Intracranial tumors represent the second most common group of malignant neoplasms in childhood, with an incidence of 3/100,000 children. They are most commonly situated in the posterior fossa in 70% of cases, and in the supratentorial region in 30%, and can occur at any age although the most frequent age is between two and five years. Many sellar and suprasellar tumours in childhood, such as craniopharyngioma and Rathke’s cysts do not originate from the central nervous system and are not “brain tumous”. This is why we have used the more comprehensive description of intracranial tumors.

The relationship between tumor location and tumor type is close. The protypical hypothalamic lesions are usually hypothalamic hamartoma, low grade astrocytoma, Langerhans cell histiocytosis (LCH), dermoid and epidermoid tumors. Tumors such as craniopharyngioma and germinoma tend to affect the hypothalamus indirectly, originating in the peripituitary or pituitary region, and extending upwards. The pituitary stalk is typically affected from lesions such as germinomas and craniopharyngioma. The anterior pituitary is frequently affected from benign pituitary adenomas, whereas the posterior pituitary is the common location of pilocytic astrocytoma and LCH. In this article, we have focused on those midline tumours involving the pituitary gland, pituitary stalk and hypothalamus, which may be related to endocrine dysfunction with various symptoms and signs, and often present in an insidious onset.

Headaches, vomiting and papilloedema, due to raised intracranial pressure, may occur as the initial and most common symptom. Focal neurological signs, cranial nerve palsies, effect on vision and hypothalamopituitary dysfunction may also occur, representing approximately one-third of cases as the initial presentation. Pituitary and pituitary hypothalamic tumor syndromes are characterized by a collection of associated clinical features, depending on age, tumor type and tumor site. Pituitary syndromes are often present with symptoms of hypo, although occasionally hyper, secretion of pituitary hormones, which are usually easy to recognize, whereas hypothalamo-pituitary syndromes are characterized by an association of variable endocrine disturbances, occurring in association with hypothalamic dysfunction. The hypothalamus is important for the control of many basic cerebral functions, such as appetite, emotion and temperature homoeostasis, and tumors in this area are often difficult to detect. For this reason, they often present late and are difficult to diagnose and treat. In addition, there is the difficulty of surgical approach to the tumor. Usually, until the age of approximately eight years, the sphenoid sinus is not adequately aerated and the nasal cavity is too narrow to allow a trans-sphenoidal approach, so craniotomy will be necessary with the associated increased morbidity and mortality.

Raised Intracranial Pressure

Raised intracranial pressure results from expansion of tumor size and obstruction of the cerebro-spinal fluid pathways. This may produce symptoms such as headache, often occurring in the early morning and associated with nausea and vomiting, visual disturbance, change in personality and regression of motor skills. Obstruction of the cerebro-spinal fluid pathways may occur even from a small-sized tumor and produces the clinical features of hydrocephalus; head enlargement, alteration of consciousness, visual disturbance, morning headache and vomiting. The acute onset of hydrocephalus is a medical emergency.

Visual dysfunction

Craniopharyngioma and peripituitary lesions with suprasellar extension may cause visual difficulties due to the compression of the optic nerves and/or chiasm. Visual field defects and, in the worst cases, complete loss of vision may occur. Diplopia may be noted, because of paralysis of the lateral rectus muscles due to a sixth nerve palsy. Children are often not able to describe diplopia, but they usually blink and rub their eyes and show intermittent strabismus as the initial sign. Often visual defects in children are not appreciated until too late; with children being progressively moved towards the front of the class every few months. Sadly, one-third of children with craniopharyngioma have severe visual impairment at presentation (1).

