Normal linear growth

Human linear growth can be divided into three phases – infancy, childhood. and puberty as described by Karlberg (Karlberg 1989 – see Figure 3.1). These are not distinct entities, for the process of growth is a continuum. However, during these periods of development distinct features of growth can be recognized, corresponding with different regulatory mechanisms.

Infantile phase

This can be regarded as a continuation of the foetal growth curve, beginning at conception. The infantile curve is rapid but decelerating, with a mean of 25 cm of growth in the first 12 months of life, and 12.5 cm during the second year. The major regulating influences on growth in infancy are nutritional and thyroidal status. Intrauterine growth restriction (IUGR) results in impairment of the infantile growth curve.

Childhood

The childhood growth pattern starts from approximately six months of age and predominates from the age of three years. During childhood, nutrition becomes less important and hormonal influences, particularly the effects of the growth hormone (GH)–insulin‐like growth factor (IGF) axis and thyroid hormones – become the principal regulating mechanisms for linear growth. Impairment of the childhood growth curve will result from GH or thyroxine (T4) deficiency.

Puberty

During puberty, the pattern of human growth changes dramatically, but differs in important ways between females and males, as described by Tanner (Tanner 1986 – Figure 3.2).

In females, the adolescent growth spurt starts approximately two years earlier than in males. Its onset coincides with breast development, the first sign of puberty. Peak height velocity (PHV) occurs on average at approximately 12 years of age and menarche (the onset of menstruation) follows PHV by a variable interval, being close to PHV in early developers and more distant in late developers. Consequently, menarche occurs when height velocity is falling and is followed by approximately two years of gradually diminishing growth rate. A further difference between females and males is the amplitude of PHV which, in females reaches, on average, approximately 8 cm per year compared with 10 cm per year in males.

In males, the adolescent growth spurt begins when puberty is already well established and coincides with a testicular volume of 10–12 ml. PHV is reached at an average age of approximately 14 years (15 ml testicular volume). The average difference in adult height between males and females is 12.5–14 cm, (roughly 5 in.) according to UK standards, being accounted for by two additional years of prepubertal growth, a greater amplitude of the adolescent growth spurt, and greater prepubertal height in males.

Absence of the pubertal acceleration, with prolongation of the childhood curve, will be seen with delayed puberty. Lack of a pubertal growth spurt despite normal pubertal development is seen in isolated GH deficiency, indicating that both sex steroids and GH are required for a peak to occur.

GH secretion

GH is the major endocrine regulator of postnatal linear growth. GH is a single‐chain polypeptide consisting of 191 amino acids, which circulates in the blood bound to growth hormone binding protein (GHBP) that results from cleavage and shedding of the extracellular part of the GH receptor. The predominant form (75%) of GH exists as a 22 kDa protein with 5–10% of pituitary GH release represented by a smaller 20 kDa form that lacks amino acids in positions 32–46. GH is secreted by somatotroph cells of the anterior pituitary gland under the dual regulation of two hypothalamic peptides: growth hormone‐releasing hormone (GHRH), which is stimulatory, and somatostatin, which is inhibitory to GH release. These two peptides are, in turn, influenced by central neurotransmitters. Ghrelin, secreted from the gut, is a third GH secretagogue. GH is secreted in an episodic or pulsatile manner, reflecting the interaction of GHRH and somatostatin. Secretion of GH, mostly via its hypothalamic control, is influenced by a wide variety of environmental, genetic, and physiological factors including nutrition, sleep, exercise, and stress.

The growth hormone‐insulin‐like growth factor (GH‐IGF) axis

Figure 3.3 shows the GH‐IGF axis. The insulin‐like growth factors (IGF‐I, IGF‐II) are related peptides, so named because of their close structural relationship with proinsulin and their weak insulin‐like metabolic effects. GH is believed to have little direct effect on linear growth. IGF‐1 is directly responsible for linear growth, particularly during the childhood and pubertal phases.

IGF‐1 is primarily secreted by the liver into the circulation and exerts an endocrine effect on target tissues, including bone. IGF‐1 is also synthesized by bone, the cells exerting an influence on adjacent cells – the paracrine effect – as well as on the cells which secrete it – the autocrine effect. The relative contribution of endocrine versus paracrine IGF‐1 on bone remains unclear (Crane and Cao 2014).

IGF‐I is a single‐chain polypeptide of 70 amino acids which is encoded from a complex gene on chromosome 12. IGF‐I synthesis occurs after binding of GH to its receptor in the liver and other target organs. The concentration of IGF‐I in the circulation is closely related to physiological secretion of GH, although this relationship may be disturbed in pathological states. IGF‐I interacts specifically with soluble proteins called insulin‐like growth factor‐binding proteins (IGFBPs). The principal carrier protein for IGF‐I is IGFBP‐3, the systemic levels of which depend on GH status. When IGFBP‐3 has an IGF molecule bound to it, it can then associate with another GH‐dependent glycoprotein, ‘acid‐labile subunit’ (ALS), to form a ternary complex.

