REVIEW

Review

Growth hormone deficiency and related disorders: insights into

causation, diagnosis, and treatment

Mehul Dattani, Michael Preece

Advances in molecular biology have led to the identification of mutations within several novel genes associated with the
phenotype of isolated growth hormone deficiency, combined pituitary hormone deficiency, and syndromes such as
septo-optic dysplasia. Progress has also been made in terms of the optimum diagnosis of disorders of stature and their
treatment. The use of growth hormone for the treatment of adults with growth hormone deficiency and conditions such
as Turner’s syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure has changed the
practice of endocrinology, although cost-benefit implications remain to be established.

The height of an individual is the culmination of an rate during infancy is principally dependent on nutrition,
interaction between their genes, nutritional status, although endocrine factors in the form of the growth
hormonal milieu, and various environmental factors. Both hormone-IGF axis have an increasingly important role
fetal and post-natal components of growth ultimately affect from 1 year of age. During the first 2 years, a period of
an individual’s stature. We address here those issues that catch-up or catch-down growth commonly takes place
we believe are most important in terms of the while the infant establishes their own growth trajectory.
understanding of growth regulation or achieving the best Subsequently, the correlation between height and final
treatment of growth disorders. Focusing on disorders of height increases greatly (r=0·8 by age 3 years), as does that
the hypothalamo-pituitary-somatotroph axis leading to between the child’s height and parental height (r=0·7).
short stature, we describe advances in our understanding By 6 years of age, average growth velocity has fallen to
of the development of the pituitary gland, genetic causes of 5–5·5 cm/year, with minimum sexual dimorphism in the
short stature, and the indications for growth hormone growth rate until the onset of puberty. Childhood growth
treatment. is mainly dependent on endocrine factors (growth
hormone and thyroxine). Pubertal growth depends on the
Normal growth normal secretion of growth hormone and sex steroids; its
Fetal growth is critical and has major implications for the timing is extremely variable, and gives rise to, on average in
ultimate stature of an individual. A crown-rump growth the UK, a 14 cm difference in adult height between the
velocity of 50–60 cm per year represents the fastest rate of sexes.
growth achievable. This growth is largely independent of
growth hormone and is mediated by maternal nutrition Short stature
and growth factors such as insulin-like growth factors Traditionally, short stature is defined as a height that lies
(IGF-I and IGF-II), fibroblast growth factor, epidermal below –2SD for age compared with sex-specific standards
growth factor, transforming growth factors ␣ and ␤, and based on an appropriate healthy population. In multiethnic
insulin. Growth hormone does have a small role in fetal societies, comparison of children with controls from the
growth during the last few weeks of intrauterine life. general population who are matched for ethnic
Compromise in maternal nutrition or in the production of background is important. Additionally, the genetic
these growth factors is associated with intrauterine growth background of an individual’s family is crucial.
restriction (IUGR). The poor correlation between mid- Investigators have shown that the expected height SD
parental height and size at birth (r=0·3), indicates the score (SDS) for a child should be calculated after
dominant effect of intrauterine environment over adjustment for regression to the mean, and, using this
genotype. Intrauterine growth restriction is associated with
increased risk of health problems later in life, including Search strategy and selection criteria
hypertension, cardiovascular and cerebrovascular disease,
insulin resistance, and non-insulin dependent diabetes We searched PubMed using the terms growth hormone and
mellitus,1 possibly due to a defect in programming of the pituitary development as an initial screen. We refined the
insulin and growth hormone-insulin-like growth factor results with the terms: treatment, aetiology, diagnosis,
axes in these individuals. clinical features, genes, and physiology. The search was not
The post-natal growth trajectory of any individual can confined to English language publications, but no foreign
be described by the infancy-childhood-pubertal model of language articles that justified translation were identified. The
growth.2,3 The three components represent different modes search was mostly concentrated over the past 10 years,
of regulation. The rapid but sharply decelerating growth although a few highly regarded and relevant earlier
publications have been included when necessary. The
Lancet 2004; 363: 1977–1987 reference list was modified during the peer-review process on
the basis of reviewers’ comments. A few review articles or
Institute of Child Health, University College London, London book chapters were included because they provided
WC1N 1EH, UK (M Dattani MD, Prof M Preece MD) comprehensive overviews that were beyond the scope of this
Correspondence to: Prof Michael Preece Review.
(e-mail: [email protected])

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REVIEW

Panel 1: Causes of short stature exclusion of disease made on a clinical or biochemical

