Growth hormone receptor (GHR) gene polymorphism and scoliosis in Prader-Willi syndrome

https://doi.org/10.1016/j.ghir.2017.12.001Get rights and content

Highlights

  • Prader-Willi syndrome is a genetic obesity disorder with growth hormone deficiency.

  • Growth hormone receptor gene polymorphism (GHR d3) impacts growth and scoliosis.

  • Case control study of growth hormone receptor on scoliosis in Prader-Willi syndrome.

  • GHR d3 correlated with lower body weight in Prader-Willi syndrome and scoliosis.

Abstract

Objective

A growth hormone receptor (GHR) gene polymorphism impacts sensitivity to endogenous and exogenous growth hormone (GH) to moderate growth and development. Increased sensitivity may accelerate spinal growth and contribute to scoliosis, particularly in GH-deficient and treated populations such as Prader-Willi syndrome (PWS). Therefore, we examined the relationship between GHR genotype and scoliosis (case and control) in PWS cohorts.

Design

We utilized a case-control design in a study of 73 subjects (34M; 39F) with genetically confirmed PWS in 32 individuals previously diagnosed with moderate to severe scoliosis (mean age = 16.9 ± 10.2 years; age range of 1 to 41 years) and 41 adults with no evidence of scoliosis (mean age = 30.8 ± 9.7 years; age range of 18 to 56 years). The GHR gene polymorphism was determined using PCR specific primers to capture the two recognized GHR gene fragment sizes [i.e., full length (fl) or exon 3 deletions (d3)].

Results

Twenty-three (72%) of the 32 case subjects with scoliosis required surgical correction with an approximately equal balance for gender and PWS genetic subtype among cases and 41 control subjects without scoliosis. The GHR d3/d3 genotype was identified in N = 2 of 8 (25%) cases with scoliosis and the d3/fl genotype was identified in N = 11 of 25 (44%) cases with scoliosis but the distribution difference did not statistically differ. The GHR fl/fl genotype was correlated with a significantly faster rate and heavier weight gain among case subjects.

Conclusion

Our examination of demographic and genetic markers associated with scoliosis and surgical repair in PWS found no evidence to support differences in gender, PWS genetic subtype or GHR d3 allele distributions among the case vs control groups. Those with fl/fl alleles were heavier than those with d3/d3 or d3/fl genotypes and warrant further study with a larger sample size and possibly to include other vulnerable populations requiring growth hormone treatment.

Introduction

Prader-Willi syndrome (PWS) is a rare genetic obesity-related disorder occurring in about 1 in 15,000–30,000 births [1], [2], [3], [4]. PWS results from the loss of paternally expressed genes from the genomic imprinted 15q11-q13 region [1], [2], [3] usually from a de novo paternally derived 15q11-q13 deletion [5]. PWS is characterized by infantile central hypotonia with failure to thrive, a poor suck and feeding difficulties; growth and other hormone deficiency leading to short stature, small hands and feet and decreased muscle mass; hypogonadism with genital hypoplasia in both males and females and reduced cognition with behavioral problems [1], [2], [3], [6], [7], [8]. Increased feeding and hyperphagia in early childhood leads to precocious obesity without strict oversight and obesity-related morbidity and mortality [1], [2], [3], [9]. Both hyperphagia and decreased growth in PWS are hormone-based due to dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis [1], [2], [3], [6], [7], [8], [9], [10].

Individuals with PWS respond to treatment with growth hormone (GH) approved by the FDA in 2000 for children with PWS with increased stature, lean body mass and physical activity with reduced obesity status [9], [10], [11], [12], [13], [14], [15]. The vast majority of children with PWS in the United States are treated with GH with a positive impact on growth and body composition by as little as two years of treatment [15]. Furthermore, GH exposure for at least 40% of the life span results in near normal height by 18 years of age according to syndrome-specific standardized PWS growth charts [16]. However, increased growth associated with growth hormone treatment combined with lower muscle mass and strength and severe hypotonia, common in PWS at baseline, may increase the risk or propensity for scoliosis defined as a skeletal back curve > 10° using standing X-rays [2], [17].

Before the approval of GH therapy in PWS, scoliosis was reported in 44% of individuals [1]. Later, about 30% of individuals treated with GH during childhood typically presented with lumbar or thoracolumbar skeletal curves [18]. Musculoskeletal manifestations following physical, orthopedic and radiological evaluations of the spine, hip joints and lower extremities found that scoliosis and limb malalignment were present in 64% of patients with PWS. Scoliosis correlated with a higher body mass index (BMI) which generally followed a bimodal distribution pattern developing prior to 4 years of age or later at the time of normal puberty which is delayed in PWS [17]. In addition, central hypotonia and effects on development of infantile spinal curvature may be impacted by GH treatment in PWS. GH-mediated effects are influenced by genetic factors that may influence the rate of skeletal growth, muscle response and the development of scoliosis including the growth hormone receptor (GHR). Growth hormone is the endogenous ligand of this transmembrane receptor which is responsible for intra- and intercellular signaling pathways which leads to growth.

A common polymorphism of the GHR gene includes a deletion of exon-3 (d3) which is seen in about 50% of Caucasians [19]. Two recognized isoforms [full length (fl); exon 3 deletion (d3)] exist with the GHR d3 polymorphism associated with increased sensitivity to growth hormone [19], [20]. This gene polymorphism leads to an accelerated growth rate including for PWS when treated with GH [19], [21]. It is not clear if increased sensitivity towards growth hormone associated with the GHR d3 polymorphism influences the rate of scoliosis and severity. The aims for our study were to assess the relationship between GHR gene allele subtypes and risk for scoliosis in a cohort of individuals with PWS and GH treatment by studying those with moderate to severe scoliosis and those without a history of scoliosis.

Section snippets

Subjects

Seventy-three subjects (34M; 39F) were studied with genetic confirmation of PWS and available genetic subtypes (15q11-q13 deletion, N = 38; maternal disomy 15 (UPD), N = 30; imprinting defect, N = 5) with medical, skeletal and surgical information including growth hormone therapy data. Case reports and samples were drawn from existing clinical trial data and longitudinal study of PWS clinical course. A case-control study design was undertaken of individuals with PWS from the clinical setting

Results

Thirty-two (44%) of the 73 subjects with genetically confirmed PWS were diagnosed with scoliosis (12 males, 20 females), and of those, 23 (72%) required surgical correction due to severe scoliosis (8 males, 15 females; see Table 1). The number of male and female participants had nearly equal representation in both case and control subject groups. The distribution of PWS genetic subtypes among subjects were also in approximately equal proportions for those with or without scoliosis with a

Discussion

Our examination of the distribution of demographic and genetic markers associated with scoliosis and surgical scoliosis repair in PWS did not find evidence to support differences in gender, PWS genetic subtype or GHR d3 allele distribution among case vs control groups. Individuals with scoliosis and scoliosis related surgery were significantly more likely to have prior GH treatment particularly in childhood (60–70% vs 20–40%) and for a significantly longer period of treatment time (6.2 years vs

Conflict of interest

The submitted manuscript contains original material not submitted or under consideration elsewhere and addresses an important issue in the treatment and care of individuals with Prader-Willi syndrome. We have no conflict of interests in the conduct and reporting of this research to declare.

Acknowledgements

We thank the participating families and Prayer Will Support PWS Organization (Family & Friends of Kyleigh Ellington) and acknowledge support from the Heartland Genetics Collaborative and NICHD grant HD02528.

References (23)

  • G. Elena et al.

    Prader-Willi syndrome: clinical aspects

    J. Obes.

    (2012)
  • View full text