Unlike insulin, most IGF‐I circulates in an inactive or bound form. The IGFBPs extend the half‐life of the IGF peptides, transport them to target cells and modulate their interaction with their respective receptors. IGF‐I binds to the type 1 IGF receptor in target tissues, such as the growth plate at the ends of long bones.

Growth at puberty: the effect of sex hormones on the GH‐IGF axis and growth plate

Estradiol is the key hormone influencing the GH‐IGF axis at puberty in both sexes (Figure 3.4). The enzyme aromatase is responsible for estradiol synthesis from testosterone in the Leydig cell of the testis; and from androstenedione in the granulosa cell of the ovary.

The effect of serum estradiol on growth is paradoxical and relates to the level of secretion. Small to moderate levels of serum estradiol accelerate growth by stimulating the hypothalamus to enhance GHRH secretion, resulting in an increase in the amplitude of GH secretion, especially at night (Rose et al. 1991), and increased GH secretion raises IGF‐1 levels. Larger amounts of estradiol inhibit growth through action on the growth plate, accelerating epiphyseal fusion. Thus, estradiol is indirectly responsible for the pubertal growth spurt and directly responsible for the cessation of linear growth in both sexes.

Techniques of measurement

Accurate measurement is essential for growth assessment and an important clinical skill. Errors may be the result of unreliable equipment and faulty measurement technique. To optimize the accuracy of measurement, a single trained measurer – or, at the most two – should measure children in a single clinic. The following techniques enable reliable data to be collected from the most commonly used measurements.

Measurement of supine length in children from birth to two years of age

Neonates and toddlers are notoriously difficult to measure accurately. The supine table and neonatometer, both consisting of a flat surface with a fixed headboard and moving baseplate, are two devices developed to reduce error in measuring babies and children too young to stand up (Figure 3.5). Two people are necessary to obtain a reliable measurement. The assistant holds the child’s head in firm contact with the headboard, so that the Frankfurt plane is vertical; with neonates, it is also advisable to use the forefingers to pin the shoulders down. At the same time, the legs of the (by now almost always crying) child are straightened and when the measurer is satisfied that the head is still in contact with the headboard, the measurement can be taken.

Calculation of height velocity

Height velocity should be calculated using measurement intervals of 6–12 months (minimum/maximum 4/14 months), dividing the difference in height (cm) by the difference in interval (years). For example, a child born on 28 March 2002, measuring 132.6 cm on 3 February 2011 and 138.2 cm on 4 January 2012 will have decimal ages at the times of 8.854 and 9.772 so that the height velocity is:

An idea of height velocity can also be obtained by examining the growth curve constructed from a series of accurate measurements. A height curve which crosses the centile bands downwards or upwards indicates a change in height velocity from the norm which requires an explanation.

Parental height and target range

Parents should be measured whenever possible. Reported parental heights are notoriously inaccurate, especially in fathers (Cizmecioglu et al. 2005). The mean height difference in men and women from the United Kingdom is 13 cm (Tanner et al. 1970). When a boy is seen in the clinic, the father’s height is plotted directly on the right‐hand side of a growth chart for boys (see Figure 3.6). The mother’s height is then plotted after adding 13 cm to her height. The mid‐parental height (MPH) centile is the mid‐point between the father’s height and the mother’s corrected height. The target range is calculated as the MPH ± two standard deviations = 8.5 cm (6.5–10 cm depending on population data) and represents the 95% confidence limits.

When a girl is seen in the clinic, the mother’s height is plotted directly, the father’s height is plotted after subtracting 13 cm. The MPH and target range are then calculated as for boys.

With normal parents and healthy children, the children’s final heights will be normally distributed around the MPH, with only a 5% probability of falling outside the target range.

Pubertal staging

Staging of pubertal development using the criteria of Tanner and the Prader orchidometer in boys is important in the clinical assessment of all patients, irrespective of age. Details of the criteria for pubertal staging are given in Chapter 5.

Height and height velocity standard deviation score

Height for chronological age and bone age can be expressed as standard deviation scores (SDSs) according to the following formula:

Height velocity SDS can be calculated according to the following formula:

The SDS for height and height velocity at different ages can be obtained by consulting the original publications from which local growth standards have been derived or by downloading software such as Professor Tim Cole’s LMS system, based on UK 1990 data which is available as a free download: http://www.healthforallchildren.com/shop‐base/shop/software/lmsgrowth. Using SDS to express height and height velocity values enables data on groups of children of both sexes and different ages to be pooled and compared statistically. It is also more informative to express extremely short or tall stature as SDS rather than < or ≪ 0.4th centile, > or ≫ 99.6th centile, etc. When SDS values are calculated for patients in puberty, adjustments must be made for the pubertal stage of the child and the age at which PHV occurred.

