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Rev Esp Endocrinol Pediatr 2011; 2 (Suppl) doi: 10.3266/Pulso.ed.RevEspEP2011.vol2.SupplCongSEEP Advances in the diagnosis, treatment and molecular genetics of pituitary tumors in childhood Constantine A. Stratakis, MD, D (Med) Sci.
Section on Endocrinology Genetics, Program on Developmental Endocrinology Genetics (PDE-GEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NI-CHD), National Institutes of Health (NIH), Bethesda, MD20892, USA. AIP mutations may be more frequent among spe- Pituitary tumors are rare in childhood and adoles- cific subgroups of patients, such as in children and cence, with a reported prevalence of up to 1 per young adults with growth hormone-producing ade- million children. Only 2-6% of surgically treated pi- nomas. In this presentation, we review the most re- tuitary tumors occur in children, with some variation cent data on clinical diagnosis and outcomes, as attributed to a lack of consensus for a pediatric age well as in the molecular pathogenesis of pituitary range and whether age at surgery or age at onset adenomas and discuss some of the most recent of symptoms was used. Although pituitary tumors in findings from our laboratory. Guidelines for genetic children are almost never malignant and hormonal screening and clinical counseling of patients with secretion is rare, these tumors may result in signifi- cant morbidity. Pituitary adenomas produce a varie- ty of hormonal conditions such as hyperprolactine- Keywords: Pituitary adenomas, familial syndromes, mia, acromegaly or gigantism, or Cushing disease. molecular pathways, clinical picture, multiple endo- Sporadic lesions comprise the majority of pituitary tumors in children and there is sparse information about genetic causes. However, in children more frequently than in adults, pituitary tumors may be a manifestation of genetic conditions such as Car- The pituitary gland has an essential role in the ney complex, McCune-Albright syndrome, multiple maintenance of homeostasis, normal growth, and endocrine neoplasia type 1 (MEN 1), and familial reproductive function. Although pituitary tumors are isolated pituitary adenoma (FIPA). The study of pi- rare in childhood and adolescence, and typically tuitary tumorigenesis in the context of these gene- histologically benign; significant morbidity may re- tic syndromes has advanced our knowledge of the sult due to their location, mass effect, and/or inter- molecular basis of pituitary tumors and may lead to ference with normal pituitary hormone functions. (1) new therapeutic developments. Molecular unders- Early identification of pituitary tumors in children is tanding of pituitary adenoma formation is essential necessary to avoid serious adverse effects on both for the development of medical therapies and the physiological and cognitive outcomes as a result of treatment of post-operative recurrences. In general, pituitary hormone dysregulation during the critical mutations in genes involved in genetic syndromes periods of growth in childhood and adolescence. In associated with pituitary tumors are not a common this report, we review recent findings on the diagno- finding in sporadic lesions. In contrast MEN1 and sis, evaluation, treatment, and molecular genetics of pituitary adenomas presenting in childhood.
