transforming-growth-factor-alpha and Hamartoma

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.

Topics: Child; Child, Preschool; Comorbidity; Drug Resistant Epilepsy; Endocrine System Diseases; Epilepsies, Partial; Female; gamma-Aminobutyric Acid; Gonadotropin-Releasing Hormone; Hamartoma; Hormones, Ectopic; Humans; Hypothalamic Diseases; Hypothalamus; Infant; Male; Nerve Net; Puberty, Precocious; Transforming Growth Factor alpha

Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor alpha (TGFalpha), and GRM1A, which encodes the type 1 metabotropic glutamate receptor alpha isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release.. Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFalpha, KISS1, GPR54, and GRM1A.. Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFalpha, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP.. Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.

Topics: Adolescent; Child; Child, Preschool; Female; Gene Expression; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Infant; Kisspeptins; Male; Puberty, Precocious; Radiography; Receptors, LHRH; Seizures; Transforming Growth Factor alpha; Tumor Suppressor Proteins

Hypothalamic hamartomas (HHs) are congenital lesions composed of neurons and astroglia. Frequently, HHs cause central precocious puberty (CPP) and/or gelastic seizures. Because HHs might express genes similar to those required for the initiation of normal puberty, we used cDNA arrays to compare the gene expression profile of an HH associated with CPP with three HHs not accompanied by sexual precocity.. Global changes in gene expression were detected using Affymetrix arrays. The results were confirmed by semiquantitative PCR, which also served to examine the expression of selected genes in the hypothalamus of female monkeys undergoing puberty.. All HHs were associated with seizures. Ten genes whose expression was increased in the HH with CPP were identified. They encode proteins involved in three key cellular processes: transcriptional regulation, cell-cell signaling, and cell adhesiveness. They include IA-1 and MEF2A, two transcription factors required for neuronal development; mGluR1 and VILIP-1, which encode proteins involved in neuronal communication, and TSG-6 that encodes a protein involved in cell adhesiveness. Of these, expression of mGluR1 also increases in the female monkey hypothalamus at puberty.. Increased expression of these genes in HHs may be relevant to the ability of some HHs to induce sexual precocity.

Topics: Adolescent; Adult; Animals; Cell Adhesion Molecules; Child; Child, Preschool; DNA-Binding Proteins; Female; Gene Expression Profiling; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Kisspeptins; Macaca mulatta; Male; Oligonucleotide Array Sequence Analysis; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, Metabotropic Glutamate; Repressor Proteins; Sexual Maturation; Transforming Growth Factor alpha; Tumor Suppressor Proteins

Activation of LH-releasing hormone (LHRH) secretion, essential for the initiation of puberty, is brought about by the interaction of neurotransmitters and astroglia-derived substances. One of these substances, transforming growth factor alpha (TGFalpha), has been implicated as a facilitatory component of the glia-to-neuron signaling process controlling the onset of female puberty in rodents and nonhuman primates. Hypothalamic hamartomas (HH) are tumors frequently associated with precocious puberty in humans. The detection of LHRH-containing neurons in some hamartomas has led to the concept that hamartomas advance puberty because they contain an ectopic LHRH pulse generator. Examination of two HH associated with female sexual precocity revealed that neither tumor had LHRH neurons, but both contained astroglial cells expressing TGFalpha and its receptor. Thus, some HH may induce precocious puberty, not by secreting LHRH, but via the production of trophic factors--such as TGFalpha--able to activate the normal LHRH neuronal network in the patient's hypothalamus.

Topics: Astrocytes; Child, Preschool; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hamartoma; Human Growth Hormone; Humans; Hypothalamic Diseases; Immunohistochemistry; Infant; Luteinizing Hormone; Magnetic Resonance Imaging; Neurons; Puberty, Precocious; Transforming Growth Factor alpha