basis. The genetic control of height is poorly understood
Non-pathogenic
and only two genes have been implicated in familial or
Constitutional delay of growth and puberty
idiopathic short stature. Mutation of the SHOX gene at
Familial short stature
Xp22 or Yp11.3 accounts for about 1% of short children,9
Nutritional
whereas heterozygous mutations of the growth hormone
receptor gene have been identified in a few individuals.10,11
Intrauterine growth restriction Non-endocrine and syndromic causes of short stature
Syndromic—eg, Silver-Russell syndrome should be excluded (panel 1). Remaining endocrine causes
Non-syndromic include growth hormone deficiency, growth hormone
Systemic disorders insensitivity, Cushing syndrome, and hypothyroidism.
Cardiovascular disease—eg, congenital heart disease
Renal—eg, chronic renal failure, renal tubular disease Development of the anterior pituitary gland
Respiratory—eg, cystic fibrosis, asthma The pituitary gland, which consists of anterior,
Gastrointestinal disease—eg, inflammatory bowel disease intermediate, and posterior lobes, is a central regulator of
Neurological—eg, brain tumour growth, metabolism, and development. Its complex
Psychosocial—eg, anorexia nervosa, child abuse functions are mediated via hormone signalling pathways
that regulate the finely balanced homoeostatic control in
Endocrine causes vertebrates by co-ordinating signals from the
Growth hormone related causes hypothalamus to peripheral endocrine organs (thyroid,
Growth hormone (GH) deficiency; isolated or combined with adrenals, and gonads). The mature anterior pituitary gland
other pituitary hormone deficiencies is populated by five neuroendocrine cell types, defined by
GH resistance the hormone produced: corticotropes (adrenocorticotropic
Hypothyroidism hormone), thyrotropes (thyroid stimulating hormone),
gonadotropes (luteinising hormone, follicle stimulating
Glucocorticoid excess
hormone), somatotropes (growth hormone), and
Cushing syndrome
lactotropes (prolactin).12 The posterior gland secretes
Poorly managed congenital adrenal hyperplasia
vasopressin and oxytocin. The origins of the anterior and
Exogenous corticosteroid administration
posterior lobes of the pituitary gland are embryologically
Chromosomal and genetic causes distinct. Rathke’s pouch, the primordial anterior pituitary,
Turner’s syndrome arises from the oral ectoderm whereas the posterior
Noonan syndrome pituitary derives from neural ectoderm. Development of
Down’s syndrome the anterior gland follows a similar pattern in several
Skeletal dysplasias: hypochondroplasia, achondroplasia, species, but has been best studied in rodents.
spondylo-epiphyseal dysplasia In mice, anterior pituitary development takes place in
Seckel syndrome four distinct stages: pituitary placode formation; the
Prader-Willi syndrome development of a rudimentary Rathke’s pouch; the
Other syndromes—eg, Rothmund-Thompson syndrome, formation of a definitive pouch; and, finally, the terminal
Leri-Weill syndrome, Progeria, mucopolysaccharidoses differentiation of the various cell types in a temporally and
spatially regulated manner (figure 1). The apposition of
Rathke’s pouch and the diencephalon, which later
calculation, more than 90% of children had values within develops into the hypothalamus, is maintained throughout
1·4 SD of their expected SDS (just over two centile the early stages of pituitary organogenesis13 and is critical
spaces).4 for normal anterior pituitary development. Several
Most children with short stature do not have an signalling molecules and transcription factors—Fgf8,13,14
underlying hormonal or genetic disease5 (panel 1). To Bmp4,13,14 and Nkx2.115—that are expressed in the neural
identify pathological characteristics, consideration should ectoderm and not in Rathke’s pouch are thought to play a
be given to the diagnostic return on assessment. For significant part in normal anterior pituitary development,
example, the classic threshold of a height SDS of –2·0 or as shown by the phenotype of mouse mutants that are
less identifies 14% of children with an organic cause, either null or hypomorphic for these alleles. These
whereas reducing the threshold to –3·0 increases the yield signalling molecules can then activate or repress key
to 58%.6,7 Genetic background is also crucial in regulatory genes encoding transcription factors such as
determination of stature, and any child with a height of Hesx1, Lhx3, and Lhx4 within the developing Rathke’s
more than 1·4 SD below the mid-parental height warrants pouch that are essential for subsequent development of the
assessment. pituitary.12,13,16
Assessment of history and examination with meticulous The terminal differentiation of the progenitor cells into
auxological assessment should be done in any child the distinct cell types found within the mature pituitary
presenting with short stature, with emphasis on associated gland is tightly regulated by extrinsic factors (Fgf8, Bmp2,
features suggestive of chromosomal disorders or other Bmp4, and Bmp7) from the surrounding infundibulum and
syndromes. Height velocity can be a sensitive indicator of the juxtapituitary mesenchyme. These factors then
disease, and any child with a persistently slow rate of establish gradients of transcription factors (Lhx3, Six3,
growth needs assessment to identify an underlying Prop1, Pit1, Nkx3·1, Isl1, Lhx4, Six1, Brn4, and P-frk17–20)
disorder. However, poor growth velocity on its own cannot which in turn lead to a wave of cell differentiation
clearly differentiate between short healthy children and (figure 1).21,22
those with organic disease for periods of less than 1 year Pituitary development in human beings seems to be
since growth could be seasonal.8 similiar to that in the rodent. Spontaneous or artificially
The commonest cause of short stature is familial, the induced mutations in mice have led to important insights
diagnosis usually being made on the basis of a height SDS into human pituitary disease, and identification of
that falls within the target range for the family and the mutations associated with such disease have been

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 REVIEW

A
1 2 3 4

PO
MB
NP
I
PL DI PL
I PP P
F I HB IL
OM
N RP AL
AN OC
N
O SC
H
O
H
N

Oral ectoderm Rudimentary pouch Definitive pouch Pituitary gland

Rat 8·5 11 14·5 19·5

Mouse 8·0–8·5 9·5 12 17
Embryonic
days
B
E10 E11 E12 E13 E14 E15 E16 E17 E18
HesX1
Lhx3
Lhx4
Prop1
␣Gsu
Pit1
Gh
Prl
Tsh␤
Ghrhr
Gh
Prl
HesX1 Prop 1 Pit 1
Tsh␤
Titf 1 Lhx3 Lhx4 Ghrhr