Body mass index

The relationship between weight and height of an individual can be expressed as body mass index (BMI) which is calculated as body weight (in kilogrammes)/height²\(metres). This method has been criticized for assessment of obesity in children because the average values for BMI vary considerably with age. Normal standards for BMI are available for British children using UK 1990 data (Freeman et al. 1995) or since 2009 the UK‐World Health Organization data (see Chapter 11 and Appendix 1 for more information)

Assessment of skeletal maturity

Several methods have been developed to assess the skeletal maturity or ‘bone age’ of growing children using an X‐ray of the left wrist. The two most commonly used methods are the ‘atlas method’ (e.g. Greulich and Pyle) and the ‘bone‐specific scoring system’ (e.g. Tanner–Whitehouse). Figure 3.6 shows how bone age is represented on the growth chart as an open circle using height at the time of measurement and bone age as coordinates, and linking bone and chronological age with a broken line.

Automated bone age assessment

In recent years automated systems for bone age assessment have been introduced in clinical practice, with evidence to show comparable accuracy with single‐observer assessment and the advantage of saving labour (Lee et al. 2017). Since 2012, bone age in Glasgow has been calculated using an automated system (http://www.bonexpert.com).

Auxology

The following should be carried out before the child/adolescent and family enter the consulting room:

• Measurement: The heights of patient and both parents should be obtained and the patient weighed.
  
• Calculation: Decimal age, MPH and target range; and height velocity (when previous height data are available).
  
• Plotting: Patient and parental height data are plotted onto an appropriate growth chart as shown in Figure 3.6.

History

• Presenting complaint. Establish who is worried about what (e.g. parents but not child concerned about small size).
  
• History of presenting complaint (three sections). Growth history (supplemented by previous measurements if available); general health, including energy levels and activities; and degree of psychological upset in the child/adolescent.
  
• Past medical history. Birth weight and length, gestation and mode of delivery; history of atopy (an important factor in constitutional delay); relevant medical events (e.g. orchidopexy for cryptorchidism).
  
• Family history. Name, age, and health of each family member; parental and sibling heights/height status; consanguinity; size during childhood and pubertal history in father and mother (including age at menarche in the latter).
  
• Social and educational history. Name of school; school year (whether age‐appropriate or not); school attendance, academic status (including need for extra help), relationship with peers (teasing and bullying) and authority figures; sport and leisure activities.
  
• System review (where appropriate).

Examination (with child standing initially)

• General appearance and nutrition
  
• Body proportions
  
• Dysmorphic features
  
• Systemic examination, including heart and blood pressure measurements
  
• Fundi
  
• Pubertal status

Clinical diagnosis

The most likely diagnosis and differential diagnosis should be formulated before any investigations are contemplated.

Laboratory investigations for short stature

Once the decision has been made to perform laboratory investigations on the child with short stature, the doctor must proceed as a general paediatrician and not as a paediatric endocrinologist. If the approach is too specialized, disorders such as anaemia, malabsorption, renal disease, Crohn disease, or even Turner syndrome can easily be missed. Baseline investigations for short stature are shown in Table 3.2. Note that no investigations of GH status other than IGF‐1 are included at this stage.

The decision to investigate GH secretion is made only after the above investigations have been performed and documented to be normal. At the second and third consultations additional auxological information, particularly on height velocity, will be available. Further investigation of the child can now be considered. Indications and procedures for investigation of possible GH insufficiency are covered in section on the diagnosis of GH deficiency, which discusses this disorder in detail.

Normal short stature

Familial/Genetic short stature

This is the most common cause for referral of a child with short stature. Essentially, the child is perfectly healthy but has inherited short stature genes from one or both parents or, occasionally, a more distant relative. There is no endocrine abnormality and the bone age is usually not delayed, unless there is also a component of growth delay.

NB: Do not assume that familial short stature is always normal. If one of the parents is markedly short, a dominantly inherited growth disorder, such as a skeletal dysplasia, neurofibromatosis, or GH deficiency, should be considered.

Constitutional growth delay

The diagnosis of constitutional growth delay (see Figure 3.6) is suggested when the child is healthy but looks young for his/her age, has evidence of late maturation in terms of bone age and pubertal delay, and often the history that one parent or second degree relative (e.g. an uncle) was short during childhood with subsequent delay in puberty. A history of atopic asthma, often mild, is common. The condition is seen more often in boys and typically there is a component of genetic short stature since it is the shorter children who tend to show slow maturation.

Frequently, the slow maturation starts in early childhood and the delay of physical development accumulates. Consequently, an 11‐year‐old boy could well have the physical maturity, bone age, height, and appearance of an 8‐year‐old. The short stature in this situation is then compounded by the delay in pubertal development. Typically, final adult height is within but in the lower half of the parental target range (see Figure 3.6).