Constantine A. Stratakis, MD, D (Med) Sci, SEGEN, PDEGEN & Pediatric Endocrinology Program, NICHD, NIH, Building 10, CRC (East Laboratories), Room 1-3330, 10 Center Dr., Due to the rarity of pituitary tumors in children and adolescents, accurate information regarding the Tel. 301-496-4686/496-6683, fax 301-301-402-0574/480- prevalence and incidence of pituitary tumors is lac- king. Data from autopsy studies (primarily adults) show that pituitary adenomas develop in approxi- nomas are significantly smaller than other types of mately 17-25% of the population. (1, 2) In addition, pituitary tumors (usually 3 mm or less). Rarely, they studies with radiological imaging report a similar in- can be exophytic, growing into the subarachnoid cidence of pituitary gland lesions in the general po- space, or invade the cavernous sinus or wall. In pulation (up to 20%) with no gender predilection. (3) addition, there are case reports of tumors that origi- Approximately 3.5 to 8.5% of all pituitary tumors are diagnosed prior to the age of 20 years and they ac- count for approximately 3% of all diagnosed intra- Clinical presentation, evaluation, and treatment In children, the most characteristic clinical presen- tation of Cushing disease (CD) is significant weight The majority of pituitary tumors are sporadic; howe- gain concomitant with a decrease in linear height ve- ver in children more commonly than in adults, they locity. Other typical symptoms include headaches, can be part of a genetic condition predisposing to delayed pubertal development and amenorrhea pituitary and other tumors. However, even sporadic (despite significant virilization and hirsutism), hy- tumors may harbor significant genetic abnormalities. pertension, and glucose intolerance. Children and Most pituitary tumors are monoclonal lesions and younger adolescents usual y do not report problems modifications in expression of various oncogenes with sleep disruption, muscle weakness, or pro- or tumor suppressor genes, including GNAS, PTTG, blems with memory or cognition, compared to older HMGA2, and FGFR-4 have been identified. (9, 10) adolescents and adults with Cushing disease. (26) Pituitary tumor development and cell growth are likely influenced by both pituitary and hypothala- Our group recently suggested a 3-day inpatient mic factors. (1, 11, 12) Other factors and genetic events evaluation of children suspected of having Cus- seem to be implicated in pituitary cell clonal ex- hing syndrome for confirmation of the diagnosis pansion, and oncogene activation is necessary to and investigation of a corticotropinoma. (27) A mid- propagate tumor growth. (9, 13) An example of this night serum cortisol value of 4.4 ug/dL confirmed secondary phenomenon is the widespread presen- the diagnosis of Cushing syndrome in al children ce of GNAS activating mutations in sporadic GH- (sensitivity of 99% and specificity of 100%). Mor- secreting pituitary tumors (in up to 40% of all such ning corticotropin levels were elevated in patients with CD (median of 18 pg/mL); a cutoff value of 29 pg/mL had 100% specificity and 70% sensiti- ACTH-producing adenomas are probably the most vity. A decrease in morning cortisol of 20% with common functional pituitary tumors in early child- the high dose overnight dexamethasone suppres- hood, although they are still considerably rare. No sion test (120 ug/kg, maximum dose 8 ug) provided genetic defects have been consistently associated the highest sensitivity (97.5%) in differentiating CD with childhood corticotropinomas, which only rarely from primary adrenal disorders. MRI of the pituitary occur in the familial setting, and then, most com- gland identified a lesion in 63% and CT imaging of monly in the context of multiple endocrine neoplasia the adrenals showed bilateral adrenal hyperplasia in 53% of children with CD. Bilateral inferior petro- sal sinus sampling is usual y reserved for patients The second most frequently found functional pi- with confirmed ACTH-dependent CS and a negati- tuitary tumors in early childhood are GH- and/or ve pituitary MRI; or in situations where there is in- PRL-secreting, and these tumors in children occur consistency in the biochemical data and the MRI is almost always in the familial setting or in the context suggestive of a pituitary lesion, to exclude an ecto- of known genetic defects: GNAS, menin, PRKAR1A, pic source of ACTH production. Our group recently AIP and p27 (CDKN1B) mutations. (6, 18-22) In late reported that in an experienced center, BIPSS was childhood, adolescence and adulthood somato- safe; however lateralization of the ACTH gradient and/or mammotropinomas become significantly during BIPSS is a poor predictor of lateralization of more frequent than corticotropinomas.