NORD is very grateful to John F. Kerrigan, M.D., Associate Professor of Clinical Pediatrics and Neurology, University of Arizona College of Medicine; Director, Hypothalamic Hamartoma Program, Barrow Neurological Institute at Phoenix Children's Hospital, for assistance in the preparation of this report.
Synonyms of Hypothalamic Hamartoma
- HH (hypothalamic hamartoma)
- hypothalamic hamartoblastoma
- central precocious puberty
- epilepsy and related neurobehavioral symptoms
Hypothalamic hamartomas (HH) are rare, tumor-like malformations that occur during fetal development and are present at birth. They are non-progressive lesions and do not expand, spread or metastasize to other locations. They grow in proportion to normal brain growth, and consequently their relative size to the rest of the brain is the same for the lifetime of the patient when viewed with serial imaging. There is tremendous diversity in the type and severity of symptoms from patient to patient. However, symptoms are apparent during childhood in the overwhelming majority of patients. Although significant overlap exists, two clinical phenotypes of HH are recognized: Central precocious puberty and epilepsy and related neurobehavioral symptoms.
For those with central precocious puberty only, symptoms may occur as early as 2-3 years of age. These patients present with precocious (abnormally early) development of the physical changes associated with puberty. Neurological problems, such as epilepsy, are usually absent. Magnetic resonance (MR) imaging on patients with central precocious puberty typically shows attachment of the HH lesion in an anterior location in the hypothalamus, in the region of the tuber cinereum or pituitary stalk.
For those with epilepsy, gelastic (laughing) seizures, is the presenting symptom, often during infancy. Associated symptoms can include developmental delay, cognitive deterioration, and psychiatric symptoms such as rage behaviors. MR imaging on patients with epilepsy typically shows attachment of the HH in a posterior location in the hypothalamus, in the region of the mammillary bodies. Approximately 40% of HH patients with epilepsy also have precocious puberty. These patients tend to have larger lesions, which are broadly attached both anteriorly and posteriorly in the hypothalamus.
Anti-epilepsy medications usually do not control the gelastic seizures associated with HH, and seizures often worsen with additional seizures types that begin around 4-7 years of age. Cognitive deficits and psychiatric symptoms may also present at this time. For some patients, HH can be a progressively disabling condition. For others, symptoms may be stable and represent little or no disability.
Patients with precocious puberty can usually be treated successfully with medications, specifically with a class of drugs known as gonadotropin-releasing hormone agonists. Medications, specifically anti-epilepsy drugs (AEDs) are less successful for controlling the seizures associated with HH, and therefore surgical intervention may be needed. There has been rapid progress over the past 10 years on developing various surgical approaches for treating HH. The selection of the most appropriate surgical technique is individualized to the clinical symptoms and HH anatomy of each patient.
Central precocious puberty (CPP) is one of the hallmark clinical syndromes associated with HH. Puberty is abnormally early if it occurs prior to the age of 8 years in girls or 9 years in boys. "Central" indicates that the disease process responsible for triggering the developmental program of puberty at an abnormally early age involves the brain, usually by premature pulsatile release of gonadotropin-releasing hormone (GnRH) which then signals the ovaries or testes to begin production of sex hormones (such as estrogen in females and testosterone in males).
Central precocious puberty has many causes, and requires evaluation by a pediatric endocrinologist to identify and treat the underlying etiology. Hypothalamic hamartoma is one of the most important causes and is notable in that puberty associated with HH can occur at particularly early ages, even 2 or 3 years of age. The health consequences of abnormally early puberty include short stature and problems with age-appropriate psychosocial adjustment.
For girls, physical signs associated with CPP include breast development and the appearance of mature-appearing pubic and axillary hair. For untreated girls, menses (first menstrual bleeding) would usually follow. For boys, physical signs begin with testicular growth, followed by enlargement of the penis and maturation of the scrotum, with the development of pubic and axillary hair. Associated features include deepening of the voice and acne.
