Last updated:
8/8/2023
Years published: 1993, 1995, 2003, 2013, 2016, 2019, 2023
NORD gratefully acknowledges Roger J. Packer, MD, Children’s National Medical Center, Senior Vice President, Center for Neuroscience and Behavioral Medicine; Director, Brain Tumor Institute and Director, Gilbert Family Neurofibromatosis Type 1 Institute; for assistance in the preparation of this report.
Diencephalic syndrome is a rare disorder caused by a tumor that is usually located in the diencephalon, a portion of the brain just above the brainstem. The diencephalon includes the hypothalamus and the thalamus. Affected infants and young children may develop symptoms that include the failure to gain weight and grow as would be expected based upon age and gender (failure to thrive) and abnormal progressive thinness and weakness (emaciation). Affected infants and children may behave in an alert, happy and outgoing manner, which contrasts with their physical appearance. However, more frequently, infants and young children are irritable. Additional symptoms such as vomiting, vision abnormalities, nystagmus, headaches and pallor can also develop. Diencephalic syndrome can progress to cause severe, life-threatening complications. Diencephalic syndrome is treated by surgery, radiation, chemotherapy and/or molecular-targeted therapy. The reason for the development of the tumor that causes diencephalic syndrome is unknown. Diencephalic syndrome was first described in the medical literature in 1951 by Dr. Russell.
The specific symptoms and severity of diencephalic syndrome can vary from one person to another. The disorder can potentially cause severe, even life-threatening complications. Onset is usually in infancy or early childhood. Usually, there is a period of normal development and weight gain, followed by a prolonged period of failure to gain weight and weight loss.
The most striking feature of diencephalic syndrome is profound emaciation including a uniform loss of body fat (adipose tissue). Emaciation occurs despite normal or near normal caloric intake. Emaciation may progressively worsen. Because of the loss of body fat, affected children may appear muscular. Although weight is affected, length (linear growth) may be normal. Emaciation and failure to thrive may occur following an initial period of normal growth.
Although overall development is slowed, neurological development may be normal. However, detailed neurologic examination often discloses subtle abnormalities. Affected children are usually mentally alert. Some children are overactive and restless (hyperkinesia); others are happy and outgoing, which is not in keeping with their outward appearance. Some affected children are described as intensely excited or happy (euphoric). Others may, in contrast, act irritable.
Rapid, involuntary, “jerky” movements of the eyes (nystagmus) can be seen in children with diencephalic syndrome. Nystagmus is a notable feature of this disorder but does not occur in all patients. It may affect one or both eyes. Additional nonspecific symptoms include pallor, vomiting (emesis) and headaches. Degeneration of the nerve that transmits visual stimuli from the eyes to the brain (optic nerve) may also occur (optic atrophy). Vision loss can potentially occur in some patients.
Some affected infants and children develop hydrocephalus, a condition in which excessive cerebrospinal fluid (CSF) in the skull causes pressure on the brain, resulting in a variety of symptoms including a head that appears large in comparison to the rest of the body, swelling of the optic disk (papilledema).
Less often, additional symptoms have been reported including low blood sugar (hypoglycemia), excessive sweating (hyperhidrosis) and high blood pressure (hypertension). In rare instances, disproportionately large hands and feet have developed.
Diencephalic syndrome is caused by a tumor, most commonly located in the hypothalamus or the optic chiasm. The hypothalamus is a special area in the brain that is divided into several regions that have different functions. The hypothalamus controls the pituitary gland by controlling the gland’s release of certain hormones. The hypothalamus also helps regulate basic functions of the body including sleep, hunger, thirst and body temperature. The optic chiasm is the region where the optic nerves pass through to the brain.