Pitx 1

Figure 1: Pituitary development

Mid-sagittal or parasagittal section drawings of rat embryos showing pituitary development (A): (1) growth of pre-infundibular portion of neural plate and
establishment of presumptive Rathke’s pouch area; (2) formation of a rudimentary pouch— with absence of mesoderm between pouch and floor of
diencephalons; (3) formation of definitive pouch and posterior lobe with invasion of neural crest and mesenchymal tissue, and separation of brain and oral
cavities; (4) nascent pituitary gland. Corresponding stages in mouse and rat development indicated. NP=neural plate. O=oral cavity. OC= optic chiasma.
OM=oral membrane. P=pontine flexure. PL=posterior lobe. PO=pons. PP=prechordal plate. RP=Rathke’s pouch. SC=sphenoid cartilage. AL=anterior lobe.
IL=intermediate lobe. AN=anterior neural pore. I=infundibulum. H=heart. F=forebrain. MB=midbrain. HB=hindbrain. From Sheng and Westphal20 with
permission. Cascade of transcription factors that regulate anterior pituitary development (B): the approximate timing of mRNA expression in the mouse is
shown for transcription factors (green bar) and other marker genes (blue bars). Arrows represent activation and truncated lines represent repression. Black
solid arrows indicate effects supported by analysis of pituitary mutants. Broken arrows hypothetical interactions that might be revealed by analysis of
expression in other pituitary mutants. E=embryonic day. Adapted with permission from Watkins-Chow and Camper.16

invaluable in defining the genetic cascade responsible for human beings and other organisms.26–28 The endogenous
the development of this complex structure. ligand for the growth hormone secretagogue receptor,
ghrelin, has been isolated from the stomach and is an
The hypothalamo-pituitary-somatotroph axis octynylated peptide consisting of 28 aminoacids.29 It is
Somatotropes secrete growth-hormone in the anterior expressed predominantly in the stomach, but smaller
pituitary gland in a pulsatile manner. Secretion varies amounts are also produced within the bowel, pancreas,
considerably with age,23,24 and shows a sexually dimorphic kidney, the immune system, placenta, pituitary, testis,
pattern,25 with a greater average daily output in women. ovary, and hypothalamus.27,29–31 Ghrelin leads not only to the
The pulsatility results from the interaction between the secretion of growth hormone, but also stimulates prolactin
hypothalamic peptides growth hormone-releasing hormone and adrenocorticotropic hormone secretion. Additionally, it
and somatostatin. affects endocrine pancreatic function and glucose
Recent use of synthetic growth-hormone-releasing metabolism, gonadal function, appetite, and behaviour. It
peptides has led to the identification of a growth hormone can also control gastric motility and acid secretion, and has
secretagogue receptor (GHSR type 1a). The receptor is cardiovascular and antiproliferative effects. The role of
strongly expressed in the hypothalamus, but specific endogenous ghrelin in normal growth during childhood
binding sites for growth hormone-releasing peptides have remains unclear. Both ghrelin and growth-hormone-
also been identified in other regions of the CNS and releasing peptides release growth hormone synergistically
peripheral endocrine and non-endocrine tissues in both with growth-hormone-releasing hormone but the

