Measurement

Growth must be measured accurately, with attention to correct technique and accurate plotting of the data:

• Weight – readily and accurately determined with electronic scales but must be performed on a naked infant or a child dressed only in underclothing as an entire month’s or year’s weight gain can be represented by a wet nappy or heavy jeans, respectively.

• Height – the equipment must be regularly calibrated and maintained. In children over 2 years of age, the standing height is measured as illustrated in Figure 11.2. In children under 2 years, length is measured lying horizontally (Fig. 11.3), using the mother to assist. Accurate length measurement in infants can be difficult to obtain, as the legs need to be held straight and infants often dislike being held still. For this reason, routine measurement of length in infancy is often omitted from child surveillance, but it should always be performed whenever there is doubt about an infant’s growth.

• Head circumference – the occipitofrontal circumference is a measure of head and hence brain growth. The maximum of three measurements is used. It is of particular importance in developmental delay or suspected hydrocephalus

These measurements should be plotted as a simple dot on an appropriate growth centile chart. Standards for a population should be constructed and updated every generation to allow for the trend towards earlier puberty and taller adult stature from improved childhood nutrition. In 2009, the UK adopted the World Health Organization (WHO) new global Child Growth Standards for infants and children 0–4 years old (See Appendix Fig. A1). The new charts are based on the optimal growth of healthy children totally breast-fed up to the age of 6 months. These charts allow for the lower weight of totally breast-fed infants and are therefore less likely to identify some breast-fed babies as underweight and may also allow early identification of bottle-fed babies gaining weight too rapidly.

Height in a population is normally distributed and the deviation from the mean can be measured as a centile or standard deviation (Fig. 11.4). The bands on the growth reference charts have been chosen to be two-thirds of a standard deviation apart and correspond approximately to the 25th, 9th, 2nd and 0.4th centiles below the mean, and the 75th, 91st, 98th and 99.6th centiles above the mean. The further these centiles lie from the mean, the more likely it is that a child has a pathological cause for his short or tall stature. For instance, values below the 0.4th or above the 99.6th centile will occur by chance in only 4 per 1000 children and can be used as a criterion for referral from primary to specialist care. A single growth parameter should not be assessed in isolation from the other growth parameters: e.g. a child’s low weight may be in proportion to the height if short, but abnormal if tall. Serial measurements are used to show the pattern and determine the rate of growth. This is helpful in diagnosing or monitoring many paediatric conditions. The WHO charts include an adult height predictor and a BMI centile ready-reckoner.

Puberty

Puberty follows a well-defined sequence of changes that may be assigned stages, as shown in Figures 11.5 and 11.6. Over the last 20 years, the mean age at which puberty starts in girls has lowered. However, the age at which menarche occurs has remained stable. Therefore, females now remain in puberty for longer.

In females the features of puberty are:

In males:

• Testicular enlargement to >4 ml volume measured using an orchidometer (Fig. 11.7) – the first sign of puberty

• Pubic hair growth – follows testicular enlargement, usually between 10 and 14 years of age

• Height spurt – when the testicular volume is 12–15 ml, after a delay of around 18 months.

The height spurt in males occurs later and is of greater magnitude than in females, accounting for the greater final average height of males than females.

In both sexes, there will be development of acne, axillary hair, body odour and mood changes.

If puberty is abnormally early or late, it can be further assessed:

• Bone age measurement from a hand and wrist X-ray to determine skeletal maturation (Fig. 11.8)

• In females, pelvic ultrasound can be used to assess uterine size and endometrial thickness.

Menstruation has a wide range of normal variation. The normal cycle length varies between 21 and 45 days. The length of blood loss varies between 3 and 7 days and the average blood loss per cycle is <80 ml – passage of blood clots or the use of more than six pads per day implies heavy bleeding, which needs evaluation. Rarely, it can indicate clotting disorders such as von Willebrand disease.

Short stature

Short stature is usually defined as a height below the second centile (i.e. two standard deviations (SD) below the mean) or 0.4th centile (−2.6 SD). Only 1 in 50 children will be shorter than the 2nd centile and 1 in 250 (4 in 1000) shorter than the 0.4th centile. Most of these children will be normal, though short, with short parents, but the further the child is below these centiles, the more likely it is that there will be a pathological cause. However, the rate of growth (measured as height velocity; Fig. 11.1) may be abnormal long before a child’s height falls below these values. This growth failure can be identified from the child’s height falling across centile lines plotted on a height velocity chart (Fig. 11.1). This allows growth failure to be identified earlier, even though the child’s height is still above the 2nd centile.

