After reading this chapter you should:
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know the causes and management of pituitary and hypothalamic disorders
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be able to assess, diagnose and manage disorders of the adrenal glands
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be able to assess, diagnose and manage disorders of thyroid and parathyroid glands
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be able to identify endocrine complications of other diseases and refer appropriately
Many complex interactions of normal cellular function are controlled by hormones released by the organs and glands of the endocrine system. Control of electrolytes, both within the cells and circulating in the extracellular spaces, are finely controlled by feedback mechanisms involving hormones. Growth, development and pubertal changes are all under the orchestration of interdependent hormone release which bring about changes evident in everyday paediatric practice. The consequences of untreated endocrine pathology are significant and will have a major impact on the child or young person.
Pituitary and hypothalamic disorders
Anterior pituitary hormone deficiency
Damage to the hypothalamus, pituitary stalk or pituitary gland—congenital or acquired—can cause pituitary hormone deficiencies that can present at any age. The hormones produced ( Figure 25.1 ) by the anterior pituitary are:
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growth hormone
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thyroid stimulating hormone
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luteinising hormone
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follicular stimulating hormone
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adrenocorticotrophic hormone
With expanding knowledge of the genes that direct pituitary development and hormone production, an increasing proportion of pituitary disorders in children can be attributed to specific genetic abnormalities, especially where there is consanguinity or a relevant family history.
Congenital causes increase the likelihood of developing multiple pituitary hormone deficiency (MPHD) and are often linked to other abnormalities of brain development. Examples of these conditions include holoprosencephaly and septo-optic dysplasia with incomplete septum pellucidum, optic nerve hypoplasia and midline abnormalities.
Acquired causes include trauma, post-infection, tumours, surgery and cranial irradiation.
Clinical presentation
Neonates
Craniofacial and pituitary gland development are closely related, so any baby born with midline anomalies such a median cleft palate should be recognised and investigated as they may have holoprosencephaly and be at high risk of evolving MPHD. Most affected babies, however, have no outward signs at birth. Hypoglycaemia and prolonged conjugated jaundice are the most common presenting features. Isolated pituitary hormone deficiencies such as growth hormone deficiency rarely present at this age.
Neonates with suspected hypopituitarism may also display:
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dysmorphic features including subtle craniofacial abnormalities
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roving eye movements and nystagmus due to optic nerve hypoplasia
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nystagmus
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micropenis and maldescended testes (boys)—suggesting gonadotrophin deficiency
Older children
Growth hormone deficiency is the most common axis to be affected, so slow growth is almost always the presenting problem in children over the age of 2 years when the predominantly nutrition-driven phase of growth is completing. Other symptoms suggestive of pituitary hormone deficiency include:
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tiredness and malaise
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muscle weakness
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headache
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visual field defects
Investigations
Neonates
Hypoglycaemia is the commonest presenting feature as a result of cortisol and growth hormone deficiencies, and the hypoglycaemia screen taken at the time of hypoglycaemia must include:
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glucose (laboratory)—to confirm a true low glucose
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cortisol—should show appropriate stress response to the hypoglycaemia
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growth hormone—should show appropriate stress response to the hypoglycaemia
Thyroid function tests will show an inappropriately low TSH for the prevailing Free T4. An initial cranial ultrasound may show abnormalities such as an absent septum pellucidum or other midline anomalies, and an MRI scan will provide further details. A prolonged conjugated hyperbilirubinaemia may be the result of MPHD.
Older children
The investigation of children with short stature and growth failure due to growth hormone deficiency are outlined in Chapter 4 Growth and Puberty. Involvement of the thyroid axis can be detected from standard tests of Free T4 and TSH, and pubertal development is best assessed clinically rather than by formal LHRH testing. Any child found to be deficient of any pituitary hormone must have an MRI scan and DNA analysis where appropriate.
Associations
Prader-Willi Syndrome is a rare condition with significant hypothalamo-pituitary involvement. Infants have poor suck and other feeding problems, but from the age of 2 years children manifest uncontrolled appetite with rapid development of obesity unless access to food is strictly controlled. Further details on clinical features and management are presented in Chapter 5 Genetics and Chapter 27 Neurodevelopmental Medicine.