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REVIEW

effectiveness of these compounds as growth-promoting Several genetic abnormalities have been identified in
agents is poor.32,33 children who were previously thought to have idiopathic
The human growth hormone gene (GH-N or GH1) growth hormone deficiency or combined pituitary hormone
forms part of a cluster of five homologous genes (GH1, deficiency (table 1).44–47 Additionally, advances in molecular
CSHL1, CSH1, GH2, and CSH2) located on the long arm biology have clarified the basis of previously identified
of chromosome 17. Its expression is regulated not only by a genetic conditions. For example, type II deficiency is
proximal promoter, but also by a locus control region autosomal dominant and is associated with splice site
15–32 kb upstream of GH1. The locus control region mutations within the GH1 gene. These mutations lead to
confers pituitary-specific, high-level expression of growth the production of two alternatively spliced molecules of
hormone.34,35 The full-length transcript from the GH1 gene 20 kDa and 17·5 kDa. The 17·5 kDa form of the hormone
encodes a 191 aminoacid 22 kDa protein that accounts for has a dominant negative effect and prevents the secretion of
85–90% of circulating growth hormone. Alternative the normal wild-type 22 kDa hormone, with a consequent
splicing of the mRNA transcript generates a 20 kDa form of deleterious effect on pituitary somatotropes. In mice with
the hormone that accounts for the remaining 10–15%. this dominant negative mutation, there is evolution of the
Within both the proximal promoter and the locus control phenotype with later failure of prolactin, thyroid
region are located binding sites for the pituitary-specific stimulating hormone, and gonadotropin secretion.48
transcription factor Pit1.35 Mutations in an exon splice enhancer within exon 3 of GH1
In the circulation, growth hormone binds to two binding have been associated with autosomal dominant deficiency
proteins—one with high affinity and the other with low of the hormone.49 This mutation is associated with the
affinity.36,37 Little is known about the low affinity protein preferential use of stronger splice sites that lead to the
that accounts for about 10–15% of growth hormone production of 17·5 kDa and 20 kDa forms of the hormone,
binding, with a preference for binding to 20 kDa protein. with a dominant negative phenotype.
On the other hand, the high affinity binding protein is a 61 Midline abnormalities such as holoprosencephaly, nasal
kDa glycosylated protein that represents a soluble form of encephalocele, single central incisor, and cleft lip and palate
the extracellular domain of the growth hormone receptor might be associated with growth hormone deficiency. A
that can bind to both 20 kDa and frequent cause of such deficiency is a space-occupying
22 kDa hormone, and thereby lengthen its half-life. lesion in the pituitary fossa or suprasellar region. The
Investigators of in-vivo studies have co-administered tumour most seen in childhood is a craniopharyngioma, a
growth hormone and its binding protein to congenital squamous cell tumour that arises from remnants
hypophysectomised and growth hormone deficient rats and of Rathke’s pouch. Although classified as a benign tumour,
shown a potentiation of weight gain and bone growth, it is locally invasive, compressing the optic tracts and
although similar investigations have not as yet been done in
man.38 Panel 2: Causes of GH deficiency
Growth hormone receptor is present in several tissues.
The hormone sequentially dimerises its receptor, activating Congenital
a receptor-associated tyrosine kinase (JAK2) that in turn is Genetic
auto-phosphorylated and also phosphorylates the growth
Associated with structural defects of the brain
hormone receptor. This phosphorylation leads to signal
Agenesis of the corpus callosum
transduction through the MAPK, STAT, and PI3 kinase
Septo-optic dysplasia
pathways. The result is activation of several genes that
Holoprosencephaly
mediate the effects of growth hormone. These include early
Encephalocele
response genes encoding transcription factors such as c-jun,
Hydrocephalus
c-fos, and c-myc implicated in cell growth, proliferation,
and differentiation, and insulin-like growth factor I (IGF1) Associated with midline facial defects
that mediates the growth-promoting effects of growth Cleft lip or palate
hormone.39,40 IGF-I and IGF-II are single-chain polypeptide Single central incisor
hormones that are widely expressed, and, together with a Acquired
family of specific binding proteins, are believed to mediate Trauma
most of the actions of growth hormone. Extensive and Perinatal trauma
authoritative reviews cover this aspect of the hormone’s Postnatal trauma
axis.41
Infection
Growth hormone deficiency Meningitis or encephalitis
Epidemiology and causation CNS tumours
The frequency of growth hormone deficiency is reported to Craniopharyngioma
be about one in 3000 to one in 4000,5,42 although this is Pituitary germinoma
probably an overestimate in view of the reversibility of this Pituitary adenoma
deficiency in 25–75% of patients. Anecdotally, the Optic glioma
incidence of the deficiency is thought to vary substantially
between countries. The incidence of isolated growth Langerhans cell histiocytosis
hormone deficiency relative to multiple pituitary hormone Postcranial irradiation
deficiencies is also believed to vary greatly. However, few
Postchemotherapy
reliable data exist; large postmarketing surveillance
databases are not helpful since data submitted are selective. Pituitary infarction
Some of the apparent differences are probably due to great Neurosecretory dysfunction
variation in tests and criteria used in different centres.43
Panel 2 shows the causes of growth hormone deficiency. Psychosocial deprivation
Idiopathic growth hormone deficiency is by far the most Hypothyroidism
common, and most poorly defined, diagnosis.

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 REVIEW

Loss of function phenotype in mice Human phenotype Inheritance (mouse/human)

Gene (mouse/human)
Hesx1/HESX1 Anophthalmia or microphthalmia, Variable: Septo-optic dysplasia (midline forebrain, Dominant or recessive in both.
(paired-like family) agenesis of corpus callosum, eye and pituitary defects), CPHD, IGHD with ectopic Variable penetrance with dominant
absence of septum pellucidum, posterior pituitary inheritance
pituitary dysgenesis or aplasia
Sox3/SOX3 (Sox family) Unknown Isolated GHD with mental retardation X-linked in both
Lhx3/LHX3 (LIM family) Hypoplasia of Rathke’s pouch GH, TSH, gonadotropin deficiency with pituitary Recessive in both
hypoplasia. Corticotrophs spared. Short, rigid cervical
spine with restricted rotation
Lhx4/LHX4 (LIM family) Mild hypoplasia of anterior pituitary GH, TSH, cortisol deficiency, persistent cranio- Recessive in mouse, dominant in
pharyngeal canal, and abnormal cerebellar tonsils man
Prop1/PROP1 Hypoplasia of anterior pituitary with Highly variable GH, TSH, prolactin, and gonadotropin Recessive in both
(Paired-like family) reduced somatotrophs, lactotrophs, deficiency. Evolving ACTH deficiency. Enlarged
thyrotrophs, and gonadotrophs pituitary (tumour-like) with later involution.
Pit1/POU1F1 (PIT1) Anterior pituitary hypoplasia with Variable GH, TSH, and prolactin deficiencies. Recessive in mouse,
(POU-family) reduced somatotrophs, lactotrophs, Anterior pituitary size variable (normal/hypoplastic) dominant/recessive in man
and thyrotrophs
Ghrhr/GHRHR Reduced somatotrophs with anterior Type 1B GH deficiency with anterior pituitary Recessive
pituitary hypoplasia hypoplasia
Gh-1/GH1 GH deficiency Recessive (type 1A, 1B), dominant
(Type II)
IGHD=isolated growth hormone deficiency. CPHD= combined pituitary hormone deficiency. GHD=growth hormone deficiency. GH=growth hormone. TSH=thyroid
stimulating hormone. ACTH=adrenocorticotropic hormone.
Table 1: Genes implicated in isolated growth hormone deficiency and combined pituitary hormone deficiency

