Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder
© Saenger and Reiter; licensee BioMed Central Ltd. 2012
Received: 6 October 2011
Accepted: 19 March 2012
Published: 15 May 2012
The term small for gestational age (SGA) refers to infants whose birth weights and/or lengths are at least two standard deviation (SD) units less than the mean for gestational age. This condition affects approximately 3%–10% of newborns. Causes for SGA birth include environmental factors, placental factors such as abnormal uteroplacental blood flow, and inherited genetic mutations. In the past two decades, an enhanced understanding of genetics has identified several potential causes for SGA. These include mutations that affect the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, including mutations in the IGF-1 gene and acid-labile subunit (ALS) deficiency. In addition, select polymorphisms observed in patients with SGA include those involved in genes associated with obesity, type 2 diabetes, hypertension, ischemic heart disease and deletion of exon 3 growth hormone receptor (d3-GHR) polymorphism. Uniparental disomy (UPD) and imprinting effects may also underlie some of the phenotypes observed in SGA individuals. The variety of genetic mutations associated with SGA births helps explain the diversity of phenotype characteristics, such as impaired motor or mental development, present in individuals with this disorder. Predicting the effectiveness of recombinant human GH (hGH) therapy for each type of mutation remains challenging. Factors affecting response to hGH therapy include the dose and method of hGH administration as well as the age of initiation of hGH therapy. This article reviews the results of these studies and summarizes the success of hGH therapy in treating this difficult and genetically heterogenous disorder.
KeywordsGrowth hormone Small for gestational age Insulin-like growth factor Acid-labile subunit deficiency Uniparental disomy
Definition and epidemiology of small for gestational age (SGA)
Factors associated with increased incidence of SGA birth
Gross structural placental factors
-Single umbilical artery
-Very young age
-Infarcts, focal lesions
-Collagen vascular diseases
Insufficient uteroplacental perfusion
-Suboptimal implantation site
Maternal and paternal race
History of SGA
-Low prepregnancy weight
-Low pregnancy weight
Genetic factors influencing SGA
Transcription of the gene for IGF-1 is mediated by the binding of pituitary GH to specific GH receptors on hepatocytes. The secretion of IGF-1 from the liver then stimulates cell growth (particularly bone) and inhibits secretion of GH from the pituitary . Consequently, mutations of the IGF-1 gene affect growth and GH secretion and have been correlated with SGA births. A homozygous partial deletion of exons 4 and 5 of IGF-1 was observed for one patient born SGA. The mutation truncated the IGF-1 peptide sequence from 70 to 25 amino acids and was followed by an out-of-frame nonsense sequence and stop codon. In addition to growth defects, the patient suffered from bilateral sensorineural deafness and mental retardation, a feature indicating the importance of IGF-1 in central nervous system development . When treated with hGH at a 0.1 U/kg dose for 4 days, no detectable IGF-1 level could be observed in the patient. However, when treated with recombinant human IGF-1 (rhIGF-1) therapy for one year (three months at 40 mcg/kg/day, nine months at 80 mcg/kg/day), insulin sensitivity, bone mineral density, and line growth of this patient were improved .
A second patient born SGA with sensorineural deafness and mental retardation was evaluated for IGF-1 defects. Investigators observed a T→A transversion in the 3′-untranslated region of exon 6 that caused the expression of a truncated version of exon 6 and an altered E domain of the IGF-1 prohormone. hGH therapy for this patient (200 mcg hGH/day intramuscular doses for seven days) afforded no improvement in IGF-1 levels . It should be noted that a second research group later sequenced IGF-1 (exons 1–6) in 53 children born SGA and determined that none of the mutations in the coding region of IGF-1 correlate with SGA stature .
