Rev Esp Endocrinol Pediatr

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Rev Esp Endocrinol Pediatr 2021;12 Suppl(1):14-18 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2020.Dec.633
Different Responses to rhGH Treatment in SGA Children: Patients with Mutations in their IGF-1 Receptor, a view from the research lab to the clinic
Diferencias en la respuesta al tratamiento con GH en niños PEG: pacientes con mutaciones en el receptor de IGF-1, un enfoque del laboratorio de investigación para la clínica

Sent for review: 24 Dec. 2020 | Accepted: 24 Dec. 2020  | Published: 19 Jan. 2021
Eric Göpel, Roland Pfäffle
University Hospital for Children & Adolescents. Division of Pediatric Endocrinology, University of Leipzig. Leipzig (Germany)
Correspondence:Eric Göpel, University Hospital for Children & Adolescents, Division of Pediatric Endocrinology, University of Leipzig, Liebigstr. 20a, 04103, Leipzig, Germany
E-mail: roland.pfaeffle@medizin.uni-leipzig.de
Figure 1 - Growth profiles of patients with IGF1RM and SGA control
Figure 2 - Growth of treated IGF1RM (blue line) and treated SGA controls (black line) before treatment, during the first 4 years of rhGH treatment and at near final height
Figure 3 - Change in growth velocity during the first 4 years of treatment in patients with IGF1RM (closed circles) and SGA controls (open circle)
Anexos 1 - Conference presentation

Introduction

Although IGF1 receptor mutations (IGF1RM) overall are rare, they can be frequently detected among patients born small for gestational age that show pronounced growth retardation without catch-up growth. Their phenotypic characteristics have been described in several case reports. Here, however, we try to give a comprehensive statistical analysis of their growth profile and evaluate the benefit of recombinant growth hormone (rhGH) treatment. In this study we analyzed IGF1RM carriers (n = 23) regarding birth parameters, growth response to rhGH therapy, near final height and glucose/insulin homeostasis retrospectively and compared them with children born small for gestational age (SGA) (n = 34). Part of this talk has been previously published [1].

The IGF1R belongs to the family of tyrosine receptor kinases and shares a high homology (>50 %) with the insulin receptor [2,3]. Molecular defects in the IGF1R usually results in severe growth retardation starting before birth. This specific group of children born small for their gestational age (SGA) does not show catch-up growth within the first 4 years of life and result in a persistent postnatal growth retardation. There seem to be some phenotypic characteristics, which, however, are not found in all patients. Next to reduced head circumference, clinodactyly, triangular face, hypotelorism, low set ears, thin upper lip, and high-arched palate, as well as a high-pitched voice and mild mental retardation were reported [4-10].

Some studies also discussed an impaired glucose tolerance, insulin resistance or even overt diabetes with other comorbidities [6,7,11-13].  In the serum of IGFRM patients elevated or high-normal serum concentrations of IGF1 and IGF binding protein 3 (IGFBP3) can be found [5].  

Treatment with rhGH has proven to be effective in SGA children lacking catch up growth [14] , although being less efficient compared to patients with GH-deficiency [15]. The response to rhGH treatment in SGA patients is influenced by several parameters, including midparental height (MPH), age and weight at rhGH initiation, and rhGH dose [16].

 

Methods

In our hospital screening for IGF1R mutations was performed in children being born SGA, who lacked catch-up growth (height <‑2.0 SDS at the age of 4 years) and when IGF1 serum concentrations were >- 0.5 SDS. In 322 children, who were analyzed, we found 23 as carriers of dominant or recessive IGF1RMs. IGF1RM carriers comprise 13 individual patients and 10 related patients from 5 families. 17 of the 23 IGF1RM carriers had received rhGH treatment for a minimum of one year, while 6 patients had received no rhGH.

A control cohort (referred to as SGA control) was chosen from our CrescNet database that matched the IGF1RM cohort in respect to showing no catch-up growth, having been treated with rhGH for at least 1 year, showing serum IGF1 serum levels >‑2.0 SDS, with no other known disease-causing short stature, and not having a detectable IGF1R mutation.

In order to analyze health consequences in adulthood in IGF1RM we also investigated 11 adult IGF1RM carriers and 11 adults born SGA matched for age and gender. These individuals with IGF1RM were either parents of index patients (n = 5) or former patients (age >23 years) invited to participate in the study (n = 6). The study was conducted in accordance with the Declaration of Helsinki and written informed consent to participate in the study was obtained from the probands, parents or legal guardians.

Data was collected retrospectively as baseline data prior to rhGH initiation and follow-up data at 12 (± 2) month intervals over a period of 4 years. We considered the last reported height as near final height (NFH) when growth velocity was <2cm/year, or bone age ≥16 years for boys and ≥14 years for girls, or chronological age ≥ 16 years, and analyzed only, when patients were treated more than 3 years.

Endocrine testing was performed at the Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (University of Leipzig, Germany). Fasting glucose and insulin were determined after a fasting period of at least 8 hours. Insulin resistance (HOMA‑IR) was calculated as previously published [17].

Mutation screening of the IGF1R was done with denaturing high-performance liquid chromatography (dHPLC) (WAVE, Transgenomic, Omaha, NE, USA) using IGF1R PCR products of patients’ genomic DNA extracted from whole blood samples (QIAamp® DNA Blood Midi Kit; Qiagen, Inc., Valencia, CA, USA). Samples showing abnormal chromatograms were then sequenced (ABI PRISM 310 Genetic Analyzer; Applied Biosystems, Foster City, CA, USA). The IGF1R variants are classified according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) [18].