A glioma or astrocytoma is the most common tumor associated with diencephalic syndrome. An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive tissue of the brain includes oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue are collectively referred to as gliomas. Technically, an astrocytoma is a subtype of gliomas, but occasionally the terms are used interchangeably. Astrocytoma that occurs in association with diencephalic syndrome tends to be more aggressive and to develop at an earlier age than other astrocytoma arising in the same area. Juvenile pilocytic astrocytoma is the most common cause of diencephalic syndrome. NORD has a report on this tumor. For more information, choose “juvenile pilocytic astrocytoma” as your search term in the Rare Disease Database.
Pediatric low-grade gliomas frequently demonstrate specific molecular genetic alterations, such as BRAF V600E variants, activating BRAF-fusions, NF1 gene variants and FGFR variants. All these abnormalities increase signaling through the RAS-MAPK signaling pathway and are the cause of tumor growth. CDKN2A/B loss or ATRX variants may occur at the same time the more frequent genetic abnormalities are seen and are associated with more aggressive tumor growth.
Gliomas in the hypothalamus or optic chiasm can sometimes be associated with neurofibromatosis type 1, a rare genetic disorder characterized by the development of multiple noncancerous (benign) tumors of the skin and nerves (neurofibromas). The development of a tumor in the hypothalamus and optic chiasm in neurofibromatosis type 1 and the subsequent development of diencephalic syndrome is not common but does occur. For more information, choose “neurofibromatosis” as your search term in the Rare Disease Database.
In some instances, the causative tumor is unclassified. In extremely rare cases, a different type of tumor such as an ependymoma, dysgerminoma or ganglioma has been associated with diencephalic syndrome.
The exact underlying way these tumors cause the symptoms of diencephalic syndrome is not fully understood.
Diencephalic syndrome is an extremely rare disorder that affects both males and females. The incidence and prevalence of this disorder in the general population is unknown. The disorder is most often seen in infants or young children but has also been reported in older children and adults.
The diagnosis of diencephalic syndrome is suspected in a child who has failed to thrive despite eating an apparently normal diet. A history of relatively normal development followed by a period of weight loss and lack of clear-cut stomach or intestinal problems is suggestive of diencephalic syndrome. A detailed patient history, a thorough clinical evaluation and a variety of specialized imaging techniques are used to establish a diagnosis.
Clinical Testing and Workup
Imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues such as brain tissue.
Examination of cerebrospinal fluid can show elevated protein levels, as well as the presence of abnormal cells in cases of tumor dissemination. Lumbar cerebrospinal fluid sampling should not be done when there is a major mass effect by the tumor or untreated obstructive hydrocephalus. MRI of the entire neuro-axis is needed, in most cases, to rule out tumor dissemination and should be performed in at least 2 planes with and without contrast agents (i.e., gadolinium).
Most patients will require at least a biopsy to confirm the diagnosis. Increasingly, the tissue removed at the time of surgery will also be sent for molecular analysis to help guide therapy. The exception to this is in patients with NF1 in whom biopsy is often not needed.
Treatment
The treatment of diencephalic syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, neurologists, oncologists, radiation oncologists and other healthcare professionals may need to plan an affect child’s treatment systematically and comprehensively.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size and specific location; specific tumor type; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Psychosocial support for the entire family is essential as well.
There is no agreed upon consensus for the best treatment for individuals with diencephalic syndrome and there are no standardized treatment protocols or guidelines. However, protocols and often clinical trials are available for specific tumor types that cause the syndrome. Various treatments have been reported in the medical literature as part of single patient reports, small series of patients or more extensive, tumor-type based studies. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with diencephalic syndrome.
Surgery, radiation, chemotherapy, and molecular-targeted therapy alone or in various combinations have been used to treat the diencephalic syndrome. In some patients, physicians may recommend surgical excision and removal of as much of the tumor as possible (resection). However, because of the area of the brain that is usually affected, surgical removal of the entire tumor is rarely possible. Additionally, surgery, even to remove only a portion of the tumor, carries risks due to the tumor’s location deep within the brain. However, as noted previously, biopsy is usually indicated to not only determine the histological subtype of the tumor, but its molecular subtype; this is especially useful in low-grade gliomas where molecular findings can guide therapy.