For patients with epilepsy and neurological symptoms, there is a great deal of variability with respect to the age of onset, severity and changes over time. This clinical diversity must be borne in mind when considering the diagnosis of HH, and are equally important when considering treatment options, including the timing of therapeutic intervention.
Gelastic seizures are the most characteristic symptom associated with HH. Superficially resembling laughter, they have a peculiar appearance relative to true laughter, and most family members can readily distinguish between the two. Not uncommonly, patients may have seizures that more closely resemble crying rather than laughter (known dacrystic seizures). Gelastic seizures can be quite subtle, and may be mistaken for other conditions, particularly during infancy, including colic and gastroesophageal reflux disease (GERD).
They are brief, sometimes just a few seconds, and usually less than 30 seconds in duration. They can be very frequent, however, with multiple seizures per day, and even multiple seizures per hour in more severely affected patients. Gelastic seizures may or may not be associated with altered consciousness (altered awareness of the event). However, making this determination in infants and young children can be challenging.
Gelastic seizures associated with HH usually begin at an early age, and are usually the first seizure type. The correct diagnosis can be delayed by the unusual nature of the seizure. However, in retrospect, parents can identify the onset of these peculiar laughing spells at a very early age. In our series of patients with HH and epilepsy, the mean age of onset for gelastic seizures is 10.4 months, and 71% of all patients had onset before one year of age. Gelastic seizures become less frequent after 10 years of age, and may disappear entirely as other seizure types develop. Uncommonly, patients with HH may not develop gelastic seizures until early adulthood.
Other seizure types that are more disabling to the patient develop in approximately 75% of children with HH and gelastic seizures, most commonly between 4-7 years of age. Virtually all possible types of seizures have been reported, and individual patients may have multiple active seizure types, including complex partial, generalized tonic-clonic, and absence.
Cognitive deficits are evident in the majority of patients with HH and epilepsy. Difficulties with processing speed and short-term memory are most common. Here again, there is significant diversity from patient to patient. A recent study with neuropsychological testing in 49 HH patients undergoing evaluation for surgical treatment showed that 35% tested with normal or near-normal results, 18% showed significant deficits without mental retardation, and 47% qualified for a diagnosis of mental retardation. Factors contributing to a greater degree of cognitive impairment in this and other studies include 1) the number of anti-epilepsy medications taken at the time of testing, 2) larger HH lesion size, 3) younger age of seizure onset, and 4) higher seizure frequency. Conversely, patients with HH and central precocious puberty without epilepsy typically do not have developmental or cognitive deficits.
Behavioral and psychiatric symptoms are also common in the group of patients with HH and epilepsy. Episodes of behavioral aggression associated with poor frustration tolerance, often described as rage attacks, are particularly problematic and are a hallmark symptom of HH. Rage attacks are usually reactive to external (often minor) stimuli, and consist of explosive anger. These behaviors can be the most disabling feature of the disease for some patients.
Psychiatric symptoms are reported in over 80% of children and adults with HH and epilepsy. A wide range of symptom types, symptom severity and psychiatric diagnoses can be involved. In children with HH, these include oppositional-defiant disorder (83%), attention-deficit/hyperactivity disorder (75%), conduct disorder (33%) and mood disorder (17%), which are far more common in affected patients compared to their unaffected siblings.
Roughly half of children with HH and epilepsy can experience deterioration (worsening) of their symptoms over time, with a decline in cognitive functioning and worsening of behavioral symptoms. Worsening seizures, cognitive decline, and behavioral deterioration often occur simultaneously, and probably share a biological link. HH appears to be a clinical model for epileptic encephalopathy, although the basic mechanisms responsible for the deterioration experienced by some patients are poorly understood.
The underlying cause for hypothalamic hamartomas remains unknown. Over 95% of cases are sporadic (that is, there is no prior family history and the identified patient remains the only affected individual in the family). A defect in factors that regulate fetal development of the hypothalamus is most likely.
