13 Growth and puberty

Normal human growth can be divided into two distinct phases: prenatal (foetal) and postnatal.

This is the fastest period of growth, accounting for around 30% of eventual height. Factors that determine growth during this period include maternal size, maternal nutrition, and intrauterine environment. Hormonal factors such as insulin, insulin-like growth factor (IGF)–II, and human placental lactogen are important regulators of growth during this period.

This is classically divided into three overlapping periods.

From birth to 18–24mths of age. Rapid but decelerating growth rate (growth velocity range: 22–8cm/yr). Growth is largely under nutritional regulation during this period. Some infants (15–20%) may show significant catch-up or catch-down in length and weight. By age 2yrs, height is more predictive of final adult height than at birth.

From age 2yrs until onset of puberty. Characterized by a slow, steady growth velocity (range 8–5cm/yr). Growth is primarily dependent on growth hormone (GH), provided there is adequate nutrition and health.

Growth during this period is dependent on growth hormone (GH) and the actions of sex steroid hormones (testosterone and oestrogen). This combination induces the characteristic ‘growth spurt’ of puberty. In both males and females, oestrogen induces the maturation of the epiphyseal growth centres of the bones, eventually resulting in fusion of the growth plates, the cessation of linear growth, and the attainment of final height.

The onset of the pubertal growth spurt is earlier in females compared with males. Females are therefore, on average, taller than males between the ages of 10 and 13yrs. In males, the pubertal growth spurt is later in onset and greater in magnitude. As a result males are, on average, 12–13cm taller than females at final height.

Puberty is a well-defined sequence of physical and physiological changes occurring during the adolescent years that culminates in attainment of full physical and sexual maturity.

In females, peak growth (height) velocity occurs relatively earlier in girls (Tanner stage 2–3) compared with boys (Tanner stage 3–4; testicular volumes 10–12mL).

Growth must be measured accurately. Equipment used to measure weight and height must be regularly maintained, checked, and calibrated. Ideally, growth measurements should be carried out by someone specifically training and experienced in measurement techniques (e.g. an auxologist). This will minimize measurement error.

Weight and height measurement data should be plotted on a simple sex and age range appropriate standard growth centile chart (e.g. the UK 1990 Growth Reference charts). A UK-WHO growth chart for children from birth to 4yrs of age has been developed based on the WHO child growth standards. These describe optimal growth of healthy breast-fed children. Previous UK growth charts based on data from studies on breast- and formula-fed children, do not reflect normal weight fluctuations of breast-fed infants in first few weeks (see Fig. 13.1). Height measurements should be plotted on specific population growth charts where necessary or applicable, e.g. Turner’s syndrome; Down’s syndrome.

Single growth measurements should not be assessed in isolation from other previous measurements. Serial measurements are used to show a pattern of growth and to determine growth rate. To minimize error in the assessment of growth rate, calculation of height velocity (cm/year) should be taken from measurements a minimum of 6mths apart, ideally using the same equipment and by the same person.

Final height is the height reached after the completion of puberty and is estimated to be achieved when growth velocity has slowed to <2.0cm/year. This can be confirmed by finding epiphyseal fusion of the small bones of the hand and wrist on assessing the bone age X-ray.

Final height is largely genetically determined. A target height range can be estimated in each individual from their parent’s heights, first calculating the mid-parental height (MPH).

MPH (boys) = [(Mother’s ht (cm) + Father’s ht (cm))/2] + 6.5cm

MPH (girls) = [(Mother’s ht (cm) + Father’s ht (cm))/2] – 6.5cm

Target height range = MPH 9 10cm

This is a measure of skeletal maturation, which can be assessed by the appearance of the epiphyseal centres of the long bones. Conventionally this is quantified from X-rays of the left hand and wrist, with either compared with standard radiograph images (e.g. Gruelich and Pyle method) or assessed using an individual bone scoring system (Tanner–Whitehouse methods).

