Topic of the month...Neuro-endocrinal dysfunction in the pediatric age group


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Topic of the month...Neuro-endocrinal dysfunction in the pediatric age group

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Topic of the month...Neuro-endocrinal dysfunction in the pediatric age group

  1. 1. INDEX  INTRODUCTION  NORMAL EMBRYOLOGY AND DEVELOPMENT OF PITUITARY- HYPOTHALAMIC STRUCTURES  NEUROENDOCRINE DISORDERS OF CHILDHOOD  CONGENITAL AND DEVELOPMENTAL ABNORMALITIES OF THE PITUITARY- HYPOTHALAMIC AXIS  ACQUIRED ABNORMALITIES  INFECTIOUS AND INFLAMMATORY DISORDERS IMAGING OF NEUROENDOCRINE DISORDERS OF CHILDHOOD Neuroendocrine disorders of childhood result from a variety of abnormalities of the developing hypothalamic-pituitary axis. These disorders include hypopituitarism, growth failure, diencephalic syndrome, delayed puberty, precocious puberty, diabetes insipidus, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and hyperpituitarism. [14,52] NORMAL EMBRYOLOGY AND DEVELOPMENT OF PITUITARY- HYPOTHALAMIC STRUCTURES The anterior and posterior lobes of the pituitary gland develop separately and from different origins. The anterior pituitary gland (adenohypophysis) develops from Rathke's pouch or cleft, which becomes separated from the oropharynx between 6 and 7 weeks of gestational age. More recent evidence suggests that the pouch originates from the neuroectoderm rather than the buccal cavity. [109] At week 7, the anterior pituitary cells adjacent to the posterior pituitary develop into the pars intermedia. Cells of the anterior pituitary proliferate until the lobe constitutes 90% of the total gland at midgestation and 78% at term. [8] The anterior lobe of the pituitary makes numerous hormones, including prolactin, growth hormone, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone. The posterior lobe of the pituitary (neurohypophysis) develops as a downgrowth of the hypothalamus, and connections are maintained to the hypothalamus via the pituitary stalk and the hypothalamohypophyseal tract. Hormones made in the hypothalamus are stored in the posterior lobe and include antidiuretic hormone (ADH) or vasopressin and oxytocin. The infundibulum can be identified at 6 weeks. The infundibulum is normally not more than 2 mm in diameter. [100] There are numerous nuclei within the hypothalamus, including the supraoptic and paraventricular nuclei, which secrete vasopressin and oxytocin. [72] Groups of hypothalamic cells also produce peptidergic- releasing hormones. Some of these releasing hormones stimulate synthesis and promote release, and others inhibit hormonal release from anterior lobar cells. These include releasing hormones for corticotropin, follicle-stimulating hormone, luteinizing hormone, thyrotropin, and somatotropin and the release-inhibiting
  2. 2. hormones for melanocyte-stimulating hormone, somatostatin, and prolactin. [114] The pituitary gland is primarily supplied by the hypophyseal portal system. The superior hypophyseal artery from the supraclinoid internal carotid artery supplies the hypothalamus, pituitary stalk, and superior surface of the pituitary gland. The inferior hypophyseal artery, from the cavernous internal carotid artery, supplies the posterior lobe of the pituitary and the lateral surfaces of the anterior lobe of the pituitary. Fetal histochemical studies have shown considerable differentiation and activity of the pituitary cells during gestation. On T1- weighted imaging, the pituitary gland at birth has uniformly high signal intensity involving both the anterior and the posterior lobes, as compared with the adjacent brain. [31,116] Possibly the rapid differentiation of the gland in utero with an accompanying increase in protein synthesis accounts for the short T1 values. Beginning at 18 days of life, the high signal intensity of the anterior lobe gradually disappears, but the posterior pituitary remains as a high-intensity structure and is separately identified by the age of 6 weeks. [27,115] The decrease in intensity of the anterior pituitary gland may be the result of a reduction of its high protein synthesis activity to a normal postnatal state. The hyperintensity of the posterior pituitary may be due to its phospholipid content, although another theory attributes the high intensity to vasopressin (ADH) and its neurophysin-carrier protein. [25,60,63] The bright signal of the posterior pituitary gland is seen in 90% to 100% of healthy subjects [42,62] and always in healthy children. [5] The size and shape of the pituitary gland varies with age. [27,36,100,106,107] Below 6 weeks of gestation, the gland is globular in shape and flattens with growth. The pituitary gland is prominent at birth, during puberty (particularly in girls), and during pregnancy. This appearance should not be mistaken for tumor. The pituitary gland changes during puberty [27,36] and reaches a maximal height of 10 mm in adolescent girls with a spherical or upwardly convex margin. In pubertal boys, it may reach 7 mm in height. [6] During pregnancy and the postpartum period, the anterior lobe may appear Tl hyperintense. [74, 82]   Figure 1. Normal appearance of the pituitary gland, notice the upper concave border,the diffuse enhancement of the pituitary gland and the well corticated sellar floor. The pituitary gland lies within the sella turcica of the sphenoid bone. The surrounding structures include the sphenoid sinus anteriorly and inferiorly, the suprasellar cistern superiorly, the basilar artery and brain stem posteriorly, and the cavernous sinuses bilaterally The suprasellar cistern contains the optic chiasm and nerves, hypothalamus, infundibulum, and arterial structures of the circle of Willis. The diaphragms sella covers the sella turcica except for a tiny defect that allows the passage of the infundibulum. NEUROENDOCRINE DISORDERS OF CHILDHOOD  Hypopituitarism The earliest and the most common manifestation of hypopituitarism in childhood