Measuring height velocity is a sensitive indicator of growth failure. Two accurate measurements at least 6 months but preferably a year apart allow calculation of height velocity in cm/year (Fig. 11.1). This is plotted at the midpoint in time on a height/velocity chart. A height velocity persistently below the 25th centile is abnormal and that child will eventually become short. A disadvantage of using height velocity calculations is that they are highly dependent on the accuracy of the height measurements and so tend not to be used outside specialist growth units.

The height centile of a child must be compared with the weight centile and an estimate of their genetic target centile and range calculated from the height of their parents. This is calculated as the mean of the father’s and mother’s height with 7 cm added for the mid-parental target height of a boy, and 7 cm subtracted for a girl. The 9th–91st centile range of this estimate is given by ±10 cm in a boy and ±8.5 cm in a girl (see examples in Fig. 11.9).

Most short children are psychologically well adjusted to their size. However, there may be problems from being teased or bullied at school, poor self-esteem and they are at a considerable disadvantage in most competitive sport. They are also assumed by adults to be younger than their true age and may be treated inappropriately.

Examination and investigation

Plotting present and previous heights and weights on appropriate growth charts, together with the clinical features, usually allows the cause to be identified without any investigations (Fig. 11.9a-i). Previous height and weight measurements should be available from the parent-held personal child health record. The bone age may be helpful, as it is markedly delayed in some endocrine disorders, e.g. hypothyroidism and growth hormone deficiency, and is used to estimate adult height potential. Investigations that may be indicated are shown in Table 11.1.

Table 11.1

Investigations considered for short stature

Investigation	Significance
X-ray of wrist and hand for bone age	Some delay in constitutional delay of growth and puberty
	Marked delay for hypothyroidism or growth hormone deficiency or other endocrine causes
Full blood count	Anaemia in coeliac or Crohn disease
Creatinine and electrolytes	Creatinine raised in chronic renal failure
Calcium, phosphate, alkaline phosphatise	Renal and bone disorders
Thyroid-stimulating hormone (TSH)	Raised in primary hypothyroidism
Karyotype	Turner syndrome shows 45XO, other chromosomal disorders
Endomysial and anti-tissue transglutaminase IgA antibodies	Usually present in coeliac disease
CRP (acute-phase reactant) and erythrocyte sedimentation rate (ESR)	Raised in Crohn disease
Growth hormone provocation tests (using insulin, glucagon, clonidine or arginine in specialist centres)	Growth hormone deficiency
IGF-1	Disorders of the growth hormone axis, including IGF-1 deficiency
0900 cortisol and dexamethasone suppression test	Cushing syndrome
MRI scan if neurological symptoms/signs	Craniopharyngioma or intracranial tumour
Limited skeletal survey	Skeletal dysplasia, scoliosis

Summary

Tall stature

This is a less common presenting complaint than short stature, as many parents are proud that their child is tall. However, some adolescents (mainly females) become concerned about excessive height during their pubertal growth spurt. The causes are shown in Table 11.2. Most tall stature is inherited from tall parents. Obesity in childhood ‘fuels’ early growth and may result in tall stature; however, because puberty is often somewhat earlier than average, it does not increase final height.

Secondary endocrine causes are rare. Both congenital adrenal hyperplasia and precocious puberty lead to early epiphyseal fusion so that eventual height is reduced after an early excessive growth rate.

Marfan (a disorder of loose connective tissue) and Klinefelter (XXY – an excess of SHOX dose) syndromes both cause long-legged tall stature, and in XXY there is also infertility and learning difficulties.

Tall children may be disadvantaged by being treated as older than their chronological age. Excessive height in prepubertal or early pubertal adolescent females and males can be treated with oestrogen therapy and testosterone therapy, respectively, to induce premature fusion of the epiphyses, but as it produces variable results and has potentially serious side-effects, it is seldom undertaken. Surgical destruction of the epiphyses in the legs may also be considered in extreme cases.

Abnormal head growth

Most head growth occurs in the first 2 years of life and 80% of adult head size is achieved before the age of 5 years. This largely reflects brain growth, but small or large heads may be familial and the mid-parental head percentile may need to be calculated. At birth, the sutures and fontanelle are open. During the first few months of life, the head circumference may increase across centiles, especially if small for gestational age. The posterior fontanelle has closed by 8 weeks, and the anterior fontanelle by 12–18 months. If there is a rapid increase in head circumference, raised intracranial pressure should be excluded.