The difference between bone age (BA) score and chronological age at the time of assessment may be used as an estimation of the tempo of growth. The BA may also be used as an indicator of the likely timing of puberty, which usually starts when BA is around 10.5yrs in females and 11.5yrs in boys. The relationship between BA and age of onset of menarche is more robust.

Girls usually reach skeletal maturity at a BA of 15.0yrs and boys when BA is 17.0yrs. The BA can therefore be used as an estimation of the remaining growth potential and can be used to predict final adult height.

Puberty stage can be rated using the Tanner staging system. This involves identification of pubertal stage particularly by assessment of stage of breast development in girls and of testicular volume (by comparison with an orchidometer) in boys.

Defined as a height 2 SDs or more below mean for the population. On a standard growth chart this represents a height below the 2nd centile. Note: abnormalities of growth may be present long before height falls below this level and can be identified much earlier by monitoring growth velocity and observing a child’s height crossing centile lines plotted.

These are summarized in the Box 13.1. The most common cause is familial, where either one or both parents will also be short. Height correlates well with parental height and is probably of polygenic inheritance, but it should be noted that short parents may have a dominantly inherited growth disorder.

Pregnancy illness/drugs/complications

Chronic asthma

Corticosteroids

Headaches/visual disturbance

Examine previous growth records if available

The following baseline screening tests should be carried out:

Where clinically indicated:

This will depend on the underlying cause (see later sections of this chapter). The diagnosis of a child with short stature is often a shock to the family, and they should be offered detailed, reliable information about their child’s condition and informed where to get additional support and advice. In the UK the Restricted Growth Foundation (www.restrictedgrowth.co.uk) is a good resource. Familial short stature does not require any specific treatment.

Relative short stature occurs because of a delay in the timing of onset of puberty. It is a variation in the timing of normal puberty, rather than an abnormal condition. It usually presents in early adolescence, although it may be recognized in earlier childhood. There is often a familial basis, often having occurred in one of the parents. It is much commoner in males, although this may reflect a bias in the level of concern.

Characteristic features include short stature and delayed pubertal development by greater than 2 SDs. Typically, there is a mild degree of skeletal disproportion with evidence of a shorter back (sitting height percentile) relative to leg length. There is invariably delay in BA maturation, which usually remains consistent over time. Height velocity is appropriate for BA.

Laboratory investigations are normal, including GH provocation tests.

Usually no treatment is required as the onset of puberty and the accompanying growth spurt will occur spontaneously and an appropriate final adult target height is achieved.

Treatment is sometimes indicated in those adolescents who have difficulty coping with their short stature or with the delayed physical development. Administration of sex steroids for a period of 3–6mths can be used to induce pubertal changes and to accelerate growth rate (boys: testosterone 50–100mg IM every 4wks).

See also  p.111. IUGR refers to reduction and restriction in expected foetal growth pattern. IUGR affects 3–10% of pregnancies and 20% of stillborn infants are thought to have evidence of IUGR. Perinatal mortality rates are 4–8 times higher for growth-retarded infants, and morbidity is present in 50% of surviving infants.

In placental causes of IUGR, ‘catch-up growth’ occurs after birth in the majority of infants during the first 1–2yrs of life, with infants regaining their genetically determined weight and height centiles. However, in approximately 15–20% of infants with IUGR, catch-up growth does not occur and patients are at risk of short stature. Recent studies also implicate IUGR in adult onset of hypertension and CHD, and in early onset obesity, polycystic ovarian disease, and type 2 diabetes. These studies suggest that IUGR has long-term effects on insulin sensitivity and on endocrine function.

See also  p.948. This condition must always be considered in girls presenting with short stature, or height below parental target height range. Karyotype confirms the diagnosis.

The majority of girls with Turner’s syndrome will not have the classical phenotype of dysmorphic features and it may be difficult to identify, particularly where there is mosaicism in the karyotype.

Treatment with daily SC injections of high dose recombinant human growth hormone (rhGH 10mg/m²/wk) increases final height, although individual responses are variable. Oral oestrogen (ethinylestradiol) is required to induce puberty between ages 12 and 14yrs. Combination therapy, which also includes the anabolic steroid, oxandrolone, may further improve final height.