Sequence of endocrinopathy

A tumor involving the hypothalamo-pituitary area often produces a loss of endocrine function during a characteristic sequence in time; an evolving endocrinopathy. As a generalization, GH secretion is initially lost, followed by gonadotrophins, ACTH and TSH. In children, in contrast to adults, the loss of GH secretion is usually more obvious with growth failure and possibly hypoglycemia. In adults, GH deficiency is more difficult to detect clinically and, usually, symptoms from hypogonadism are the more obvious initial endocrine presentation from a tumor. In normal children, gonadotrophin secretion is suppressed from six months of age until late pre-puberty – and hence, gonadotrophin (GnRH) deficiency is usually not appreciated until the peripubertal age range. Isolated ACTH insufficiency, such as may occur in lymphocytic hypophysitis (although this condition is not a malignant tumor but presents as the differential diagnosis of a pituitary mass) is very unusual in children.

Although in adults, the onset of diabetes insipidus usually points to the presence of a tumor, this may not be so in a child. However, the onset of diabetes insipidus, followed by an evolving anterior pituitary endocrinopathy, is very suggestive of a space-occupying lesion. Children with congenital midline intracranial defects, especially septo-optic dysplasia, may develop diabetes insipidus, but often not as the initial endocrine deficiency This is usually an anterior pituitary endocrinopathy which occurs either before or contemporaneously with diabetes insipidus (2). Of course, the presence of diabetes insipidus may be masked by cortisol insufficiency and not revealed until glucocorticoids have been administered as replacement or therapeutically (3). This may mask the natural history of the sequence of the endocrinopathy. Hereditary diabetes insipidus, due to a mutation in the neurophysin gene (not the vasopressin gene), does not present congenitally and so may confuse the differential diagnosis of diabetes insipidus, especially the distinction between occult intracranial tumours and congenital midline defects.

Septo-optic dysplasia

This is a congenital abnormality and not a tumor, but often provides confusion in the differential diagnosis of the endocrinopathy which results, as well as hypothalamic symptoms. Septo-optic dysplasia is a congenital intracranial midline defect and is part of the spectrum of midline defects from a single incisor, uni or bilateral optic nerve hypoplasia, midline cleft lip, clefts of the hard palate, absence of the corpus callosum, encephaloceles and holoprosencephaly (2). The commonest abnormality of this group of midline conditions is septo-optic dysplasia, which is also known as De Morsier’s syndrome, and has the highest incidence of endocrinopathy – indeed, the presence of hypothalamic pituitary endocrine abnormalities is part of the definition of this condition. Two out of three components are necessary for the diagnosis; optic nerve hypoplasia, absence of the septum pellucidum and a hypothalamic pituitary endocrinopathy (4). Although a congenital defect and not a tumor, its discussion is included here because it must feature in the differential diagnosis with consideration of the possibility of a a hypothalamopituitary tumour, especially the presence of diabetes insipidus. The septum pellucidum may be normal on neuro-imaging (this is why the term De Morsier’s syndrome is often preferred). The endocrinopathy may commonly evolve throughout childhood and into adult life; diabetes insipidus is not usually the initial endocrine deficiency. Interestingly, it has a unique feature of panhypopituitarism (including diabetes insipidus) and the preservation of gonadotrophin secretion; indeed, gonadotrophin dependant precocious puberty may occur (5).

Seizures

Epilepsy may be the initial presenting feature of an intracranial tumor. This may be due to the structural abnormality caused by the space-occupying lesion, but may be secondary to the associated endocrinopathies of hypoglycemia (GH and/or cortisol insufficiency), hypernatremia from diabetes insipidus, especially if associated with abnormalities of thirst or hyponatremia (from the syndrome of inappropriate ADH secretion). Hypoglycemia is especially common in young children with hypopituitarism, especially in association with intercurrent viral infections. It is important not to assume that fits are due to the presence of a tumor. It may be that fits are related to both the tumor mass and endocrine disturbance. For example, in children with septo-optic dysplasia, associated with structural central nervous system defects, 50% of fits, especially in young children, are due to metabolic disturbance, most commonly hypoglycemia (6).