is growth failure as a result of growth hormone deficiency and thyroid deficiency Hypopituitarism has numerous causes and may result from congenital abnormalities, such as pituitary aplasia or hypoplasia, or may be associated with anencephaly, holoprosencephaly, septo-optic dysplasia, empty sella, midface anomalies, solitary central maxillary incisor, basal cephalocele, genetic and chromosomal abnormalities, and cleft lip or cleft palate. The acquired causes of hypopituitarism include common neoplasms of childhood, such as craniopharyngioma, pituitary adenoma, and optic and hypothalamic gliomas. In addition, other acquired causes of hypopituitarism include infection such as meningitis, cranial irradiation, surgery, trauma, hemorrhage, hypoxic-ischemic encephalopathy, histiocytosis, lymphocytic hypophysitis, tuberculosis, sarcoidosis, hemochromatosis (idiopathic and after multiple blood transfusions), and cerebral edema. [14,16]  Growth Failure
  3. 3. Growth failure may result from a variety of causes. Pathologic causes of short stature include nutritional and endocrine abnormalities, chromosomal defects, bone development disorders, metabolic causes, chronic illness, chronic drug intake, and numerous others. [70] The endocrine causes of short stature include isolated growth hormone deficiency, hypothyroidism, hypopituitarism, hypercortisolism, and precocious puberty [70] There are numerous syndromes and conditions associated with growth hormone deficiency or insensitivity, which include genetic disorders as well as embryologic defects, some of which are elucidated earlier for hypopituitarism. [80]  Diencephalic Syndrome The diencephalic syndrome is a rare but important cause of failure to thrive in infancy and early childhoods' The syndrome is characterized by profound emaciation with normal caloric intake, an absence of cutaneous adipose tissue, locomotor hyperactivity, euphoria, and alertness. [2,28,30,84,85,91] It commonly occurs in association with chiasmatic and hypothalamic gliomas. [2,28,30,84,85,91] It has also been described in association with other lesions, such as midline cerebellar astrocytoma, suprasellar ependymoma, and suprasellar spongioblastoma.  Delayed Puberty Normal puberty depends on normal hypothalamic and anterior pituitary gonadotropic control of gonadal hormone activity. Disorders of pubertal development include delayed puberty and precocious puberty. Pubertal development is delayed if the initial physical changes of puberty are not seen in girls by 13 years of age or boys by age 14 or if puberty started and then is not progressing normally. Causes of delayed or lack of pubertal development may be secondary to hypergonadotropic states (primary gonadal failure), including chromosomal or genetic disorders (e.g., Turner's syndrome, Klinefelter's syndrome, and Noonan's syndrome) or acquired disorders, such as autoimmune disorders, radiation therapy and chemotherapy, surgery, torsion, trauma, or infection. Hypogonadotropic (hypothalamic-pituitary defect or lag) states may also cause a delay or lack of pubertal development. These states include hypothalamic-pituitary deficiencies, such as gonadotropin deficiency and endocrinopathies. Delayed or deferred function may be constitutional or re-rated to chronic illness, drug abuse, obesity, endocrinopathies, or malnutrition. [68]  Precocious Puberty Precocious puberty is defined as pubertal development occurring before the age of 8 years in girls and before 9.5 years in boys. [67[ Central precocious puberty is more common in girls than in boys and is more often idiopathic. If present in boys, there may be underlying pathology, such as a central lesion. Central nervous system causes of precocious puberty include congenital anomalies, such as arachnoid cyst, hydrocephalus, hypothalamic hamartoma, and septo-optic dysplasia. Acquired abnormalities include abscess; chemotherapy; cranial surgery; radiation therapy; trauma; and tumors such as hypothalamic astrocytoma, craniopharyngioma, ependymoma, and rarely pituitary adenoma. Precocious puberty may also be associated with syndromes, such as the McCune-Albright syndrome and neurofibromatosis 1 (NF-1) (especially in the setting of optic or hypothalamic glioma). Other causes of precocious puberty include non-central nervous system tumors, such as adrenal adenoma or carcinoma, gonadotropin producing choriocarcinoma, teratoma, hepatoblastoma, and ovarian and testicular tumors. Precocious puberty may also be associated with hypothyroidism, exogenous steroids or gonadotropins, ovarian cysts, and congenital virilizing adrenal hyperplasia. [68]  Diabetes Insipidus Diabetes insipidus (DI) may result from vasopressin (ADH) deficiency or resistance (central DI), primary renal disease (nephrogenic DI), or rarely primary polydipsia. Central DI may result from traumatic or surgical injury of the pituitary stalk; tumors such as germinoma, glioma, or rarely craniopharyngioma; and infiltrative diseases, such as Langerhans' cell histiocytosis, sarcoidosis, tuberculosis, and Wegener's granulomatosis. Other causes include congenital malformations, infections, autoimmune hypophysitis, and hereditary conditions. Central DI may be idiopathic, but in approximately 20% of cases, it precedes the signs and symptoms of hypothalamic tumor by months or years. [5,17]  Syndrome of Inappropriate Antidiuretic Hormone Secretion SIADH is characterized by the central nervous system sequelae of fluid and electrolyte imbalance. These patients may have symptoms as severe as encephalopathy, seizures, and brain swelling. SIADH in children most commonly results from intracranial or pulmonary disease. [17] Central nervous system causes include hydrocephalus, meningitis or encephalitis, abscess, tumor, demyelinating disease, and psychosis. Non-central nervous system causes include pneumonia, intrathoracic neoplasm, drugs such as tricycle antidepressants, chemotherapeutic agents such as vincristine, and neoplasms elsewhere in the body.