Similarly, an IGF-1 defect was observed for a third patient who had initially been evaluated at the age of 21 years for SGA birth size . In addition to SGA size, the patient initially presented with bilateral hearing loss, microcephaly, and severe mental retardation. When investigators re-evaluated the patient at 55 years of age, unusually high serum levels of IGF-1 were noted, which varied from the patient phenotypes described by Woods and Bonapace [11–13]. Furthermore, both insulin-like growth factor binding protein-3 (IGFBP-3) and insulin-like growth factor-1 receptor (IGF-1R) levels were normal. However, by sequencing IGF-1, investigators detected a nucleotide substitution at position 274 (G→A) in the sequence, which caused an amino acid substitution at position 44 of the IGF-1 protein (V44M). The modified IGF-1 protein displayed a 90-fold-lower binding affinity for IGF-1R than the wild-type derivative, although the mutated protein had normal binding capacity for IGFBPs. This reduced affinity of IGF-1 for IGF-1R resulted in diminished phosphorylation of IGF-1R and downstream-acting signaling proteins, particularly Akt/PKB [16, 17].
Phenotypic characteristics and response to hGH therapy for patients with IGF-1 mutations
Deletion of exons 4 and 5
Birth weight −3.9 SD; birth length −5.4 SD; sensorineural deafness and mental retardation; nearly undetectable IGF-1 levels
Woods, 1996 
Truncated version of exon 6
Birth weight −4 SD; birth length −6.5 SD; sensorineural deafness and mental retardation; low serum IGF-1 levels
Bonapace, 2003 
Birth weight −3.9 SD score; birth length −4.3 SD score; bilateral hearing loss, microcephaly, severe mental retardation; elevated GH levels and IGF-1 levels but normal IGFBP-3 levels
Birth weight −2.5 SD score; birth length −3.7 SD score; mild mental development delay; reduced IGF-1 levels but increased IGFBP-3 levels
Netchine, 2006 
Various compound heterozygous mutations throughout the coding sequence of IGF-1R have been described for multiple families, with each case exhibiting phenotype variations . Typically, IGF-1R mutations can be classified as point mutations or partial deletions. When one patient born SGA with significantly delayed postnatal growth was evaluated for IGF-1R mutations, investigators determined that two point mutations in exon 2 of IGF-1R caused two single-base pair substitutions in the codons for amino acid 108 (CGG→CAG) and 115 (AAA→AAC) of the corresponding protein. This change resulted in two-thirds-lower binding affinity of IGF-1 to IGF-1R in fibroblasts as compared with controls. When treated with hGH therapy (37.5 mcg/kg/week), the patient’s growth rate was increased to the 75th percentile for her age .
Similarly, a second patient born SGA who suffered from postnatal growth delay, microcephaly, and mild mental retardation was evaluated for IGF-1R mutations. A heterozygous point mutation CGA to TGA (Arg59Ter) in exon 2 of IGF-1R caused early termination of transcription of the IGF-1R protein, leading to reduced receptor expression on the cell surface, as well as decreased autophosphorylation and phosphorylation of signaling proteins . When treated with hGH at 30 mcg/kg/day starting at age 6 years, the patient’s height increased by 1.01 SD after two years of therapy, indicating that hGH therapy can improve quality of life for SGA patients with this mutation .
When 24 children born SGA were evaluated by direct sequencing of IGF-1R to identify causal mutations, two patients were observed to have a heterozygous missense mutation (C→T) of IGF-1R, which altered the cleavage site of the proreceptor of IGF-1R from RLRR to RLQR (R709Q). This mutation inhibited the expression of mature IGF-1R from the IGF-1R precursor protein. Interestingly, the two patients who presented with this mutation had different levels of mental development. While patient 1 displayed mental retardation, patient 2 had normal intellectual development. Thus, no link exists between the heterozygous IGF-1R mutation and intellectual development .
