Growth and puberty

Embryology of the pituitary

The anterior pituitary is derived from the ectoderm, specifically Rathke's pouch, originally part of palatal development, whereas the posterior pituitary derives from the neuroectoderm. The anterior wall of Rathke's pouch develops to fill the pouch and form the pars distalis, which forms the bulk of the anterior pituitary, where most hormone production occurs, and the pars tuberalis, which forms a sheath which extends up to the pituitary stalk. The clinical importance of Rathke's pouch is that it is from this embryonic tissue that a craniopharyngioma is formed. The posterior wall of the pars distalis forms the poorly-defined pars intermedia, which separates the anterior from the posterior pituitary.

Mutations of at least eight genes encoding transcription factors involved in pituitary development have been associated with multiple pituitary hormone deficiency. Identification of an underlying genetic defect allows the clinician to anticipate likely pituitary hormone deficiencies that will arise and which will need monitoring. Some of these mutations are listed in Box 12.1 .

Endocrine regulation of growth

Growth hormone (GH) exerts the major influence on postnatal growth. It is an amino-acid polypeptide, which circulates bound to a GH-binding protein, which is derived from the extracellular component of the GH receptor. GH is secreted from somatotroph cells under the dual regulation of hypothalamically-derived GH-releasing hormone and somatostatin, the combination of which is necessary to produce the episodic pulses, seen mostly overnight and which are essential for normal growth. These hypothalamically-derived regulators of GH secretion are themselves regulated by central neurotransmitters, which integrate input from a variety of stimuli including nutrition, sleep, exercise and stress ( Fig. 12.1 ).

GH stimulates the synthesis from the liver and a number of other organs of insulin-like growth factors (IGF-1 and IGF-2), which share a degree of structural homology with proinsulin and may exert weak insulin-like effects. IGF-1 is thought to be a major regulator of GH action. It circulates bound to IGF binding protein-3 (IGFBP-3), whose concentrations are also regulated by GH. This complex associates with another GH-dependent glycoprotein known as acid-labile subunit, the combination forming a ternary complex. Most IGF-1 circulates in bound or inactive forms and the IGF-binding proteins (IGFBPs) prolong the half-life of IGFs, allowing them to be transported to target cells such as in the growth plate, where they interact with IGF receptors to produce their biological effects. We will return to the issue of how IGF-1 can be useful in determining GH abnormalities later in this chapter.

Physiology

The pattern of normal growth can be subdivided into three phases, which correspond to the three main influences on growth. The infancy component, which is largely driven by nutritional factors, depends on normal placental function and nutritional intake in early life. It can be considered to start from conception and it persists through fetal life, ending during the first two years of postnatal life. The childhood phase, which is GH, IGF-1 and thyroxine dependent, starts postnatally and persists until the end of puberty. The final phase is the pubertal component, which is driven by increasing gonadal production of sex steroids, which stimulate GH secretion. These three phases, when superimposed, produce the normal growth pattern ( Fig. 12.2 ) seen through childhood in which height velocity falls rapidly during the first two years of life from approximately 25 cm/year to a fairly steady state of 5–7cm/year through mid-childhood before the onset of the pubertal growth spurt. In girls, the pubertal growth spurt starts at the onset of breast development, peaking a year later at an average age of 12 years, whereas in boys the growth spurt is typically two years later, peak height velocity coincident with testicular volumes of 15 mL. The average difference of 12.5–14 cm in the adult height of men and women is caused by the longer prepubertal contribution to growth and greater peak height velocity seen in boys.

History

Growth failure can arise from genetic abnormalities, nutritional and endocrine problems and defects in almost any organ system. Therefore, when assessing a child referred with a possible growth disorder, a detailed and wide-ranging history is required. Details should be sought of:

• Family history, including parental heights and their timing of puberty, given the important influence of genetics on such factors

• Pregnancy, mode of delivery and birth weight, which may impact on the infant phase of growth

• Feeding history

• Development of signs of puberty

• Headache, visual disturbance or symptoms to suggest pituitary dysfunction or intracranial disease

• Details of systemic symptoms that might suggest any coexistent medical disorder

• Social history, including details of how the short stature is affecting the child.