chiasm as well as the hypothalamus. Both the condition and face, a single central incisor, or optic nerve hypoplasia.
its treatment (surgery and radiotherapy) are associated with Metabolic effects include increased low-density lipoprotein
considerable morbidity and mortality.50 Intriguingly, some cholesterol at diagnosis.
of these children continue to grow with a normal height The principal mode of presentation of idiopathic growth
velocity despite their growth hormone deficiency. This hormone deficiency is with short stature and low growth
growth is usually associated with hyperphagia and weight velocity for age.54 That growth hormone has a role in fetal
gain and is believed to be due to hyperinsulinism and high growth is evidenced by a reduction in birthweight and
concentrations of IGF1.51 Other intracranial tumours length in individuals with the deficiency compared with
include gliomas, astrocytomas, and germinomas. controls.55 Subsequently, there is a rapid reduction in height
Langerhans cell histiocytosis is also associated with SDS during the first 2 years.56 Children with untreated
deficiency of growth hormone, although the commonest severe growth hormone deficiency achieve only 70% of
associated endocrinopathy is diabetes insipidus.52 The their full growth potential, leading to a deficit on average of
pituitary stalk is usually thickened on magnetic resonance 38 cm in males and 33 cm in females. Children with less
imaging scanning. severe deficiency present later in life with short stature and
Cranial irradiation used for the treatment of solid brain reduced growth velocity.
tumours and as prophylaxis for leukaemia can lead to
abnormal hypothalamopituitary function. The sensitivity of Diagnosis
the hypothalamopituitary axis to radiation depends on the The diagnosis of growth hormone deficiency is based on an
dose, fractionation, tissue location, and the age of the inadequate response of the hormone to provocation.57 The
patient.53 Growth hormone secretion is the most sensitive to use of provocation tests and their interpretation is
radiation, followed by secretion of thyroid stimulating considerably controversial,58–62 not least because of safety
hormone, adrenocorticotropic hormone, and issues.63 The situation is complicated by the availability of
gonadotropins. Doses in excess of 30 Gy are associated up to 34 growth hormone provocation tests, and many
with growth hormone deficiency in 85% of children within monoclonal assays for its measurement. The National
5 years of treatment. These children generally enter puberty Institute for Clinical Excellence (NICE) in the UK have
early, further impairing mature height. Lower doses of recommended that at least two tests of growth hormone
radiation (24 Gy) are also associated with such deficiency in provocation should be done to establish a diagnosis of
roughly 30–60% of cases. Craniospinal irradiation used in deficiency or insufficiency. In those with defined CNS
the treatment of posterior fossa tumours, and total body pathology, a history of irradiation, multiple pituitary
irradiation used in conditioning regimens for bone marrow hormone deficiencies, or a genetic defect, one test will
transplant are also associated with epiphyseal damage with suffice.64 Even with these stringent criteria, most patients
subsequent disproportionate short stature. can have a reverse in terms of biochemical growth hormone
deficiency when re-tested after 1–6 months.65
Clinical presentation Low plasma concentrations of IGF-I and IGFBP3, both
Severe growth hormone deficiency as part of a combined of which are regulated by growth hormone, might aid in
pituitary hormone deficiency phenotype often presents in diagnosis, although in isolation, the specificity and
the first few days of life with jaundice, hypoglycaemia, and sensitivity of the test are poor.66,67 The secretion of other
micropenis, often with undescended testes and pituitary hormones such as thyroid stimulating hormone,
hypothyroidism. Phenotypic features of growth hormone prolactin, the gonadotropins, and cortisol will also need to
deficiency include characteristically immature facies with a be assessed.
prominent forehead and depressed midline development. Neuroimaging has been proposed as a valuable adjunct
Bone maturation and dentition are delayed. Body to the diagnosis of isolated cases of this deficiency and
composition is characterised by low muscle bulk and combined pituitary hormone deficiency.68,69 The technique
increased subcutaneous fat. The hair may be thin and should be done in all children with late onset growth
sparse, nail growth slow, and the voice high-pitched. hormone deficiency to exclude underlying space-occupying
Associated abnormalities include midline defects of the lesions such as a tumour. Midline abnormalities such as