Similarly, two more patients were evaluated and determined to present with a missense mutation in the intracellular kinase domain of IGF-1R. The older patient, a 35-year-old mother, showed above-average intelligence and no dysmorphic features, but her height (−4.0 SD score) and head circumference (−3.0 SD score) showed growth retardation. Her daughter, patient 2, was born SGA and showed normal mental development but delayed motor development by the age of 15 months. Both patients showed increased IGF-1 levels. Sequence analysis of IGF-1R showed a heterozygous G→A nucleotide substitution, which changed the amino acid sequence of IGF-1R at position 1050 from glutamic acid to lysine. This mutation did not affect expression of IGF-1R protein, but the sequence alteration reduced autophosphorylation of IGF-1R and activation of PKB/Akt . Similarly, a 13.6-year-old girl who displayed short stature (−5.0 SD score) and reduced bone age (9.7 years), as well as elevated IGF-1 levels and no improvement in height following six months of treatment with hGH therapy at a daily dose of 70 mcg/kg/day, was evaluated for IGF-1R mutations. A heterozygous G→A point mutation at position 1577 of IGF-1R resulted in substitution of arginine with glutamine at residue 481 of the corresponding protein (R481Q). This mutation altered the α-subunit of IGF-1R, leading to reduced phosphorylation and cell growth . Recently, a third report has described a similar IGF-1R mutation in which alanine replaced glycine at position 1125 in seven patients from the same family, causing reduced receptor autophosphorylation and phosphorylation of downstream kinases .
Phenotypic characteristics and response to hGH therapy for patients with IGF-1R mutations
Birth weight −3.5 SD score; delayed motor skill development; psychiatric anomalies; normal IGF-1 levels, delayed motor development
Abuzzahab, 2003 
Birth weight −3.5 SD score; birth length −5.8 SD score; microcephaly, mild retardation, and delayed motor and speech development;
Abuzzahab, 2003 
Birth weight −1.5 SD score; birth length −1.0 SD score; significant mental retardation
Kawashima, 2005 
Birth height −0.3 SD score, birth weight −2.1 SD score; height at 35 years −4.0 SD score; head circumference at 35 years −3.0 SD score; no dysmorphic features; high IGF-1 levels
Walenkamp, 2006 
Height −4.9 SD score, reduced bone age, elevated IGF-1 levels
Inagaki, 2007 
Birth weight −1.7 SD score; head circumference at birth −3.7 SD score; normal mental development
Kruis, 2010 
Birth weight −2.3 SD score; birth head circumference <3rd percentile; high IGF-1 levels; mental retardation
Wallborn, 2010 
In addition to point mutations, distal deletions of the terminal long arm of chromosome 15 have also been linked to patients born SGA, although these mutations are quite rare. Often, these patients present with symptoms resembling Prader-Willi or Angelman syndrome, two diseases resulting from deletions in the 15q11q13 region . One patient born SGA who exhibited continued growth retardation at the age of 4.5 years was evaluated for such distal deletion. It was determined that the patient presented with partial monosomy 15q26.2→15qter, correlating to a deleted critical region of approximately 5.7 Mb . This deletion includes the region 15q26.3, to which the IGF-1R gene has been assigned . A similar deletion was observed for a patient born SGA who displayed a heterozygous 8.58 Mb deletion in the same region . Similarly, a patient born SGA who showed significant growth retardation by the age of 2 years was evaluated for deletions in chromosome 15. Results indicated that the maternally derived chromosome 15 had a 4.7 Mb deleted region, which included 15q26.2 . The smallest deletion of chromosome 15 that has been observed to cause SGA birth involves a mutation in exons 11–21 of the IGF-1R gene (a 0.095 Mb deletion) and was associated with SGA births over three generations in a single family . Typically, patients with partial deletions in this region display mental and psychomotor developmental retardations more often than patients with point IGF-1R mutations .
Fortunately, patients with partial deletions of chromosome 15 respond favorably to hGH treatment. A patient born SGA who displayed a heterozygous loss of 15q26.2→15qter began hGH treatment at the age of 5.3 years at a dose of 1 mg/m2/day (approximately 30 mcg/kg/day). Rapid growth catch-up was observed, and by the age of 15 years the patient had nearly reached her target height (−1.6 SD score) . Similarly, two patients displaying deletions in exons 1–21 and exons 3–21 were treated with hGH therapy at a dose of 1 mg/m2/day (approximately 30 mcg/kg/day). For both patients, treatment resulted in moderate increase in height of approximately +1 SD after one year .