Treatment and management
Hormone deficiencies are almost always lifelong chronic conditions and so management must be holistic. The principles are:
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replacement of hormones in doses that vary with age or size
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verbal and written instructions about the management of intercurrent illness in children with ACTH and cortisol deficiency with annual review of competence of carer and child or young person. They also need open access to an acute unit
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regular monitoring of growth and development by a team with specialist expertise
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regular clinical and biochemical surveillance for the emergence of other deficiencies
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regular surveillance for adherence to, and safety of, replacement treatment
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induction of puberty at an appropriate age
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effective transition to adult endocrine services
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counselling and support for families and affected children and young people
Relevant pharmacological agents used
Replacement hormones are almost always biologically identical to the natural hormone but it is often not possible to deliver them in a dose regime that mimics physiological production. For example, growth hormone is given as a single daily injection in contrast to the 3–4 nocturnal peaks and troughs seen physiologically. Steroid replacement tries to mimic the diurnal rhythm of cortisol production but inevitably fails because the lower dose given at night means that levels the following morning may be unrecordably low, but giving a higher dose can affect sleep patterns and growth. Provided doses are appropriate, side effects are rare and parents can be reassured.
However, there are some side effects that are more common and important:
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growth hormone—headache, idiopathic intracranial hypertension, lipohypertrophy
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hydrocortisone—features of Cushing syndrome if doses are consistently too high
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thyroxine—sleep and behaviour problems, headache, idiopathic intracranial hypertension
Inappropriate or excess anterior pituitary hormone production
Any damage to the brain, not just the hypothalamopituitary axis, can lead to inappropriate gonadotrophin production causing early puberty, particularly in girls. Causes include:
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cerebral palsy and metabolic disorders
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low dose cranial irradiation
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optic nerve or hypothalamic gliomas—seen in children with NF1
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hypothalamic hamartomas
Rarely children will present with symptoms suggestive of pituitary hormone excess due to a hormone secreting tumour. Prolactinomas usually present in older children with:
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galactorrhoea
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headache due to raised intracranial pressure
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visual problems
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pubertal delay
They are usually managed very successfully with dopamine agonists such as cabergoline, but children should be screened for other pituitary problems. Prolactin is a stress hormone and levels should be interpreted with caution before concluding they are pathological.
Cushing disease is very rare and in children is usually caused by an ACTH-secreting pituitary adenoma. Pituitary gigantism due to GH excess is even more rare.
Posterior pituitary hormone deficiency
In children, the most common disturbance of posterior pituitary function is diabetes insipidus (DI) which is described as either:
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cranial DI—insufficient antidiuretic hormone (ADH—also known as arginine vasopressin AVP) release—congenital or acquired
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nephrogenic DI—renal resistance to ADH action
Congenital causes of cranial DI include midline anomalies such as holoprosencephaly or septo-optic dysplasia.
Acquired causes include tumours (germinoma), infiltration (histiocytosis), infection, trauma and post neurosurgery (especially for craniopharyngioma).
Cranial DI is rare but life threatening if not identified. The symptoms are polyuria and polydipsia, but the challenge is to distinguish between children with DI and the vast majority with polyuria and polydipsia who have habitual water drinking. The history and examination, plus some simple blood and urine tests, should help distinguish between the two.
Certain features in the history and examination are suggestive of DI:
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presentation in an older school age child or teenager
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inability to sleep through the night due to thirst and needing a drink
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seeking fluid from other sources (flower vases, toilets) if denied a drink
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features suggestive of anterior pituitary involvement such as slow growth
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symptoms of raised intracranial pressure
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developmental problems including vision
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dysmorphic features
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evidence of midline defects
Investigations
These may not be necessary if it is clear from the history and examination that the cause is habitual water drinking. If there is doubt, a fasting serum sodium, potassium, creatinine and osmolality with a paired, fasting urine sodium and osmolality should be requested, but the child must be allowed open access to sugar-free fluids even if they are not encouraged. A normal fasting response will show a serum osmolality of 275–295 mOsmol/kg and a urine osmolality of greater than 850 mOsmol/kg, although the latter may be lower if the child has been allowed fluids.
Must only be performed in a unit that has experience and expertise in both running the tests and interpreting the results. The test is potentially dangerous.