(23) Recent studies report the use of post-contrast spoiled gradient-recalled acquisition (SPGR) in the The most common type of pituitary adenomas in pre- steady state in addition to conventional T-1 weighted pubescent children are corticotropinomas; however spin echo (SE) acquisition MRI. (29, 30) SPR-MRI was the frequency decreases during puberty and in late superior to conventional MRI imaging for the diag- adolescence, when the incidence of prolactinomas nostic evaluation of corticotropinomas and, in gene- becomes more prevalent. The cumulative incidence ral, for investigation of the pituitary gland in children of corticotropinomas (Cushing disease) in children does not exceed a tenth of the annual incidence of 2-5 new cases of Cushing syndrome per million Transphenoidal adenomectomy or hemihypophy- people per year. (7, 24, 25) Typically, corticotroph ade- sectomy is considered first-line treatment for CD Rev Esp Endocrinol Pediatr 2011; 2 (Suppl) // doi: 10.3266/Pulso.ed.RevEspEP2011.vol2.SupplCongSEEP Advances in the diagnosis, treatment and molecular genetics of pituitary tumors in childhood in childhood and adolescence. Hemihypophysec- ne), with the goals of normalization of prolac- tomy has been shown to be nearly 90% curative in tin levels and pituitary function and the reduc- situations where the surgical exploration is negati- tion of tumor size. Dopamine agonists have ve. In situations when surgical intervention has not demonstrated effectiveness in reducing tumor been successful, radiation or gamma-knife therapy size and control ing prolactin levels in approxi- is the next line of treatment. (24, 26) An option for ino- mately 80-90% of patients with microadeno- perable or recurrent CD is bilateral adrenalectomy; mas and about 70% of macroadenomas. (40) however it is associated with a significant risk of de- Cabergoline, a selective D2 receptor agonist, is velopment of Nelson’s syndrome. (31, 32) more effective and often better tolerated than bro- mocriptine, and has been shown to be effective in treatment of tumors resistant to other dopami- ne agonists. (41) For some patients treatment with Prolactinomas account for approximately 50% of pi- dopaminergic agents can be withdrawn and PRL tuitary adenomas overall and are the most common levels wil remain within normal limits. (42) pituitary adenomas in adolescents, with a female preponderance (33-36). Prolactinomas may be seen Patient compliance is often a problem in long-term in several inherited syndromes, including MEN 1, management of prolactinomas. Commonly reported Carney complex, and familial isolated pituitary ade- side effects of dopamine agonist treatment inclu- de nausea, dry mouth, dyspepsia, or dizziness at the initiation of therapy. (43, 44) Cessation of medical Clinical presentation, evaluation, and treatment treatment leads to recurrence of hyperprolactinemia The clinical presentation of prolactinomas varies and tumor re-growth. Treatment doses of 2.5 to 10 depending on the age and gender of the child. mg daily (bromocriptine) or 0.25 to 2 mg weekly (ca- Growth arrest is typically noted in children and ado- bergoline) have not been associated with long-term lescents prior to ephiphyseal fusion. Macroprolacti- nomas are found more frequently in males, perhaps due to lower detection rates during the initial phase Recent reports in the New England Journal of Medi- of tumor development. Consistent with a later diag- cine 45-47 of cardiac valve regurgitation in patients nosis and larger tumor size, males with prolactino- treated with long-acting dopamine agonists have mas also have a higher incidence of neurological raised concerns about the safety of these medica- and opthalmological abnormalities (i.e. cranial ner- tions. The safety of cabergoline was evaluated in ve compression, headaches, visual loss), growth a nested case-control study of patients in the UK or pubertal arrest and other pituitary dysfunctions. general practice database and a study of 1200 pa- Gynecomastia is not a common finding. Females tients with Parkinson’s disease (control ed and un- may present with pubertal