Asymmetric heads

Skull asymmetry may result from an imbalance of the growth rate at the coronal, sagittal or lambdoid sutures, although the head circumference increases normally. Occipital plagiocephaly, a parallelogram-shaped head with flattening of the back of the skull, is seen with increased frequency since the advice to parents that babies should sleep lying on their back to reduce the risk of sudden infant death syndrome. It improves with time as the infant becomes more mobile. Plagiocephaly is also seen in infants with hypotonia. Preterm infants may develop long, flat heads from lying on their sides for long periods on the hard surface of incubators unless provided with a soft surface to lie on and their head position is changed frequently (see Fig. 11.11). Under these circumstances, it is not associated with abnormal development.

Case History

11.1 Microcephaly

Figure 11.10 shows the head circumference chart of Tim, who was healthy and was developing normally. At 9 months of age, he was rushed to hospital as he was unrousable from profound hypoglycaemia secondary to the deliberate administration of insulin by his mother, who had diabetes. Although Tim was taken into care and had no further hypoglycaemic episodes, his head circumference shows cessation of growth. He has developed moderate learning difficulties and mild cerebral palsy.

Craniosynostosis

The sutures of the skull bones start to fuse during infancy but do not finally fuse until late childhood. Premature fusion of one or more sutures (craniosynostosis) may lead to distortion of the head shape. Craniosynostosis is usually localised (Box 11.2). It most often affects the sagittal suture, when it results in a long narrow skull (Fig. 11.12). Rarely it affects the lambdoid suture to result in skull asymmetry, which needs to be differentiated from plagiocephaly, where there is asymmetric flattening of one side of the skull from positional moulding.

Abnormal head shape

Box 11.2   Forms of craniosynostosis

Localised

• Sagittal suture – long narrow skull

• Coronal suture – asymmetrical skull

• Lambdoid suture – flattening of skull

Generalised

• Multiple sutures resulting in microcephaly and developmental delay

• Genetic syndromes, e.g. with syndactyly in Apert syndrome, with exophthalmos in Crouzon syndrome.

Craniosynostosis may be generalised (Box 11.2), when it may be a feature of a syndrome (Fig. 11.13). The fused suture may be felt or seen as a palpable ridge and confirmed on skull X-ray or cranial CT scan. If necessary, the condition can be treated surgically because of raised intracranial pressure or for cosmetic reasons. Such operations are performed in specialist centres for craniofacial reconstructive surgery.

Premature sexual development

The development of secondary sexual characteristics before 8 years old in females and 9 years old in males is defined as outside the normal range in the UK. It may be due to:

Precocious puberty

Precocious puberty (PP) may be categorised according to the levels of the pituitary-derived gonadotropins, follicle-stimulating hormone (FSH) and luteinising hormone (LH), (Fig. 11.14) as:

• Gonadotropin-dependent (central, ‘true’ PP) from premature activation of the hypothalamic–pituitary–gonadal axis

• Gonadotropin-independent (pseudo, ‘false’ PP) from excess sex steroids.

Females

This is usually idiopathic or familial and follows the normal sequence of puberty. Organic causes are rare and are associated with:

• dissonance, when the sequence of pubertal changes is abnormal, e.g. isolated pubic hair with virilisation of the genitalia, suggesting excess androgens from either congenital adrenal hyperplasia or an androgen-secreting tumour

• rapid onset

• neurological symptoms and signs, e.g. neurofibromatosis.

Ultrasound examination of the ovaries and uterus is helpful in establishing the cause of precocious puberty. In the premature onset of normal puberty, multicystic ovaries and an enlarging uterus will be identified.

 Precocious puberty in females is commonly due to the premature onset of normal puberty.

Males (see Case History 11.2)

This is uncommon and usually has an organic cause, particularly intracranial tumours. Examination of the testes may be helpful:

• Bilateral enlargement suggests gonadotropin release, usually from an intracranial lesion

• Small testes suggest an adrenal cause (e.g. a tumour or adrenal hyperplasia)

• A unilateral enlarged testis suggests a gonadal tumour.

Tumours in the hypothalamic region are best investigated by cranial MRI scan.

 Central precocious puberty in males more often has an organic cause.

Management

The management of precocious puberty is directed towards:

• detection and treatment of any underlying pathology, e.g. intracranial tumour in males, and reducing the rate of skeletal maturation if necessary. Skeletal maturation is assessed by bone age. An early growth spurt may result in early cessation of growth and a reduction in adult height.

