGF-1 for patients with severe primary IGFD have been published, including both single case reports and retrospective studies with small number of patients. This paper will focus mainly on the results of the larger studies and specifically on the patient cohort that reached adult height (AH) or near-adult height (NAH). The patients in question were treated by investigators at the University of North Carolina at Chapel Hill and Cincinnati Children’s Hospital Medical Center. Anabolic and metabolic assessment of the first IGFD child treated with rhIGF-1 was initially documented to determine the likelihood of also achieving an adequate growth response longterm. [6] Recombinant human IGF-1 was infused for several days to achieve the highest possible daily dose without the expected risk of hypoglycemia. Recombinant human IGF-1 infused intravenously produced a 56 percent decrease in the serum urea nitrogen and a 47% decrease in urinary urea nitrogen excretion. [6] At the same time urinary calcium excretion increased to 2.5-fold and urinary phosphate

Journal Pre-proof excretion decreased by 30 percent. These are all effects recognized to occur when GH is given to patients with GH deficiency. [6] The endogenous GH decreased during the IGF-1 infusion, as well as insulin and c-peptide concentrations. The studies demonstrated that IGF-I has anabolic (and therefore also growth promotion) potential in patients with GH insensitivity.

Long-term studies with rhIGF-1 in patients with severe primary IGFD

-p

ro

of

The clinical trials that treated patients with rhIGF-1 until AH or NAH included 21 patients with severe primary IGFD. [7] The patients were treated for a mean period of 10.7 years and received a mean rhIGF1 dose of 112 mcg/kg twice daily (given subcutaneously). To be included in the studies patients had to have GH insensitivity: (a) either because of GH receptor deficiency or dysfunction, or, (b) because they had developed growth-attenuating GH anti-bodies after being initially treated with GH for severe GH deficiency due to a GH gene deletion. The former cohort had to have GH excess, as well as deficiency of GHBP and IGF-I. Prior to inclusion they also had failure to respond to exogenous GH therapy. For patients with GH gene deletions, GH antibodies had to be measured for a GH binding capacity > 10 mcg GH/mL. The baseline characteristics of patients treated to AH/NAH cohort are described in Table 1.

Jo

ur

na

lP

re

Growth response. Treatment with IGF-I stimulated linear growth independent of the degree of shortness or diagnostic category. The mean baseline height velocity (HV) of 3.1 cm/year increased to 7.4 cm/year during the first year of treatment (p < 0.0001). Although the HV’s after the first year of therapy were lower, they remained above baseline for up to 12 years of therapy. Mean HV during the second year of therapy was 5.6 cm/year; and ranged between 3.9 to 5.0 cm/year during years 3 to 12. The mean change in height SDS at (N)AH was +1.9 (range +0.1 to +4.7). [7] There was significant variability in the change in height SDS, so that nine patients improved their height SDS, at final analysis, ≥ +2.0, whereas 12 patients only had an improvement in height SDS by ≤ +1.7. The change in height SDS for nine patients who were also treated with gonadotropin releasing hormone (GnRH) analog therapy was +2 SDS, better than the non-GnRH analog treated group (only height SDS improvement of +1.6 SDS). The change in height achieved at the end of IGF-1 therapy relative to the predicted height change (i.e. growth along the centiles for untreated Laron syndrome), shows the observed mean height gain was 13.4 cm more than expected. [7] The individual growth during IGF-1 therapy, compared with the US national Center for Health Statistics standards and compared with the mean ± 2 SDS for untreated Laron syndrome patients, shows that after initial catchup linear growth is parallel to the growth curves for the normal US population. Most patients improved their height, but did not experience ongoing catchup growth, and only three 3 patients reached a height within the normal range. (Figure 2 A & B) Adverse events. Several adverse events of special interest have been reported with long-term IGF-1 treatment. In the specific US cohort described above the most common adverse events of special interests include lipohypertrophy (71 percent), hypoglycemia (67 percent), and snoring, tonsillar hypertrophy, and hypoacusis (60 to 71 percent). These latter events are a consequence of hypertrophy observed of the soft tissues of the oropharynx. Three patients had documented increased intracranial pressure/intracranial hypertension. [8] Cephalometric radiography, to evaluate the growth of the facial bony structures, are available for six years of IGF-1 treatment in a subset of eight patients. Before IGF-1 therapy, these patients had reduced facial dimensions with small, retrognathic mandible and maxilla. After 6 years of therapy with IGF-1, most patients were still behind with their craniofacial development, but both linear and angular craniofacial parameters had improved. There did not appear to be any