Short stature related to smallness‐for‐gestational age and intrauterine growth restriction

Smallness‐for‐gestational age (SGA) is linked with, but distinct from, intra‐uterine growth restriction (IUGR) (see Figure 3.7). SGA is defined according to weight and varies with the paediatric discipline involved. Neonatologists define SGA as birth weight below the 9th or 10th centile for gestational age, recognizing that this population is at risk of postnatal hypoglycaemia, and should be targeted for early feeding and capillary glucose monitoring. Endocrinologists define SGA in auxological terms – birth weight below the 2nd or 3rd centile (i.e. more than 2 SD below the mean). Using the latter definition of SGA will include many small normal babies. Short stature at birth can only be reliably identified if birth length is measured accurately, and is only roughly correlated with birth weight (Sardar et al. 2015).

IUGR means intrauterine growth failure. Affected infants are usually but not always light/short at birth (see Figure 3.7). The diagnosis of IUGR is secure if serial antenatal ultrasound has demonstrated growth failure; and in defined syndromes such as Russell‐Silver; likely in the context of severe SGA; and can be inferred in SGA or non‐SGA infants with birth weight < 25th centile and a combination of postnatal feeding difficulties and impaired infantile growth curve.

If weight, length, and head circumference are proportionate at birth, the SGA is termed symmetrical and reflects either a small/normal baby or IUGR related to early growth failure. Asymmetrical SGA, when weight is reduced but with preservation of head and linear growth, occurs because of late deprivation of nutrients usually related to placental insufficiency and is the foetal equivalent of failure to thrive. Babies with asymmetrical SGA are more likely to show postnatal catch‐up growth. The overall catch‐up rate within two years of birth in SGA subjects is 87% (Albertsson‐Wikland and Karlberg 1994).

SGA also can be classified according to the cause:

• foetal: genetic syndromes, intrauterine infection, exposure to irradiation, smoking, alcohol;
  
• placental: impaired placental function, especially during 3rd trimester;
  
• maternal: chronic illness such as renal disease and hypertension.

Dysmorphic syndromes

Dysmorphic syndromes can be defined as conditions arising from a specific event – chromosomal, genetic, environmental – during foetal life and resulting in a variable constellation of features (Jones 1997). These include:

• unusual phenotype (especially face, hands, body proportions);
  
• growth problems – usually short but sometimes tall stature;
  
• developmental delay/learning disability;
  
• congenital anomalies (especially cardiac, renal, and gastrointestinal);
  
• gonadal problems.

Diagnosis is important not only to provide a cause for the short stature but also to identify associated problems (e.g. ovarian failure in Turner syndrome) and giving the patient and family a prognosis.

The paediatrician seeing children with short stature needs to become experienced in recognizing clinical patterns suggestive of a dysmorphic process, and being aware of the heterogeneity of each syndrome. Professor James Tanner taught that identification of dysmorphic features is easier with the patient standing opposite the seated doctor. Every patient in Professor Tanner’s clinic was photographed, which also accentuated unusual features. The involvement of a clinical genetic colleague is invaluable, particularly in assessing the many patients with dysmorphism who do not fit into an obvious diagnostic category.

A detailed account of all the relatively common recognizable dysmorphic syndromes is beyond the scope of this chapter; however, a selection of six syndromes which may present undiagnosed to the growth clinic are briefly described here.

Russell‐silver syndrome

Birth weight is usually <2nd centile and almost invariably <9th centile, feeding difficulties are the rule, and nocturnal sweating (suggestive of hypoglycaemia) is common. On examination, affected individuals are short and thin, some showing asymmetry with hand, foot, arm, or leg shorter on one side. Head is relatively large, often with expanded vault, and facies are characteristically triangular with down‐sloping eyes. Intelligence is normal. The condition results from maternal and/or paternal iso‐ and heterodisomy causing abnormal methylation in imprinted genes. Causes include, but are not confined to, hypomethylation at 11p15.5 and to maternal disomy of chromosome 7 (Dias et al. 2012). Hypomethylation at 11p15.5 has been shown to affect postnatal mRNA expression of IGF‐2.

Foetal alcohol spectrum disorder (FASD)

Birth weight is invariably reduced, and there is postnatal short stature associated with poor concentration, behaviour and learning difficulties. Facies are variable but may show smooth philtrum, short palpebral fissures, and malar hypoplasia. Head circumference is reduced. A history of maternal alcohol ingestion is crucial to making the diagnosis but is not always evident at initial presentation. Hence, SGA/IUGR children with developmental delay and poor concentration should be followed up so that foetal alcohol spectrum disorder (FASD) can be recognized.

