Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

14

IGF1 molecular anomalies demonstrate its critical role

in fetal, postnatal growth and brain development
Irène Netchine, MD, PhD a, b, c, *, Salah Azzi, PhD a, b, c, Yves Le Bouc, MD,
PhD a, b, c, Martin O. Savage, MD, Emeritus Professor of Paediatric
Endocrinology d
a
APHP, Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes, 75012 Paris, France
b
INSERM U 938 team 4, 75012 Paris, France
c
UPMC – Université Pierre et Marie Curie, Paris 75005, France
d
Department of Endocrinology, William Harvey Research Institute, Barts and the Royal London School of Medicine & Dentistry,
London, UK

Keywords:
The phenotype caused by human genetic insulin-like growth factor-I
IGF1 gene (IGF-I) defects is characterised by the association of intrauterine and
IGF-I deficiency postnatal growth retardation with sensorineural deafness and intel-
small for gestational age lectual deficit. This syndrome is extremely rare and only four cases
intrauterine growth restriction have been reported. Addition clinical features may include micro-
fetal growth cephaly and later in life adiposity and insulin resistance. Partial
microcephaly gonadal dysfunction and osteoporosis may also be present. A case of
IGF-I treatment
partial IGF-I deficiency has recently been described and was associated
short stature
with pre- and postnatal growth retardation and microcephaly but the
brain development
deafness developmental delay was mild and hearing tests were normal. IGF-I
deficiency is transmitted as an autosomal recessive trait and is caused
by homozygous mutations in the IGF1 gene. Currently these patients
can benefit from recombinant IGF-I which is now available for treat-
ment. These observations demonstrate that the integrity of IGF-I sig-
nalling is important for normal growth and brain development.
Ó 2010 Elsevier Ltd. All rights reserved.

Introduction

Fetal growth is a complex process involving maternal, placental and fetal factors.1 The mechanisms
underlying human fetal growth retardation remain unknown in many cases.2 In mammals, the insulin-
like growth factor (IGF) system plays a crucial role in growth and development. The IGF system is

* Correspondence to: Irène Netchine, MD, PhD, APHP, Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes,
INSERM UMR-S 938 team 4, 75012 Paris, France. Tel.: þ33 1 44 73 64 48; Fax: þ33 1 44 73 61 27.
E-mail address: irene.netchine@trs.aphp.fr (I. Netchine).

1521-690X/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.beem.2010.08.005
182 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190

comprised of two ligands (IGF-I and IGF-II) that structurally resemble pro-insulin. IGF signal trans-
duction occurs via the type 1 IGF receptor (IGF-1R), a tyrosine kinase receptor similar to the insulin
receptor. Insulin-like growth factor 1 (IGF-I) is essential for fetal, postnatal growth, brain development
and metabolism.3 The involvement of the entire IGF systems (IGF-I, IGF-II, IGF-1R) in fetal development
has been demonstrated in a variety of murine models.4–8
The secretion of IGF-I in utero is independent of growth hormone (GH) action and is autocrine/
paracrine secreted mainly in response to nutritional regulation. In contrast, in childhood and adult life
endocrine IGF-I is secreted by the liver and is controlled by GH. In addition to GH, nutritional status
positively regulates IGF-I biosynthesis. IGF-I production is increased by about three-fold during the last
trimester of pregnancy in humans9–11, its concentration then rapidly increasing after birth.9,10 IGF-I
forms a large, high molecular weight complex with IGF-binding protein 3 (IGFBP-3) and acid-labile
subunit (ALS), thereby increasing its half-life in the circulation and its bio-availability. During postnatal
life, these three components are GH-dependent.12

Role of IGF-I in the control of somatic growth

The somatomedin hypothesis had been proposed over 50 years ago in an attempt to understand the
mechanisms regulating somatic growth.13,14 This hypothesis has been challenged by several studies
demonstrating that endocrine GH does not act directly on tissues to promote growth but instead it acts
mainly via its major effector, IGF-I. Experiments in animals highlighted the importance of IGF-I in the
regulation of pre- and postnatal growth. Isolated invalidation of Igf1 resulted in restrictions of fetal
development (40% delay comparing with wild type mice) and postnatal growth was further impaired
to reach only 30% of normal mice.6,7 In contrast, the knockout of Igf2 resulted also of 40% decrease of
birth weight but the mice retained the same postnatal growth rate as wild type mice15 (Fig. 1). These
experiments clearly demonstrated that IGF-I is a major regulator of both pre- and postnatal growth.
Circulating IGF-I after birth originates largely from the liver16, but IGF-I is also produced by most, if
not all, tissues.17,18 This pattern of secretion gives IGF-I a dual effect: an endocrine (hepatic secretion) and
an autocrine/paracrine effect (tissue-specific secretion), which poses questions about the respective