Journal Pre-proof evidence of acromegaloid growth. The changes noted in the facial bones were accompanied by growth of the soft tissues of the face, which was more obvious when patients were undergoing pubertal changes: thickening of the eyebrows, tip and alae of the nose, and the lips. [8] This soft tissue enlargement improved considerably after discontinuation of rhIGF-1 therapy.

of

The efficacy and safety data of the above described cohort, as well as additional information on another 50 patients, were submitted to the regulatory agencies in both the USA and Europe. In United States rhIGF-1 is now approved and indicated for long-term treatment of growth failure in children with severe primary IGFD, defined as height and IGF-I SDS ≤ -3, with normal/elevated GH or with GH gene deletion plus development of neutralizing antibodies to GH. In Europe, rhIGF-1 therapy is indicated for long-term treatment of growth failure in children with severe primary IGFD, defined as a height SDS ≤ -3 and basal IGF-I concentrations < 2.5 percentile, with GH insufficiency and exclusion of secondary forms of IGF-I deficiency.

ro

Clinical approach to therapy with rhIGF-1 in patients with severe primary IGFD.

lP

re

-p

Starting a patient with severe primary IGFD deficiency on therapy with rhIGF-1 should always be individualized. The recommended starting dose is 0.04 mg/kg twice daily via subcutaneous injection. If this is well tolerated, that dose may be increased by 0.04 mg/kg per dose after at least one week of observation. The maximum dose is 0.12 mg/kg given twice daily. Parents should administer a snack or meal shortly before the rhIGF-1 injection is administered. Caregivers should also consider glucose monitoring at treatment initiation if frequent symptoms of hypoglycemia occur. Those at highest risk for hypoglycemia are the very young and shortest patients. [7, 8]

Jo

ur

na

These recommendations are based on the knowledge that there exists a significant dose effect for rhIGF-1 therapy during the first year of treatment. Other investigators have argued against the use of the higher dose range, i.e. above 80 mcg/kg per dose, and a study was done to test the hypothesis that a lower dose may be as effective as a higher dose to promote growth. [9] Guevara and Rosenbloom report no differences in HV or height SDS increment comparing 80 and 120 mcg/kg IGF-1 dosage regimens over three years. [9] Skeletal maturation over that period was reportedly nearly twice as rapid with the higher dose (120 mcg/kg) than with the lower dose. However, in the US study the mean bone age/chronological age ratio changed from 0.6 at baseline to 0.9 at the end of the rhIGF-1 therapy. [7] Skeletal maturation therefore typically progressed in accord with the advancing chronological age during therapy, something that has been observed repeatedly by others. It should be noted that, in the US trials, nine patients were - on average 2.9±1.8 years (range 0.6 to 6.4) on treatment with GnRH analogue agents. It is possible that patients within this subgroup would have experienced more rapid skeletal maturation had they received rhIGF-1 therapy alone. Sub-analysis of those treated only with rhIGF-1 yielded a mean change in bone age of 10.9±3.7 years over 9.6±3.6 years. This contrasts with a change in bone age of 11.0±5.0 years over 11.0±5.5 years of therapy for the GnRH agonist + IGF-1 group, with a mean delta bone age/chronological age of 1.2±0.3 versus 1.1±0.1, respectively. [7] Against the objection from Guevara and Rosenbloom to avoid IGF-1 dosing above 80 mcg/kg is the knowledge that their study was not randomized, and those patients assigned the higher dosage of 120 mcg/kg began treatment before any of the other patients were assigned the lower dose. In addition, the patients who received the 80 mcg/kg twice daily were markedly younger than the patients in the higher dosage group. Real world experience is available from the European Increlex® Growth Forum Database. [10] The HV at year 1 in treatment naïve/prepubertal patients with a mean IGF-1 ≤ 100 mcg/kg twice a day versus > 100