  4. 4.  Hyperpituitarism Hyperpituitarism may be primary or secondary. Primary hyperpituitarism is related to hypersecretion by tumor. Secondary hyperpituitarism is related to target organ failure. Hypersecretory pituitary adenomas that occur in childhood include prolactin-secreting adenomas, which may present as microadenomas or macroadenomas. Endocrine disorders such as growth hormone excess cause tall stature (pituitary gigantism). Nonendocrine disorders that are associated with tall stature include cerebral gigantism (Soto's syndrome), Kline- felter's syndrome, other chromosomal abnormalities such as the XXY male, Marfan syndrome, homocystinuria, and constitutional tall stature. [41] Excessive growth hormone secretion is associated with pituitary adenomas. Cushing's disease (hypercortisolism resulting from an ACTH-producing pituitary adenoma) is extremely rare in childhood.  Imaging Evaluation Neuroimaging evaluation of the child with a neuroendocrine disorder is best done with high-resolution magnetic resonance (MR) imaging using thin section coronal and sagittal T1-weighted images through the pituitary-hypothalamic axis before and after the intravenous administration of gadolinium. Fluid attenuating inversion recovery (FLAIR) and T2-weighted fast spin- echo (FSE) or conventional spin-echo (CSE) images are also important. MR imaging provides multiplanar imaging with high resolution and fine anatomic detail of the hypothalamic-pituitary region, including adjacent structures such as the optic chiasm, the cavernous sinuses, and the circle of Willis. CT may be needed to confirm calcification or hemorrhage. CONGENITAL AND DEVELOPMENTAL ABNORMALITIES OF THE PITUITARY- HYPOTHALAMIC AXIS  Hypoplasia or Absence of the Pituitary Gland Hypoplasia or absence of the pituitary gland is extremely rare. It may include absence or hypoplasia of the gland or the stalk. [10] There may be associated midline anomalies of the cranial and facial structures, the optic nerves, and the septum pellucidum as well as hypoplasia of the adrenal glands, ovaries, and testes. [63] Clinically the patient presents with pituitary- hypothalamic dysfunction and associated growth failure. On MR imaging, the pituitary gland and sella turcica are absent or small in size.  Ectopic Posterior Pituitary Ectopic posterior pituitary is associated with pituitary dwarfism and has been noted in 40% of patients with idiopathic growth hormone deficiency [1, 56] Other additional hormone deficiencies may occur. On MR imaging, there is a small sella and pituitary gland, absence or hypoplasia of the pituitary stalk, and an ectopic posterior pituitary bright spot. [65] If necessary, an ectopic posterior pituitary may be differentiated from a hypothalamic lipoma by the lack of fat suppression). The initial theories for the ectopic posterior pituitary and pituitary dwarfism have included birth trauma [43] in particular breech delivery, leading to damage of the infundibulum and its blood supply. These patients may have associated midline defects, therefore invoking the theory that it is related to abnormal development of the hypothalamus and pituitary. [110] In addition, there have been numerous hereditary syndromes of growth hormone deficiency or insensitivity described. [110] One of the growth hormone deficiency syndromes is related to an abnormality of the Pit-I gene. The Pit-1 gene of chromosome 3 is responsible for a pituitary-specific transcription factor, which binds to and transactivates promoters of growth hormone and prolactin genes. [81] Mutations in this gene may lead to a combined pituitary hormone deficiency, including growth hormone failure, and may explain some cases of pituitary dwarfism. In one report of three siblings with combined pituitary hormone deficiency, an unusual and unexplained pattern of enhancement was observed consisting of rim enhancement of a normal or minimally enlarged pituitary. [37]  Septo-optic Dysplasia Some of the syndromes that may be associated with pituitary-hypothalamic dysfunction include septo-optic dysplasia, Kallmann's syndrome, and empty sella syndrome. In addition, other developmental anomalies may be associated with pituitary-hypothalamic defects, including agenesis of the corpus callosum, holoprosencephaly, and basal cephaloceles. Septo-optic dysplasia, a disorder of ventral induction, is considered a mild form of holoprosencephaly. It is a disorder of abnormal induction of the midline mesoderm occurring at the same time as the development of the optic vesicles. Failure of differentiation of the mesoderm into the optic stalk results in aplasia of the stalk. [47] Septo-optic dysplasia is characterized by absence or hypoplasia of the septum pellucidum associated with hypoplasia of the optic nerves as first described by DeMorsier. [29] Associated hypothalamic-pituitary dysfunction occurs in two thirds of patients. [76,102,103] Patients may have hypopituitarism that ranges from panhypopituitarism to growth hormone deficiency, thyroid-stimulating hormone deficiency,