However, HH can also occur in patients with identified genetic disorders. Of these, Pallister-Hall syndrome accounts for the vast majority. This is a rare dysmorphology syndrome that can include HH, extra digits and other deformities of the hands and feet (postaxial polydactyly and syndactyly), abnormalities of the larynx (bifid epiglottis), imperforate anus, abnormal facial features, and others. Pallister-Hall syndrome is known to be associated with a genetic mutation in the GLI3 gene, which acts as a transcription factor (a regulator protein for turning on and off gene expression). This is a genomic (or genome-wide) mutation, which is to say, a mutation present in every cell in the body. (For further information, choose "Pallister-Hall" as your search term in the Rare Disease Database.)
Knowing that Pallister-Hall syndrome is due to a mutation in GLI3, researchers have recently examined the possibility that a somatic (tumor-only) mutation of GLI3 was present in the sporadic HH cases. Using tissue removed at surgery, it was discovered that up to 25% of patients have a somatic mutation of GLI3 in HH tissue. Accordingly, it appears likely that some patients have HH due to a mutation in this gene. It is possible that improved genotyping technology will identify a larger number of GLI3 mutations. It is also likely that other, as yet unidentified mutations in other genes can be responsible. At this time, mutation analysis of GLI3 is not recommended for routine clinical care of patients with HH.
Hypothalamic hamartomas are relatively rare. Population-based research has shown that HH with epilepsy occurs in 1 of 200,000 children and adolescents. The prevalence of HH with only precocious puberty is unknown. At least for HH with epilepsy, males appear to have a slightly higher risk than females (approximately 1.3 to 1 ratio). HH occurs worldwide, without any obvious geographical concentration of cases. It is currently felt that all ethnic groups are at equal risk. There are no identified maternal risk factors or fetal exposures that increase the risk of HH.
As malformations of the ventral (inferior) hypothalamus, hypothalamic hamartomas are rather distinct from other conditions. It is important to note that tumors that occur in the same region (such as craniopharyngiomas, astrocytomas, optic nerve gliomas, etc) usually do not cause gelastic seizures. These tumors can, however be associated with endocrine dysfunction, which includes precocious puberty under rare circumstances.
Brain imaging with magnetic resonance (MR) techniques is the single most important diagnostic test. MR imaging is sufficient to establish (or rule out) the diagnosis of HH. However, there are important considerations to imaging for HH. Imaging must be technically adequate to permit detailed visualization of the hypothalamus. Movement artifact resulting from restlessness of the patient within the scanner can obscure small HH lesions. Accordingly for children or other patients with limited cooperation, a sedated study is recommended. Additionally, the choice of specific imaging sequences is also important. We recommend including the coronal T2 fast spin echo (FSE) sequence, with thin slices and no gap or space between slices. Lastly, the radiologist should be informed that HH is one of the clinical conditions under consideration, so as to include careful inspection of that region of the brain. Most patients (over 90%) have normal brain findings on MR imaging aside from the HH. A small number of patients may have additional abnormalities, such as malformations of cortical development.
Computed tomography (CT) imaging is not adequate for detecting small HH lesions, and has the added disadvantage of radiation exposure.
Physical signs of precocious puberty require evaluation by an endocrinologist. The hypothalamus and pituitary together produce a number of different hormones, including the reproductive hormones responsible for puberty. Consequently, evaluation of patients with HH should include testing for other factors such as thyroid, adrenal, and growth-related hormones.
Electroencephalography (EEG) testing is routinely performed in patients with epileptic seizures or suspected epileptic seizures, and can be useful in evaluating patients with HH and epilepsy. However, it must be recognized that EEG results may be normal, particularly at younger ages when gelastic seizures are the only seizure type. This includes video-EEG monitoring that captures gelastic seizures. That is, the EEG may show no change even during the actual gelastic seizure event. This is due to the fact that gelastic seizures arise in the HH, and as a structure located deep at the base of the brain, it is distant from EEG electrodes on the scalp. This can lead to incorrect diagnoses.
EEG studies can show abnormal results, particularly in older patients who have developed other types of seizures. A wide variety of findings is possible, and can suggest either focal or generalized disturbances. Consultation with a neurologist experienced with evaluating patients with HH and epilepsy is recommended whenever possible. This expertise is usually available at regional epilepsy referral centers.