Journal Pre-proof mcg/kg twice a day was 7.2 and 7.4 cm per year, respectively. In previously treated/pubertal patients with a mean IGF-I dose ≤ 100 mcg/kg twice a day versus > 100 mcg/kg twice a day, the first year HV was 6.0 and 6.5 cm per year, respectively. These differences are not significantly different, but it is observed that many clinicians escalate IGF-1 dosing too slowly, resulting in undertreatment at the time when most catchup growth can be expected. [10]

Treatment of patients with milder forms of primary IGFD.

-p

ro

of

More recently it has become clear that primary IGFD is not a single entity, but more likely represents a broader diagnostic category composed of a range of molecular defects of the GH/IGF-I axis. [11] Short patients, previously described as having idiopathic short stature, may have defects that involve genes for proteins regulating GH binding, signal transduction, or IGF-I synthesis itself. [11, 12] Some of these defects may lead to milder forms of IGFD or GH insensitivity. [13, 14] Therefore, the spectrum of IGFD, previously thought to include predominantly patients with extreme high deficits (in the range of 5 to 8 SDS below the mean), will also contain children who may only have mild height deficits, such as -2 to -4 SDS below the mean.

Jo

ur

na

lP

re

Until the last several years the existence of such mild or ‘nonclassical’ GH insensitivity was not well appreciated. However, recent accumulation of evidence for the existence of milder IGFD phenotypes suggest that the prevalence may be as high or higher than for severe primary IGFD. [11, 12] A range of atypical physical features (compared with the classic severe IGFD presentation) and biochemical abnormalities has now been reported, as patients are diagnosed more rapidly from a molecular perspective. [11, 12] As these new molecular defects in the GH receptor and other genes are described, new diagnostic categories have included individuals with heterozygous dominant negative mutations of the GH receptor [13], homozygous intronic pseudoexon GH receptor mutations [14], dominant negative mutations of STAT5B [15], variants of IGF-II [16], patients with mutations of IGFALS (the acid-labile subunit of the ternary complex) [17, 18], and patients with pregnancy–associated plasma protein A2 (PAPPA-2) deficiency. [19, 20] In the next paragraph some discussion is provided for those patients for whom data are available on the effect of rhIGF-1 therapy. Recombinant human IGF-1 therapy for IGFD due to dominant negative GH receptor mutations. a. Less severe GH insensitivity due to heterozygous dominant-negative GH receptor variants may be observed in patients with postnatal growth failure and IGF-I insufficiency, but with a relatively normal facial phenotype. [13] One of these patients was started on rhIGF-1 therapy at age 8 years and 8 months, and this with incremental dosing over the course of 6 weeks (up to 120 mcg/kg per dose twice daily). The HV improved from 4 cm/year before therapy to 8.1 cm/year on therapy. Another patient improved a pretreatment HV of 4.2 cm/year to 8.0 cm/year on treatment for one year. After 3 years of therapy this patient was added GH therapy. This combination therapy further increased HV to 10 cm/year. [13] b. Recombinant human IGF-1 therapy in patients with homozygous intronic pseudoexon GH receptor mutations. A recent study assessed the growth response to rhIGF-1 in 15 patients with GH receptor pseudoexon mutations. [14] Mean baseline height velocity was 4.7 ± 1.1 cm/year. The mean HV increased significantly in the first year of treatment (7.4 ± 1.8 cm/year (P = 0.001). The overall response