Turner syndrome

Turner syndrome (see Table 3.4 and Figure 3.8) occurs in about 1 in 2500 liveborn girls. There is loss or abnormality of the second X chromosome in at least one major cell line in a phenotypic female. The principal features are outlined in Table 3.4 and include dysmorphic traits (see Figure 3.8), short stature (an almost constant sign) and ovarian dysgenesis (in about 90%). Associated features include congenital heart disease (15%), middle ear disease which can be very troublesome (65%), hypertension and aortic root dilatation, renal anomalies (common but rarely problematic), a predisposition to autoimmunity, specific learning difficulties (particularly with mathematics), and a degree of social vulnerability.

Genetic aspects

Partial inactivation of the second X chromosome in all the body’s cells from early foetal life partly explains the remarkably mild phenotype of Turner syndrome. However 30% of the short arm genes of the second X chromosome are not inactivated, and these include the Short Stature Homeobox (SHOX) gene. Loss of this and other genes results in skeletal dysplasia with short stature. Loss of genes controlling lymphogenesis, ovarian function, and skin naevi result in lymphoedema, accelerated atresia of oocytes, and increased naevi (particularly on the face), respectively. The second chromosome may be completely lost (45,X), undergo duplication of the long arm (q) with concomitant loss of the short arm (p) to form an isochromosome (isoXq), undergo ring formation (rX), or deletion in the short or long arm (Xp⁻ or Xq⁻). Complete 45,X monosomy accounts for 40–60% of the karyotypes on peripheral blood lymphocytes, while most of the remaining karyotypes show a mosaic pattern; for example, 45,X/46,XX, 45,X/46,X,iXq, 45,X/46,XY, 45,X/46,X,rX. There is little specific phenotype/genotype correlation for most karyotypes but phenotype is milder in the 45,X/46,XX and 45,X/47,XXX variants.

Growth (see Appendix 2)

All three components of Karlberg’s ICP model are impaired in Turner syndrome, with a degree of IUGR (usually mild) in almost all cases; subnormal growth during infancy and childhood with 15 cm loss in height compared with normal girls between the ages of 3 and 12 years; and impaired pubertal growth spurt even with oestrogen therapy, related to the underlying skeletal dysplasia. Adult height in European populations ranges from 142 to 147 cm (Ranke 1998). There is a positive correlation between adult height and parental height.

Diagnosis and follow‐up

Because of the subtlety and variable incidence of many of these features, Turner syndrome is easily missed. The diagnostic key is short, or borderline short, stature in a girl whose height is inappropriate for the parental target range centiles (Ouarezki et al. 2017). Karyotype analysis is indicated in this situation and/or in the context of dysmorphic features, middle ear disease, and cardiac anomalies. Follow‐up is required to pre‐empt associated problems such as autoimmune thyroiditis, middle‐ear disease, learning difficulties, and hypertension and is best provided in designated Turner syndrome clinics, with good hand‐over arrangements for specialist adult care.

Noonan syndrome

Noonan syndrome (see Table 3.5, Figure 3.9 and Appendix 2) refers to a heterogeneous group of conditions resulting from various gene mutations, of which four have been identified – PTPN11 (encoding SHP‐2), SOS1, KRAS, and RAF‐1. Sporadic mutations are commonest, affected individuals then transmit the condition in autosomal dominant fashion (see Figure 3.9). Prevalence is estimated at between one in 1000–2500 live births. The principal features of Noonan syndrome are shown in Table 3.5. Growth is usually affected with height velocity being subnormal and puberty is typically delayed and associated with a blunted adolescent growth spurt. Adult heights are approximately 162 cm in males and 152 cm in females (Ranke et al. 1998).

Williams syndrome

This condition arises from a spontaneous deletion affecting 7q11.23 and may present with short stature in a child with intellectual disability but with aptitude for music, increased fearfulness, engaging behaviour described as ‘cocktail party manner’, hyperacusis, and characteristic facies – button nose, full lips, and ‘elfin’ appearance. Associated problems include infantile hypercalcaemia, supravalvular aortic stenosis, pulmonary artery stenosis, hypertension, and scoliosis.

Aarskog syndrome

This condition results from a mutation in the FGDY1 gene located on Xp11.21. The phenotype – hypertelorism, interdigital webbing, short broad hands, and shawl scrotum in males – is milder in affected females and more pronounced in their sons. Intelligence is normal and the degree of short stature usually insufficient to warrant intervention.