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REVIEW

absence of the septum pellucidum can be seen in children of IGF-I and IGFBP3 concentrations, and MRI of the
with septo-optic dysplasia. Reduction in the size of the brain and pituitary could actually reduce the false positive
anterior pituitary, an attenuated or absent hypothalamo- rate associated with provocative growth hormone testing.
pituitary stalk, and a posterior pituitary that has remained
ectopically positioned at or just below the tuber cinereum Treatment
(40–60% of growth hormone deficient patients) are all Recombinant growth hormone is used for the treatment of
associated with pituitary dysfunction70,71 (figure 2). In some growth hormone deficiency. In children treated early,
children with isolated deficiency due to mutations within catch-up growth is excellent, with a normal final height. A
GH1 or in association with other pituitary hormone final height gain of 30 cm can be expected on average,75 but
deficiencies due to mutations within POU1F1 (the human this figure is affected by variables such as birthweight, age at
homologue of Pit1) or PROP1, the size of the anterior start of treatment, extent of this deficiency, duration of
pituitary might in fact be normal or even enlarged.72 treatment, and frequency of growth hormone injections,
Neoplasia, Rathke’s pouch cysts, and a thickened pituitary height at start of treatment, and height at the start of
stalk indicative of either a germinoma or histiocytosis can puberty.76–81 Final height gain can be especially variable in
also be identified on MRI. children who have had treatment for malignant disease.
In some patients, the identification of a genetic mutation Growth hormone deficiency is often complicated by
within the GH-1 or GHRHR genes, or one of the skeletal damage after total body or craniospinal irradiation,
transcription factors associated with combined pituitary early puberty, hypothyroidism, gonadotropin deficiency,
hormone deficiency can definitively determine the malnutrition, and concomitant chemotherapy. Treatment
diagnosis. Thus far, no genetic basis has been established with gonadotropin-releasing hormone analogue to stop
for most patients with isolated growth hormone deficiency. early puberty has been used in conjunction with growth
Rarely, the response of the hormone to classic provocative hormone treatment in this group of patients, with
testing is normal in a child who is growing slowly but in encouraging results.82 The analogue reduces the
whom spontaneous growth hormone secretion over 24 h is concentration of sex steroid, delaying epiphyseal fusion.
impaired, leading to low concentrations of IGF-I and However, growth hormone and gonadotropin-releasing
IGFBP3. The term growth hormone neurosecretory hormone analogue combination therapy in children with
dysfunction is often used to describe children with this growth hormone deficiency83 is not widely used at present.
condition.73 Investigators using the arginine plus growth It could be beneficial under certain circumstances—for
hormone releasing hormone test in these individuals have example, where the diagnosis of the deficiency has been
shown a normal peak growth hormone response compared delayed. The long-term effects of the analogue are
with growth hormone deficient patients, although this is unknown, and, additionally, the cost of this combination
much lower than that of healthy controls, suggesting a treatment would need to be weighed against the benefits.
reduction in the pituitary growth hormone releasable pool.74 Growth hormone treatment has also been used in patients
In view of the absence of reproducibility that is inherent with growth hormone neurosecretory dysfunction, with
in provocative tests of growth hormone secretion, the variable improvements in height velocity. Effects of
considerable inter-individual and intra-individual variability treatment on final height remain to be established.84,85
in growth hormone responses and difficulty in Growth hormone treatment in childhood can also
interpretation of results is not surprising. The reversibility normalise body composition, with a reduction in body fat,
of the hormone’s response to provocation suggests that although effects on lean body mass are less evident. It is
many of the children diagnosed as having idiopathic growth also associated with reversible insulin insensitivity and an
hormone deficiency in the absence of any congenital or increase in the ratio of high-density lipoprotein to total
acquired structural anomaly of the hypothalamo-pituitary- cholesterol. Glomerular filtration rate is increased, and
somatotroph axis might have been incorrectly diagnosed. bone remodelling accelerated, which increases bone
Some of these children will have been diagnosed in the mineral mass.86 Previously, growth hormone treatment was
peripubertal period when growth hormone secretion is discontinued when linear growth was complete. However,
generally blunted. Priming with sex steroid, measurement data now suggest that the hormone has other effects in
adulthood.87 Discontinuing such treatment in young adults
with growth hormone deficiency results in reduced lean
body mass with diminished muscle strength, increased fat
mass88 and decreased bone mass.89 Additionally, there is
reduced physical and cardiac performance, insulin
resistance, and fibrinolysis, and an abnormal lipid
profile.87,90 Lowered levels of vitality, energy, physical
mobility, decreased libido, and feelings of social isolation
are also part of the adult growth hormone deficiency
syndrome.87,91–93 Cardiovascular mortality is increased in
OC
PP patients with hypopituitarism, especially women. 94–96
Many of these changes are reversed by treatment,
although the effectiveness of growth hormone in terms of
APH reductions in cardiovascular disease, bone fracture, and
mortality and improvement in quality of life still remains
unknown.97,98 Short-term (4 months) improvements in lean
body mass,99–102 exercise capacity, and muscle strength103–106
have been documented with reduction in total body fat.
Improvement in cardiac function has also been
Figure 2: Sagittal MRI scan showing anterior pituitary
documented in one report,107 with a return to pre-treatment
hypoplasia
values 6 months after cessation of hormone treatment. In
APH= anterior pituitary hypoplasia. PP=posterior pituitary, which is ectopic
on this image. OC=optic chiasm., normal here. The infundibulum some investigations, quality of life measures such as energy
connecting the pituitary to the hypothalamus is not shown. levels, mood, emotional lability, and physical mobility