Neuropsychological testing can be an important tool for patient management, particularly those with HH and epilepsy. These patients are "at-risk" for developmental and cognitive deficits. For some patients, these difficulties may be progressive, with deterioration or worsening in their level of function. Neuropsychological testing can help define the pattern of functioning (i.e., strengths and weaknesses) in the various skills of higher brain functioning (such as memory, language, problem-solving, etc). This can help with adaptive therapies and provides a baseline for those patients who may be declining. Additionally, neuropsychological testing is very important for those undergoing surgical intervention in order to clarify changes (for either the better or worse) that may accompany surgical treatment.
Central precocious puberty (CPP) can usually be treated successfully with medication. Surgery is not required for most patients with CPP. Effective treatment consists of administration of gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate [Lupron], which have the effect of feedback inhibition of the pulsatile (pulse-like) release of GnRH that is required to trigger puberty. Leuprolide acetate is customarily administered as a once-monthly intramuscular injection for the duration of time that puberty needs to be suppressed. Once discontinued, puberty occurs normally. Treatment options that avoid once-monthly injections have also been developed. Consultation with an endocrinologist experienced in the treatment of CPP is important to review the treatment options and for discussion of possible side effects.
Gelastic seizures usually do not respond to antiepilepsy drugs (AEDs). Exceptions to this appear to be rare. Additionally, while the other seizure types that occur later in childhood may be helped with AED therapy, it is unlikely that these seizures will be completely controlled ("treatment-resistant"). Consequently, other treatment interventions are usually required, as discussed below.
The timing of surgical intervention (including gamma knife radiosurgery) is a major decision point facing the patient, family and doctor. Surgical intervention carries the risk of complications and should not be performed until the degree of clinical severity calls for it. For example, relatively brief and infrequent gelastic seizures are usually not significantly disabling. If the child is making good developmental progress, a decision to withhold surgical intervention may be appropriate. However, under these circumstances, the clinical course needs to be observed carefully for any adverse changes in symptoms, such as worsening of seizures, slowing of developmental progress, or emergence of psychiatric symptoms.
However, our current understanding of epilepsy associated with HH also argues against excessive delay in surgical treatment, since it appears that some patients undergo a process known as secondary epileptogenesis, in which uncontrolled seizures from the original location can incite a process by which seizures can then begin to arise from a second, distant location elsewhere in the brain. If this occurs (likely over a period of years rather than months) then surgery that removes the HH lesion may be less successful for completely controlling seizures. Outcome studies of surgery for HH associated with epilepsy have shown that success in controlling seizures is inversely related to the patent’s age, that is, older patients are less likely to gain complete seizure control.
Gelastic seizures begin in the HH lesion and removing (or otherwise damaging) the HH can eradicate the seizure disorder. Until recently, HH with epilepsy was considered not treatable, since surgery on the hypothalamus was too dangerous. However, since 2000, several treatment approaches have been developed that are recognized as potentially effective and safe. These treatment decisions (selecting one of several surgical approaches or radiosurgery) are highly individualized to the unique circumstances of each patient. This includes an assessment of their clinical course and symptoms, but also the exact anatomy of their HH lesion. Consequently, consultation at a referral center that specializes in the treatment of HH is highly recommended.
A brief discussion of each of these treatment modalities follows. The relative merits of any of these therapies for an individual patient require consultation with a specialist in the field of HH treatment.
Gamma Knife Radiosurgery: Gamma Knife Radiosurgery (GKR) is a relatively non-invasive radiosurgical technique in which a stereotactic frame is temporarily attached to the patient’s head along with a helmet-like device with multiple radiation entry ports. These ports are aligned (targeted) so that multiple beams of radiation are delivered to converge upon the selected target, injuring this tissue, but delivering doses well below the threshold for tissue injury to the rest of the brain. The safety profile for GKR is excellent relative to surgical resection. A small number of patients have transient temperature irregularities following treatment or experience a temporary increase in seizure frequency several weeks after treatment. The biggest disadvantage to GKR is that the therapeutic effect is delayed, typically 6-18 months, but sometimes up to 2-3 years following treatment. This therapy is most appropriate for patients who are clinically stable with respect to their seizures and other symptoms, and can tolerate waiting for effectiveness. Currently published data suggests that 35% of patients treated with GKR will be completely free of seizures upon follow-up.