Skeletal dysplasias

This is a varied and complex group of disorders requiring input from colleagues in other disciplines including genetics, radiology, and orthopaedics, as well as endocrinology. Patients may present with severe short stature and obvious disproportion (abnormal upper:lower segment ratio, sitting height, and arm span relative to height), in which case the diagnosis of skeletal dysplasia is obvious. Less severe cases may present with short stature of uncertain cause requiring a diagnosis, and shrewd assessment may be needed to detect mild disproportion. The limbs will be short in disorders principally affecting the long bones, for example, achondroplasia, hypochondroplasia, and metaphyseal dysplasia; the back will be short in disorders affecting the spine as well as the long bones, for example, spondylo‐epiphyseal‐dysplasia (SED). Table 3.6 shows the key features of three important disorders – achondroplasia, hypochondroplasia, and spondylo‐epiphyseal‐dysplasia. The following points should be borne in mind:

• Skeletal dysplasia may be only one component of a wider disorder, for example, Turner syndrome, neurofibromatosis, and the mucopolysaccharidoses; careful evaluation of other systems including eyes, hearing, neurodevelopment, and phenotype is therefore important.
  
• Many skeletal dysplasias are autosomal dominant in inheritance. The clinician should be wary of assuming normal familial short stature when one parent is particularly short.
  
• Sitting height must be measured, plotting both this and the derived leg length onto standard growth charts in both child and parent.
  
• Assessment should also include examination of the hands (looking for short, stubby fingers), the proportions of the upper and lower segments of the arms and legs, skull shape and circumference, and the spine for exaggerated lordosis.
  
• Typically bone age is advanced, and pubertal growth response is blunted.
  
• Some children display a pattern of mild/no disproportion in the context of short stature with advanced bone age, normal skeletal survey, poor growth response to puberty, and lower adult than childhood height centile. It is possible that some of these cases (currently classified as ISS) will be found to represent mild forms of skeletal dyplasia which are undetectable with standard radiology.

Chronic disease

Chronic illness is a potent cause of impaired linear growth in childhood and adolescence, and pubertal delay (Kao et al. 2018). The child may already be diagnosed, and referred to evaluate the contribution of various components including the disease (e.g. chronic arthritis) and its treatment (e.g. systemic steroids) to the poor growth. By contrast, chronic disease may be an unsuspected cause of short stature. Gastrointestinal disorders, such as coeliac disease and inflammatory bowel disease, can present in this way, while chronic renal disease is notoriously silent. The degree of growth failure varies considerably from a relatively mild effect, usually with constitutional delay, in mild to moderate asthma to potentially severe short stature in Crohn disease and juvenile chronic arthritis. The three principal mechanisms for poor growth and short stature in chronic disease are:

• secretion of pro‐inflammatory cytokines, particularly TNF, IL1 and IL6, in conditions such as Crohn disease and juvenile idiopathic arthritis (primary effect of disease);
  
• undernutrition (secondary effect of disease);
  
• steroid treatment (iatrogenic effect).

Other factors include delayed maturation and puberty; hypoxia (cyanotic congenital heart disease); metabolic disturbance (glycogen storage disease, renal failure); and partial GH resistance (Crohn disease, renal failure)

Psychosocial deprivation

There is an established relationship between socioeconomic status and physical growth. However, it can be difficult to weigh up the contribution of the social environment to short stature and poor growth in the individual. This is because factors such as SGA, poor diet, respiratory illness related to parental smoking, and parental short stature may be contributory and of variable relation to the poor social circumstances.

Adverse family and social factors can delay a child’s physical and emotional development. David Skuse and colleagues described a striking variant of psychosocial growth failure featuring abnormal behaviour with hyperphagia and polydipsia. Investigation shows GH insufficiency which is resistant to exogenous GH therapy but is reversible on moving the child to a favourable environment (Skuse et al. 1996).

Psychosocial deprivation should always be considered when a child is referred with short stature, and the clinician must take a thorough family and social history. Careful follow‐ up of suspected cases, with sequential height and weights, is crucial not only in confirming the diagnosis, but also in documenting the child’s needs in terms of future care and placement.

Endocrine disorders

GH insufficiency and deficiency

Definition and cut‐offs

These are controversial! GH insufficiency can be defined in terms of a peak GH level which is below an agreed arbitrary cut‐off level. Assays vary between centres while the intra‐patient variability of peak GH secretion is high. Severe GH insufficiency can be defined as a maximum stimulated GH concentration of <3 μg/L), partial GH insufficiency as 3‐7μg/L. It is important to recognize that low GH levels can be encountered in virtually any short child and that low levels are not indicative of permanent impairment of the hypothalamo–pituitary (H‐P) axis. It follows that GH status should be measured judiciously and carefully interpreted in the clinical context. A significant proportion of peripubertal children with short stature, slow height velocity, and low stimulated GH levels will show normal GH status on retesting once final height is attained. In retrospect, many such children would have been displaying constitutional delay with hypothalamo–pituitary ‘dormancy’.

The term GH deficiency (as opposed to GH insufficiency) can be used to refer to permanent impairment of the GHRH‐GH axis, due to either congenital or acquired disease. According to this nomenclature, therefore, GH deficiency is a subset of GH insufficiency. We recommend using the term ‘GH deficiency’ if actual impairment of GH secretion is either certain or very likely, and the term ‘GH insufficiency’ when GH levels are low but definite H‐P axis abnormality has not been demonstrated.