Journal Pre-proof was comparable to that reported in patients with other homozygous GH receptor defects and other patients with severe primary IGFD. [14] Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Consistent with other studies these patients did not achieve an AH within the normal range. However, as previously reported in patients with severe primary IGFD, AH SDS was higher than pretreatment height SDS. [14]

na

lP

re

-p

ro

of

c. RhIGF-1 therapy in patients with PAPPA-2 deficiency. Pregnancy-associated plasma protein A2 is a member of the lysin family of metalloproteinases. [21] Although the function of PAPPA-2 in human physiology is largely unknown, this enzyme specifically cleaves IGFBP-3 and IGFBP-5, and therefore regulates the release of free IGF-I in the extravascular space. [21] Consequently, mutations in PAPPA-2 lead to short stature due to low IGF-I availability. [22] Due to the PAPPA-2 deficiency the IGF-I/IGFBP3/ALS ternary complex does not get proteolyzed and free IGF-I concentrations will be very low. Low free IGF-I leads to decreased feedback to the pituitary with increased GH secretion as a result. The increase in GH secretion leads to further production of ALS, IGF-I, IGFBP-3 and IGFBP-5 which results in an increase in total IGF-I. [22] PAPPA-2 deficiency therefore presents with short stature associated with high total IGF-I, and low free IGF-I. Patients with PAPPA-2 deficiency have postnatal growth retardation and may present with height SDS between -2.8 and -3.8. [23] They also have some subtle dysmorphic findings, such as frontal prominence and mild midface hypoplasia with a small jaw. They can also have narrow fibulae and elongated digits on x-ray. [23] Treatment of these patients with rhIGF-1 for more than three years allows linear growth to be parallel with normal growth curves, without yielding any significant catchup growth (personal communication). Insulin resistance is often a characteristic in PAPPA-2 patients, and this improves which the rhIGF-1 treatment. Munoz-Calvo et al. also showed that treatment with rhIGF-1 is effective in promoting short-term growth in patients with PAPP-A2 deficiency, with a short-term HV response in the higher range of that observed in patients with severe GH insensitivity treated with rhIGF-1. [20]

ur

Conclusion

Jo

The efficacy and safety of rhIGF-1 therapy in patients with primary IGFD has been evaluated for more than two decades. [24] Most of the therapeutic experience comes from observations in severely affected patients with a phenotype characteristic for GH receptor deficiency or Laron syndrome. [24, 25] Although most patients do not experience catchup growth that is enough to bring their height well into normal range, many patients still achieve an adult height significantly greater than expected in the absence of therapy. With increasingly more patients being diagnosed with milder forms of IGFD, controlled studies with rhIGF-1 are needed in those patient cohorts affected by a milder phenotype and less severe short stature.

Acknowledgments. The author would like to acknowledge his co-investigators in the long-term studies conducted in the United States: Drs. Louis E Underwood and Steven D Chernausek. Further, the study coordinators Samantha Blum and Vinny Duncan, as well as contributors Joyce Kuntze and Jim Frayne, and Vivian Hwa, Andrew Dauber, and Leah Tyzinsky.

Journal Pre-proof References [1] Martindale A. Mantegna's Camera picta as wall decoration. In: The court of the Gonzaga in the age of Mantegna: 1450-1550. Bulzoni, 1997: 179-186. [2] Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone - a new inborn error of metabolism? Isr J Med Sci. 1966 Mar-Apr;2(2):152-5. PMID: 5916640

of

[3] Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigamo K, Wagner TE, Baumann G, Kopchick JJ. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mo use). Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13215-20. PMID: 9371826

ro

[4] Rosenbloom AL, Guevara Aguirre J, Rosenfeld RG, Fielder PJ. The little women of Loja--growth hormone-receptor deficiency in an inbred population of southern Ecuador. N Engl J Me d. 1990 Nov 15;323(20):1367-74. PMID: 2233903

re

-p

[5] Baumbach L, Schiavi A, Bartlett R, Perera E, Day J, Brown MR, Stein S, Eidson M, Parks JS, Cleveland W. Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome). J Clin Endocrinol Metab. 1997 Feb;82(2):444-51. PMID: 9024234

lP

[6] Walker JL, Ginalska-Malinowska M, Romer TE, Pucilowska JB, Underwood LE. Effects of the infusion of insulin-like growth factor I in a child with growth hormone insensi tivity syndrome (Laron dwarfism). N Engl J Med. 1991 May 23;324(21):1483-8. No abstract available. PMID: 2023608

ur

na

[7] Backeljauw PF, Kuntze J, Frane J, Calikoglu AS, Chernausek SD. Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I. Horm Res Paediatr. 2013;80(1):47-56. doi: 10.1159/000351958. Epub 2013 Jul 20. PMID: 23887143