Radiation therapy can be used to directly destroy cancer cells or to destroy cancer cells left over after surgery. However, the potential for serious short and long-term side effects exists. Radiation therapy is especially avoided in children less than 5 years of age because of the potential for serious side effects.
Chemotherapy, the use of one or more anti-cancer drugs, has also been used to treat individuals with diencephalic syndrome, particularly those with low grade gliomas. Chemotherapy may be used instead of radiation in very young children to avoid damage to the developing brain. Chemotherapy may also be administered after radiation to destroy any cells that remain or may be given during radiation treatment. The type of chemotherapeutic drug therapy used is determined by a neuro-oncologist who examines the grade of tumor, previous treatment and current health status of the affected individual. Chemotherapeutic drugs that have been used for diencephalic syndrome include carboplatin, carboplatin-vincristine, carboplatin-vincristine-temador, low dose cisplatin-etoposide and other drug regimens.
Recently, molecularly targeted therapies (biologic therapy) have become available for treatment of low-grade pediatric gliomas.
Bevacizumab, which targets vascular endothelial growth factor, has been successfully used for some patients with diencephalic gliomas. Agents interfering with RAS-MAPK signaling have shown great promise for treatment of diencephalic tumors. Doctors have used oral MEK inhibitors for BRAF-fusion associated tumors and BRAF inhibitors, alone or in combination with MEK inhibitors, for tumors with BRAF variants. These trials require molecular characterization of the tumor for a patient to be eligible.
Prospective, randomized trials have demonstrated the superiority of dabrafenib and trametinib compared to standard chemotherapy for gliomas with BRAF. variants. Prospective, randomized trials are underway comparing a MEK inhibitor to chemotherapy for both patients with NF-1 associated tumors and BRAF-fusion associated low-grade gliomas.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Ullrich, NJ, and Cohen, BH; Pediatric Low-Grade Glioma, In: Swaiman’s Pediatric Neurology: Principles and Practice, 6th Edition, Elsevier, New York, New York, 985-990, 2018.
Pina-Garza, JE. In: Fenichel’s Clinical Pediatric Neurology: A Signs and Symptoms Approach. 7th ed. Elsevier Saunders. Philadelphia, PA; 2013:321-322.
Brodsky MC. Russell Diencephalic Syndrome of Infancy. In: Pediatric Neuro-Ophthalmology,2nd ed. Springer. New York, NY. 2010:412-413.
Packer RJ. Diencephalic Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:528-529.
JOURNAL ARTICLES
D’Angelo F, Ceccarelli M, Tala et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat Med. 2019; 25(1):176-187.
Jones DTW, Kieran MW, Bouffet E, Alexandrescu S, Bandopadhayay P, Bornhorst M, Ellison D, Fangusaro J, Fisher MI, Foreman N, Fouladi M, Hargrave D, Hawkins C, Jabado N, Massimino M, Mueller S, Perilongo G, Schouten-van Meeteren AYN, Tabori Um Warren K, Waanders AJ, Walker D, Weiss W, Witt O, Wright K, Zhu Y, Bowers DC, Pfister SM, and Packer RJ. Pediatric low-grade gliomas: next biologically driven steps. Neuro-Oncology 2018; 20(2), 160-173. doi:10.1093/neuonc/nox141PMID: 29016845.
Kaley T, Touat M, Subbiah V et al. BRAF inhibition in BRAF-mutant gliomas: results from the VE-BASKET study. J Clin Oncol. 2018; 36(35):3477-3484.
Reinhardt A, Stichel D, Schrimpf D, et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma
with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 2018;136(2):273-291.
Wagner LM, Myseros JS, Lukins DE, Willen CM, Packer RJ, Targeted Therapy for Infants with Diencephalic Syndrome: A Case Report and Review of Management Strategies, Pediatric Blood and Cancer 2018; May 65(5):e26917. doi: 10.1002/pbc.26917. Epub 2018 Jan 25.