While classic and severe growth hormone deficiency is clinically easy to diagnose (see Figure 3.10), milder forms are difficult to separate from normal variant short stature. The features of these two ends of the spectrum are shown in Table 3.7 and the causes of GH deficiency are shown in Table 3.8.

Severe GH deficiency

Presents before age three years (unless acquired)

Obvious short stature

Subnormal height velocity from birth, becoming more abnormal with age

Neonatal hypoglycaemia and hyperbilirubinaemia

Micropenis

Possible associated anterior pituitary hormone deficiencies (TSH, ACTH, LH, FSH)

Excess subcutaneous fat, increasing with age

Mid‐facial hypoplasia (only in extreme cases)

Possible features of septo‐optic dysplasia

Delayed skeletal maturation

Maximum stimulated GH concentration < 3 μg/L

Mild GH deficiency

Unlikely to present before school entry

Less severe short stature

Subnormal height velocity documented by careful auxology over minimum interval of 12 months

Isolated GH insufficiency

Normal subcutaneous fat

Delayed skeletal maturation

Delayed puberty

Maximum stimulated GH concentration 3–7 μg/L (3–10 μg/L in some centres)

Abbreviations: ACTH, adrenocorticotrophic hormone; FSH, follicle‐stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid‐stimulating hormone.

Transient GH insufficiency: Conditions in which GH levels may be <7 μg/L on initial stimulation testing but normal on retesting

Constitutional delay in growth and adolescence

Short stature following smallness for gestational age

Hypothyroidism

Psychosocial deprivation

Permanent GH deficiency: Conditions in which GH levels are < 7 μg/L due to impairment of hypothalamo–pituitary axis

Congenital

Inherited causes

GHRH mutations

GH‐1 mutations (autosomal recessive, autosomal dominant, X‐linked)

Pit‐1, Prop‐1 mutations

Structural defects

Septo‐optic dysplasia

Agenesis of corpus callosum

Holoprosencephaly

Hypopituitarism with single central incisor

Hypothalamic disorders

Prader–Willi syndrome

Acquired

Tumours adjacent to hypothalamo–pituitary axis

Craniopharyngioma

Suprasellar germinoma

Optic glioma

Head injury

Surgery to the H‐P axis

Cranial radiotherapy (e.g. for medulloblastoma)

Granulomatous disease

Langerhans cell histiocytosis

Sarcoidosis

Isolated GH insufficiency and deficiency

Idiopathic isolated GH insufficiency

In >80% of cases, GH insufficiency is ‘isolated’, i.e. not associated with other anterior pituitary hormone deficiencies and may (see above) turn out to be a transient insufficiency rather than a permanent deficiency, falling into the ‘mild’ rather than ‘severe’ category described above. It is now known that the basic defect in most true isolated GH deficiency cases is in the synthesis or release of the hypothalamic peptide GHRH, but the precise pathogenesis is unknown. However, these patients respond to administration of exogenous GHRH by secreting GH, indicating that the somatotroph cells are functional and that the primary defect is in the hypothalamus. Magnetic resonance imaging (MRI) imaging and genetic studies are normal.

True isolated GH deficiency related to genetic and structural MRI abnormalities presents as:

1. GH deficiency of genetic origin: These disorders are very rare, occurring in the context of consanguinity and closed communities. Severe GH deficiency is the rule. Disorders result from the following:
   
   
   
   • GHRH receptor gene mutations.
     
   • Deletions of the GH‐1 gene resulting in four variants of hereditary hGH deficiency:
     
     
     
     • type IA (recessive, absent GH, blocking antibodies to hGH develop upon therapy)
       
     • type IB (recessive, low GH, response to hGH therapy)
       
     • type II (dominant, low GH, response to hGH therapy)
       
     • type III (X‐linked, low GH, response to GH therapy)
   
   
2. GH deficiency with MRI abnormality: The following three MRI abnormalities have been well documented in relation to either isolated GH deficiency or multiple pituitary deficiency (Figure 3.11):
   
   
   
   • small anterior pituitary;
     
   • interrupted pituitary stalk;
     
   • ectopic posterior pituitary (EPP).

Of these three features, EPP has the lowest inter‐observer variability and is the most strongly predictive of GH deficiency.

Auxology

• Short stature
  
• Height inappropriately low for parental target range centiles
  
• Subnormal height velocity (<25th centile for age).

Hypothyroidism

This is discussed in Chapter 6. Unless diagnosed early, congenital hypothyroidism leads to severe stunting of growth. The introduction of neonatal screening has eliminated this cause of short stature. By contrast, acquired hypothyroidism caused by autoimmune thyroiditis may present with short stature and growth failure, hence the need to include thyroid function testing in all short children requiring investigation.