Fig. 1. Effects of disruption of one or a combination of genes of the IGF system on fetal growth in mice, expressed as a percentage of
normal body weight. Reproduced with permission from the bulletin de l’Académie Nationale de Médecine, Le Bouc 2003; 187: 1225
-1243 Copyright 2003 Bulletin de l’Académie Nationale de Médecine.
 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190 183

roles of circulating versus local IGF-I in promoting growth. Former experiments, consisting of direct GH
or IGF-I injection to the epiphyseal plates of rats demonstrated that local rather than circulating IGF-I
is required for promoting longitudinal bone growth.19–21 Although these findings demonstrated the
effect of GH on cartilage growth, most probably through IGF-I stimulation, the direct (IGF-I-indepen-
dent) effect of GH could not be excluded. How is it therefore possible to distinguish the IGF-I endocrine
effect from its autocrine/paracrine effects? This question was addressed by conditional knockout of Igf1
in liver or specific tissues using the cre/loxP recombination system in mice.
Yakar et al. and Sjögren et al. made the first mouse models lacking liver-derived IGF-I16,22
demonstrating that circulating IGF-I is mostly from hepatic origin since the total inactivation of the
Igf1 gene in the liver resulted in a 75–80% decrease in serum IGF-I. However, the authors did not
observe any difference in growth parameters between hepatic-Igf1 null mice and wild type littermates,
suggesting that IGF-I autocrine/paracrine function (local production under GH control) rather than
endocrine function regulates growth.23 Other studies also demonstrated the importance of the locally
produced IGF-I for the growth of various tissues especially bone accretion.24,25 However, in contrast to
the former experiments, subsequent studies demonstrated that liver-derived IGF-I exerted a small but
significant effect on cortical periosteal bone growth and on adult axial skeletal growth while it was not
required for the maintenance of the trabecular bone in adult mice.26–28 In addition to this subtle effect
on bone growth, this study revealed that circulating IGF-I regulates carbohydrate, lipid metabolism and
blood pressure.27,29 Furthermore the endocrine function of circulating IGF-I acts negatively on GH
secretion since hepatic-Igf1 null mice demonstrated up-regulation of growth hormone releasing
hormone (GHRH) and growth hormone secretagogue receptor (GHS-R) and consequently elevation of
serum GH.16,27,30 It should be noted that all these experiments were performed in the context of locally
secreted IGF-I, which could explain the slight effect observed on longitudinal growth.
To address the endocrine effect of IGF-I, Stratikopoulos et al. generated transgenic mice expressing
Igf1 exclusively in the liver while it was silenced in all other tissues.31 This study demonstrated that the
endocrine IGF-I plays a very significant role in mouse growth, as its action contributes to approximately
30% of the adult body size and sustains postnatal development, including the reproductive functions in
mice of both sexes. These two mouse models are mutually complementary and demonstrate that,
contrary to the conclusion of previous studies, IGF-I endocrine function does exert a significant role in
postnatal growth. Recently, Wu et al. developed a new model to study the IGF-I endocrine function in
mice.32 They showed that overexpression of the rat Igf1 transgene in null-Igf1 mice livers lead to
elevated IGF-I serum level which supported normal body size during and after puberty. However, the
elevated serum IGF-I was insufficient to fully support the female reproductive system which suggested
that autocrine/paracrine function of IGF-I was necessary for female reproduction. More recently, Elis
et al.33 showed that overexpression of the rat Igf1 transgene in mice with normal background Igf1
expression resulted in increased serum IGF-I with greater body mass and enhanced skeletal size,
architecture, and mechanical strength. By contrast, when the transgene is overexpressed in livers of
null-Igf1 mice, elevated serum IGF-I failed to overcome growth and skeletal deficiencies during
neonatal and early postnatal growth, whereas, between four and sixteen weeks of age, elevated serum
IGF-I leads to complete recovery of both body weight and length; in addition, skeletal structure was
restored to control levels by adulthood. These two experiments together demonstrated that the
autocrine/paracrine function of IGF-I is essential for organ growth and function in early postnatal life
and the delay of this function can be compensated by elevated endocrine IGF-I function but only later in
postnatal life and this compensatory effect seems to be sex specific.
In summary, these studies demonstrate that both IGF-I functions (endocrine as well as autocrine/
paracrine) are important to achieve correct somatic development and are therefore not exclusive. The
respective roles of endocrine and autocrine/paracrine IGF-I may also vary at different periods of life
(fetal development, neonatal and postnatal periods) and in different tissues.