There are specific types of epilepsy which may occur in hypothalamic disease, especially when a hamartoma is present. These are gelastic seizures (laughing fits) and may be difficult to diagnose. If fits are very frequent, then it is possible to surgically resect a hypothalamic hamartoma to reduce the frequency of convulsions. However, there is usually residual hypothalamic damage. Although hypothalamic tumors may result in gelastic seizures and central precocious puberty, it is unusual to have a child with both conditions contemporaneously.

There is often sleep-wake cycle disturbance associated with hypothalamic tumors, particularly with children who are post-operative craniophayngioma and have a suprasellar tumor that has expanded both superiorly and posteriorly. The increased sleepiness during the daytime may well interfere with school performance, and the lack of sleep at night is often associated with the development of mood and personality disorders. Although melatonin can be used to modify sleep-wake cycle disturbance, it has little, or no effect on the frequently associated hyperphagia and rapid weight gain. Modafinil is a drug licensed for use in narcolepsy and can induce daytime wakefulness, and allow the child to have improved sleep at night. One of its adverse effects is anorexia, which may well be beneficial in this group of patients. Although it is difficult to diagnose in childhood, it is important to exclude narcolepsy, which is a hypothalamic sleep disorder..

CENTRAL PRECOCIOUS PUBERTY

This is defined as signs of puberty (breast development in girls, and increase in testicular volume in boys) under the age of eight years in a girl and 8 ½ years in a boy. Gonadotrophin dependant (or central) precocious puberty may be the only manifestation of an occult intracranial tumor in both girls, as well as boys (7). Of course, we have realised that boys with central precocious puberty commonly have a hypothalamic tumor (8). Even up to the middle of the last decade, many authors did not consider that neuro-imaging procedures in girls were necessary. However, Cacciari et al demonstrated the common presence of a hamartoma of the hypothalamus on high resolution CT scanning in the early 1980’s (9). However, large multi-centre studies in France (10) and Italy (11) have shown the incidence of tumors in six to eight year old girls with precocious puberty to be between 5 and 8%. Although girls less than four years of age, with high LH concentrations (not related to menstruation) and high oestrogen concentrations, are more likely to have an occult intracranial tumor, there is no way of excluding this possibility without neuro-imaging. Indeed, it is the ages of five to eight years that occult intracranial tumors presenting with central precocious puberty may be due to an astrocytoma – and early diagnosis is associated with potential cure.

Intracranial tumors causing central precocious puberty in girls are histologically specific, despite being in the same anatomical site – involving the hypothalamus between the mamillary bodies and the median eminence (7). Hamartoma, optic nerve glioma, ependymomas and astrocytoma are commonly associated with gonadotrophin releasing hormone (GnRH) stimulation, whereas craniopharyngioma, LCH and germinoma are only rarely associated with central precocious puberty. No explanation for this phenomenon is available, but it may well be due to the secretion of specific local growth factors. If surgery is undertaken for a hypothalamic hamartoma in an attempt to arrest pubertal development, it is very unlikely to be successful, despite a good outcome on suppression of the frequency of epileptic convulsions. Cranial irradiation, given as treatment for a tumor, may result in central precocious puberty, especially in girls (12). This can be due to either low-dose cranial irradiation given as prophylaxis in the treatment of acute lymphoblastic leukemia, or high-dose irradiation for tumors distant from the hypothalamic pituitary axis.

DELAYED PUBERTY

Hypothalamopituitary tumors in the peripubertal age range may present as failure to enter puberty or arrested pubertal development. They represent a spectrum of GnRH insufficiency, rather than gonadotrophin deficiency. Tumors, such as craniopharyngioma, commonly present with failure to enter puberty or arrested puberty, with an abnormal growth spurt; they usually demonstrate an absence of the normal consonance (harmony) of puberty (13). In such clinical circumstances, this points to the necessity of endocrine evaluation and neuro-imaging.