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The child must be supervised at all times by a senior endocrine doctor or specialist nurse who is immediately available
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allow free fluids until the start of fasting
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weigh and calculate weight with 5% loss—and document both
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fluid balance is monitored throughout
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close supervision to avoid inadvertent access to water
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serum and urine electrolytes and osmolality measured at start and at intervals
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child is weighed at regular intervals through the test
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end test if weight loss exceeds 5% or tests confirm presence or absence of DI
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fast should not exceed 8 hours—but the result is usually clear sooner
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if DI is confirmed, a test dose of desmopressin (DDAVP) is given and fluid balance and investigations monitored over the next few hours
In DI, there is inappropriately dilute urine (<750 mOsm/kg) despite a serum osmolality >295 mOsm/kg. If the results are not conclusive, a water deprivation test must be undertaken at a centre with expertise as it has potentially dangerous consequences.
| Time into fast (mins) | Weight (kg) | Serum osmolality mOsmol/kg (275–295) | Urine osmolality mOsmol/kg (>850 after 12 hour fast) | Serum sodium (mmol/l) (133–146) |
|---|---|---|---|---|
| 0 | 15.4 | 276 | 110 | 131 |
| 30 | 15.4 | 278 | 130 | 133 |
| 60 | 15.1 | 282 | 275 | 137 |
| 90 | 15.0 | 287 | 450 | 138 |
| 120 | 15.0 | 290 | 680 | 138 |
| 180 | 14.9 | 293 | 875 | 141 |
Interpretation of the above test:
The urine at T = 0 is very dilute and the serum sodium slightly low because the child has been allowed free fluids, but as time progresses the urine concentrates normally; the serum osmolality remains within the reference range and the sodium normalises. There is no significant weight loss. These all confirm a diagnosis of habitual water drinking and the parents can be reassured that it is safe to limit fluids if they wish.
If cranial DI is diagnosed the child needs serum tumour markers beta-HCG and AFP plus MRI scanning of the hypothalamo–pituitary axis to exclude infiltrative disorders. They may also need anterior pituitary function testing.
Treatment and management
Cranial DI is treated with desmopressin (DDAVP) usually given orally but it can be administered nasally to babies and small children or parenterally after neurosurgery. It is introduced slowly and the doses gradually increased to avoid dilutional hyponatraemia that can be more dangerous than untreated DI. The reason to treat is to control unpleasant symptoms and patients with intact thirst can still drink to correct any water depletion whilst the doses are optimised.
Posterior pituitary hormone excess
Syndrome of inappropriate antidiuretic hormone (SIADH)
SIADH is characterised by impaired water excretion leading to hyponatraemia with hypervolaemia or euvolaemia as a result of unsuppressed or increased levels of ADH (vasopressin).
Symptoms are unusual where the sodium is 125–135 mmol/l, but levels below this put a child at risk of cerebral oedema and progressive neurological symptoms. In severe acute hyponatraemia (< 120 mmol/l), the child is at risk of:
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headache
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vomiting
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reduced level of consciousness
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seizures and death
Chronic hyponatraemia, developing over 24 hours or more, may have more subtle features such as restlessness, weakness, fatigue or irritability due to brain adaptation.
Associated conditions
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respiratory infections—pneumonia, bronchiolitis and TB
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central nervous system infections, trauma, raised intracranial pressure
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drugs that increase ADH release, e.g. cyclophosphamide, carbamazepine, sodium valproate
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pain
Investigations
In addition to serum sodium, samples for paired urine and serum osmolality and urine sodium should be obtained. Characteristically, these will show an inappropriately high urine osmolality (>100 mOsmol/kg) for the low serum osmolality (<275 mOsmol/kg) plus high urine sodium (>10 mOsmol/kg) due to excess ADH causing water, but not solute, retention.
Management and complications
Awareness of the possibility of SIADH and treatment of any underlying cause are the important steps in management. In at-risk patients, strict fluid balance, regular weights and blood and urine electrolytes should be undertaken along with the use of isotonic fluids which are volume restricted to 50% to 66% of calculated requirements to maintain euvolaemia.
Urgent correction of hyponatraemia is rarely necessary and any rapid rises in sodium can cause irreversible osmotic demyelination syndrome—dysarthria, confusion and coma—that can present days after sodium has normalised. Unless the child is seizing, sodium levels should not increase by more than 8 mmol/l in 24 hours. This is usually achieved by treating the underlying cause, restricting fluids as mentioned above and resisting the suggestion to administer hypertonic saline . If the child is fitting, then the sodium can be increased more rapidly using hypertonic saline, but this must be undertaken with caution as rapid rises are potentially harmful.