Jo

[8] Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE; GH Insensitivity Syndrome Collaborative Group. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007 Mar;92(3):902-10. Epub 2006 Dec 27. PMID: 17192294 [9] Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab. 2013 Feb;98(2):839-45. doi: 10.1210/jc.2012-3704. Epub 2013 Jan 22. PMID: 23341492 [10] Bang P, Polak M, Woelfle J, Houchard A; EU IGFD Registry Study Group. Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex® Growth Forum Database Experience. Horm Res Paediatr. 2015;83(5):345-57. doi: 10.1159/000371798. Epub 2015 Mar 21. PMID: 25824333 [11] David A, Hwa V, Metherell LA, Netchine I, Camacho-Hübner C, Clark AJ, Rosenfeld RG, Savage MO. Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endocr Rev. 2011 Aug;32(4):472-97. doi: 10.1210/er.2010-0023. Epub 2011 Apr 27. Review. PMID: 21525302

Journal Pre-proof [12] Storr HL, Chatterjee S, Metherell LA, Foley C, Rosenfeld RG, Backeljauw PF, Dauber A, Savage MO, Hwa V. Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action. Endocr Rev. 2019 Apr 1;40(2):476-505. doi: 10.1210/er.2018-00146. PMID: 30265312 [13] Vairamani K, Merjaneh L, Casano-Sancho P, Sanli ME, David A, Metherell LA, Savage MO, Del Pozo JS, Backeljauw PF, Rosenfeld RG, Aisenberg J, Dauber A, Hwa V. Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency. J Endocr Soc. 2017 Apr 1;1(4):345-358. doi: 10.1210/js.2016-1119. Epub 2017 Mar 8. PMID: 29188236

of

[14] Chatterjee S, Shapiro L, Rose SJ, Mushtaq T, Clayton PE, Ten SB, Bhangoo A, Kumbattae U, Dias R, Savage MO, Metherell LA, Storr HL. Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation. Eur J Endocrinol. 2018 May;178(5):481-489. doi: 10.1530/EJE-18-0042. PMID: 29500309

-p

ro

[15] Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz ID, Rockstroh D, Colombo R, Sanchez MA, Vokurkova D, Kowalczyk J, Metherell LA, Rosenfeld RG, Pfäffle R, Dattani MT, Dauber A, Hwa V. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun. 2018 May 29;9(1):2105. doi: 10.1038/s41467-018-04521-0. PMID: 29844444

lP

re

[16] Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Büttel HM, Schweizer R, van Workum W, Binder G, Eggermann T. Paternally Inherited IGF2 Mutation and Growth Restriction. N Engl J Med. 2015 Jul 23;373(4):349-56. doi: 10.1056/NEJMoa1415227. Epub 2015 Jul 8. PMID: 26154720

ur

na

[17] Högler W, Martin DD, Crabtree N, Nightingale P, Tomlinson J, Metherell L, Rosenfeld R, Hwa V, Rose S, Walker J, Shaw N, Barrett T, Frystyk J. IGFALS gene dosage effects on serum IGF-I and glucose metabolism, body composition, bone growth in length and width, and the pharmacokinetics of recombinant human IGF-I administration. J Clin Endocrinol Metab. 2014 Apr;99(4):E703-12. doi: 10.1210/jc.2013-3718. Epub 2014 Jan 13. PMID: 24423360