• addressing psychological/behavioural difficulties associated with early progression through puberty.

Case History

11.2 Precocious puberty in a boy

This 6-year-old boy presented with precocious puberty (Fig. 11.15a,b). He was noted to have multiple café-au-lait spots consistent with a diagnosis of neurofibromatosis type 1. An MRI scan showed a mass in the hypothalamus which proved to be an optic glioma. He was treated with radiotherapy, although full remission was not possible to achieve. The site of injection of gonadotropin super-agonist treatment to suppress his sexual development is covered by the plaster.

Deciding whether to treat a girl who is simply going through puberty early needs further consideration. If treatment is required for gonadotropin-dependent disease, gonadotropin-releasing hormone (GnRH) analogues are the treatment of choice. In gonadotropin-independent cases, the source of excess sex steroids needs to be identified. Inhibitors of androgen or oestrogen production or action (e.g. medroxyprogesterone acetate, cyproterone acetate, testolactone, ketoconazole) may be used.

Delayed puberty

Delayed puberty is often defined as the absence of pubertal development by 14 years of age in females and 15 years in males. The causes of delayed puberty are listed in Box 11.3.

In contrast to precocious puberty, the problem is more common in males, in whom it is mostly due to constitutional delay in growth and puberty (CDGP). This is often familial, usually having occurred in the parent of the same sex. It may also be induced by dieting or excessive physical training. Children affected with constitutional delay in growth and puberty are short during childhood, with a delay in sexual maturation and have delayed skeletal maturity on bone age. The legs will be long in comparison to the back (eunuchoid body habitus). Eventually the target height will be reached as growth in affected children will continue for longer than in their peers. The condition may cause considerable psychological upset from teasing, poor self-esteem and disadvantage in competitive sport.

In boys, assessment includes:

In girls, karyotype should be performed to identify Turner syndrome, and thyroid and sex steroid hormones should be measured. The aims of management are to:

Following reassurance that puberty will occur, treatment is usually not required. Should treatment be wanted, oral oxandrolone can be used in young males. This weakly androgenic anabolic steroid will induce some catch-up growth but not secondary sexual characteristics. In older boys, low-dose intramuscular testosterone will accelerate growth as well as inducing secondary sexual characteristics. Females may be treated with oestradiol.

Case History

11.3 Premature thelarche

This 18-month-old female developed enlargement of both breasts (Fig. 11.16). There was no pubic hair growth, sweatiness or body odour and her height was in the mid-parental range. Her bone age was only mildly advanced (21 months) and a pelvic ultrasound showed a prepubertal uterus, small volume ovaries with two cysts in the left ovary. Her subsequent growth rate was normal. A diagnosis of premature thelarche was made.

Disorders of sexual differentiation (DSD)

The fetal gonad is initially bipotential (Fig. 11.17). In the male, a testis-determining gene on the Y chromosome (SRY) is responsible for the differentiation of the gonad into a testis. The production of testosterone and its metabolite, dihydrotestosterone, results in the development of male genitalia. In the absence of SRY, the gonads become ovaries and the genitalia female.

Rarely, newborn infants may be born with a disorder of sexual differentiation and there may be uncertainty about the infant’s sex. A disorder of sexual differentiation may be secondary to:

All parents and their relatives are desperate to know the sex of their newborn baby. However, if the genitalia are abnormal, the infant’s sex must not be assigned until detailed assessment by medical, surgical and psychological specialists has been performed followed by full discussion with the parents. Birth registration must be delayed until this has been completed.

Sexuality is complex and depends on more than the phenotype, chromosomes and hormone levels. Before the most appropriate sex of rearing is decided upon, the karyotype needs to be determined, adrenal and sex hormone levels measured, and ultrasound of the internal structures and gonads performed. Sometimes laparoscopic imaging and biopsy of internal structures are necessary. In many disorders of sexual differentiation, it has been usual to raise the child as a female, as it is easier to fashion female external genitalia, whereas it is not possible surgically to create an adequately functioning penis. However, it may be impossible to predict the sexual identity of the child in eventual adult life and further support or gender reassignment may be required. For this reason, there is a move toward delaying definitive surgery to allow the affected individual to give informed consent to any reconstructive procedures. This is a controversial area and is best managed by experienced multidisciplinary teams.