It is important to consider the time of onset of GnRH insufficiency. If this is congenital, with micropenis and bilateral small undescended testes, then neuro-imaging of the pituitary gland will be normal (14) and if neuro-imaging is required, it would be more appropriate to image the olefactory bulbs/grooves to seek evidence of Kallmann’s syndrome. Secondary GnRH insufficiency is suspicious of an intracranial tumor. Sometimes it can be difficult to distinguish constitutional delayed puberty and GnRH insufficiency, and a definitive endocrine diagnosis may have to wait until the end of puberty. However, if there is reasonable suspicion of secondary GnRH insufficiency, then neuro-imaging should be undertaken.

PROLACTINOMAS

An elevated serum prolactin concentration requires the distinction between stalk compression with moderate rise in prolactin (the ``pseudoprolactinoma` syndrome) from the very high prolactin concentrations associated with a prolactin-secreting tumor (15). Macroprolactinomas usually have a very high prolactin secretion and there is little ambiguity about the diagnosis. These are rare tumors in childhood. In adults, the common type of tumor is a microadenoma, predominantly occurring in females of reproductive age (16). In children and adolescents, they are usually macroprolactinomas and occur in both sexes (17). The commonest presentation is delayed/absent puberty due to prolactin suppression of gonadotrophin pulsatility, combined with gynaecomastia in boys, and galactorrhea in girls. The presentation may be part of Multiple Endocrine Neoplasia Type I (MEN I). Macroprolactinomas usually extend upwards and encroach on the visual pathway and often are accompanied by visual field defects. It is important to measure serum prolactin in every child with a pituitary enlargement, as the primary treatment of a macroprolactinoma is medical and does not usually require surgery.

CUSHING'S DISEASE

The term Cushing’s disease describes the symptoms and signs of hypercortisolism, due to a pituitary over-production of ACTH, and has to be distinguished from Cushing’s syndrome, which results from any aetiology causing glucocorticoid excess. Symptoms and signs of Cushing’s disease are similar to those of adults and often these have been present for many years prior to diagnosis: obesity, hirsuitism, acne, moon facies, buffalo hump on the back of the neck, muscular weakness, psychiatric disturbance, depression, hypertension and osteoporosis. However, the initial and most characteristic symptom/sign in childhood is growth arrest and this, combined with rapid weight gain, should point to the diagnosis. In young children, Cushing’s syndrome usually has an adrenal etiology, including McCune-Albright syndrome. However, in older children and adolescents, it is more likely to be Cushing’s disease with excessive ACTH production from a tumour of the anterior pituitary. It is usual that MRI imaging does not reveal a distinct tumor, but the pituitary gland is usually enlarged with a convex superior border and there may be unilateral enlargement. Lateralisation, using petrosal sinus sampling, as well as trans-sphenoidal surgical approach (18), is difficult in young children. However, the ACTH-secreting adenoma is usually more obvious at inspection from a trans-sphenoidal approach than it is from MRI imaging, even though the histology at surgery is not usually helpful. Plasma cortisol measurements the day after surgery will confirm surgical cure. Ectopic ACTH production is extremely rare in childhood and, when it does occur, is usually from a carcinoid tumour of the lung.

PITUITARY GIGANTISM

Pituitary gigantism is a rare disorder due to growth hormone hypersecretion, usually secondary to an adenoma of the anterior pituitary. Over-production of GH secretion is responsible for gigantism in a patient with open epiphyses, and of acromegaly in a patient with closed epiphyses. The physical signs of GH excess are common to both disorders, but the signs in pituitary gigantism are usually less obvious because of the shorter duration of the endocrinopathy. From what data is available, such children appear to continue to grow for many years, even after epiphyseal closure. GH-secreting tumors may occur in Multiple Endocrine Neoplasia Type I and McCune-Albright syndrome. Pituitary gigantism is a rare component of McCune-Albright syndrome (19), whereas the more usual manifestations are characteristic cutaneous pigmentation, polyostotic fibrous dysplasia, precocious puberty, as well as Cushing’s syndrome, thyrotoxicosis and hyperparathyroidism.

