FINAL DIAGNOSIS: HYPOTHALAMIC HAMARTOMA
Precocious puberty is a syndrome which can result from numerous etiologies including lesions or tumors of the pituitary or hypothalamus. Other disorders which have been associated with precocious puberty include neurofibromatosis, optic gliomas, Donahues' syndrome (leprechaunism), septo-optic dysplasia, post-traumatic brain damage, McCune-Albright syndrome, virilizing adrenal tumor, familial male precocious puberty and idiopathic causes (1). In this case, the radiological evidence of a mass in the tuber cinereum was classic for hypothalamic hamartoma.
Hypothalamic hamartomas are an interesting neuropathologic entity which are considered to be malformative (congenital) lesions. They can be incidental findings at autopsy or on radiographic examination (2), however their true prevalence is unknown. They are more common in males. Symptoms are rare. Sometimes these lesions are brought to attention by abnormalities of endocrine function which often appear in childhood, but can appear in adults. As these are non-growing lesion, there are no symptoms related to mass-effect on nearby structures such as the optic chiasm. In children, the most common symptom (when present) is precocious puberty. This has, in some cases, been attributed to overproduction of gonadatropin releasing hormones by neurons within the lesion, however, in other cases there is no endocrine dysfunction despite demonstrable production of these releasing factors (2). More rarely, the hamartomas may release somatotrophic releasing factors which can result in increased growth in children or acromegaly in adults (2). Even more uncommon are psychiatric abnormalities and in some pediatric cases gelastic seizures (which are highly distinctive episodes of laughter) can be present (3).
These lesions are fairly well-defined masses attached to the floor of the third ventricle or associated with the tuber cinereum. They are typically about 1-2 cm in diameter, but some may be very large and protrude into the third ventricle. Typically there is no calcification or cystic component, which can help distinguish them from a ganglioglioma radiographically. Microscopically, the tissue resembles cerebral gray matter with a jumbled, disordered appearance to the neurons. The neurons may be large ganglionic cells, small neurons or sometimes stellate-shaped. A normal component of glial cells is expected and there may be bundles of myelinated or unmyelinated fibers coursing through the hamartoma. In some cases these have been demonstrated to form connections with portions of nearby brain (4).
In this case, both the clinical and radiological presentations are classic for hypothalamic hamartoma. If the presentation had been one of mass effect (i.e., hydrocephalus, seizures or visual problems related to the optic chiasm) the possibility of a neoplasm would have to be considered more likely than a hamartoma. Ganglioglioma, craniopharyngioma and pilocytic astrocytoma would be among the top tumors in the differential diagnosis of a neoplasm in this locale. Other far less likely candidates for tumors in this area in a child would be pituitary adenoma, meningioma, epidermoid cyst and chordoma. The radiographic location of the tumor makes several of these diagnoses even less likely. The lack of contrast enhancement and the absence of a cystic space argue against a pilocytic astrocytoma. Gangliogliomas are often accompanied by calcification or cystic spaces as well. As it is, the diagnosis of a hypothalamic hamartoma is straightforward in this case and was confirmed by the neuropathologic examination.
Clinical treatment is by surgical removal and there is no recurrence. Symptoms generally disappear and often secondary sexual features will regress. In this case, six months after removal, there were still behavioral problems (aggressiveness), but her pubic hair had started to fall out and her bone age had stabilized.
Contributed by Ronald L. Hamilton, M.D.