Also see  p.336. Coeliac disease may be asymptomatic or atypical in its presentation with few if any gastrointestinal symptoms or signs. Poor height velocity and evolving short stature may be a presenting feature.

Poor growth and short stature is a common feature of long-term inflammatory conditions such as inflammatory bowel disease and rheumatic disorders. It may be a presenting feature in Crohn’s disease when GI symptoms are initially minimal (see  p.332).

Short stature is due to long-term use of immunosuppressive agents (e.g. corticosteroids) and to the generation of inflammatory factors (e.g. IL-6). Both lead to GH/IGF-I resistance and suppression of bone growth.

Management should be aimed at minimizing inflammation, and reducing immunosuppressive therapy. rhGH may have a role in treatment.

This heterogeneous group of disorders includes achondroplasia and hypochrondroplasia. Most disorders are characterized by severe short stature and often evidence of disproportion in body segment development. Skeletal survey may allow identification of specific condition (see  pp.766–767, 950).

GH is secreted from the somatomammotropic cells of the anterior pituitary gland in a pulsatile pattern. Secretion is diurnal and largely nocturnal and is controlled by a rhythmically changing equilibrium between two hormones secreted by the hypothalamus: GH releasing hormone (GHRH) and GH-inhibiting hormone (or somatostatin). GHRH induces GH synthesis and secretion whenever somatostatin is low. Different factors act at the level of the hypothalamus to regulate GH hormone secretion. GH secretion is regulated by negative feedback by circulating insulin-like growth factor-I (IGF-I) at the pituitary and hypothalamus, and by short loop-feedback by GH on the hypothalamus.

These may be primary (or congenital) or secondary (acquired) in origin. In clinical practice the most frequent cause of GH deficiency is 2° to cranial radiotherapy (Box 13.2).

Presentation depends on the age of onset of GH deficiency.

May present with hypoglycaemia. Co-existing deficiencies in the adrenal, thyroid, and gonadal axes may cause prolonged jaundice and micropenis. Size at birth and growth during the 1st year of life may be normal as growth during this period is not GH-dependent.

Typically presents with slow growth rate and short stature. Other characteristics include increased subcutaneous fat, truncal obesity, and decreased muscle mass. Children with congenital GH deficiency develop relative hypoplasia of the mid-facial bones, frontal bone protrusion, and delayed dental eruption. Delayed closure of the anterior fontanelle may also be observed.

All tests should be performed in the morning after an overnight fast and serial blood samples are collected. The insulin tolerance test (ITT) is considered the gold-standard test. GH provocation test should only be performed in those centres with experience and with appropriate technical and laboratory support.

GH deficiency is treated with rhGH, which is administered as a once daily SC injection (0.7–1.0mg/m²/day or 23–39microgram/kg/day).

Treatment with rhGH is continued until final adult height is achieved. At this point the GH deficiency should be reconfirmed, particularly in those with isolated or so-called idiopathic GH deficiency where the cause is unclear. Up to 50% of patients with the latter may have normal GH secretion when retested in early adulthood. Those patients with persisting GH deficiency should be offered the opportunity to continue rhGH therapy (0.2–0.5mg/day). Studies have demonstrated that rhGH replacement in adulthood may maintain lean body mass, muscle strength, and bone mineral density. In addition, improved quality of life has been reported with treatment.

Cranial radiotherapy used in the treatment of tumours (intracranial, face, and nasopharynx) may cause GH deficiency. The GH axis is the most sensitive to radiotherapy, followed by the gonadal and adrenal axes, and finally the thyroid axis, which is least sensitive. There is a good correlation between radiotherapy dose and the occurrence of hypothalamic–pituitary dysfunction (Table 13.2). Risk of dysfunction is also related to dose fractionation (single is more toxic than divided), and age (younger more sensitive).

Children subjected to physical or emotional abuse may exhibit growth failure. This may be due to a reversible inhibition of GH secretion that improves within 3–4wks of being removed from the adverse environment. Catch-up growth is usually dramatic.