Jo

[18] Işık E, Haliloglu B, van Doorn J, Demirbilek H, Scheltinga SA, Losekoot M, Wit JM. Clinical and biochemical characteristics and bone mineral density of homozygous, compound heterozygous and heterozygous carriers of three novel IGFALS mutations. Eur J Endocrinol. 2017 Jun;176(6):657-667. doi: 10.1530/EJE-16-0999. Epub 2017 Mar 1. PMID: 28249955 [19] Cabrera-Salcedo C, Mizuno T, Tyzinski L, Andrew M, Vinks AA, Frystyk J, Wasserman H, Gordon CM, Hwa V, Backeljauw P, Dauber A. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density. J Clin Endocrinol Metab. 2017 Dec 1;102(12):45684577. doi: 10.1210/jc.2017-01411. PMID: 29029190 [20] Muñoz-Calvo MT, Barrios V, Pozo J, Chowen JA, Martos-Moreno GÁ, Hawkins F, Dauber A, Domené HM, Yakar S, Rosenfeld RG, Pérez-Jurado LA, Oxvig C, Frystyk J, Argente J. Treatment with Recombinant Human Insulin-Like Growth Factor-1 Improves Growth in Patients With PAPP-A2 Deficiency. J Clin Endocrinol Metab. 2016 Nov;101(11):3879-3883. Epub 2016 Sep 20. PMID: 27648969 [21] Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem. 2001 Jun 15;276(24):21849-53. Epub 2001 Mar 22. PMID: 11264294

Journal Pre-proof [22] Dauber A, Muñoz-Calvo MT, Barrios V, Domené HM, Kloverpris S, Serra-Juhé C, Desikan V, Pozo J, Muzumdar R, Martos-Moreno GÁ, Hawkins F, Jasper HG, Conover CA, Frystyk J, Yakar S, Hwa V, Chowen JA, Oxvig C, Rosenfeld RG, Pérez-Jurado LA, Argente J. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016 Apr 1;8(4):363-74. doi: 10.15252/emmm.201506106. PMID: 26902202 [23] Andrew M, Liao L, Fujimoto M, Khoury J, Hwa V, Dauber A. PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence. J Endocr Soc. 2018 May 28;2(7):646-656. doi: 10.1210/js.2018-00106. eCollection 2018 Jul 1. PMID: 29942928

of

[24] Backeljauw PF, Chernausek SD. The insulin-like growth factors and growth disorders of childhood. Endocrinol Metab Clin North Am. 2012 Jun;41(2):265-82, v. doi: 10.1016/j.ecl.2012.04.010. Review. PMID: 22682630

Jo

ur

na

lP

re

-p

ro

[25] Guevara-Aguirre J, Guevara A, Guevara C. Treatment of growth failure in the absence of GH signaling: The Ecuadorian experience. Growth Horm IGF Res. 2018 Feb;38:53-56. doi: 10.1016/j.ghir.2017.12.009. Epub 2017 Dec 20. Review. PMID: 29306560

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

Figure 1. Severe postnatal growth failure characteristic of Laron syndrome. The horizontal arrow to the left shows the marked delay in skeletal maturation.

Journal Pre-proof Figure 2. A. Individual growth response for males (n: 12) with severe primary IGFD treated with rhIGF-1 for a mean of 10.7 years. B Similar individual growth response for females (n: 9).

Jo

ur

na

lP

re

-p

ro

of

A.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

B.

Journal Pre-proof Table 1. Baseline characteristics of patients (n: 21) treated long term with rhIGF-1 until AH/NAH. BMI = body mass index, CDC = center for disease control, GHIS = growth hormone insensitivity syndrome, GnRH = gonadotropin-releasing hormone analogue, HV = height velocity, SDS = standard deviation score Mean (SDS)

Etiology

n (%)

GH Receptor Defect (or GHIS)

16 (76%)

GH gene deletion + GH antibodies

5 (24%)

Female - n (%)

9 (43%)

Baseline age (yr)

7.4

Baseline bone age (yr)

4.5

Baseline CDC height SDS

-6.6 (2.1)

Baseline weight for age SDS

-8.2 (5.6)

re

-p

ro

of

Characteristic

-0.6 (1.0)

lP

Baseline BMI SDS Pretreatment HV (cm/yr)

3.1 (2.0) 10.7 (3.2)

Jo

ur

GnRH analog treatment - n (%)

na

Treatment duration (yr)

9 (43)

Journal Pre-proof Highlights.

of ro -p re lP na



ur



The efficacy and safety of rhIGF-1 therapy in patients with primary IGFD has been evaluated for more than two decades. Most patients with IGFD treated with rhIGF-1 do not experience catchup growth enough to bring their height into normal range. More data to evaluate the benefit of growth promoting therapy in patients affected by a milder IGFD phenotype and less severe short stature are needed.

Jo