Banerjee A, Jakacki R, Onar-Thomas A et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent of refractory low-grade glioma: a pediatric brain tumor consortium (PBTC) study. Neuro Oncol. 2017; 19 (8): 1135-1144.
Lassaletta A, Zapotocky M, Mistry M, et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J of Clin Oncology 2017; 35(25):2934-2941.
Packer RJ, Pfister S, Bouffet E, et al. Pediatric low-grade gliomas: implications of the biologic era. Neuro Oncol. 2017 Jun 1; 19(6):750-761 pii: now209. DOI: 10.1093/neuonc/now209 PMID: 27683733
Wells EM, Ullrich NJ, Seidel K, Leisenring W, Sklar CA, Armstrong GT, Diller L, King A, Krull KR, Neglia JP, Stovall M, Whelan K, Oeffinger KC, Robison LL, Packer RJ. Longitudinal assessment of late onset neurologic health conditions in survivors of childhood central nervous system tumors: A report from the childhood cancer survivor study cohort; Neuro-Oncology 2017 Aug 22;20(1):132-42
Mistry M, Zhukova N, Merico D et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J of Clin Oncology 2015; 33:1015-1022.
Crawford JR, Shayan K, Levy ML. Delayed presentation of diencephalic syndrome associated with leptomeningeal dissemination in a child. BMJ Case Rep. 2013; doi:10.1136/bcr-2013-010265. https://www.ncbi.nlm.nih.gov/pubmed/23774711
Singh G, Wei XC, Hader W, et al. Sustained response to weekly vinblastine in 2 children with pilomyxoid astrocytoma associated with diencephalic syndrome. J Pediatr Hematol Oncol. 2013;35:e53-e56. https://www.ncbi.nlm.nih.gov/pubmed/23042016
Sardi I, Bresci C, Schiavello E, et al. Successful treatment with a low-dose cisplatin-etoposide regimen for patients with diencephalic syndrome. J Neurooncol. 2012;109:375-383. https://www.ncbi.nlm.nih.gov/pubmed/22717669
Marec-Berard P, Szathmari A, Conter C, et al. Improvement of diencephalic syndrome after partial surgery of optic chiasm gliomas. Pediatr Blood Cancer. 2009;53:502-504. https://www.ncbi.nlm.nih.gov/pubmed/19489055
Packer RJ, Jakacki R, Horn M, et al. Objective response of multiply recurrent low-grade gliomas to bevacizumab and irinotecan. Ped Blood and Cancer. 2009;52:791-795. https://www.ncbi.nlm.nih.gov/pubmed/19165892
Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118,1739-1749. https://www.ncbi.nlm.nih.gov/pubmed/18398503
Huber J, Sovinz P, Lackner H, et al. Diencephalic syndrome: a frequently delayed diagnosis in failure to thrive. Klin Padiatr. 2007;219:92-94. https://www.ncbi.nlm.nih.gov/pubmed/17405074
Brauner R, Trivin C, Zerah M, et al. Diencephalic syndrome due to hypothalamic tumor: a model of the relationship between weight and puberty onset. J Clin Endocrinol Metab. 2006;91:2467-2473. https://www.ncbi.nlm.nih.gov/pubmed/16621905
Fleischman A, Brue C, Poussaint TY, et al. Diencephalic syndrome: a cause of failure to thrive and a model of partial growth hormone resistance. Pediatrics. 2005;115:e742-748. https://www.ncbi.nlm.nih.gov/pubmed/15930202
Packer RJ. Chemotherapy: low-grade gliomas of the hypothalamus and thalamus. Pediatr Neurosurg. 2000;32:259-263. https://www.ncbi.nlm.nih.gov/pubmed/10965273
Gropman AL, Packer RJ, Nicholson HS, et al. Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control. Cancer. 1998;83:166-172. https://www.ncbi.nlm.nih.gov/pubmed/9655307
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