Moderate to severe short stature may be due to GH resistance. This may be due to a defect in the GH receptor or to a defect in post-receptor GH signalling.

Complete GH insensitivity syndrome (GHIS) results in severe short stature. It may be inherited as an autosomal recessive trait (Laron syndrome). Affected individuals have high GH levels and low circulating IGF- I levels. Exogenous rhGH administration fails to increase IGF-I levels further (IGF-I generation test).

Referral for tall stature is much less common than that for short stature. Socially, it is more acceptable to be tall, particularly for boys. Nevertheless, tall stature, particularly when it is associated with inappropriately increased growth rates, may indicate an underlying growth disorder.

In the majority tall stature is genetic in origin and inherited from tall parents. Other causes, although rare, need to be considered:

A detailed history should be obtained.

E.g. headaches/visual disturbance.

The following baseline screening tests should be carried out:

Where clinically indicated GH suppression test (i.e. modified oral glucose tolerance test; GH levels normally suppressed to low levels).

In familial tall stature, reassurance and information about predicted final height are usually sufficient. Early induction of puberty using low dose sex-steroid to advance the pubertal growth spurt and to cause earlier epiphyseal closure is occasionally considered. However, this produces variable results and there is a theoretical risk of complications (including thromboembolic disease and oncogenic risk).

This is defined as the lack of initiation and progress of pubertal development > +2 SD later than the average age of onset of puberty for the population. In the UK, this is to >14yrs for females and >16yrs for males.

The causes of delayed puberty are shown in Box 13.3.

A detailed history should screen for the many possible physical and functional causes of delayed puberty. Make careful enquiry about age at puberty onset (including menarche in females) in other family members.

The following baseline screening tests should be carried out.

Note. In males, testosterone therapy does not promote testicular growth and testicular size remains prepubertal unless spontaneous puberty occurs.

This is the most common cause of delayed puberty. Usually observed in boys, this condition reflects a delay in the timing mechanisms that regulate the onset of puberty. There is often a family history of delayed puberty in parents or siblings.

It is likely that most children with CDGP are not referred for medical attention, as they and their parents will not perceive that there is a problem. However, for many others, concerns about the lack of physical development and the lack of anticipated adolescent growth spurt would be a source of much anxiety and psychological stress.

There is often evidence of delayed or slow growth in childhood, which is most pronounced in the peripubertal years due to lack of anticipated growth spurt. Children will also have evidence of delayed skeletal maturation on bone age assessment.

No specific therapy is required. For many children and families, explanation of the benign nature of the condition and reassurance that puberty will occur normally is sufficient. However, children who are experiencing significant social or psychological difficulties may request treatment. In this situation, low dose sex steroids may be used (e.g. boys: testosterone, 50mg IM monthly for 4–6mths). This approach will:

Thus puberty may continue once the administration of sex steroids has been stopped.

Any decision regarding whether therapy is required or not must include the views of the child and their parents, who should be part of the decision process.

This indicates impaired gonadotrophin release from the pituitary gland. Congenital and acquired causes are recognized (see Box 13.3,  p.477). The condition is characterized by low or undetectable gonadotrophin levels either under basal or stimulated (GnRH test) conditions.

Congenital causes of HH may be characterized by micropenis and undescended testis at birth in boys, whereas in girls physical signs are absent.

A genetic disorder characterized by the association of HH and anosmia (absent sense of smell). This arises due to a defect in the co-migration of GnRH releasing neurons and olfactory neurons that occurs during early foetal development. X-linked, autosomal dominant, and autosomal recessive modes of inheritance are recognized. The X-linked form of KS results from a mutation in the KAL gene (encoding the glycoprotein, anosmin-1). It is also characterized by a range of clinical features including synkinesia (mirror-image movements), renal agensis, and visual problems as well as craniofacial anomalies, although their expression is highly variable.

This is defined as the early onset and rapid progression of puberty. Age criteria vary. In White European children, precocious puberty (PP) is defined as <8yrs in females and <9yrs in males.