TSH-SECRETING TUMORS

It is important to distinguish TSH-secreting adenomas (20), which are extremely rare, from the pituitary hyperplasia associated with longstanding primary hypothyroidism. After prolonged and severe primary hypothyroidism, with increased TSH secretion, there is usually an increased size of the pituitary gland, which may attain a suprasellar extension and compression of the optic chiasm/nerves. Thyroid function tests (as well as serum prolactin concentration) are always required prior to surgery of a suspected pituitary tumour. With thyroxine therapy, serum TSH concentration decreases and the size of the pituitary gland shrinks into the pituitary fossa within three months (21).

Primary hypothyroidism, with very high TSH secretion, may be accompanied by a gonadal form of premature sexual maturation which is not true puberty (21). It is associated with increased FSH secretion, and not LH, which causes isolated breast development in girls, (with no other signs of puberty and no growth acceleration) and large testicular volumes in males with minimal virilisation. These signs of premature maturation decrease or resolve following the decrease in TSH secretion within six months of commencing appropriate thyroxine replacement.

GROWTH FAILURE

The commonest endocrinopathy associated with hypothalamic pituitary tumors is growth hormone deficiency and this usually results in growth failure. In the rare syndrome of “growth without growth hormone” normal, or accelerated growth continues despite the patient having growth hormone deficiency and this occurs at the expense of hyperphagia and rapid weight gain. It is considered that the etiology of this condition is related to insulin and insulin-like peptides which allow growth without growth hormone secretion. This usually occurs post-craniopharyngioma surgery. Despite growth hormone deficiency being present in one third of patients at presentation with a craniopharyngioma, the usual symptoms at presentation are those related to raised intracranial pressure, or visual disturbance (1).

Patients who have an intracranial tumor that has resulted in growth failure, either from the orginal tumor or the associated treatment, will usually grow in response to growth hormone therapy ( link to Savage chapter).A recurrence of the intracranial tumor may well induce growth failure as the initial sign, despite continuing growth hormone therapy.

HYPOTHALAMIC DISORDER

Hypothalamic tumors may present with symptoms that are not related to an endocrinopathy. These commonly involve appetite disorders, hyperphagia and obesity or anorexia, thirst abnormalities, tiredness, temperature intolerance, sleep disorders and behavioral difficulties. Any of these features in association with a hypothalamic pituitary endocrinopathy should raise the suspicion of a presence of a hypothalamic tumor. Treatment of the underlying endocrinopathy is relatively simple, compared to the treatment of the hypothalamic disorder.

One of the most difficult hypothalamic diseases to treat during childhood is hypo or adipsia, combined with diabetes insipidus (3). This usually results in difficult management of diabetes insipidus and repeated episodes of hyper or hyponatremia associated with an intercurrent infection, especially with gastroenteritis. The condition is usually managed by training the child to take a fixed intake by mouth every hour, and then titrate the dose of vasopressin that is required. Although relatively easy to achieve homoeostasis when the child is well, the predominant problems revolve around intercurrent illnesses, especially if the child has concurrent anterior pituitary failure and has seizures treated with carbamazepine and/or lamotrigine (3). It is unusual for children with adipsia and diabetes insipidus to survive childhood.

DIABETES INSIPIDUS

Approximately 90% of vasopressin secretion needs to be interrupted before there is clinical diabetes insipidus. The commonest tumors causing diabetes insipidus in childhood are craniopharyngioma and germinoma. The latter are often occult for many years and patients require serial neuro-imaging before the diagnosis may be revealed. It may be as long as 21 years from the onset of diabetes insipidus to imaging the tumor (22). In a child who has diabetes insipidus, it is important to monitor carefully growth and screen for an evolving anterior pituitary endocrinopathy.