Adrenal disorders
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adrenal insufficiency
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Cushing syndrome
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phaeochromocytoma
The adrenal cortex produces glucocorticoids (cortisol), mineralocorticoids (aldosterone) and androgens (dehydroepiandrosterone—DHEA).
Adrenal insufficiency
Increased generalised pigmentation of the skin, especially parts of the body which are not exposed to the sun, suggests primary adrenal insufficiency. Characteristic darkening occurs as a consequence of increased ACTH breakdown leading to increased levels of melanocyte stimulating hormone (MSH) and the subsequent skin pigmentation. Pigmentation does not occur in secondary adrenal insufficiency when the ACTH level is low.
The metabolic derangements in primary adrenal insufficiency, as a consequence of both cortisol and aldosterone deficiency, include:
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hyponatraemia
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hyperkalaemia
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metabolic acidosis
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hypoglycaemia
Adrenal insufficiency in the neonate
The most common cause for primary adrenal insufficiency in infancy is congenital adrenal hyperplasia (CAH) which typically presents in the first 2 to 3 weeks of life with:
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poor weight gain
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vomiting
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increased pigmentation of mucous membranes, scrotum, palmar creases, nipples
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eventual adrenal crisis—with tachycardia and hypotension
The most common enzyme deficiency causing CAH is 21-hydroxylase deficiency, which occurs in 90 percent of all patients. Affected females with CAH are usually identified earlier than males by varying degrees of clitoromegaly and virilisation leading to diagnostic evaluation, even before the onset of an adrenal crisis.
Adrenal insufficiency in the older child and adolescent
Causes include:
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Addison disease (autoimmune adrenalitis) which may be part of the autoimmune polyendocrinopathy syndromes and can present with:
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nonspecific symptoms (vomiting, lethargy, malaise, anorexia)
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significant weight loss
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hyperpigmentation
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hypoglycaemia
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shock
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secondary adrenal insufficiency
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congenital hypopituitarism (septo-optic dysplasia; isolated ACTH deficiency)
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surgery for suprasellar tumours
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cranial irradiation
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pituitary dysfunction from trauma or meningitis
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exogenous use of steroids
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results in iatrogenic Cushing syndrome and can also cause secondary adrenal insufficiency.
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Alternative diagnoses and differing features
Differential diagnoses to consider for primary adrenal insufficiency depend on the presenting feature. Severe hyponatremia can also occur in pseudohypoaldosteronism (PHA), a condition which mimics hypoaldosteronism. However, PHA is due to a failure of response to aldosterone, and the aldosterone levels are significantly elevated. In contrast to primary adrenal insufficiency, patients with PHA do not have hyperpigmentation (as the ACTH level is not elevated) and they do not suffer from hypoglycaemia (as there is no cortisol deficiency).
Investigations and expected results in primary adrenal insufficiency
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electrolytes—hyponatraemia, hyperkalaemia
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glucose—hypoglycaemia
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blood gas—metabolic acidosis
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short synacthen stimulation test suboptimal cortisol levels despite stimulation
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ACTH—elevated in primary adrenal insufficiency
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urinary steroids—elevated serum 17-hydroxyprogesterone and serum testosterone levels in females would indicate the diagnosis of 21-hydroxylase deficiency
Treatment and management
In acute adrenal crisis, the patient is often in shock and needs urgent administration of:
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hydrocortisone—IV or IM
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fluid resuscitation with 0.9% saline
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10% dextrose IV to correct hypoglycaemia
For ongoing maintenance:
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oral hydrocortisone to replace glucocorticoid deficiency
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oral fludrocortisone to replace mineralocorticoid deficiency
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young infants also require oral sodium chloride supplementation
Excessive dosage of hydrocortisone will result in iatrogenic Cushing syndrome whilst inadequate hydrocortisone replacement dose can lead to tiredness, malaise with poor weight gain and increased pigmentation. Girls with salt-wasting CAH who have inadequate glucocorticoid replacement may experience increasing androgenisation with progressive clitoromegaly and acne. In both boys and girls with salt-wasting CAH and inadequate glucocorticoid replacement, the excessive androgen levels can induce a growth spurt and early growth plate fusion, which may limit the final height.