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
 REVIEW

improved with this treatment.90,92,108,109 Recent guidelines degree of pigmentation of nevi, but is not associated with
published by NICE have recommended that growth the development of melanoma.130 Other adverse effects
hormone treatment should only be considered for adults include benign intracranial hypertension, particularly in
who have fulfilled criteria on a quality of life questionnaire. girls with Turner’s syndrome and children with
The dose recommended by the Growth Hormone Research craniopharyngioma. This is usually seen within the first few
Society is 0·15–0·3 mg/day.110 weeks of treatment, but can be later.131 Discontinuation of
Some researchers have suggested that, at the end of treatment resolves the problem, and a gradual
statural growth, growth hormone secretion should be re- reintroduction of hormone is not associated with
assessed in all patients after a wash-out period of at least recurrence. Slipped capital femoral epiphysis has been
1–3 months.111–113 The investigation of choice is an insulin reported as a side-effect of growth hormone treatment, but
tolerance test,60 although the arginine plus growth hormone the frequency of the complication is only increased in
releasing hormone test has recently been proposed as a children with organic hormone deficiency, and not in those
safer alternative, especially in patients with a whose deficiency is idiopathic.132 Growth hormone
contraindication to an insulin tolerance test.114 In 25–75% treatment is associated with insulin resistance.133 The
of patients, the growth hormone response to provocation is frequency of type 1 diabetes mellitus is not higher in
in the normal range.114 In the remainder, treatment should patients with idiopathic deficiency than in the general
be continued in those with severe deficiency (peak growth population, but the occurrence of type 2 diabetes mellitus is
hormone less than 3 ␮g/L). Patients with moderate greater in patients treated with growth hormone.134 In
deficiency (peak growth hormone 3–7 ␮g/L) should be adults, the most common side-effects are oedema and
followed up by an endocrinologist specialising in treatment arthralgia or myalgia. Treatment in adults needs to be
of adults. In these individuals, adverse changes in body carefully monitored, and IGF-I concentrations should be
composition, quality of life, and bone mineral density can regularly measured while on treatment.
be an indication to recommence treatment,61 although these
individuals are less likely to develop adult growth hormone Bioinactive growth hormone syndrome
deficiency syndrome.115 In patients with multiple pituitary Some individuals who have a poor height velocity with
hormone deficiency, growth hormone deficiency due to a normal growth hormone concentrations but low IGF-I
congenital lesion or secondary to radiotherapy, surgery, or a have heterozygous mutations within the GH1 gene,
mass lesion, the deficiency is highly unlikely to reverse.59 resulting in the generation of abnormal growth hormone.135
Overall, growth hormone is believed to be safe. Long- These mutations are associated with a dominant negative
term follow-up of patients taking this treatment has shown effect, with a defect in dimerisation of the growth hormone
a higher than expected incidence and mortality of colonic receptor by growth hormone. The defect can be overcome
cancer and Hodgkin’s disease.116 However, these data need by exogenous growth hormone treatment, with an increase
to be put in context. The affected patients had been treated in both the growth velocity and IGF-I concentration.
with high doses of growth hormone two to three times per
week. Hence, IGF-I concentrations generated by the Growth hormone insensitivity syndrome
growth hormone could have been excessive. IGF-I Growth hormone insensitivity syndrome or Laron
concentrations at the upper end of the normal range (top syndrome is a rare autosomal recessive disorder clinically
quartile for colon and prostate and top tertile for breast) characterised by hypoglycaemia in infancy, with subsequent
have been associated with colon, prostate, and breast dysmorphism and severe childhood growth failure.
cancer.117–121 Since lower doses of the hormone are given on Biochemically, the condition is characterised by high
a daily basis, extrapolation of data from earlier studies to circulating concentrations of growth hormone and low
present treatment regimens would be incorrect. basal IGF-I and IGFBP3 that show no response to
Concerns have been raised about a possible increased stimulation with exogenous growth hormone.136 Although
risk of relapse in children who had previously received growth hormone binding protein is absent in most patients
treatment for malignant diseases such as brain tumours and with hormonal insensitivity, about 20% have normal
leukaemia. However, data do not support an increased risk binding protein.137 Craniofacial features include a
of tumour recurrence in children subsequently treated with prominent forehead, hypoplasia of the bridge of the nose,
growth hormone.122 Additionally, there is no evidence of an and decreased vertical dimension of the face.
increased risk of neoplasia in children without additional Mutations in the growth hormone receptor have been
risk factors.123–125 In the two largest international databases identified in several patients with growth hormone
and surveillance studies of the use of growth hormone in 86 insensitivity syndrome. Recessive mutations include
000 children, representing almost 250 000 treatment years, missense, frameshift, and splice site mutations leading to
there is only one report of a gastrointestinal carcinoma.126 the production of an abnormal growth hormone receptor
Indeed, untreated growth hormone deficiency has been protein with low concentrations of growth hormone
linked to an increased risk of leukaemia,127 although of the binding protein.136–139 Homozygous mutations in GHR
six cases described in this report, four had other tumours affecting the ability of the receptor to homodimerise, and
and would therefore be at risk of another malignant disease mutations within the intracellular domain are associated
anyway. It would nevertheless be sensible to use growth with normal or high concentrations of growth hormone
hormone with caution, and treatment is contraindicated in binding protein.140
syndromes with an increased risk of chromosomal Two heterozygous GHR mutations have been associated
breakages and malignant diseases such as Down’s with familial short stature and biochemical growth
syndrome, Bloom syndrome, Fanconi anaemia, and hormone insensitivity. One of these mutations has a
neurofibromatosis-1.128,129 Additionally, children with solid dominant negative effect inhibiting the function of the wild-
tumours or leukaemia should not be given growth hormone type receptor by heterodimerisation.10 Goddard and
while the malignant disease is active or during the first year colleagues11 investigated the GHR gene in 100 children with
after treatment, and those with medulloblastomas or idiopathic short stature, and recorded seven heterozygous
ependymomas should not be treated with growth hormone mutations and one compound heterozygote individual.
during the first 2 years after treatment. Since obligate heterozygote carriers for GHR mutations are
Growth hormone might increase the number, size, or not shorter than healthy controls or non-carrier siblings,137