Acid-Labile Subunit (ALS) Deficiency
Type of mutation
Frameshift, premature stop codon
Frameshift, premature stop codon
Frameshift, premature stop codon
In-frame insertion of 3 amino acids, SLR
In-frame insertion of 3 amino acids, LEL
Frameshift, premature stop codon
Obesity and diabetes
For many individuals born SGA, health concerns such as obesity, type 2 diabetes, hypertension, and ischemic heart disease are often encountered later in life [48–50]. In one study, DNA samples from 546 patients (227 children born SGA and 319 born AGA) were analyzed for 54 single nucleotide polymorphisms (SNPs) associated with diabetes or obesity. Genetic variations in five of these SNPs (KCNJ11, BDNF, PFKP, PTER, and SEC16B) correlated with SGA size. Therefore, genetic factors that contribute to obesity and type 2 diabetes likely correlate with SGA .
Angiotensinogen gene variants
Angiotensinogen (AGT) is an α2-globulin precursor to angiotensin II that regulates blood pressure and overall homeostasis . In one study, 174 women and their 162 infants born SGA were compared with 400 women and their 240 infants born AGA. The study evaluated these individuals for a methionine to threonine substitution at codon 235 (235Met >Thr) in the AGT gene, a mutation associated with pregnancy complications such as preeclampsia . The results showed a higher frequency of the 235Thr allele in both mothers (0.60 for SGA versus 0.36 for controls) and infants (0.59 for SGA versus 0.38 for controls) who were associated with SGA births . However, the mechanism by which the 235Met >Thr mutation affects maternal-placental and fetal-placental circulation and, consequently, fetal growth is not understood. Interestingly, a prior study found no correlation between this polymorphism and an increased risk of SGA birth. The differences between the findings of the two investigations were attributed, in part, to variation in ethnic diversity between the two study groups .
Deletion of exon 3 growth hormone receptor (d3-GHR)
The d3-GHR polymorphism, a 2.7 kB deletion in exon 3 of the GHR gene, is a common genetic defect in individuals with normal height and those born SGA . However, for patients born SGA, the d3-GHR polymorphism has been investigated as a potential mutation that affects hGH therapy due to its role in GH signaling. When response to hGH therapy was compared between children born SGA who had only full-length GHR versus at least one d3-GHR allele, results showed that patients with the d3-GHR polymorphism responded 1.7 to 2 times better to hGH therapy than patients with only the full-length gene . Similarly, SGA patients with either two full-length GHRs (fl/fl) or one (d3/fl) or two (d3/d3) d3-GHR alleles were administered hGH for 12 months at a mean dose of 56 ± 11 mcg/kg/day. At the end of 12 months, carriers of either one or two d3-GHR alleles were observed to respond slightly better to hGH therapy than patients with two full-length alleles, although the difference was not statistically significant. The authors suggested that response to hGH therapy for patients with this mutation depends on the specific causes of short stature, such as IGF-1 insensitivity or IGF-1 deficiency . Consequently, children born SGA with the d3-GHR mutation appear to be prime candidates for hGH therapy, although these results are still controversial.
For instance, a comparison was made between the GHR genotype (ie, fl/fl, d3/fl, or d3/d3) of patients with GH deficiency and the individual’s response to hGH treatment. Patients were treated with hGH at a mean dose of 0.2 mg/kg/week for one year and then evaluated for height SD score, height velocity, and height velocity SD score. No statistically significant difference with respect to the measured outcomes could be observed between the patients with the d3-GHR allele and patients who were homozygous for the full-length GHR. Furthermore, this study observed that there was no relationship between an individual’s baseline phenotype and his/her GHR genotype, suggesting that the d3-GHR allele does not affect height in GH deficiency . This lack of correlation between d3-GHR genotype and response to hGH treatment was also confirmed in studies for patients born SGA [60, 61].