Role of IGF-I in brain development and in inner ear

The role of IGF-I is not limited to linear growth and weight gain during fetal and postnatal devel-
opment, but is also crucial in promoting brain and inner ear development. Indeed, several in vivo and in
vitro studies demonstrated that IGF-I regulates proliferation, survival and differentiation of major brain
184 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190

cell lineages.34 Transgenic mice overexpressing Igf1 have 55% larger brain than those of normal
littermates by postnatal day 55 due to an increase of cell size and cell number and most brain struc-
tures appeared to be affected.35 In contrast, Igf1 null-mice exhibit a reduction of brain development
(38%) affecting all major brain areas.36 To determine whether the action of IGF-I signalling was con-
ducted via IRS-1, Ye et al. have cross-bred transgenic mice overexpressing Igf1 and IRS-I null mice.37
Similarly to previous reports, they showed that transgenic mice presented about 50% increase in
total brain weight. Interestingly, double mutant mice (transgenic Igf1/IRS-I /) also exhibited an
increase of brain weight suggesting that the effect of absence of IRS-I can be compensated by other
members of the IRS protein family. IGF-I also promotes neurogenesis and myelination.34 It has been
found that the number of neurones as well as the expression of myelin basic protein (MBP) and pro-
teolipid protein (PLP), two major myelin-specific proteins, is increased in IGF-I-overexpressing
mice.35,37 In contrast, in Igf1 null mice the number of neurones was decreased and myelination was
altered.36,38
Furthermore, Camarero et al. investigated the development of the inner ear in Igf1 null mice at
different postnatal days.39 They found that mutant mice showed a reduction in size of the cochlea and
cochlear ganglion, an immature tectorial membrane and a significant decrease in the number and size
of auditory neurons. In addition, the fibres innervating the sensory cells of the organ of Corti showed
decreased levels of neurofilament and myelin. All these data suggest that IGF-I plays a crucial role in the
development of almost all regions of brain and inner ear and that lack of IGF-I or inactive IGF-I may
severely affect survival, differentiation, and maturation of several neurones and subtypes of neuronal
cells and therefore compromises the normal development of the individual.

Association between IGF1 polymorphisms and small for gestational age

Intrauterine growth retardation or short for gestational age (IUGR/SGA) is defined by decreased
birth weight and/or length compared to gestational age. This disorder exposes the patients to
increased risk of adult life morbidity with metabolic and cardiovascular diseases. SGA may result from
fetal, maternal or placental origins but around 30% of cases remain without etiology. This affects
2.5–10% of the general population and about 10% will not have a significant catch-up growth. Given the
crucial role of IGF-I in the regulation of pre- and postnatal growth, the involvement of minor genetic
variations of the IGF1 gene has been hypothesized to affect growth.40 Arends et al. scanned for three
microsatellite markers located in the IGF1 gene in a cohort of 124 SGA children and showed that two of
these markers presented transmission disequilibrium; with one allele (191-allele) being more
frequently transmitted than the other.41 Patients carrying the 191-allele had significantly low serum
IGF-I level and their head circumference remained smaller compared to those patients without this
allele. Subsequently, study of several SGA cohorts suggested that polymorphisms of the IGF1 gene were
associated with low serum IGF-I and this could consequently alter birth as well as postnatal growth
and metabolic parameters.41–44
Although these data are interesting and showed an association between IGF1 polymorphisms and
SGA-related outcomes, the functionality of these polymorphisms have not so far been proved.
Furthermore, some of these data are controversial. As an example, many studies have investigated the
study of the 192 bp CA repeat in the IGF1 promoter; some observing that carriers of the 192-bp allele
were taller than subjects with other genotypes in an elderly population44,45, whereas others showed
that the haplotype containing the 192 bp CA repeat was associated with short SGA subjects.43 More-
over, Ester et al. investigated the –G1245A polymorphism (SNP; rs35767), also located in the IGF1
promoter, in 439 short SGA and 196 SGA catch-up subjects46 and found that 1245 A-allele was
associated with a small head size and less brain sparing in SGA born subjects, whereas this haplotype
was not associated with birth weight, birth length and postnatal length. More recently, Maas et al.
studied the association between insulin gene variable number of tandem repeats (INS VNTR located 50
of IGF2 gene) and 192-bp allele in IGF1 gene promoter with body composition in early childhood in 738
children for whom growth parameters in early childhood were available.47 This study did not show any
associations between the different subgroups of genotype and body composition in early infancy.
It appears from all these data that it is difficult to ascertain a clear association between IGF1
polymorphisms and SGA-related outcomes. The results provided from the studies of the 192 bp CA
 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190 185