  5. 5. elevated prolactin, or ACTH or ADH deficiency. [51] Visual symptoms include nystagmus, amblyopia, or hemianopsia. This syndrome may result from in utero injury or genetic abnormalities. [10] Environmental factors implicated are maternal diabetes, quinidine ingestion, anticonvulsants, alcohol or drug abuse, and cytomegalovirus. [76] There may be associated anomalies of neuronal migration, such as schizencephaly and gray matter heterotopias. Figure 2. Septo-optic dysplasia associated with schizencephaly. Arrows in A,B point to absent septum pellucidum, arrow in C, and black arrowhead in D point to open lip schizencephaly, white arrow head point to polymicrogyria in D On imaging, there is absence or hypoplasia of the septum pellucidum resulting in a box- like appearance of the frontal horns. [9,38,39] Hypoplasia of the optic disks is often diagnosed by an ophthalmologist; however, optic nerve, optic tract, or optic chiasm hypoplasia may be seen in 50% of patients on imaging. [9] Other associated abnormalities include absence of the fornix and callosal dysgenesis. [19] On MR imaging, two patterns of involvement have been described in septo-optic dysplasia. [9,19] One group has neuronal migration anomalies such as schizencephaly and gray matter heterotopias, hypothalamic-pituitary dysfunction, and partial absence of the septum pellucidum. The other group has complete absence of the septum pellucidum with cerebral white matter hypoplasia. This group may be associated with hypoplasia of the genu of the corpus callosum or hypoplasia of the anterior falx cerebri. Another group of these patients with ectopia of the posterior pituitary has also been described. [19] Other anomalies that may be associated with complete or partial absence of the septum pellucidum include holoprosencephaly, hydranencephaly, basilar cephaloceles, dysgenesis of the corpus callosum, chronic hydrocephalus, Chiari II malformation, and schizencephaly. [3,11,48]  Kallmann's Syndrome Kallmann's syndrome consists of agenesis of the olfactory lobes and bulbs associated with hypogonadotropic hypogonadism. [54] The inheritance is autosomal dominant, recessive, or X-linked. It is the most common form of isolated gonadotropin deficiency. [18] There is failure of normal neuronal migration of the olfactory cells and the cells that produce luteinizing hormone-releasing hormone from the olfactory placed into the forebrain. The migration of these cells depends on neural cell adhesion molecules (NCAMs), which are absent because the gene responsible for NCAM expression is missing. [40,96] The clinical presentation includes anosmia or hyposmia, hypogonadism, and delayed puberty. [52] MR imaging may help to make the diagnosis because the olfactory sulcus and olfactory apparatus are absent or hypoplastic on thin-section coronal Tl or T2 images. [111,119, 120]
  6. 6. Figure 3. Kallmann's syndrome in a child with hypogonadotropic hypogonadism. Normal olfactory sulcus and olfactory apparatus (A). Coronal T2-weighted MR image demonstrates absence of the olfactory sulci bilaterally and hypoplasia of the olfactory apparatus (B).  Empty Sella Syndrome The empty sella syndrome results from a deficiency of the diaphragms sella, which allows the suprasellar cistern to herniate into the sella. This herniation produces sellar expansion and flattening of the pituitary gland. This syndrome occurs more commonly in adults but may occur in children. [26,77] It may be associated with hypothalamic-pituitary dysfunction in children as well as visual symptoms and cerebrospinal fluid rhinorrhea. [52, 98] There is often an association with pituitary hypotension, particularly multiple hormone deficiencies, although pituitary hyperfunction may occur. [21] On MR imaging, the pituitary gland is flattened, the stalk is midline, and the sella is enlarged and filled with cerebrospinal fluid. ACQUIRED ABNORMALITIES  Chiasmatic or Hypothalamic Gliomas The most common neuroendocrine disorders associated with chiasmatic or hypothalamic gliomas are precocious puberty, diencephalic syndrome, and hypopituitarism. These tumors constitute 10% to 15% of supratentorial tumors of childhood. [10] These optic or hypothalamic tumors are often low-grade astrocytomas and pilocytic. They are rarely anaplastic. Often, it is difficult to distinguish whether the tumor originates from the chiasm or the hypothalamus. Between 20% and 50% of patients with chiasmatic or hypothalamic tumors have NF-1. Optic gliomas are the most common tumor of the central nervous system seen in NF-I. [4] These gliomas may involve any portion of the optic pathway, including one or both optic nerves, the chiasm, tracts, the lateral geniculate bodies, or the optic radiations. Other intracranial lesions that may be seen in NF-1 include NF-1 spots, plexiform neurofibromas, and other astrocytomas. The clinical presentation most often includes decreased visual acuity, although visual field defects, optic atrophy, hydrocephalus, and hypothalamic dysfunction and papilledema may be seen. [13] MR imaging is the modality of choice for evaluating these tumors. These lesions are usually T1 hypointense and T2 hyperintense with homogeneous gadolinium enhancement. Heterogeneous enhancement may be seen when the tumors are large. With the use of fat suppression, MR imaging visualizes all portions of the optic pathways. [101] Computed tomography (CT) may also be helpful in evaluating the intraorbital optic nerves. On CT, chiasmatic or hypothalamic tumors are usually isodense or low density. [13] Calcification, cyst, hemorrhage, and tumor hyperdensity are rare.