Stereotactic Thermoablation (with or without intraoperative MR thermography): This technique involves stereotactic (image-guided targeting) of thin probes into the HH and then heating the lesion to approximately 60°C, injuring the tissue and eradicating its ability to generate seizures. When effective, this therapy works immediately. Multiple passes of the probe into the brain may be required to treat the entire lesion, depending upon its size. A recent development (2011) includes the use of real-time MR thermography to build in safeguards so that the heating is limited to pre-determined safety targets as it spreads to healthy tissue. The safety profile to date has been favorable. The effectiveness of this technique has shown substantially different results from different treatment centers (24 - 70% seizure control). Group data with thermoablation with MR thermography are not yet available.
Transcallosal Interforniceal Resection: Popularized by Dr. Jeffrey Rosenfeld in Melbourne, Australia, this was the first innovative approach to HH surgery, in which the surgeon approaches the HH from above (between the two hemispheres of the brain) rather than below (traversing under the temporal or frontal lobes). Although a longer distance, this approach turns out to be safer and more effective. The HH lesion (and its connection) is directly visualized by the surgeon. We favor this technique in younger patients with larger lesions including bilateral connections to the hypothalamus, where surgical visualization is particularly critical. We favor open resection procedures in circumstances where the child is deteriorating, and the delay in treatment effectiveness inherent with gamma knife radiosurgery is not acceptable. Surgical outcome results from two large series have been published with very similar results (complete seizure control in 52% and 54% of patients, respectively). The potential for surgical complications are important to consider: 8% of patients have residual decrease in short term memory function, for example.
Transventricular Endoscopic Resection: This approach involves placing a small burr hole in the skull and then passing an operating endoscope into the ventricular system, entering the third ventricle (the fluid-filled space between the right and left halves of the hypothalamus). This approach is ideal for those who require prompt intervention and who have relatively small HH lesions with unilateral attachment to the wall of the hypothalamus. The effectiveness is comparable to the transcallosal resection (49% seizure-free after one year), but the procedure is more easily tolerated with a shorter length of stay in the hospital. Short-term memory is still at-risk however, with 8% of patients experiencing a decline in short-term memory function following endoscopic surgery.
Pterional (Orbitozygomatic)Resection: While surgical approaches from below (under the frontal or temporal lobes) is to be discouraged as a solution of all patients with HH and epilepsy, there is still a substantial number of patients (perhaps 10% of the entire group with epilepsy) where a pterional or orbitozygomatic approach is the most appropriate choice. This approach is chosen for those patients in whom the HH is attached below the hypothalamus as the most direct way of getting to the lesion and visualizing its attachment to the brain. (Most HH cases with precocious puberty alone have this anatomy.)
Combined or Staged Resection for Large HH Lesions: Patients with HH and epilepsy associated with giant HH lesions may require two approaches from both above and below to optimize resection and/or disconnection. These HH lesions have complicated planes of attachment within the third ventricle but also below the hypothalamus. It is difficult for the surgeon "to see around corners", and therefore two procedures may be required.
Antiepilepsy Drugs (AEDs): Ongoing research into the basic cellular and molecular mechanisms of seizure onset within HH tissue has begun to identify some of the single-cell and network phenomenon that are likely responsible for seizure activity. These findings have suggested drug classes that could be effective for improving seizure control in patients with HH and epilepsy. As one example, L-type calcium channel blockers appear to attenuate the pacemaker-like cell firing activity of small HH neurons. A small pilot study of amlodipine (an L-type calcium channel blocker) in children with frequent gelastic seizures yielded indeterminate results (as yet unpublished), but further investigation of this novel drug class for treating epileptic seizures may be warranted.