repeat are conflicting, which makes it difficult to reach definitive conclusions regarding the contri-
bution of this polymorphism to the etiology of SGA. These discrepancies could be explained by the
biased population studied. Indeed, although a consensus was established to define SGA (birth length
and/or weight <2 SDS), this was not always respected when the cohorts were selected. Furthermore,
patients born SGA with persistent short stature are relatively rare and their etiology is heterogeneous
which makes it difficult to constitute homogenous patient populations. Currently increasing amounts
of data are generated from genome wide SNP studies to establish association of haplotype disequi-
librium transmission in some diseases which might lead to identification of SNPs in the IGF system
associated with SGA.

IGF1 molecular defects in humans

The first human IGF1 gene defect was described in 1996 by Woods et al.48 The patient, a male, was
born by Caesarian-section because of poor fetal growth from a consanguineous union. Placental weight
was diminished (350 g). He had severe intrauterine growth retardation [Birth weight of 1.4 kg
(3.9 SDS) and birth length of 37.8 kg (5.4 SDS)] including microcephaly [Head circumference of
27 cm (4.9 SDS)]. His growth failure worsened during the postnatal period. At 15.8 years, the boy’s
height was 119.1 cm (6.9 SDS) and his weight was 23.0 kg (6.5 SDS). He had persistent microcephaly,
delayed psychomotor development, sensorineural deafness, adiposity and during adolescence became
insulin resistant. No IGF-I was detected in the serum even after 4 days of stimulation with GH in an IGF-
I generation test (IGFGT). Spontaneous12-h GH secretion showed abnormally elevated peaks and an
elevated baseline between peaks. ALS and IGFBP-3 values were within the normal range. Molecular
analysis revealed a homozygous deletion of exons 4 and 5 of the IGF1 gene. If translated, the resulting
protein would be severely truncated, lacking 45 of the 70 IGF-I amino acids.48 At 16.07 years (bone age,
14.2 years) recombinant IGF-I therapy was initiated and resulted in beneficial effects on insulin
sensitivity, body composition, bone size, and linear growth.49
In 2003, a patient was reported with a similar clinical phenotype. He was born at 39 weeks of gestation
from a consanguineous union. His birth weight was 1480 g (4 SDS), length was 41 cm (6.5 SDS) and
head circumference was 26.5 cm (7.5 SDS). He also presented with sensorineural deafness and delayed
psychomotor development. Biochemical analysis showed low serum IGF-I levels (1 ng/mL) with no
increase during an IGFGT. He also had elevated GH peaks after a stimulation test. IGFBP-3 levels were
normal. Sequencing of the IGF1 gene showed a homozygous T > A transversion in exon 6, that would result
if translated into an altered E domain of the IGF-I precursor.50 However, a later study showed that this
nucleotide variation could not explain the abnormal phenotype, as it was identified in homozygous and
heterozygous states in controls of normal height, corresponding to 4% of the studied alleles.51
In 2005, a patient born from a consanguineous union was identified with a homozygous missense
mutation (a homozygous G > A nucleotide substitution at position 274, changing valine at position 44
in the A domain of the mature IGF-I protein to methionine (V44M) of the IGF1 gene.52 The phenotype of
this 55-year-old patient was similar to the two patients previously described with an IGF1 defect and
had a final height of 118 cm. He was born after 8 months of gestation with a birth weight of 1420 g
(3.9 SDS) and length of 39 cm (4.3 SDS). His youngest brother was born at term with a birth weight
of 1900 g (4.5 SDS). Both brothers had bilateral hearing loss, microcephaly, severe mental retardation
and elevated GH.53 The youngest brother died aged 32 years. The oldest brother was re-investigated at
55 years. He had partial gonadal dysfunction and osteoporosis was also noted. Of interest, his IGF-I level
in the serum was very increased (þ7.3 SDS), explained by the fact that the resulting recombinant
protein (IGF-1 V44M) produced allowed normal binding to IGFBP-3 but a dramatic decreased affinity
(90 folds) to its receptor, IGF-1R. The family members who were heterozygous carriers of this IGF1
mutation were shorter and had lower head circumferences than the non-carriers family members.
Recently, the fourth patient with a quite different clinical phenoytpe was reported with an IGF1
molecular defect. This non-dysmorphic male patient was born from a consanguineous union after 40
weeks of gestation54 (Fig. 2). His birth weight was 2350 g (2.5 SDS), length was 44 cm (3.7 SDS) and
head circumference was 32 cm (2.5 SDS). Hearing tests were normal and he showed mild develop-
mental delay only. Serum IGF-I at 2.7 years, measured with an IRMAÒ kit, was extremely low (11 ng/ml)
with IGFBP-3 and ALS serum levels in the upper normal range or above. Serum IGF-I concentrations
186 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190