  7. 7. Figure 4. Hypothalamic pilocytic astrocytoma The diencephalic syndrome is a rare cause of failure to thrive in infancy as described earlier and is commonly associated with hypothalamic or chiasmatic astrocytomas. The tumors associated with this syndrome are often larger in size, occur at a younger age, and are more aggressive than those associated with other presentations. Despite low-grade histologic findings, these tumors may seed throughout the cerebrospinal fluid pathways. [88] Figure 5. A, Optic nerve glioma causing fusiform enlargement of the optic nerve, B, bilateral optic nerve gliomas
  8. 8. Figure 6. Bilateral optic nerve gliomas extending into the optic chiasma in the parasellar region. Notice the contrast enhancement. Histopathology revealed a pilocytic astrocytomas of the optic pathways in a patient with neurofibromatosis I  Craniopharyngioma The most common neuroendocrine presentation in craniopharyngioma is growth hormone deficiency. Panhypopituitarism or diabetes insipidus is rare. Craniopharyngioma is a benign but aggressive neoplasm arising in the suprasellar or intrasellar region. Generally thought to arise from remnants of Rathke's pouch (i.e., craniopharyngeal duct), the tumor is composed of characteristic squamous epithelium. [90,92] These tumors represent 3% of all intracranial tumors and constitute 50% of suprasellar tumors seen in childhood. [10] These tumors occur in childhood and adolescence and are more common in boys. The clinical presentation includes headache, visual field defects, diplopia, and short stature. Hydrocephalus and papilledema may be present. Although craniopharyngiomas may be solid, they are more characteristically cystic tumors, and the cysts are typically filled with a cholesterol-rich fluid grossly resembling motor oil. Although histologically benign, craniopharyngiomas tend to compress, envelop, or infiltrate adjacent structures and produce a reactive gliosis. As a result, surgical extirpation is difficult and recurrence is likely. The tumors are usually intrasellar, suprasellar, or both. Figure 7. A, Craniopharyngioma, compressing the optic chiasma, hypothalamus and extending upward into the lateral ventricle. The tumour is partially cystic with calcified material. B, A sagittal section of the brain shows a large craniopharyngioma below the cerebral ventricle. Note the stippled pattern of the tumor. On CT, 90% of craniopharyngiomas are cystic and calcified. [59] On MR imaging, these tumors have variable signal characteristics depending on the contents of the cyst and the presence of calcium. The solid component of the tumor may be isodense or hypodense on CT and T1 isointense to hypointense with isointensity to hyperintensity on MR imaging. The calcified component is of increased attenuation on CT and often T2 hypointense on MR imaging. The cystic component may be of high or low Tl intensity and T2 hyperintense. After gadolinium administration, there is usually peripheral enhancement of the cyst and heterogeneous enhancement of the solid component. [59,119] Craniopharyngioma is to be differentiated from a cystic, calcified glioma or a teratoma.
  9. 9. Figure 8. Classic adamantinoma-like appearance of a craniopharyngioma. The pink region corresponds to brain tissue (BT) at the interface with the tumor and is mainly composed of reactive astrocytes. The tumor itself is composed of epithelial cells arranged around cystic spaces. The cells proximal to the spaces are cuboidal in shape and arranged in palisades, above this cell layer the epithelium became squamous. Some cysts are empty but others contain keratin debris (K). B, Gross pathological specimen of a craniopharyngioma Figure 9. Epithelial lesion with peripheral palisading of basal squamous epithelium surrounding loosely arranged epithelial cells, the so-called quot;stellate reticulumquot; and nodules of keratin and variable calcification are typical histologic features of a craniopharyngioma.
  10. 10. Figure 10. CT scan precontrast A, and postcontrast B,C,D. A heavily calcified suprasellar cystic craniopharyngioma, with subfrontal extension, the lesion also showed suprasellar extension to the foramen of monro causing obstructive hydrocephalus. Dense contrast enhancement occurred in some parts of the tumour. Figure 11. Parasellar craniopharyngioma: A, Precontrast CT scan (left) and postcontrast CT scan (right), B, postcontrast MRI T1 image (left) and precontrast MRI T1 image (right). Notice the calcification, the mild postcontrast enhancement, the MRI signal heterogeneity and the associated hydrocephalus.  Rathke's Cleft Cyst The most common neuroendocrine presentation in Rathke's cyst is hypopituitarism and delayed puberty. Rathke's pouch represents an embryonic upward growth of ectoderm from the primitive oral cavity (stomodeum). It is the precursor of the anterior and intermediate lobe of the pituitary as well as the pars tuberalis. Persistence of the intrasellar extremity of Rathke's pouch occasionally results in formation of an epithelium-lined Rathke's cleft cyst. The cyst is usually located between the pars distalis and the pars nervosa of the pituitary and, if large, may lead to compression of the pituitary or adjacent structures. Although usually intrasellar and lined by cuboidal or columnar mucus-secreting epithelium, Rathke's cleft cysts may occur in the suprasellar region, undergo squamous metaplasia or hemorrhage, and overlap pathologically with craniopharyngiomas. [92]
  11. 11. Figure 12. Rathke's cleft cyst Figure 13. T1-weighted sagittal image obtained before contrast enhancement depicts a well-marginated sellar mass, a Rathke cleft cyst, extending into the suprasellar cistern. Note that the mass has homogeneous high signal intensity relative to the brain parenchyma., T2-weighted axial image shows the mass, a Rathke cleft cyst, is isointense relative to the cortex., After contrast enhancement, no significant enhancement is seen in the Rathke cleft cyst. Note the normally enhancing pituitary infundibulum dorsal to the mass. Figure 14. T1-weighted sagittal image obtained before contrast enhancement demonstrates a well-defined Rathke cleft cyst in the sella that is isointense relative to the cerebrospinal fluid. Note the normal high signal intensity in the posterior pituitary, which is draped over the dorsal aspect of the cyst., The Rathke cleft cyst is isointense relative to the cerebrospinal fluid, as shown on this coronal proton density–weighted image obtained through the sellar region. The mass effect on the optic chiasm is well depicted., T1-weighted coronal image shows a subcentimeter Rathke cleft cyst in the central part of the sella. The cyst is slightly hyperintense relative to cerebrospinal fluid.