Statistical analyses: Due to relatively low patient numbers nonparametric tests (Mann-Whitney U, Wilcoxon, Spearman's rank correlation with pairwise deletion) were applied and frequencies evaluated with Pearson's chi-squared and Fisher's exact test.

 

Results

Treated patients with IGF1RM did not differ significantly in sex, age, birth data and parameters influencing rhGH therapy (parental height, age at rhGH start and dose) from SGA controls. However, IGF1RM carriers showed significantly lower height at rhGH start. Also, IGF1RM patients had significantly higher IGF1 and IGFBP3 serum levels than their SGA controls, reflecting IGF1 resistance.

All groups studied showed severe growth retardation up to start of rhGH treatment. In average, however, IGF1RM patient’s hormone treatment started earlier, probably because their growth-retardation developed more profound. Although both groups showed similar birth length (‑2.57 SDS IGF1RM vs -2.81 SDSSGA), IGF1RM carriers showed a drop in height by 0.85 SDS postnatally (see Figure 1). Consequently, IGF1RM carriers were significantly smaller than SGA controls (by 0.70 SDS) at the start of treatment. Untreated IGF1RM patients continued to fall in height behind the treated IGF1RM carriers and the SGA controls (see Figure 2).

IGF1RM carriers, however, showed less height increment than SGA controls within the first year of GH treatment (0.29 SDSIGF1RM vs. 0.65 SDSSGA, p <.01), although this difference became less pronounced, as the in the following 3 years the annual height increment in IGF1RM carriers remained constant, while in SGA controls it slowed down (see Figure 3).

In order to analyze the long-term outcome of rhGH therapy, we studied the final or near final height (NFH) SDS of the patients in all three groups. Despite not being statistically significant, grown-up SGA patients, who had been treated with rhGH, were slightly taller than IGF1RM carriers (‑2.22 SDSSGA treated, ‑2.59 SDSIGF1RM treated, ‑3.24 SDSIGF1RM untreated). In order to evaluate the overall height gain in each of the groups, we also calculated Δ NFH (the difference in height SDS at birth to NFH SDS) and found that the gap between treated and untreated IGF1RM patients was bigger than between treated IGF1RM and SGA controls (+0.81 SDSSGA treated, ‑0.45 SDSIGF1RM treated, -1.72 SDSIGF1RM untreated). Because NFH data of untreated IGF1RM was very limited (3 subjects), we also included data of untreated affected parents (n = 5) for further analysis, which, however, lead to similar results (NFH -2.9 SDSIGF1RM untreated and Δ NFH ‑0.96 SDS IGF1RM untreated).

When analyzing factors known to be correlated with growth response in SGA children treated with rhGH we could only see a positive correlation between rhGH dose (mg/kg/week) and Δ height SDS in the SGA controls (R = 0.538; p < 0.001), whereas such a correlation was not observed in IGF1RM patients (R = 0.029; p = .911).

Before start of rhGH treatment Insulin resistance did not differ significantly between IGF1RM patients and SGA controls as HOM-IR were found similar. Under treatment, however, both groups showed an increase in insulin resistance, which was more pronounced in IGF1RM patients (HOMA-IR 2.11IGF1RM vs. 1.15SGA). 6 months after rhGH therapy had stopped HOMA-IR values went down in both groups with no significant difference. Other parameters of insulin sensitivity like hemoglobin A1c (HbA1c), fasting glucose concentrations, Matsuda index or Insulinogenic Index were not significantly changed by rhGH treatment.

 

Discussion

We could demonstrate that patients with IGF1RM show a profound growth retardation before rhGH therapy and show a lower growth response to rhGH-therapy compared to SGA patients without IGF1M, although they seemingly benefit to some extend from such therapy and the analysis of long-term follow up data so far does not indicate increased insulin resistance in IGF1RM carriers in later life compared to treated SGA controls.

In face of the central role that IGF1RM has for intrauterine and postnatal growth it may seem surprising that SGA children with IGF1RM respond to rhGH treatment at all. This could have different explanations: GH itself induces the proliferation of chondrocytes in the growth plate [19] , promoting growth despite missing IGF1R function. In addition, locally produced IGF1 down-regulates the expression of the GH receptor (GHR) on osteoblasts via the IGF1R [20,21]. A reduced IGF1R function therefore might lead to increased GH receptor density in the growth plate in IGF1RM carriers thereby resulting in increased GH action. Also, most IGF1RM are heterozygous and only reduce IGF1R expression instead of abolishing it completely, higher IGF1 levels induced by rhGH treatment can partially overcome the growth restriction of IGF1RM [5].

The current study, however, has some limitations: for one this is the small sample size of IGF1RM carriers, mainly due to the rare occurrence of IGF1R mutations within a single center. Additionally, IGF1RM carriers started at a somewhat although not significantly younger age with rhGH therapy and also were treated with lower rhGH doses than SGA control patients. As in most patients the presence of the IGF1RM was not known at the time of treatment initiation, we assume that this was to the more severe growth retardation in IGF1RM carriers. Similarly, the elevated IGF1 serum levels frequently seen in IGF1RM patients under treatment with rhGH possibly lead the physician to lower rhGH dose during the course of treatment.

Overall, we think that patients with IGF1RM should not be excluded from rhGH treatment, however, the individual course is highly variable, and the clinical success should be reevaluated periodically, although final judgement cannot be made after the first year of treatment.

 

Competing Interest

The authors declare no known competing financial interest or personal relationships that could have appeared to influence the work reported in this article.

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