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
REVIEW

the importance of the heterozygote mutations in the of psychosocial or academic disadvantage in the short
cohort with idiopathic short stature remains unproven.141 children while they were growing or at final height.153
A homozygous missense mutation (A630P) within To address these complex issues, Noeker and
STAT5B was identified in a 16-year-old girl with growth Haverkamp154 have suggested a conceptual framework to
hormone insensitivity syndrome.142 This finding seems to guide psychological assessment in the individual child
be the first documented case of a molecular defect in the within the context of their family and to inform clinical
post-growth hormone receptor-signalling cascade. management decisions. This process involves three
The availability of recombinant IGF-I has altered the hierarchical levels of assessment: stress exposure due to
extremely poor height prognosis of these patients, short stature (level 1), quality of coping responses (level 2),
although treatment is not without side-effects, including and occurrence of psychopathology (level 3). Clearly, the
hypoglycaemia, hypokalaemia, and papilloedema.143 psychosocial issues around stature are highly complex and
judged as specific to the patient.
Deficiency of IGF-I or its receptor
A homozygous partial deletion within the IGF1 gene was Conclusions
first described in a child with severe fetal and post-natal The past few years have led to major advances in our
growth failure in association with mental retardation, understanding of the development of the pituitary gland,
sensorineural deafness, and dysmorphic features, such as and the genetics of isolated growth hormone deficiency and
microcephaly, ptosis, and micrognathia.144 Biochemical combined pituitary hormone deficiency. Additionally,
investigations showed high circulating growth hormone growth hormone treatment is now used for several
concentrations, normal growth hormone binding protein indications other than its deficiency. In the UK, 78% of
and IGFBP3, but with undetectable IGF-I concentrations growth hormone prescriptions were for licensed
that did not respond to exogenous growth hormone. The indications, whereas 22% were for unlicensed indications.155
patient also showed evidence of insulin resistance that Randomised controlled studies in which workers
improved with recombinant IGF-I treatment. More investigated the use of growth hormone treatment in
recently, a homozygous missense mutation (V44M) was conditions such as Turner’s syndrome and intrauterine
described in the IGF1 gene in a 55-year-old man with growth retardation are few and far between, and final height
profound short stature, deafness and mental data are not available for many of these conditions—eg,
retardation.145 Prader-Willi syndrome and chronic renal failure. The use of
Additionally, investigators have identified mutations of growth hormone treatment in intrauterine growth
the IGF-I receptor in two patients with intrauterine restriction in particular should be carefully monitored, in
growth retardation and subsequent short stature. One of view of the condition’s association with Syndrome X.
the individuals, a compound heterozygote, manifested a The cost of such hormone treatment in all situations
non-verbal learning disorder whereas the second patient, therefore needs to be weighed against its benefits, especially
who was heterozygous for a nonsense mutation, was in patients with idiopathic short stature.The effects on
dysmorphic and also had microcephaly and mild quality of life have been the subject of much controversy,
retardation of motor development and speech.146 especially when the benefits might actually be indirect, as
for example, indicated by the positive relation between
Wider indications for growth hormone treatment height and hourly earnings in men.156
Growth hormone treatment is licensed for growth Recent studies have clearly shown the benefits of growth
hormone deficiency, Turner’s syndrome, chronic renal hormone treatment in adults with growth hormone
failure, Prader-Willi syndrome, and intrauterine growth deficiency on body composition, fitness, lipid profiles, bone
retardation. Many of these indications are still mineral density, and quality of life measures. These results
controversial and we shall not discuss them further here. have led to recognition of the period of transition from
Interested readers are directed to one of the several paediatric to adult endocrinology as a particularly crucial
articles already available.147–150 Additionally, the US Food time, and special transitional clinics should be encouraged
and Drug Administration has approved the use of growth to allow for the seamless management of these patients.
hormone in idiopathic short stature. Randomised studies The long-term effects of growth hormone treatment
have shown improvements of 5·4–7·2 cm in final height remain to be established, and there is clearly an argument
over baseline predicted height in 239 prepubertal patients for long-term surveillance of all patients who have received
with no growth hormone deficiency, treated with 0·24 or it. In those who are currently receiving growth hormone
0·37 mg/kg per week.151 Some of these patients might in treatment, regular measurement of IGF-I and IGFBP3 is
fact have partial forms of growth hormone resistance. highly desirable. Although much progress has been made in
understanding the pathogenesis of short stature and its
Psychosocial consequences of short stature treatment, further investigation could improve
The effect of growth-promoting therapies not only on management of the individual patient.
final height, but also on quality of life, needs to be
addressed. Although some investigators have suggested Conflict of interest statement
that short children are more likely to be disadvantaged, Both investigators have collaborated with several pharmaceutical companies
in clinical trials of recombinant growth hormone in various diagnostic
most of these studies are clearly based on clinic referrals of categories. In some of the projects, research staff were supported by grants
patients with various medical conditions, of which short from the companies. MAP is on the advisory board of Eli Lilley’s GeNeSIS
stature is but one component (reviewed by Sandberg and research programme and receives honoraria from the company.
Voss152). Nevertheless, short children suffer from
stigmatisation, juvenilisation, academic underachieve- Acknowledgments
ment, and vulnerability to physical and verbal aggression We thank P C Hindmarsh for his helpful comments during the preparation
of this manuscript.
from their peers. On the other hand, the Wessex Growth
Study, unique for recruiting an unselected population of
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1984 THE LANCET • Vol 363 • June 12, 2004 • www.thelancet.com

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 REVIEW

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