  12. 12. Figure 15. Coronal T1-weighted contrast-enhanced image shows a nonenhancing hypointense Rathke cleft cyst adjacent to the homogeneously enhancing pituitary gland., On this T2-weighted coronal image, the Rathke cleft cyst is isointense relative to cerebrospinal fluid., The variable appearance of Rathke cleft cyst is readily demonstrated on this image. A large, lobulated, and well-marginated cystic mass is centered in the sella turcica, extending both in a suprasellar plane and into the sphenoid and ethmoid sinus regions. This lesion is hyperintense relative to cerebrospinal fluid on this T1-weighted sagittal image; this signal intensity likely reflects its high protein content. Figure 16. The Rathke cleft cyst is hyperintense relative to cerebrospinal fluid on this axial proton density–weighted image. Note expansion of the sella with lateral deviation of the mildly effaced but patent cavernous internal carotid arteries., T2- weighed axial image demonstrates a large hyperintense Rathke cleft cyst., T1-weighted axial gadolinium-enhanced image demonstrates no enhancement of the Rathke cleft cyst. The majority of these lesions are asymptomatic. When symptomatic in children, there may be deficiencies of growth hormone or prolactin. [112] These cysts may contain serous or mucoid material. They rarely contain calcification and usually do not enhance. On CT, the cysts are similar to cerebrospinal fluid in attenuation. On MR imaging, the appearance of the cyst is variable depending on its contents. T1 images often show isointensity to hyperintensity compared with cerebrospinal fluid and isointensity to hypointensity or hyperintensity compared with cerebrospinal fluid on T2 images. [24,64,75] The differential diagnoses for these lesions include craniopharyngioma, cystic or hemorrhagic pituitary adenoma, partially empty sella, and arachnoid or pituitary cyst.  Hypothalamic Hamartoma The most common neuroendocrine presentation with hypothalamic hamartoma is precocious puberty. These lesions represent mature ganglionic tissue and are located between the pituitary stalk and mammary bodies involving the region of the tuber cinereum. Often the patients are boys, and the presenting symptoms include precocious puberty, gelastic seizures, hyperactivity, and developmental delay. [10] A subgroup of patients have hypothalamic hamartoma and associated congenital anomalies, including hypoplasia of the olfactory bulbs, absence of the pituitary gland, cardiac and renal anomalies, imperforate anus, craniofacial anomalies, syndactyly, and a short metacarpal (Pallister-Hall syndrome). [92] These patients commonly have hypopituitarism related to hypothalamic deficiency. [99] The transmission of the disease has been linked to chromosome 7 with autosomal dominance. [55]
  13. 13. Figure 17. Hypothalamic Hamartoma On imaging, hypothalamic hamartomas do not show invasion, growth, or enhancement. [18,71] On CT, there is a suprasellar mass, which is isodense with gray matter, noncalcified, and rarely cystic. On MR imaging, the lesion is well defined within or adjacent to the tuber cinereum or mammary bodies. The hamartomas are Tl isointense and T2 isointense to slightly hyperintense to gray matter. [15,18,20] The differential diagnosis includes hypothalamic glioma or ganglioglioma.  Pituitary Adenoma Pituitary adenomas are uncommon in childhood and represent less than 3% of all intracranial tumors. [46,83] The clinical presentation depends on tumor size, hormonal activity, and extrasellar extent. Clinical manifestations include delayed onset of puberty, galactorrhea, primary or secondary amenorrhea, gigantism, and hypercortisolism. Symptoms such as headache or visual symptoms related to mass effect also may occur. Figure 18. Nonfunctioning pituitary adenomas with suprasellar extension
  14. 14. Figure 19. Sagittal view of the brain in a patient with acromegaly. Notice the very large tumor that had grown above the sella turcica and had extended into the third ventricle. Notice the presence of hemorrhage within the tumor. This is what is known as quot;pituitary apoplexiaquot; a devastating neurological catastrophy with the onset of sudden blindness and frequently resulting in death Pituitary adenomas are divided into hormonally active and inactive types. The majority of pituitary adenomas are hormonally active and commonly prolactin secreting. Rarely, growth hormone-secreting or ACTH-secreting adenomas may occur. Occasionally, mixed secretary tumors can occur. Approximately 25% of pituitary adenomas are nonfunctioning. [66] The majority of pediatric pituitary adenomas occur in adolescence, are often microadenomas (<l cm), and are most often prolactinomas. Adenomas associated with Cushing's syndrome, although rare in childhood, are usually small in size. On occasion, patients with Cushing's syndrome may require petrosal venous sampling for localizing the source of ACTH secretion, particularly when the MR imaging scan has been equivocal or negative. [32] Macroadenomas are greater than 1 cm in diameter and are often prolactinomas. These patients may present with headache, visual field deficits, and neuroendocrine symptoms. The majority of the macroadenomas in adolescence are hemorrhagic and often occur in boys. Hemorrhagic macroadenomas may mimic other tumors, such as craniopharyngioma and Rathke's cleft cyst, on MR imaging because they often have similar signal characteristics (i.e., Tl and T2 high intensity ). [87] Pituitary apoplexy caused by sudden enlargement in a pituitary tumor secondary to hemorrhage and infarction is rarely reported in childhood. [93,91] It is characterized by clinical findings of parasellar structural compression and meningeal irritation after pituitary hemorrhage and infarction, including headache, ophthalmoplegia, and visual impairment. [22] Imaging of pituitary adenomas is best done with high-resolution thin section MR imaging. [86] In the majority of cases, the lesion is Tl hypointense. Less frequently, the adenomas are Tl isointense or hyperintense. [61] The Tl hyperintensity is often related to the presence of intratumoral hemorrhage, which usually occurs in macroadenomas or in patients undergoing bromocriptine therapy. [118] On T2- weighted MR imaging, the adenomas are often hyperintense or isointense, and macroadenomas are usually hyperintense. [61] Occasionally, stalk deviation away from the adenoma or upward convexity of the gland is seen. Macroadenomas may invade the cavernous sinuses or extend superiorly into the suprasellar cistern to compress the optic chiasm. Gadolinium administration with a rapid bolus may improve lesion detection, particularly when the conventional MR imaging scan is negative. [15,711] Immediately after gadolinium administration, the lesion is hypointense compared with the normal gland.  Arachnoid Cyst Arachnoid cysts are usually congenital arachnoid lesions. Those arising in the suprasellar region account for 10% to 15% of all arachnoid cysts. [10,113] Suprasellar arachnoid cysts often arise from the membrane of Lilliquist. [63] Clinical findings may include precocious puberty, hypopituitarism, headache, seizures, and symptoms related to compression of adjacent structures or hydrocephalus. On CT and MR imaging, the cysts are of cerebrospinal fluid density and intensity, unless there is associated hemorrhage. There is no calcification or enhancement. The differential diagnosis includes dermoid-epidermoid and fibrillary astrocytoma. Differentiation is provided by MR imaging, including the use of FLAIR and diffusion imaging.