Recently, a meta-analysis of 15 studies investigating the effects of d3-GHR genotype and a patient’s first-year response to hGH therapy, including height gain and change in growth velocity, was conducted. The results of this analysis indicated that patients with the d3-GHR allele showed improved growth velocity when treated with hGH therapy, but the treatment outcome was affected by the dose (low doses of hGH showed best response) and age at time of treatment (older patients responded more favorably). It should be noted, however, that this meta-analysis did not discriminate with respect to the cause of short stature . In a recent 3-year review, Doerr et al conclude that the determination of GHR isoforms for deletion of exon 3 is not particularly useful in defining the overall response to GH in short SGA children .
Uniparental disomy (UPD) and imprinting effects
UPD is a process whereby a person inherits two copies of a gene or chromosome from one parent and no copies from the other parent. In most cases, UPD does not affect fetal development. However, if a UPD gene is also an imprinted gene, there may be adverse effects to the fetus, because UPD of imprinted genes is equivalent to functional nullisomy . The transcriptional regulation of imprinted genes varies from normal genes in that imprinted genes are only active from one parent allele. For instance, a gene may be active only when paternally inherited; the maternal allele of this gene is “switched off.” Conversely, imprinted genes can be maternally expressed and paternally imprinted . Thus, if a patient inherits two versions of an imprinted gene (eg, two copies of a maternal, “switched-off” gene), phenotype abnormalities may result. Studies have indicated that several UPDs can be responsible for short stature in patients born SGA.
SRS is a disorder characterized by reduced birth weight, facial features including triangular shape and pointed chin, and body asymmetry [66, 67]. Growth restrictions continue through life and often correlate with fasting hypoglycemia . hGH treatment, given daily as subcutaneous injections at a dose of 35 mcg/kg/day for up to three years, is usually suggested for these patients .
The genetic causes of SRS vary, with cases of autosomal-dominant, autosomal-recessive, and X-linked inheritance all observed (as reviewed by Hitchins and Abu-Amero) [68, 70]. However, the most referenced causal candidates for this disease involve mutations on chromosomes 7 and 11, which both contain groups of genes that undergo genomic imprinting . Since the early 1990s, maternal uniparental disomy 7 (mUPD7), both full mUPD7 and mUPD for the long arm of chromosome 7, were documented to be the cause of SRS in approximately 10% of cases . However, the phenotype of an SRS patient presenting UPD7 cannot be predicted, as the exact etiology of the mutation varies . Polymerase chain reaction with microsatellite repeat markers or Southern blot analysis with variable number of tandem repeats can effectively be used to screen patients for mUPD7 .
UPD of the long arm of chromosome 14 (UPD14) has been associated with both below-average growth and mental retardation. Initially, it was not known whether the congenital anomalies present in UPD14 patients resulted from an extra copy of an active imprinted gene (ie, two genes that were “switched on”) or the absence of gene expression caused by the presence of two repressed alleles (ie, two genes “switched off”). To determine the likely cause of the phenotype, patients with distal partial trisomy for chromosome 14 (Ts14) were evaluated to determine genotype-phenotype correlations to determine whether the partial trisomy was of maternal or paternal origin. By investigating patients with an extra copy of either maternally inherited or paternally inherited copies of chromosome 14, the investigators hoped to observe more pronounced effects of the disease if it was caused by active imprinted genes. All 13 patients with distal maternal Ts14 (mTs14) were born SGA. Conversely, over half of the patients with paternal Ts14 (pTs14) were born at weights AGA, indicating that an absence of paternal information likely causes growth retardation in patients with UPD14. The minimum trisomic regions 14q31.1-14qter and 14q24.3-14qter were identified as possibly containing the imprinted genes . Overall, the phenotype of patients with mUPD14 can be quite variable. A review of 24 cases of patients displaying mUPD14 attributes the growth retardation of these patients to confined placental mosaicism and imprinted genes that cause early skeletal maturation, although unusual phenotypes may also be caused by autosomal, recessively inherited mutations .