Fig. 2. Pedigree (a) and patient V1 with the IGF1 R36Q mutation (b and c) at the age of 8.5 years. Parents gave their informed consent
for the publication of pictures. The patient’s parents and two of his grandparents were heterozygous for the R36Q (black square)
mutation in the IGF1 gene; two grandparents did not carry this mutation (white square and circle). The hatched squares and circles
represent individuals for whom DNA was not available. Final heights are indicated in panel a, as the number of standard deviations
below the mean based on French reference values (20). Patient V1 showed no signs of dysmorphism at age 8.5 years (b and c).
Reproduced with permission from the Journal of Clinical Endocrinology and Metabolism, Netchine I. 2009: 94: 3913–3921 Copyright
2009 The Endocrine Society.

varied however according to age and nutritional state and to the immunoassay used (different
monoclonal antibodies using different epitopes and polyclonal antibody) from undetectable to >þ2
SDS. Growth hormone (GH) stimulation tests performed at age 2.8 years were normal. Spontaneous
secretion of GH was studied in the morning and showed peaks of 20.8 and 30 mUI/ml and a 24 h urinary
GH was 22 mUI/ml for a usual value <20 mUI/ml and. A higher than average hGH dose (0.4 mg/kg/week)
was required to induce catch-up growth (Fig. 3) in keeping with a partial GH resistance. Given the mis-
match between IGF-I and IGFBP-3 levels, an IGF1 anomaly was suspected. IGF1 gene analysis revealed
a homozygous missense mutation resulting in the change of a highly conserved arginine located in the
C domain of the protein into a glutamine (R36Q). Affinity for the IGF-1R was decreased to two- to three-
fold, resulting in decreased IGF-1R autophosphorylation. This partially diminished IGF-I activity had
however dramatic consequences on fetal growth and development.54 Currently, this patient is aged 13
years, has started puberty and GH therapy has just been changed to rhIGF-I (personal data).
The number of patients identified with an IGF1 molecular defect is still very small. These patients
have in common the features of severe IUGR and some degree of microcephaly. However, sensorineural
deafness is not constant and the intensity of delayed psychomotor development is variable. In terms of
biochemical characteristics, IGF-I levels are variable from undetectable to highly elevated associated
with normal to elevated IGFBP-3, ALS and GH serum levels. These characteristics are summarized in
Table 1.
 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190 187

Fig. 3. Growth of patient V1 with the IGF1 R36Q mutation [weight and height (a)], growth velocity (b) and body mass index (c)
curves between the age of one and 11.5 years. Growth curves and growth velocity are plotted on the Sempé reference charts and
body mass index (BMI) on Roland Cacherat charts. The patient received three courses of growth hormone (GH) therapy, as indicated
by the arrows. Arrow 1 indicates the start of GH treatment at 0.4 mg/kg/week, arrow 2 indicates the beginning of treatment with
a reduced dose of GH (0.2 mg/kg/week), arrow 3 indicates the arrest of GH treatment and arrow 4 indicates the period during which
GH treatment was returned to 0.4 mg/kg/week. Only treatment with 0.4 mg/kg/week allowed catch-up growth, indicating partial GH
resistance. Reproduced with permission from the Journal of Clinical Endocrinology and Metabolism, Netchine I. 2009: 94: 3913–
3921 Copyright 2009 The Endocrine Society.

IGF-I serum measurements

An extensive analysis of the IGF system is necessary to identify patients with IGF1 molecular defects and to
allow a differential diagnosis with anomalies of other components of the GH-IGF axis. An accurate IGF-I
measurement is particularly important. Indeed, different IGFBP extraction and separation methods exist.
IGF-I serum levels can be measured with an assay using different monoclonal antibodies that will recognize
different epitopes or polyclonal antibodies. The techniques also vary from RIA, IRMA to ELISA assay. Therefore,
the different assays are difficult to compare and each assay requires its own controls and normal values.