  15. 15. Figure 20. Arachnoid cyst in a 14-year-old boy with headache. Sagittal Tl -weighted MR image demonstrates a sellar and suprasellar cyst that is isointense to CSF on all sequences and causes hydrocephalus.  Germinoma The germinomas in the suprasellar region account for 35% of all intracranial germinomas. [10] Often, these patients present with central diabetes insipidus, wasting, precocious puberty, or growth failure. As compared with other germ cell tumors, pure germinomas are rarely associated with elevated cerebrospinal fluid or serum a fetoprotein or human chorionic gonadotropin. On imaging, a mass may be seen involving the suprasellar region, or there may be thickening of the infundibulum. On CT, these lesions are well defined and slightly hyperdense. On MR imaging, they are Tl hypointense, T2 hypointense, and markedly enhancing. There is usually no associated cyst or calcification. Cerebrospinal fluid seeding is not uncommon. On occasion, there may be an associated pineal region germinoma. It is often unclear whether this represents metastatic disease or a synchronous lesion. Suprasellar germinomas often present with central diabetes insipidus. On MR imaging, the normally seen posterior pituitary bright spot is absent. [25,105] Central diabetes insipidus and the absence of the posterior bright spot may precede other clinical and imaging features of hypothalamic tumor by months or years. Therefore follow- up MR imaging with gadolinium is recommended in all of these patients. [5] The normal posterior pituitary hyperintensity may be absent in patients with central diabetes insipidus, nephrogenic diabetes insipidus, pituitary dwarfism (ectopic posterior pituitary), and sellar or parasellar tumors. [5,34,44,45,56,94] The mechanism of central diabetes insipidus is thought to be the interruption of transport of the vasopressin neurosecretory granules along the hypothalamic-neurohypophyseal pathway. The mechanism in nephrogenic diabetes insipidus is the exhaustion of the ADH stores from oversecretion as a result of end-organ failure from renal tubular disease.  Teratomas and Other Germ Cell Tumors Teratomas are rare in the suprasellar region when compared with germinomas. They more commonly occur in the pineal region. They contain components of all three germ cell layers. When in the suprasellar region, they often occur in boys and may present with hypothalamic symptoms, including precocious puberty. [57] These tumors may produce u-fetoprotein and human chorionic gonadotropin. They are classified as mature or immature depending on whether the tissue components resemble mature adult tissues or immature embryonic tissues. On CT and MR imaging, the mass often contains fat, bone, or cartilage with heterogeneous density and intensity characteristics. [12] Other nongerminomatous germ cell tumors that may arise in the hypothalamic region include choriocarcinoma, embryonal carcinoma, and endodermal sinus tumor.
  16. 16. Figure 21. Parasellar teratoma A, T1 weighted sagital MRI reveals a mixed signal mass in the suprasellar region, with extension into the sella, interpeduncular cystern and inferior third ventricle. B, T1 weighted axial MRI after gadolinium reveals heterogeneous enhancement. C, T2 weighted axial MRI shows heterogeneous high signalin the tumor.  Dermoid and Epidermoid Cysts Epidermoid cysts in the suprasellar or parasellar region are rare. [53] The majority occur in the middle cranial fossa, calvaria, or cerebellopontine angle cistern. They are of ectodermal origin, are lined with stratified squamous epithelium, and often contain cellular debris and keratinous material. A slowly expanding mass results from progressive exfoliation of keratinized cholesterol-rich material into the interior of the cyst. Clinical symptoms result from mass effect and may include visual symptoms. Endocrinologic symptoms are rare. [117] On CT, epidermoid cysts appear similar to cerebrospinal fluid. On MR imaging, the cysts are Tl isointense or mildly hyperintense to cerebrospinal fluid. Fine linear septations may be present. In some cases, the cysts may be hyperintense to cerebrospinal fluid on the proton density images, although they may follow cerebrospinal fluid on all MR imaging sequences and mimic arachnoid cyst. [63] They are differentiated by FLAIR or diffusion imaging. Dermoid cysts are also of ectodermal origin and contain elements derived from skin appendages, such as hair, sebaceous glands, and sweat glands. They may contain teeth or calcification. Although commonly found in the posterior fossa or spine, they may also occur in the suprasellar region. Symptoms result from local mass effect. On CT and MR imaging, the dermoid cyst is heterogeneous in appearance depending on the presence of gland secretions and calcification. Contrast enhancement is unusual, unless there is an inflammatory reaction or a complicating infection, such as dermal sinus with dermoid and abscess. As with epidermoid cysts, if a dermoid cyst ruptures, a chemical meningitis may occur, and Tl hyperintense droplets may be seen within the basal cisterns or ventricles. [79]
  17. 17. Figure 22. Epidermoid cyst in a 12-year- old girl. Axial unenhanced CT image (A) demonstrates a low density suprasellar mass. Sagittal Tl -weighted MR image (B) demonstrates a low intensity cyst that is slightly hyperintense to CSF.  Langerhans' Cell Histiocytosis Patients with systemic Langerhans' cell histiocytosis may have involvement of the pituitary stalk and hypothalamus. [73] These patients often present with diabetes insipidus, and MR imaging shows loss of the normal posterior pituitary bright Spot. [105,108] MR imaging may demonstrate a solitary mass in the region of the median eminence of the pituitary stalk or thickening of the infundibulum. On CT, the mass is often isodense, and on MR imaging, the lesion is T1 isointense and T2 hyperintense. After gadolinium administration, there is marked enhancement. Figure 23. Langerhans' Cell Histiocytosis, Sagittal section, T1-weighted: inhomogenously thickened pituitary stalk with impingement of the optic chiasm (arrow), small anterior pituitary lobe, missing bright spot, cystic pineal gland change, and atrophy of the upper vermis.