Lesions in the pituitary stalk associated with the presence of diabetes insipidus, are usually situated in the middle of the stalk and related to a dural inflammatory process, such as sarcoidosis or Langerhans cell histiocytosis (LCH) (23). Langerhans cell histiocytosis is not a cancer, but has similar characteristics and is a clonal proliferation of abnormal histiocytes, the Langerhans cells (24). A common presentation of LCH in the middle childhood years, which used to be described as Hand-Schüller-Christian disease, are small punched-out skull lesions associated with pituitary stalk thickening and diabetes insipidus. Anterior pituitary deficiency is relatively rare and, although hypothalamic involvement with LCH is common (25), precocious puberty is extremely rare. As a generalization, children with LCH do not have anterior pituitary failure unless they have diabetes insipidus (25).

DIENCEPHALIC SYNDROME

Diencephalic syndrome was first described in 1951 and is a complex of signs and symptoms related to hypothalamic dysfunction and usually commences in the first three years of life, although 80% of patients present with symptoms within the first year. It is usually a dramatic clinical presentation. It is not caused by the endocrinopathy but can be considered as a “failure to thrive” syndrome, despite normal or excessive energy intake in a young child. It has been almost exclusively described in association with space-occupying lesions of the hypothalamic optic chiasm region, and that the tumors are usually astrocytoma and hypothalamic glioma (26). Astrocytomas associated with diencephalic syndrome are usually aggressive (27).

The main features of the diencephalic syndrome are failure to thrive, despite a normal or excessive calorie intake. Other features may be nystagmus, visual field defects, optic disc pallor, vomiting and headache. Emaciation, despite an increased appetite associated with alertness, hyperactivity and a euphoric personality may also occur. Usually, because of the difficulties of biopsy in a young child in this anatomical area, diagnosis relies on neuro-imaging. Although previous regimens relied on radiotherapy, more modern treatment approaches offer chemotherapy. Diencephalic syndrome may have very non-specific features of failure to thrive in its early stages and, where the possibility of this condition is suspected, then early recourse to neuro-imaging should be made.

EATING DISORDERS

Anorexia is a symptom/sign and needs to be distinguished from anorexia nervosa, which is a psychiatric disorder characterized by anorexia and an alteration of body image. Anorexia nervosa is more common in girls and is only rarely associated with an intracranial tumor. However, boys with anorexia, or anorexia nervosa, all require neuro-imaging as hypothalamic intracranial tumors are common (28). Children with anorexia, rather than anorexia nervosa, may have many different reasons to account for their symptoms, which most commonly are gastro-intestinal, including gastro-oesophageal reflux, as well as brainstem tumors involving the lower cranial nerve nuclei and preventing mastication.

If anorexia is present as part of a hypothalamic syndrome due to a hypothalamic tumor, then this is a relatively poor prognostic sign and indicates a large tumor. Post-operatively, such children are more likely to have extreme hyperphagia and rapid weight gain (29). Anorexia may be the only symptom/sign of a hypothalamic tumor (30).

OVERVIEW

The etiology of most children with hypothalamo-pituitary dysfunction is idiopathic. Despite this, all children with pituitary endocrinopathies should have neuro-imaging in order to aid the diagnosis, to predict the evolving nature of the endocrinopathy and to detect occult tumors. The latter are more likely in hypersecretion states of gonadotrophin dependant precocious puberty and hyperprolactinemia. However, when there are symptoms/signs of hypothalamic dysfunction, particularly abnormal thirst, anorexia, sleep/wake cycle disturbance and diabetes insipidus, they are much more likely to have a hypothalamic tumor. Some young children with a hypothalamic tumor may present with only “failure to thrive”. Patients may require serial neuro-imaging in time, in order to reveal an occult intracranial tumor. Although pituitary hormone deficiencies can be effectively treated, this is not usually the case for hypothalamic dysfunction.