hGH treatment for SGA
Class of genetic mutation
Specific genetic variant
Response to hGH therapy
Generally not effective
Good for partial distal deletions; generally not effective for point mutations
Good outcome for heterozygous carriers
Good outcome, but dose and age matter
hGH therapy is commonly used for SRS, but correlation between effectiveness and specific genetic mutation has not been carefully evaluated
mUPD7 for long arm of chromosome 7
Hypomethylation at ICR1 on 11p15
Duplication of ICR2 on 11p15
In addition to the dose and method of administration, the age of initiation of hGH therapy significantly affects the outcome. Patients treated before the onset of puberty achieve optimal results. A recent study showed that children treated for one year with hGH therapy before the age of 4 years achieved greater height gain (1.7 SD score, 12.5 cm) than those treated after 4 years of age (1.2 SD score) . Even among older patients, this trend persists. Patients receiving hGH therapy more than two years before puberty showed increased height gain (1.7 SD, ~12 cm) compared with patients treated fewer than two years before puberty (0.9 SD gain, 6 cm). However, nearly 90% of these patients achieved adult height within the normal range . Conversely, patients treated during puberty achieved height gain of only 0.6 SD score, and fewer than 50% of these patients achieved normal adult height .
In 2003, Ranke et al developed a model that essentially summarized the trends that we have described and that could be used by physicians to individualize hGH treatment for SGA patients. Using a pharmacoepidemiological survey of 613 children, various trends were elucidated. In fact, the model could be used to explain approximately 50% of the variability associated with hGH therapy response during the first and second years of treatment. Nearly 35% of the variability could be attributed to the dose, followed by the patient’s age at the start of treatment. Subsequent growth during the second year of treatment could be predicted based on a successful first year of treatment .
Use of hGH therapy in SGA children in the United States and Europe
FDA-approved indication in 2001
EMEA-approved indication in 2003
Age at start of treatment (year)
Height SDS at start
Growth velocity before treatment
No catch-up growth
Less than 0 SD for age
Reference to midparental height
Height SDS > 1 SD below midparental height SDS
Based on results from more than 20 years of research, numerous genetic causes for SGA births have been realized. Genetic defects in either IGF-1 or IGF-1R that result in SGA size typically correlate with phenotypical features such as microcephaly and mental retardation. The most predictive factors for IGF-1R deletion include small birth size, head size, and stature, as well as high IGF-1 levels, developmental delay, and micrognathia. hGH therapy in patients with mutations in IGF-1 has shown moderate success. Furthermore, for patients with IGF-1R mutations, hGH treatment has been shown to be especially promising, particularly for those with distal deletions of the terminal long arm of chromosome 15. Overall, in studies in which the genotype of SGA patients was not known and hGH therapy was conducted, improvements were observed for most of the patient population, particularly if therapy was begun at a young age.
However, despite these positive results, a number of questions regarding the effectiveness of the treatment remain. For instance, hGH therapy for children with SRS has shown positive results, but overall the improvements are often not statistically significant. Furthermore, the differences in SGA patient response to hGH therapy are still only slightly understood. While much of the diversity in response rates to hGH therapy for SGA patients correlates with the type of genetic mutation, the role of additional factors, such as ethnicity, on this treatment still requires significant research.
Appropriate for gestational age
Food and Drug Administration
Imprinting center region 1
Insulin-like growth factor binding protein-3
Insulin-like growth factor
Insulin-like growth factor-1 receptor
Maternal uniparental disomy 7
Recombinant human GH
Recombinant human IGF-1
Santé Adulte GH Enfant study
Small for gestational age
Trisomy for chromosome 14
The authors would like to thank Meredith A. Mintzer, PhD, and Emma Hitt, PhD, of MedVal Scientific Information Services, LLC, for providing medical writing and editorial assistance. This manuscript was prepared according to the International Society for Medical Publication Professionals’ Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines. Funding to support the preparation of this manuscript was provided by Novo Nordisk Inc.
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