Precocious puberty in children with neurofibromatosis type 1

Precocious puberty in children with neurofibromatosis type R e e m a Habiby, MD, Bernard Silverman, MD, Robert Listernick, MD, a n d Joel C h a r r o w , MD From the Department of Pediatrics, Northwestern University Medical School, and the Divisions of Endocrinology, General Academic and Emergency Pediatrics, and Genetics, Children's Memorial Hospital, Chicago, Illinois We undertook a comprehensive study of children with neurofibromatosis type 1 (NF-I) c a r e d for in a large multidisciplinary clinic to determine the p r e v a l e n c e of precocious puberty and its relationship to optic pathway tumors (OPTs). Precocious puberty was d i a g n o s e d in 7 of 219 children with NF-1 (5 boys and 2 girls) e x a m i n e d between Jan. 1, 1985, and April 20, 1993. All seven children had OPTs involving the optic chiasm; they represented 39% of children with NF-1 and chiasmal tumors (95% c o n f i d e n c e interval, 17% to 64%). Eleven prepubertal children ( a g e d 2 to 10 years) with NF-1 and OPTs, and age- and sex-matched NF-I control subjects without OPTs, underwent luteinizing hormone-releasing hormone (LH-RH) stimulation tests. Two boys with OPTs had pubertal luteinizing hormone (LH) responses, and testosterone levels >10 ng/dl. Basal LH levels were also e l e v a t e d in these two boys when tested with a very sensitive immunochemiluminometric assay. None of the children without an OPT had either a pubertal response to LH-RH or an e l e v a t e d basal LH level. We c o n c l u d e that precocious puberty in children with NF-I is found exclusively in those who have OPTs involving the optic chiasm; it is a c o m m o n c o m p l i c a t i o n in those children. With the use of a highly sensitive LH assay, b i o c h e m i c a l e v i d e n c e of hypothalamicpituitary-gonadal axis activation may be demonstrated, even without provocative testing. (J PEDIATR1995;126:364-7) Early maturation of the hypothalamic-pituitary-gonadal axis, leading to precocious puberty, is a recognized complication of neurofibromatosis type 1 in childhood) 5 Precocious puberty has been reported primarily in those children Supported in part by the National Center of Research Resources and General Clinical Research Centers Program, RR00078, and a grant from the Children's Memorial Institute for Education and Research. Presented in part at the Midwest Society for Pediatric Research, Nov. 4, 1992, Chicago, I11.,and the Fourth Joint Meeting of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology, June 1993, San Francisco, Calif. Submitted for publication June 10, 1994; accepted Sept. 30, 1994. Reprint requests: Joel Charrow, MD, Division of Genetics--59, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614. Copyright ® 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/20/60907

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with NF-1 who have optic pathway tumors. 58 Although there are several reports of precocious puberty in children with NF-1 in the absence of such tumors, they are flawed by imprecise definitions of NF-1 and the absence of sensitive neuroimaging techniques. 3, 4 FSH LH LH-ICMA LH-RH NF-1 OPT

Follicle-stimulatinghormone Luteinizing hormone Luteinizing hormone immunochemiluminometric assay Luteinizing hormone-releasing hormone Neurofibromatosis type 1 Optic pathway tumor

We undertook a comprehensive study of children with NF-1 being cared for in a large multidisciplinary clinic to determine the prevalence of precocious puberty and its relationship to OPTs. This report consists of both a retrospective review of all cases of precocious puberty seen in our

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T a b l e I. Prevalence of precocious puberty in children with NF-1 who underwent neuroimaging

No tumor

Nonchiasmatic OPT

Chiasmatlc OPT

Table II. Growth and maturation in children with optic pathway tumors and paired control subjects OPT

Total

Girls 0/63 0/12 2/10 2/85 Boys 0/75 0/3 5/8 5/86 TOTAL 0/138 0/15 7/18 7/171 Cases of precociouspuberty/numberof childrenwith neuroimagingin each category.

program and a controlled, prospective study of the function of the hypothalamic-pituitary-gonadal axis in prepubertal children with NF-1 and OPTs. METHODS The Children's Memorial Hospital Neurofibromatosis Clinic is a multidisciplinary clinic that provides consultation services to assist in the diagnosis and management of neur0fibromatosis in children. All children are seen at least annually and are examined by a general academic pediatrician, a geneticist, and a pediatric ophthalmologist at each visit. Patients seen in this clinic between Jan. 1, 1985, and April 20, 1993, were the subjects of this study. NF-1 was diagnosed in each subject on the basis of the criteria established by the National Institutes of Health Consensus Development Conference. 9 During the period of study we routinely recommended neuroimaging, using a special imaging protocol for the diagnosis of OPTs, once the diagnosis of NF-1 was confirmed. Before 1988, computed tomography was performed; magnetic resonance imaging has been used exclusively thereafter. Optic pathway tumors were diagnosed on the basis of accepted criteria, l° Neuroimaging was not repeated in children without OPTs or other tumors unless neurologic, ophthalmologic, or neuroendocrine symptoms appeared. We reviewed the neurofibromatosis clinic records of all children seen during the study period to identify children with precocious puberty. The diagnosis of precocious puberty was based on the appearance of breast development before age 8 years in girls or on testicular enlargement before age 9 years in boys, and a pubertal luteinizing hormone response after intravenous injection of LH-releasing hormone (see below). We prospectively examined all prepubertal children (Tanner stage 111) between the ages of 2 and l0 years who had an OPT. Children were excluded if they had received radiation or chemotherapy (one child). Age- and sex-matched control subjects were recruited for each child with an OPT who was enrolled in the study. All control subjects had NF-1, normal neuroimaging, and a complete ophthalmologic evaluation no more than 2 years be-