PP is either central or peripheral in origin. The various causes of PP are as follows.

Puberty occurs as a consequence of early physiological (true) activation of the hypothalamic–pituitary–gonadal axis (central). A normal sequence of pubertal development is observed.

Central PP may also be idiopathic and familial. Girls with central PP are more likely to have idiopathic central PP, whereas in boys there is a much greater risk of intracranial tumours.

Puberty is due to mechanisms that do not involve physiological gonadotrophin secretion from the pituitary. The source of sex steroid may be endogenous (gonadal or extragonadal) or exogenous. Endogenous hormone production is independent of hypothalamic–pituitary–gonadal activity. An abnormal sequence of pubertal development is usually observed.

A detailed history should be obtained:

Baseline screening tests should be considered.

In addition, undertake the following:

The diagnosis is based on demonstrating progressive pubertal development and increased growth rate, together with laboratory evidence of increased sex steroid production. Distinguishing central and peripheral PP and PP from other normal variants of pubertal development may be difficult (see Table 13.3). In CPP there is evidence of consonance in sequence of pubertal development in keeping with the normal physiological activation of puberty.

The management of precocious puberty is aimed at the following:

Before therapy is considered, it is essential that an explanation of the physiology and physical consequences of precocious puberty should be discussed with the parents and the child. The decision on therapy should be made jointly with the parents.

These include premature thelarche and premature adrenarche. Neither condition is associated with pubertal activation of the hypothalamic–pituitary–gonadal axis.

The clinical course is characterized by a waxing and waning of breast size, normal growth (height) rate, and the absence of any further sexual development. Breast development may be asymmetrical, and there is usually a resolution of any breast enlargement by age 4–5yrs.

The cause is unknown, but small increases in basal and stimulated serum FSH levels are usually observed. In contrast LH levels remain suppressed in the prepubertal range. Ovarian follicle development is often observed, but no changes in ovarian or uterine size are seen. Serum oestradiol levels are increased when measured by sensitive assays, but typically within normal range by standard radioimmunoassay.

The condition is benign. Bone maturation, age of onset of menarche, and final adult height are not affected. Management is conservative with re-evaluation of growth and puberty stage at 3–6-monthly intervals.

Patients have evidence of breast development, increased growth rate, and advanced skeletal maturation on bone age assessment. There may also be evidence of ovarian enlargement and raised serum oestradiol levels. For most patients the tempo of progression of pubertal development will be slow and they will have laboratory findings within normal range for age. Management is usually conservative with regular re-evaluation of growth and pubertal status at 3–6 monthly intervals. Decisions to treat (as for central PP) are based on height velocity and final height predictions.

Early onset of pubertal adrenal androgen secretion is a common variation of normal pubertal development. Premature adenarche is the result of premature secretion of androgens from the zona reticualris of the adrenal gland.

When evaluating patients for premature adrenarche it is important to assess for clinical signs and symptoms that might indicate another cause of excess androgen production (e.g. adrenal tumour; congenital adrenal hyperplasia). The later are characterized with signs of virilization, rapid growth rate, and significantly advanced bone age.

Premature adrenarche is a benign condition. The timing of onset of true puberty is normal and final adult height is unaffected. Management is conservative with reassurance after exclusion of other causes of adrenal androgen excess. Symptomatic treatment may be required if adrenarche is pronounced, particularly in females who may go on to develop features of ovarian hyperandrogenism and the polycystic ovarian syndrome.

The complex process of sexual determination and differentiation may be interrupted. Numerous disorders that can result in genital ambiguity and uncertainty about an infant’s sex are recognized. Disorders of sexual differentiation may be classified as genetic defects of gonadal determination (Box 13.4) or defects in androgen biosynthesis, metabolism, and action (excess or deficiency).

A detailed history should be obtained and should include:

In preterm girls clitoris and labia minora are relatively prominent. In preterm boys, testes remain undescended until 34wks gestation.