Congenital adrenal hyperplasia (CAH)

A number of autosomal recessive disorders of adrenal steroid biosynthesis result in congenital adrenal hyperplasia. Its incidence is about 1 in 5000 births, and it is commoner in the offspring of consanguineous marriages. Over 90% have a deficiency of the enzyme 21-hydroxylase, which is needed for cortisol biosynthesis. About 80% are also unable to produce aldosterone, leading to salt loss (low sodium and high potassium) (Fig. 11.18). In the fetus, the resulting cortisol deficiency stimulates the pituitary to produce adrenocorticotrophic hormone (ACTH), which drives overproduction of adrenal androgens.

Presentation:

• Virilisation of the external genitalia in female infants, with clitoral hypertrophy and variable fusion of the labia (see Case History 11.4)

• In the infant male, the penis may be enlarged and the scrotum pigmented, but these changes are seldom identified

• A salt-losing adrenal crisis in the 80% of males who are salt losers; this occurs at 1–3 weeks of age, presenting with vomiting and weight loss, floppiness and circulatory collapse

• Tall stature in the 20% of male non-salt losers; both male and female non-salt losers also develop a muscular build, adult body odour, pubic hair and acne from excess androgen production, leading to precocious pubarche.

There may be a family history of neonatal death if a salt-losing crisis had not been recognised and treated.

Diagnosis

This is made by finding markedly raised levels of the metabolic precursor 17α-hydroxyprogesterone in the blood. In salt losers, the biochemical abnormalities are:

• Low plasma sodium

• High plasma potassium

• Metabolic acidosis

• Hypoglycaemia.

Management

Affected females will sometimes require corrective surgery to their external genitalia within the first year but as they have a uterus and ovaries they should usually be reared as girls and are able to have children. Definitive surgical reconstruction is usually delayed until late puberty. Males in a salt-losing crisis require saline, dextrose and hydrocortisone intravenously.

The long-term management of both sexes is with:

• Lifelong glucocorticoids to suppress ACTH levels (and hence testosterone) to allow normal growth and maturation

• Mineralocorticoids (fludrocortisone) if there is salt loss; before weaning, infants may need added sodium chloride

• Monitoring of growth, skeletal maturity and plasma androgens and 17α-hydroxyprogesterone – insufficient hormone replacement results in increased ACTH secretion and androgen excess, which will cause rapid initial growth and skeletal maturation at the expense of final height; excessive hormonal replacement will result in skeletal delay and slow growth

• Additional hormone replacement to cover illness or surgery, as they are unable to mount a cortisol response.

Case History

11.4 Abnormal genitalia at birth

The appearance of this newborn infant’s genitalia is shown in Figure 11.19.

Investigation revealed:

• A normal female karyotype, 46XX

• The presence of a uterus on ultrasound examination

• A markedly raised plasma 17α-hydroxy-progesterone concentration, confirming congenital adrenal hyperplasia.

• A low sodium and a high potassium level

• A low bicarbonate (metabolic acidosis) and high urea (dehydration).

Plasma electrolytes identified a low sodium and a high potassium, indicating that the baby had the salt-losing form of CAH. After detailed explanation with her parents, she was started on oral hydrocortisone and fludrocortisone replacement therapy and oral salt replacement (NaCl). Surgery was performed at 9 months of age to reduce clitoral size and separate the labia. Her growth, biochemistry and bone age were monitored frequently at follow-up and she attained normal adult height. Psychological counselling and support were offered around puberty and further genital surgery was needed before she became sexually active.

Severe hypospadias and bilateral undescended testes – a male or virilised female? The karyotype and a pelvic ultrasound are required.

Death can occur from adrenal crisis at the time of illness or injury. Females require surgery to reduce clitoromegaly and a vaginoplasty before sexual intercourse is attempted. Females often experience psychosexual problems, which may relate to the high androgen levels experienced in utero prior to diagnosis.

Prenatal diagnosis and treatment are possible when a couple have had a previously affected child. Dexamethasone may be given to the mother around the time of conception, and continued if the fetus is found to be female, in order to reduce fetal ACTH drive and hence the virilisation.

Summary

Congenital adrenal hyperplasia

• Autosomal recessive disorder of adrenal steroid biosynthesis

• Females present with virilisation of the external genitalia

• Males present with salt loss (80%) or tall stature and precocious puberty (20%)

• Long-term medical management with lifelong glucocorticoids, mineralocorticoids/sodium chloride if salt loss

• Additional corticosteroids to cover illness or surgery

• Salt-losing adrenal crisis needs urgent treatment with hydrocortisone, saline and glucose given intravenously

• Monitor growth, skeletal maturity, plasma androgens and 17α-hydroxyprogesterone

• Surgery for females.