delay, amenorrhea, and control ed studies at doses of up to 11.5 mg/day, other symptoms of hypogonadism. The differential which exceed the maximum recommended dose diagnosis includes various factors such as neuro- for treatment of hyperprolactinemic disorders). The genic or mechanical processes that can result in risk of valvular disease appeared to be higher in loss of dopaminergic suppression of pituitary lac- patients treated with at least 3 mg per day of ca- totrophs and resultant hyperprolactinemia, such as bergoline, a dose that is 10 to 20 times higher than mass effects from craniopharyngiomas, Rathe cleft the standard regimen for macroprolactinomas. Dis- cyst, nonfunctioning adenomas, or an infiltrative cussion of potential risks of therapy with the patient and decision about the need for echocardiogram The diagnosis of prolactinoma is based on mea- surement of serum prolactin levels (indwelling line, Recently, Kars et al. (2008) reported a cross-sectio- patient resting and fasting for an hour) and neurora- nal study of patients with prolactinomas who recei- diological imaging. Basal prolactin levels of greater ved cabergoline treatment (mean 5.2 years, range than 200 ug/L are diagnostic, whereas levels bet- 1-10.3 years) and noted an increased prevalence ween 100-200 ng/mL and the presence of a mass, of aortic valve calcification with mild tricuspid re- requires additional investigation to rule out mass gurgitation; but not clinically relevant valvular heart effect versus a prolactinoma. Waas (2006) reported disease. (48) Discussion of potential risks of thera- that all but one patient in a series of 223 with non- py with the patient and decision about the need for functioning adenomas had prolactin levels less than 100 ng/mL, which provides a well-defined cutoff va- Urgent situations, such as acute threat to vision, hydrocephalus, or cerebral spinal fluid leak, or for The first line of treatment for prolactinomas is the rare tumors that grow despite exposure to in- medical management with dopamine agonists creasing doses of dopamine agonists may require (e.g. bromocriptine, pergolide, or cabergoli- XXXIII Congreso de la Sociedad Española de Endocrinología Pediátrica A GH receptor antagonist, pegvisomant, has de- monstrated effectiveness for normalization of IGF-1 Prior to the age of 20 years, somatotropinomas ac- levels with no detrimental effects on glucose meta- count for approximately 5-15% of pediatric pituitary bolism. (65, 66) Pegvisomant, on the other hand, requi- adenomas. Typically, the excess GH production res a daily injection, an important factor to be consi- results from an adenoma (usually macroadenoma); dered when initiating this type of treatment. A study however, somatotroph hyperplasia may be a rare of the long-term efficacy and safety of combination cause of excess GH that can occur in certain gene- therapy (long-acting somatostatin analog plus twice tic conditions such as McCune-Albright syndrome weekly pegvisomant) reported that IGF-1 levels nor- or Carney complex. Dysregulation of GHRH signa- malized for all patients (n=32); however, transient ling may occur as a result of a local mass effect, elevation in liver enzymes was observed in eleven for example with optic glioma seen in neurofibroma- patients, with a higher risk for patients diagnosed tosis type-1 (NF-1) and result in GH excess, (51) or with diabetes mellitus. Combination therapy can from an ectopic GHRH-producing tumor, which is offer an additional benefit since tumor suppression activity is combined with GH receptor blockade (66).
There is limited data on pegvisomant treatment in Clinical presentation, evaluation, and treatment children, mostly case studies, which report suc- The clinical presentation of somatotropinomas in children and adolescents varies depending on whe- ther the epiphyseal growth plate is open. Prior to Incidental y discovered pituitary adenomas in child- epiphyseal fusion, significant acceleration of growth hood are rare, since overal non-functioning pitui- velocity is noted, a condition also known as ‘gigan- tary tumors in childhood and adolescence are rare. tism’. When epiphyseal fusion nears completion, the Hormonal y silent tumors represent only 4 to 6% of clinical symptoms become more similar to those in pediatric cases while in series of adult patients, they acromegalic adults (coarse facial features, broade- account for approximately 33 to 50% of