Thecentral issue in precocious puberty

LETTERS

The central issue in precocious puberty To the Editor: Zacharin 1 reported that central precocious puberty may occur in neurofibromatosis type I (NF-I) in the absence of optic chiasmal glioma. This is an issue that has important practical implications, but we think that some conclusions in the article may be inaccurate on the basis of the presented data. Patient 1 in the study by Zacharin 1 was a girl with NF-I who had, as a first sign of sexual precocity, premature pubarche at the age of 2.5 years. At the age of 5.1 years she had pubarche, but thelarehe was absent. This is an uncommon finding, because thelarche is usually the first sign of central precocious puberty in girls2; in some girls, pubarche may be the first manifestation of puberty, but thelarehe usually occurs immediately or shortly thereafter. In addition, endocrine data were inconsistent with central precocious puberty in Zacharin's patient. 1 The girl could have had a premature pubarche as a result of a mild form of congenital adrenal hyperplasia and a secondary gonadotropin-dependent puberty induced by a gonadotropin-independent precocious puberty. 2 The short stature of the patient's father may also indicate a premature epiphyseal closure related to a heterozygosis for congenital adrenal hyperplasia. Because mild forms of congenital adrenal hyperplasia may occur with a frequency higher than 1 in 100, a such a disease should be ruled out in patient 1. Patient 2 in the study by Zacharin 1 was a boy with NF-I, short stature, and precocious puberty who had enlarged testes, advanced bone age, and a positive luteinizing hormone response to gonadorelin test for central precocious puberty. Indeed, the patient did not show any clinical response or suppression of testosterone levels during therapy with high doses of the G n R H analog leuprolide, whereas both testieular volume and testosterone levels regressed during administration of the inhibitor of gonadal steroidogenesis medroxyprogesterone acetate. This finding is inconsistent with a primitive central precocious puberty, 2 al-

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though it may be consistent with a male limited familial precocious puberty. 4 Although the referred family history was negative, the height of the patient's father was very low (156 cm) and similar to the mean adult height of untreated patients with male limited familial precocious puberty (158 cm). 5 Because both mild and severe forms of the disease have been described within the same family, 6 the patient and his father could be affected by an unrecognized male limited familial precocious puberty, which should be ruled out by molecular analysis of the luteinizing hormone receptor gene. 2 In summary, the data of Zacharin 1 are not completely consistent with a primitive central precocious puberty in her patients with NF-I. Indeed, the patients could be affected by NF-I and a peripheral precocious puberty. Thus the occurrence of central precocious puberty in association with NF-I in the absence of optic chiasmal glioma is not clearly supported by Zacharin's data. 1

Silvano Bertellon£A!D GiamyieroL Baroncell£AID Giaseppe Saggese,AID Endocrine Unit, Departmentof Pediatrics Universityof Pisa-I-56125 Pisa, Italy 9/35/85110

REFERENCES 1. Zacharin M. Precocious puberty in two children with neurofihromatoSis type I in the absence of optic chiasmal glioma. J Pecllatr 1997;130:155-7. 2. ShankarRR, PescovitzOH. Precociouspuberty. Adv EndocrlnolMetab 1995;6:55-89. 3. New MI. Steroid 21-hydroxylasedeficiency (congenital adrenal hyperplasia). Am ,J Med 1995;98(suppl IA):2S-8S. 4. Rosenthal SM, Grumbach MJVi, Kaplan SL. Gonadotropin- independent familial sexual precocity with premature Leydig and germinal cell maturation (familialtestotoxicosis): effects of a potent luteinizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases, d Clin Endocrinol Metab 1983;57:571-9. 5. Bertelloni S, Baroncelli GI, Lala R, Cappa M, Matarazzo P, DeSanetls C, et al. Long-

term outcome of male limited gonadotropin-independent precocious puberty. Horm Res 1997;48:235-9. 6. Evans BAJ, Bowen DJ, Smith PJ, Gregory JW. A new mutation of the LH gene in a family with familial male precocious puberty [abstract]. Horm Res 1995;44(suppl 1):15.

Neurofibromatosis type I and precocious puberty: Beyond the chasm To the Editor: We read with interest the article by Zachairin 1 regarding precocious puberty in neurofibromatosis type 1 (NF-1) in the absence of optic chiasmal gliomas. Neither of the two patients described appear to have typical central precocious puberty. Central precocious puberty occurs when there is premature activation of the hypothalamic-pituitary-gonadal axis, resulting in growth acceleration and development of secondary sexual characteristics. The first patient has prepubertal gonadotropin levels, and neither a gonadotropin-releasing hormone (GnRH) stimulation test nor pelvic ultrasonography was reported. Additionally, at the age of 11.25 years, she still has not begun menstruating. The second patient described does have a mature hypothalamicpituitary-gonadal axis, but his case is unusual in that production of GnRH cannot be suppressed with a GnRH agonist, and both he and his father are quite short. In our ongoing observational studies of NF-1, we have identified 12 children with precocious puberty from among 331 children with NF-I, 226 of whom had neuroimaging studies. One of these 12 children has no evidence of an optic chiasm glioma and was identified after the publication of our article. 2 The pathophysiologic link between NF-1 and precocious puberty appears to be the presence of an optic chiasm glioma. However, the diagnosis of NF- 1 in the absence of an optic chiasm tumor does not protect one from the population incidence of precocious puberty. Just as idiopathic precocious puberty occurs in 0.6% of the

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