Surgical Therapy: Interstitial radiosurgery (in which radioactive seeds are stereotactically placed into the HH lesion and then removed within several days) is also under investigation as a therapy for HH associated with epilepsy. Although favorable reports have been published, this work is the result of a single clinical research center, and should be regarded as investigational until confirmed by other centers.
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
For information about clinical trials sponsored by private sources, in the main, contact:
Contact for additional information about hypothalamic hamartoma:
John F. Kerrigan, M.D.
Director, Hypothalamic Hamartoma Program
Maggie Bobrowitz, R.N., M.B.A.
Program Coordinator, Hypothalamic Hamartoma Program
Barrow Neurological Institute at Phoenix Children’s Hospital
1919 East Thomas Road, Ambulatory Building B, Third Floor
Phoenix, Arizona 85016
Hypothalamic Hamartoma Resources
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Kerrigan JF. Hypothalamic hamartoma. In: Wyllie E, Cascino G, Gidal B, Goodkin H, eds. The Treatment of Epilepsy: Principles & Practice, 5th Ed. Lippincott, Williams and Wilkins, Philadelphia, 2011.
Troester M, Haine R, Chapman K, Chung S, Drees C, Ng YT, Rekate H, Kerrigan JF. EEG and video-EEG seizure monitoring has limited utility in patients with refractory epilepsy associated with hypothalamic hamartoma. Epilepsia 2011;52:1137-1143. http://www.ncbi.nlm.nih.gov/pubmed/21569021
Craig DW, Itty A, Panganiban C, Szelinger S, Kruer M, Reiman D, Narayanan V, Stephan DA, Kerrigan JF. Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus. Am J Hum Genet 2008;82:366-374. http://www.ncbi.nlm.nih.gov/pubmed/18252217
Ng YT, Rekate HL, Prenger EC, Wang NC, Chung SS, Feiz-Irfan I, Johnsonbaugh R, Varland MR, Kerrigan JF. Endoscopic resection of hypothalamic hamartomas for refractory symptomatic epilepsy. Neurology 2008;70:1543-1548. http://www.ncbi.nlm.nih.gov/pubmed/18427070
Prigatano GP, Wethe JV, Gray JA, Wang N, Chung S, Ng Y-t, Prenger E, Kerrigan JF. Intellectual functioning in presurgical patients with hypothalamic hamartoma and refractory epilepsy. Epilepsy Behav 2008;13:149-155. http://www.ncbi.nlm.nih.gov/pubmed/18375185
Regis J, Scavarda D, Tamura M, Villeneuve N, Bartolomei F, Brue T, Morange I, Dafonseca D, Chauvel P. Gamma knife surgery for epilepsy related to hypothalamic hamartoma. Semin Pediatr Neurol 2007;14:73-79.
Kerrigan JF, Ng Y-t, Chung SS, Rekate HR. The hypothalamic hamartoma: a model of subcortical epileptogenesis and encephalopathy. Semin Ped Neurol 2005;12(2):119-131. http://www.ncbi.nlm.nih.gov/pubmed/16114178
Nguyen D, Singh S, Zaatreh M, Novotny E, Levy S, Testa F, Spencer SS. Hypothalamic hamartomas: seven cases and review of the literature. Epilepsy Behav 2003;4:246-258. http://www.ncbi.nlm.nih.gov/pubmed/12791326
Weissenberger AA, Dell ML, Liow K, Theodore W, Frattali CM, Herna D, Zametkin AJ. Aggression and psychiatric comorbidity in children with hypothalamic hamartomas and their unaffected siblings. J Am Acad Child Adolesc Psychiatry 2001;40:696-703. http://www.ncbi.nlm.nih.gov/pubmed/11392348
Berkovic SF, Andermann F, Melanson D, Ethier RE, Feindel W, Gloor P. Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging. Ann Neurol 1988;23:429-439. http://www.ncbi.nlm.nih.gov/pubmed/3389755
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Report last updated: 2012/01/17 00:00:00 GMT+0
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