Children with Precocious Puberty
As of this writing, 22 patients have undergone surgery for hypothalamic hamartomas through the Barrow Hypothalamic
Hamartoma Program. All patients had intractable epilepsy and were treated surgically in the hope of alleviating their seizures and behavioral disturbances. Along with a routine neurosurgical evaluation, all patients underwent thorough preoperative testing, which included growth and development parameters and endocrinological evaluation. In a review of patients with precocious puberty, hypothalamic hamartomas were the cause of the disorder in 20% of the patients.[2] That rate was 18% in a study conducted by the National Institutes of Health.[10] As reported by their referring centers, more than half of our patients had precocious puberty as a comorbid finding. Patients' histories, radiographic findings, and postoperative courses were reviewed, and recommendations for future endocrinological evaluations were made. The relationship between precocious puberty and hypothalamic hamartomas is well established.[1,2,7-9] Either surgical resection or administration of gonadotropin-releasing hormone (GnRH) antagonist has been the treatment for precocious puberty.
Pathophysiology
Normal puberty begins with the pulsatile release of GnRH by the hypothalamus. GnRH stimulates the release of luteinizing hormone (LH) and folliclestimulating hormone (FSH). In women FSH causes the ovarian follicles to develop, and LH acts on the follicles to cause their maturation and the secretion of estrogen. In men FSH promotes spermatogenesis, and LH stimulates androgen production by the testes. [4,11]
For girls puberty normally begins between the ages of 7 and 13 years. Secondary sexual characteristics become apparent at a mean age of 10 years (Tanner Stage 1 to 2). Female secondary characteristics include breast development, pubic hair, and an increase in height. These changes occur over the next few years after the onset of puberty and include the onset of menses. Puberty for boys begins between the ages of 9.5 and 13.5 years. Their secondary sexual characteristics include increasing size of the testes (Tanner Stage 1), the appearance of pubic hair,and growth of the penis. Complete maturation requires
about 3 years.
Precocious, or early puberty, is defined as the onset of secondary sexual characteristics before the age of 8 years in girls and before the age of 9 to 9.5 years in males.[1,3,6] Precocious puberty also increases height, muscle mass, hunger, and personality changes. Precocious puberty is caused by peripheral, central, or mixed causes. Peripheral causes include congenital adrenal hyperplasia; familial male precocious puberty; McCune-Albright syndrome; or neoplasms of the ovary, testes, or adrenal glands. Central causes include disorders such as hydrocephalus, arachnoid cysts, septo-optic dysplasia, trauma, irradiation, neurofibromatosis, tuberous sclerosis, infections, or granulomas. Tumors that may also be included in the central category, include hypothalamic hamartomas, hypothalamic gliomas, germinomas, chiasmal gliomas, and craniopharyngiomas.[5,10]
Patient Population
The 22 patients included 15 boys and 7 girls (male-to-female ratio, 2:1). Their mean age was 10.2 years (age range,2-23 years). Eight of the 15 males and 4 of the 7 females became symptomatic with some sign of precocious puberty; the youngest in this group was 4.5 years. Symptoms included obesity, short stature (Pallister-Hall), and early secondary sexual characteristics.
Children were diagnosed with precocious puberty by referring centers because of deficiencies in growth hormone or unusual growth parameters. Three children were on a GnRH antagonist. One child was taking thyroid hormone. These children were taken off the medications by their referring center at the appropriate age to begin puberty.
Twenty transcallosal interforniceal approaches and two pterional orbitozygomatic approaches were performed. Surgical treatment of pedunculated hamartomas associated with precocious puberty has normalized endocrine function in a number of patients.[1,2] Postoperative Endocrine and Hypothalamic Dysfunction For 2 to 4 days after surgery, patients underwent serial serum sodium determinations every 2 to 6 hours. The levels of other hormones were checked 14 days after surgery. Six children had elevated
sodium levels after surgery, three of whom were briefly given desmopressin acetate. Because these incidents were transient, they did not meet the criteria for diabetes insipidus. Only one patient had persistent diabetes insipidis. None of the other children are on new hormone-replacement therapy. The children are being followed for endocrinological assessment by their referring centers. In all patients thyroid function after surgery was within normal limits. When patients returned home to their own medical system, it was suggested that they undergo routine evaluations of their hormonal levels late in their course. Their serum sodium levels should be elevated in 1 to 2 months. We will also follow these patients when their laboratory and growth parameter results are made available.
Satiety, obesity, and thirst were addressed in our patients. Patients undergoing transcallosal interforniceal approaches often gain weight after surgery. The pattern, however, varies, and the weight gain usually stabilizes in the first 6 weeks after surgery. Two patients who continued to gain some weight beyond that point are being followed by their endocrinologists and pediatricians at home. During stressful times, children can have high sodium levels. Originally, this finding was attributed to diabetes insipidus. Now, however, it seems likely that derangement of the thirst mechanism must play some role in this phenomenon.
Conclusion
Fifty-eight percent of our patients with a hypothalamic hamartoma and intractable epilepsy also had precocious puberty. Surgical removal of the hamartoma normalizes the regulation of sexual development. The likelihood of residual hormonal dysfunction associated with this surgery tends to be low in patients followed for 6 months.
Preoperative testing is unlikely to lead to the discovery of unrecognized preoperative endocrinopathies that would affect the decision to pursue surgery. We therefore do not recommend extensive preoperative endocrinological testing. We do, however, recommend a careful, compulsive postoperative search for endocrinopathies such as diabetes insipidus, hypothyroidism,
and hypocortisolemia. It is also important to be aware that after surgery these patients tend to have increased appetite, some weight gain, and a decreased sense of thirst. These changes may lead to hyper- or hyponatremia.