In a child with unusually tall stature, in addition to the family history, specific enquiry should be made for:

• Symptoms suggestive of precocious puberty

• Symptoms of thyrotoxicosis, Marfan's syndrome or other overgrowth syndromes.

Examination

A fundamental requirement when examining children with growth disorders is an accurate measurement of their growth. Because of the effect of time of day (human height shortens as the day progresses) and inter-observer variation on measurement, serial growth measurements should be undertaken at approximately the same time of day and preferably by the same measurer. Over the age of two years, a stadiometer (preferably wall-mounted) should be used and the child measured without shoes or socks, with heels, buttocks and shoulders against the backplate and the head in the Frankfurt plane (an imaginary line connecting the lower border of the eye socket with the external auditory meatus). There is no evidence that undertaking stretched measurements with upward pressure on the mastoid processes achieves greater consistency, but the same technique should be used when comparing sequential measures.

Under the age of two years, supine table measurements or a neonatometer and two observers are required to assess length, ensuring that the Frankfurt plane is vertical and that the child's head is in firm contact with the headboard and the foot dorsiflexed against the movable baseplate.

As skeletal dysplasias may impair growth of different parts of the skeleton differentially, the sitting height, which is a proxy for vertebral body growth, should be measured using a table-mounted stadio­meter. Subtracting sitting height from standing height produces the sub-ischial leg length, which is a measure of long bone growth in the leg. Head circumference should be measured in children under the age of two years.

Height measurements should be compared with weight (assessed in a child wearing minimal clothing) by plotting measurements on a growth chart. In the UK, the UK-WHO growth charts are used. These are a composite of the UK90 charts derived from cross-sectional growth data and the WHO growth standards, which describe the growth of healthy breastfed children from six countries. Because of the association of weight with height (taller children tend to be heavier), interpretation of weight data requires adjustment for height. This should be done by calculating the body mass index (weight in kilograms / (height in metres) ² ) and plotting this on a centile chart. To help interpret the growth pattern, height measurements should be compared with other measurements taken in the past by plotting all available measurements on a growth chart to evaluate whether crossing of centiles has occurred, which implies an abnormal height velocity. The appropriateness of the child's height for their genetic background is assessed by calculating the target height range (requires parental height measurements), which is the mid-parental centile (the mid-point between the parents' centiles) +/− 8.5 cm.

Additional features that should be assessed on thorough physical examination of a child with abnormal growth include:

• General appearance and nutritional state

• Dysmorphic features, particularly of the craniofacial skeleton or suggestive of skeletal disproportion or an underlying syndrome

• Pubertal staging, which is important in evaluating the chronology of physical development which has major influences on growth (see section on puberty)

• A detailed systems review including blood pressure, visual fields and fundoscopy, as disease of almost any system may present with growth abnormalities.

Investigations

Before considering any investigations, the findings from the history and examination should be integrated into a differential diagnosis. The following investigations should be considered:

• If features suggestive of a defect in a clinical system have been identified, then appropriate further tests of the relevant system to confirm the diagnosis should be organized

• In a short or slowly-growing child with no obvious pathology, an X-ray of the left wrist to calculate a bone age should be performed to assess the degree of delay in physical development, along with a blood sample for:

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    Full blood count, blood film and ESR or C-reactive protein

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    Urea, electrolytes and creatinine

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    Calcium and phosphate

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    Thyroid function tests

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    IgA and anti-tTG (anti-tissue transglutaminase) antibodies or other screening test for coeliac disease

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    Karyotype in girls to exclude Turner's syndrome

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    IGF-1, though this is of limited sensitivity for screening for GH deficiency and may also be affected by nutritional state

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    Formal stimulation tests of GH secretion – only indicated once the above tests have been performed and (with the exception of IGF-1) found to be normal.