Diagnostic approach

Patients born SGA with microcephaly, whose growth worsened during the postnatal period, with
sensorineural deafness and delayed psychomotor development should be screened for an IGF1
molecular defect. However sensorineural deafness is not present in all described cases and delayed
psychomotor development is variable. Microcephaly is a cardinal clinical feature and will allow
a distinction to be made with Russell Silver Syndrome patients, also born with a severe IUGR, whose
growth retardation usually also deteriorates during the postnatal period but who have a relative
macrocephaly.55 In patients with an IGF1 anomaly, IGF-I serum levels can be undetectable, low or
strikingly elevated. In case of elevated IGF-I serum levels, the clinical and biochemical phenotype is
188 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190

Table 1
Characteristics of three cases of IGF1 gene defect.

Observation Woods et al., 199648 Walenkamp et al., 200552 Netchine et al., 200954
Consanguinity Yes Yes Yes
Birth weight (SDS/gr) 3.9/14OO 2.5/142O 2.5/2350
Birth length (SDS/cm) 5.4/37.8 3/39 3.7/44
Cranial circumference (SDS/cm) 4.9/27 ? 2.5/32
Growth (SDS) 6.9 at 16 years 9 at 55 years 4.5 at 3 years
Microcephaly Yes Yes Yes
Development delay Yes Yes Mild
Deafness Yes Yes No
Adiposity Yes Yes No
IGF-I levels Indetectable þ7.3 SDS Variable
Molecular defect Del ex 4–5 V44M R36Q
IGF-1R affinity Null Extremely low Partially reduced

very similar to an IGF-1R molecular defect56, however no sensorineural deafness has been reported in
patients with a heterozygous IGF-1R defect, indicating that partial IGF-I signalling is sufficient for
normal development of the inner ear. The normal to elevated levels of IGFBP-3 and ALS in the patients
with IGF1 molecular defects will allow differentiation from patients with GH receptor anomalies or
patients with ALS anomalies who would have very low or undetectable IGFBP-3 and ALS levels.57

Summary

Both IGF-I functions (endocrine as well as autocrine/paracrine) are important to achieve correct
somatic development. The role of IGF-I is not limited to the control of linear growth and weight increase
during fetal and postnatal development, but also play a crucial role in promoting brain and inner ear
development. Growth delay due to IGF1 defects is characterised by the association of intrauterine and
postnatal growth retardation with sensorineural deafness and intellectual deficit. This syndrome is
extremely rare and only four cases have been reported. A case of partial IGF-I deficiency has recently been
described and was associated with pre- and postnatal growth retardation and microcephaly but the

Practise points

 SGA patients have heterogeneous clinical and biochemical phenotypes. Careful investigation
of these patients is therefore a primordial step to identify candidates for an IGF system
anomaly.
 In addition to a precise clinical phenotype (including head circumference), an extensive
work-up of the different components of IGF system is very useful to orient the molecular
diagnosis. It is recommended to measure IGFBP-3 and ALS serum levels both of them being
GH-dependent and to measure IGF-I serum level with different assays.
 Patients born SGA with microcephaly, whose growth deteriorate during the postnatal period,
with sensorineural deafness and delayed psychomotor development should be screened for
an IGF1 molecular defect. However, sensorineural deafness is not constant.

Research agenda

 It is important to persist in searching the molecular causes of SGA, especially for the group of
patients born SGA without postnatal catch-up growth.
 Molecular anomalies of the IGFBP should be investigated.
 Genome wide array studies will help to identify new candidate regions involved in SGA.
 I. Netchine et al. / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 181–190 189

developmental delay was mild and hearing tests were normal. These observations demonstrate that the
integrity of IGF-I signalling is important for normal growth and brain development.

Acknowledgements

We thank the patients and their families and Dr. Muriel Houang for helpful discussions and
collection of the clinical data and Laurence Perin for technical assistance.

Addendum

While this review was in process, Van Duyvenvoorde et al 58 published a novel IGF1 heterozygous
mutation in a family with two patients presenting with severe short stature, microcephaly and low IGF-
I serum levels. The IGF1 sequencing revealed a heterozygous duplication of four nucleotides inducing
a frame shift and a precocious stop codon.

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