  18. 18. Figure 24. Langerhans' cell histiocytosis in a young woman with diabetes insipidus. Sagittal Tl-weighted MR image after gadolinium demonstrates enhancing suprasellar mass. There is absence of the posterior pituitary bright spot. Figure 25. Hypothalamic histiocytosis. INFECTIOUS AND INFLAMMATORY DISORDERS The most common infectious process associated with a neuroendocrine disorder in childhood is meningitis, which may be bacterial, viral, or granulomatous. Rarely, pituitary- hypothalamic dysfunction results from other inflammatory processes, such as lymphocytic hypophysitis, tuberculosis, or sarcoidosis.  Lymphocytic Hypophysitis Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland often found in women during late pregnancy or the postpartum period. [7,104] This disorder, which is thought to be autoimmune, has been described in children, often adolescents. [23,50] It is characterized by destruction and lymphocytic infiltration of the pituitary gland. Clinical symptoms include anterior pituitary dysfunction, elevated prolactin, and diabetes insipidus. [95] On CT and MR imaging, there is diffuse enlargement of the pituitary gland, thickening of the infundibulum, or a pituitary mass. [95] There may be involvement of the cavernous sinuses as well as absence of the posterior pituitary bright spot. On MR imaging, the lesions are T1 isointense with mild heterogeneity, are T2 hypointense, and enhance heterogeneously. [95] Dynamic MR imaging may show a delay in hypophyseal vascular enhancement because of secondary inflammatory changes. [95]
  19. 19. Figure 26. Lymphocytic hypophysitis in a 10-year-old girl with diabetes insipidus and growth hormone deficiency. Sagittal Tl- weighted MR image before (A) and after (B) gadolinium demonstrates diffuse enlargement of the pituitary gland, thickening of the infundibulum, absence of posterior pituitary bright spot, and heterogeneous enhancement.  Tuberculosis Tuberculosis as a cause of a neuroendocrine disorder is rare. Tuberculous meningitis may result in extensive involvement of the basilar cisterns, which can lead to a basal arteritis and subsequent infarction. On both CT and MR imaging, there is marked enhancement of the basilar cisterns, including the suprasellar cistern. Parenchymal lesions may be single or multiple and often involve the cortical, subcortical, or basal ganglia structures. With contrast material, these lesions may show ring or nodular enhancement. Figure 27. A, Postmortem case of hypothalamic tuberculoma. B, Tuberculous infection of the hypothalamus (arrow)  Sarcoidosis Sarcoidosis is rare in childhood. In 5% of patients with sarcoidosis, there may be central nervous system involvement, including involvement of the hypothalamus, infundibular stalk, pituitary gland, meninges, and cranial nerves as well as the brain parenchyma. Patients may present with cranial nerve deficits.
  20. 20. Twenty percent of the patients with neurologic disease may have diabetes insipidus, aseptic meningitis, or anterior pituitary deficiencies. [33,63,69] On CT, the lesions are often hyperdense and enhance. There may be associated hydrocephalus. On MR imaging, the lesions are Tl isointense, are T2 hypointense, and homogeneously enhance. [49] Figure 28. Parasellar neurosarcoidosis. A patient presented with right-sided visual loss, panhypopituitarism, polydipsia, and polyuria (with normal ADH). A and B, T1-weighted contrast-enhanced MR image (400/15/2) (A) shows basal meningeal enhancement and an enhancing pituitary mass involving both lobes, the infundibulum, and the right optic nerve (not shown). Pituitary and meningeal biopsy revealed noncaseating granulomas with negative AFB and fungal stains. The visual symptoms resolved with steroid treatment; however, 21 months later she returned with a left abducens palsy. A T1-weighted image (400/12/2) shows resolution of the pituitary lesion but new involvement of the left cavernous sinus (arrows, B). References 1. Abrahams jj, Trefelnar E, Boulware S: Idiopathic growth hormone deficiency: MR findings in 35 patients. AJNR Am j Neuroradiol 12:155-160,1991 2. Addy DP, Hudson FP: Diencephalic syndrome of infantile emaciation: Analysis of literature and report of further 3 cases. Arch Dis Child 47:338-343, 1972 3. Aicardi J, Goutieres F: The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 12:319-329, 1981 4. Aoki S, Barkovich Aj, Nishimura K, et al: Neurofibromatosis types 1 and 2: Cranial MR findings. Radiology 172:527- 534,1989 5. Appignani B, Landy H, Barnes P: MR in idiopathic central diabetes insipidus of childhood. AJNR Am J Neuroradiol 14:1407-1410,1993 6. Argyropoulou M, Perignon F, Brunelle F, et al: Height of normal pituitary gland as a function of age evaluated by magnetic resonance imaging in children. Pediatr Radiol 21:247-249, 1991 7. Asa SL, Bilbao JM, Kovacs K, et al: Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: A distinct clinicopathologic entity. Ann Intem Med 95:166-171, 1981
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