the total ned nose, large hands and feet, obesity, organome- number of pituitary lesions. (5, 69, 70) Most non-functio- galy, sweating, nausea). Since somatotropinomas ning adenomas arise from gonadotroph cel s and are often macroadenomas, mass effects, such as often are macroadenomas at diagnosis; they may headaches and visual disturbances are frequently present with headaches and visual disturbances, as wel as growth and/or pubertal delay (71). Large ade- nomas may cause hydrocephalus, while pituitary Diagnosis is confirmed by elevated IGF-1 level, failu- adenomas and sel ar tumors that impinge on the op- re to suppress GH during oral glucose tolerance test tic apparatus and/or cavernous sinus can result in (1.75 g/kg), elevated IGFBP3 level, and neuroradio- cranial nerve palsies, cavernous sinus syndromes, logy imaging (MRI). Assessment of pituitary function and/or additional visual disturbances. Hormonal y should include cosyntropin stimulation test, thyroid silent adenomas may present with GH deficiency panel, gonadotropin, and prolactin measurement. (up to 75%), LH/FSH deficiency (~40%), or ACTH and TSH deficiency (~25%). (71) Although compres- Transsphenoidal surgery is the first-line of treatment sion of the pituitary stalk by pituitary adenoma has for childhood gigantism or acromegaly; however, been reported; secondary hyperprolactinemia is unlike Cushing disease, GH-producing tumors are seen in less than 20% of patients. Diabetes insi- often large and locally invasive. Transsphenoidal pidus is also rare (9 to 17%) but is more commonly surgery may be curative with small, well-circumscri- seen in patients with Rathke’s cleft cysts (34). Recom- bed tumors; while larger and locally invasive tumors mendation for surgical excision of a hormonal y si- may benefit from surgical decompression; however, lent intrasel ar tumor or cyst depends on the tumor persistent or recurrent disease is common and ad- size, location, and potential for invasiveness.
juvant therapy is needed. Radiotherapy, either pri- mary or post-surgical, has slow onset of treatment Molecular genetics of pituitary tumors effect and high treatment related morbidity of pan- Four genetic conditions associated with pituitary tumors include: Carney complex (CNC), McCune Albright syndrome (MAS), multiple endocrine neo- Pharmacologic agents are often indicated both be- plasia type 1 (MEN1), and familial isolated pituitary fore and after surgery and have been shown to be adenomas (FIPA) provide useful models to advance effective at shrinking tumor size and improving bio- our knowledge of the molecular basis of pituitary tu- chemical abnormalities. Long-acting somatostatin mors. In the remaining text of this report we briefly analogs have been shown to be effective at normali- zing IGF-1 levels in most patients.(56-62) However, sin- ce treatment with long-acting somatostatin analogs suppresses insulin secretion, this may increase the First described by Carney in the mid-1980s, Carney risk for development of glucose intolerance.(63, 64) complex is a rare autosomal dominant disorder that Rev Esp Endocrinol Pediatr 2011; 2 (Suppl) // doi: 10.3266/Pulso.ed.RevEspEP2011.vol2.SupplCongSEEP Advances in the diagnosis, treatment and molecular genetics of pituitary tumors in childhood includes a complex of endocrine overactivity, lentigi- but pituitary tumors are not typically detectable by nes, myxomas, and other tumors such as schwan- MRI.(77, 78) However, elevated GH levels in patients nomas and/or pituitary adenomas. Genetic defects with MAS may be associated with significant mor- in one of the regulatory subunits of protein kinase bidity due to exacerbation of polyostotic fibrous A (PKA) (regulatory subunit type 1 alpha, PRKA- dysplasia.(79, 80) Hypersomatotropinemia has also be R1A) causes CNC.72. An inactivating mutation in implicated in sarcomatous transformation of bone the gene encoding PRKAR1A has been identified in tumors in a MAS patient. (81) Similar to patients with approximately 60% of patients who met the diagnos- CNC, GH- and PRL- producing cell hyperplasia are tic criteria and a second, as yet uncharacterized lo- common histological findings in the pituitary.(18, 79, 82) cus at 2p16 has been implicated in some families.