In a tall or rapidly-growing child, the following investigations may be necessary:

• Bone age, which is useful to assess physical maturation

• Karyotype in boys to exclude Klinefelter's syndrome

• Thyroid function tests for hyperthyroidism

• IGF-1 to exclude GH oversecretion

• Cardiac ultrasound if Marfan's syndrome is suspected

• FMR1 gene analysis to exclude Fragile X syndrome in a boy with learning difficulties

• DNA for specific genetic syndromes (e.g. Marfan's, Beckwith–Wiedemann, Sotos syndromes).

Familial short stature and constitutionally delayed growth and puberty

Familial short stature is the most common cause of short stature referred to clinical services. Calculating the target height range is required to demonstrate familial short stature, though if one parent is particularly short, one needs to consider whether they too may have a potentially inheritable underlying growth disorder. Children with familial short stature will have a height centile consistent with their short target height range and will demonstrate growth parallel to the centiles and consistent with a normal height velocity. Extensive investigations are not indicated but a careful explanation and reassurance for the child and parents is required to alleviate anxiety.

Short stature due to constitutionally delayed puberty is discussed in the section on puberty.

Small for gestational age

Short stature due to being small for gestational age is suggested when the birth weight is below the 10th centile. Symmetrical growth failure implies adverse influences on fetal growth that have operated throughout much of development, whereas asymmetric growth failure in which head circumference is preserved implies growth failure restricted to the last part of pregnancy, often due to placental failure. There are many other underlying causes including:

• Major fetal defects (such as chromosomal and genetic defects, major structural malformations and intrauterine infection)

• Maternal influences, including ill-health and excess cigarette and alcohol consumption.

Most (80–85%) small-for-gestational-age infants will show catch-up growth postnatally but those with symmetrical growth failure are least likely to do so.

Infants who are small for gestational age are at increased risk of hypoglycaemia in the first two days of life. In the much longer term, they have been shown to be at increased risk of a range of adult diseases, such as hypertension, cardiovascular disease, type 2 dia­betes and obesity. A fetal programming hypothesis (the Barker hypothesis) has been proposed, which suggests that there are critical periods in fetal development when permanent adaptive changes occur in body structure and function to cope with nutritional insufficiency in utero and likely nutritional challenges postnatally. However, these adaptations place the individual at a disadvantage postnatally should calorie supplies become potentially unlimited.

Treatment of affected individuals involves ensuring an adequate supply of nutrition postnatally to facilitate catch-up growth. In those individuals who remain short, GH therapy at larger doses than those required to treat GH deficiency has been shown to increase final height, though whether this impacts on other risk factors for disease in later life is unknown.

Syndromic short stature

The more common syndromic causes of short stature which may present with growth concerns include Russell–Silver syndrome, fetal alcohol spectrum dis­order, Turner's syndrome and Noonan's syndrome.

Chronic disease

Chronic disease of many systems may lead to impaired growth. Mechanisms involved include a negative energy balance due to:

• Inadequate calorie intake (feeding problems)

• Malabsorption (coeliac disease or cystic fibrosis)

• Excess calorie requirement (cystic fibrosis or congenital heart disease)

• Hypoxia (congenital heart disease)

• Electrolyte abnormalities (renal disease or mineralocorticoid deficiency or resistance)

• Inflammatory cytokines (inflammatory bowel disease or juvenile idiopathic arthritis)

• Steroid treatment (asthma, chronic inflammatory disease)

• Acquired partial resistance to GH (renal failure or Crohn's disease delaying the onset of puberty).

Treatment to improve growth in these circumstances will require attention to the underlying mechanism, such as improving nutrition, reduction in steroid dosages, etc., before considering other options such as GH therapy).

Psychosocial deprivation

Adverse psychosocial factors may lead to poor growth through well-recognized mechanisms that impair fetal growth, such as maternal smoking or alcohol consumption, or through an inadequate diet or increased illnesses linked to parental smoking. Emotional deprivation or abuse may also cause growth failure through these influences producing hypothalamically-mediated suppression of pituitary GH secretion. Appropriate treatment of the growth failure requires interventions to prevent further abuse and to ensure the child is raised in a loving and supportive environment.

Endocrine disorders