If a male/mosaic karyotype is confirmed, further investigations are directed at establishing whether testicular tissue is capable of producing androgens:

This is professionally challenging and requires a multidisciplinary team including the following:

Most infants presenting with a disorder of sexual differentiation will present with ambiguous genitalia at birth.

This condition is due to defects in the androgen receptor and results in a spectrum of under-virilized phenotypes in the 46XY patient.

Deletions of the gene and certain mutations can result in a completely female phenotype.

In view of the potential risk of malignant transformation if retained, removal of the testis either soon after diagnosis or after the completion of puberty is carried out. After gonadal removal, oestrogen replacement therapy is given.

Certain mutations of the androgen receptor gene result in a partial form of AIS. There is a wide spectrum of phenotypic expression ranging from ambiguous genitalia to a normal male phenotype presenting with fertility difficulties. There is, however, poor genotype–phenotype correlation and patients with the same mutation present with different phenotypes.

Management is much more challenging. Sex assignment depends on the degree of genital ambiguity.

Individuals have both ovarian tissue with follicles and testicular tissue with seminiferous tubules either in the same gonad (ovotestis) or with an ovary on one side and a testis on the other. The aetiology of this condition is unclear. In 70% of cases the underlying karyotype is 46XX; 20% 46XX/46XY; 10% 46XY.

Ovotestes may be present bilaterally and may be located in the inguinal canal. The external genitalia are most often ambiguous, although in 10% phenotype may be female. The degree of feminization and virilization that occurs varies widely. Management is dictated by sex assignment. Dysgenetic testicular tissue should be removed because of the risk of malignant transformation.

Micropenis is often an incidental finding on newborn examination.

An intact hypothalamic–pituitary–gonadal axis is required for the formation of a normal-sized phallus and for descent of the testis. Both GH and the gonadotrophins are required for phallic growth.

The finding of micropenis warrants assessment of hypothalamic–pituitary function and exclusion of both GH deficiency and HH. Micropenis may also be part of a syndrome causing ambiguous genitalia.

Optic nerve hypoplasia/septo-optic dysplasia.

Referral to a paediatric urologist is often required. If severe micropenis is present a decision regarding sex assignment will be needed.

Treatment with a short course of IM testosterone or topical application of dihydrotestosterone cream may stimulate penile growth and improve appearances.

This is a condition affecting boys in which there is hyperplasia of the glandular tissue of the breast resulting in enlargement of one or both breasts. It is a common condition with 3 well-defined time periods of occurrence:

It is due to either an imbalance in the normal systemic or local oestrogen/androgen ratio. An absolute or relative increase in oestrogen levels, local breast tissue hypersentivity to oestrogens, or a decrease in the production, or action of free androgen levels may induce gynaecomastia.

A number of diverse causes are recognized (Box 13.6). Gynaecomastia must be differentiated from pseudogynaecomastia, which is breast enlargement due to fat accumulation.

This is most common cause of gynaecomastia in children and adolescents. The exact cause remains unclear. Proposed mechanisms include alterations in the rate of change in oestrogen and androgen production during puberty and/or hypersensitivity of breast tissue to oestrogen.

May affect 40–50% of children to some degree. It also depends on ethnicity and nutritional status. Usual age of onset of development is just before puberty (ages 10–12yrs), peaking during puberty (age 13–14yrs). In the majority of children the gynaecomastia usually involutes after 1–2yrs and is generally resolved by end of puberty (age 16–17yrs).

The diagnosis is established by excluding other possible causes of gynaecomastia by taking a detailed clinical and family history, and examination.

Investigations should include:

Where testicular/adrenal/hepatic tumour is suspected the following investigations should be considered:

Reassurance and explanation are usually sufficient for pubertal gynaecomastia. In severe cases where pubertal gynaecomastia is causing significant pyschological distress or where gynaecomastia persists beyond puberty, surgical resection of excess glandular breast tissue is warranted. The role of medical therapy with aromatase inhibitors or with selective oestrogen receptor blocking agents (e.g. tamoxifen) is currently unclear.