(73) Treatment of GH- producing tumors in MAS with Pituitary pathology has been described in a number cabergoline has consistently shown an inadequate of studies of patients with CNC and includes hyper- response; while long-acting octreotide has demons- somatotropinemia and hyperprolactinemia, which trated an intermediate response. Recently, GH-re- often begin in adolescence. Acromegaly in CNC is ceptor antagonists have been proposed as effecti- characterized by a slow progressive course and ag- ve medical intervention for patients with inoperable gressive pituitary tumors are not common. Howe- MAS pituitary tumors or hypersomatotropinemia wi- ver, in many patients clinically significant acrome- galy did not manifest until after surgical treatment of their Cushing syndrome (72% of these patients MEN1 is a disorder characterized by a predisposi- were diagnosed with CS due to primary pigmented tion to peptic ulcer disease and primary endocrine nodular adrenocortical disease), which is not surpri- hyperactivity involving the pituitary, parathyroid, and sing given the known relationship between cortisol pancreas, which is inherited in an autosomal domi- nant manner. The disorder is due to inactivating mutations in the menin gene, a tumor suppressor, It is important to identify clinically significant acro- which has been localized to chromosome 11q(13). megaly as defined by generally applied criteria Studies report that menin interacts with various pro- for patients with CNC who have elevated GH and/ teins involved with transcriptional regulation, geno- or IGF-1 (56). It is not uncommon for CNC patients me stability, cell division and proliferation.(15, 16, 84, 85) to have an abnormality of GH secretion due to the underlying pituitary hyperplasia, however almost all Pituitary adenomas are found in approximately will have negative imaging studies. (72, 74) For CNC 30 to 40% of patients with menin mutations, most patients with elevated IGF-1 levels treatment with commonly PRL (~60%) and GH (~20%)- secreting; somatostatin analogues with the goal of normalizing while ACTH-secreting and non-functional adeno- IGF-1 is recommended. (72, 75) For CNC patients with mas represent less than 15% of MEN 1-associated normal IGF-1 levels and normal pituitary imaging, pituitary adenomas.(15, 34) The frequency of pituitary but with abnormal response to oral glucose toleran- disease is significantly higher in familial versus spo- ce test, evaluations should be performed annually radic MEN (1) cases, although no genotype-pheno- to assess for changes that may require treatment. type correlation has been noted in menin mutation carriers.(15) In addition, an increased female-to-male ratio has been reported in MEN (1) patients with pitui- McCune Albright syndrome (MAS) is a genetic (but tary adenoma and acromegaly for both familial and not inherited -90) disorder characterized by polyos- sporadic cases.(1) A pituitary adenoma may be the totic fibrous dysplasia, café-au-lait pigmented le- first clinical manifestation of MEN (1), with the youn- sions, endocrine abnormalities (precocious puber- gest reported case in a 5-year old boy with a pitui- ty, thyrotoxicosis, pituitary gigantism, and Cushings syndrome) and rarely other tumors. Somatic muta- tions on the adenylate cyclase-stimulating G alpha Familial isolated pituitary adenomas (FIPA) is a clinical protein (GNAS complex locus, GNAS) are found condition that refers to kindreds with two or more pitui- in McCune Albright syndrome. (76) GNAS maps to tary adenomas that are genetical y negative for muta- chromosome 20 q(13) and encodes the ubiquitously tions in menin or PRKAR1A. Homogeneous mutations expressed Gs-α subunit of the G protein. The acti- refer to similar pituitary tumor type occurring within vation of adenyl cyclase signaling pathways results the same family and heterogeneous mutations refer in the phenotype of MAS including hypersomatotro- to families with two or more dif erent tumor types.(22) pinemia. GNAS mutations have also been identified Al pituitary tumor phenotypes have been reported in FIPA kindreds, and typical y at least one prolactin- or GH-secreting adenoma is noted in each family. Similar to patients affected by CNC or carriers of PRKAR1A mutations, GH excess in MAS is com- Vierimaa (2006) reported that inactivation mutations monly found (approximately 20% of the patients) of the gene encoding aryl hydrocarbon receptor- XXXIII Congreso de la Sociedad Española de Endocrinología Pediátrica interacting protein (AIP) were found in patients with References
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