Cushing’s syndrome

Hypercortisolaemia impairs linear growth. Consequently, most patients with Cushing’s syndrome will have a deceleration in height gain, in marked contrast to subjects with simple obesity in whom height velocity is enhanced. Exceptions are cases of Cushing’s syndrome where excess adrenal androgens are secreted, which may counteract the growth‐suppressive effect of high cortisol. Cushing’s syndrome is discussed in Chapter 8.

Constitutional delay of growth and puberty

The cornerstone of management is correct diagnosis, reassurance, and a realistic prognosis for final height, the latter being facilitated by adult height prediction in subjects aged more than 10–11 years. Some families with constitutional growth delay can be discharged after the initial consultation. Others find it helpful to receive regular 6‐monthly follow‐up until the pubertal growth spurt is well underway. In roughly half the boys seen with constitutional delay, there is no strong demand for therapy, but Table 3.10 shows some features which guide towards intervention.

Aims of treatment

Adverse events

Recombinant GH has a remarkably good safety record. The complication of Creutzfeldt‐Jakob disease associated with pituitary‐extracted GH was identified in 1985 and from this time only biosynthetic GH should have been used. Intracranial hypertension, usually seen shortly after the initiation of therapy, resolves with temporary cessation of GH followed by reintroduction at a lower dose. Slipped capital femoral epiphysis and progression of pre‐existing scoliosis should be detected by clinical awareness and monitoring, including regular examination of the spine. Any increase in cancer risk among GH‐treated patients can be largely related to previous treatment for malignancy, and a direct influence of GH is doubtful. A large study of nearly 24 000 GH‐treated patients from eight European countries showed no general increase in cancer risk, but the finding of a slight increase in bone cancer, bladder cancer, and Hodgkin’s lymphoma requires ongoing surveillance (Swerdlow et al. 2017).

GH therapy in non‐GH‐deficient disorders

The availability of recombinant GH, although admittedly at high cost, has led to its use in a number of non‐GH‐deficient disorders, where its pharmacological properties might benefit growth. Prominent among these are Turner and Noonan syndromes, short stature related to SGA, renal disease, and skeletal dysplasias. Each of these categories will be discussed briefly.

Short stature associated with SGA

GH therapy has been shown to cause a dose‐dependent increase in height velocity in short patients with a history of SGA. High‐dose therapy for a period of two years induces catch‐up growth (De Zegher et al. 1998) and a European licence was granted for the treatment of short SGA children in 2003. The recommended dose varies widely, from 35 μg/kg/day in many European centres to an FDA‐approved dose of 67–69 μg/kg/day.

However, evaluation of the safety and efficacy of GH therapy in SGA patients is challenging. The SGA population is heterogeneous and not all patients will have proven IUGR. Growth in response to GH may be restricted by an unusually rapid pubertal growth phase. Final adult height data are still limited and long‐term follow‐up data on cardiac and metabolic health are needed to evaluate safety, particularly with higher doses of GH.

We recommend careful selection of patients who might benefit from treatment, comprising those with clinical evidence to suggest IUGR rather than SGA, and in whom height by the age of four years is < ‐2SD without catch‐up growth. We suggest a starting GH dose of 35 μg/kg/day, modifying this according to growth response, serum IGF‐1 levels, and bone age. Once a decision has been taken to treat with GH, this should be continued until final height is achieved, provided that the family are compliant, since discontinuous treatment is associated with catch‐down growth.

Chronic paediatric diseases

Short stature from chronic illness is best managed by treating the primary illness itself. This is dramatically demonstrated in Crohn disease, where successful resection of the inflamed bowel results in spectacular catch‐up growth (Figure 3.12). It is important to optimize nutrition and minimize steroid dosage. Newer treatments including anti‐TNFα therapy in Crohn disease and juvenile idiopathic arthritis (JIA) have led to significant improvements in growth. Treatment with GH is reserved for patients in whom growth remains poor despite every aspect of the chronic illness being managed as well as possible. Use of high dose recombinant GH in Crohn disease and JIA significantly increases growth rate but not completely, suggesting a degree of resistance at the level of the growth plate. Long‐term data on the benefit of GH therapy for adult height is awaited and ideally patients should only be treated in the context of a prospective clinical trial.

Induction of puberty is indicated in boys aged >14 years and girls aged >13 years with no pubertal development and earlier in selected cases when pubertal progress is slow or when delayed maturation is causing distress to the patient.

Psychosocial deprivation

Psychosocial deprivation may also be regarded as a chronic disease state. The best therapy for associated growth failure is to correct or reverse the disadvantageous home setting or, if this is not possible, to remove the child to a supportive environment. GH therapy is not indicated in this context nor is it effective.