3~5

No OPT

Height (cm) 118.0 (93.4-135.3) 106.0(93.2-124.5) Height standard -0.69 (-1.5-2.12) -1.13 (-2.71-0.46) score Bone age-height -0.055 (-2.06-3.03) -0.88 (-2.17-0.50) age (yr) Mid-parental 163.7 (152.0-173.5) 165.0 (157.3-172.6) height (era) Valuesare expressedas median(range); the two pairsof subjectsin which one member of the pair had a pubertalLH-RH responseare excluded. fore entry, and were matched for age (_+ 6 months) and gender. The study protocol was approved by the institutional review board of the Children's Memorial Institute for Education and Research and was conducted at the Northwestern University Medical School Clinical Research Center. Signed, informed consent was obtained from one or both parents of each subject. The following data were obtained from each subject: stadiometer height, weight, Tanner stage, parental heights, radiograph of the left hand and wrist for bone age, and gonadotropin levels. Height standard scores were calculated by the anthropometric program of the Centers for Disease Control and Prevention. 12 Bone ages were derived with the method of Tanner et al. 13 by an investigator who was unaware of the clinical history. Pituitary gonadotropin response to L H - R H was determined after intravenous injection of 100 #g LH-RH (gonadorelin hydrochloride [Factrel]). Serum samples for determination of LH and follicle-stimulating hormone were obtained before injection of LH-RH and 15, 30, 45, and 60 minutes after injection. Testosterone was measured in boys and estradiol in girls before LH-RH injection and 60 minutes after injection. We measured LH by a standard double-antibody radioirnmunoassay to the LH /3-subunit (Amerlex LH R I A Kit, Amersham Corp., Arlington Heights, Ill.). The lower limit of sensitivity of this assay is 2.5 mlU/ml. Using this assay, our laboratory has established that a peak LH level >20 m I U / m l is a pubertal response to LH-RH. The LH was also measured with a new, very sensitive LH immunochemiluminometric assay (normal range, 0.02 to 0.3 m l U / m l ) ] 4 which allows improved discrimination between unstimulated prepubertal and pubertal LH levels. The FSH, testosterone, and estradiol levels were measured by radioimmunoassay with established methods. RESULTS Two hundred nineteen children with NF-1 were examined during the period of study, and precocious puberty was

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The Journal of Pediatrics March 1995

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Figure. Serum LH levels (measured by radioimmunoassay) after intravenous injection of 100 #g LH-RH in 11 children with OPTs (dark circles) and their age- and sex-matched control subjects (clear triangles). diagnosed in seven of them (3%). All seven children who had precocious puberty had abnormal LH-RH test results. Of the 219 children, 171 underwent neuroimaging. All the children with precocious puberty had tumors involving the optic chiasm (Table I); they represented 39% of children with chiasmal tumors (95% confidence interval, 17% to 64%). Fifty-seven percent of the children without OPTs and 64% of the children with OPTs were younger than the cutoff age for precocious puberty (8 years for girls, 9 years for boys) when last seen in the clinic, and precocious puberty could conceivably still develop. The male/female ratio was 5:2 among children with precocious puberty, and 11:22 among children with OPTs (Fisher Exact Test; p = 0.145). Eleven prepubertal children with OPTs who were between the ages of 2 and 10 years (9 girls and 2 boys), and their age- and sex-matched control subjects were examined prospectively. None of the children without an OPT had a pubertal LH response to LH-RH. Two boys with OPTs had pubertal LH responses (Figure). In one, the tumor was confined to the optic chiasm, and an accelerated growth rate was noted at the time of evaluation; no other clinical signs of puberty were apparent. The other boy, who was 9.9 years of age at the time of testing, had a tumor confined to the intraorbital portion of the optic nerve. During the next 6 months he underwent normal pubertal maturation. Basal serum LH concentrations in the two boys with pubertal LH responses to LH-RH were ___2.5 mIU/ml, the lower limit of assay sensitivity by radioimmunoassay, similar to those in the prepubertal subjects. When the same specimens were analyzed by the L H - I C M A method, basal LH concentrations were elevated only in these same two boys (0.76 and 0.88 mIU/ml, respectively). Peak L H - I C M A concentrations in response to LH-RH in these two subjects were 12.0 and 13.0 mIU/ml, compared with

1.9 + 0.8 m l U / m l (mean _+ SD; range, 0.6 to 4.0 m I U / ml) in the prepubertal children. Testosterone concentration was > 10 ng/dl only in the two boys with pubertal L H R H responses. Estradiol levels were <0.5 ng/dl in all girls. The FSH levels did not differ in children with OPTs, in comparison with those in their matched control subjects (analysis of variance, p >0.05). The mid-parental height for children with OPTs did not differ from that for control subjects (paired t test, p = 0.87). The median height of children with OPTs (excluding the two pubertal children) was 118 cm, and the median height of the control subjects was 106 cm (paired t test comparing height standard scores, p = 0.09; Table II). There was no significant difference in the discrepancy between bone age and height age. DISCUSSION The main finding of this study is that precocious puberty was found exclusively in those children with NF-1 who had OPTs involving the optic chiasm. Previous reports of this association in the absence of OPTs may have erroneously included children with McCune-Albright syndrome, in whom caf6 au lait spots and precocious puberty may also occur. Saxena 3 reported two examples of precocious puberty occurring in NF- 1 without tumors of the optic chiasm, but neither computed tomography nor magnetic resonance imaging was available at that time, which leaves open the possibility of undetected tumors. Laue et al. 4 described four children with NF-1 and precocious puberty, three of whom had optic gliomas. No information is given as to how the absence of a tumor was conclusively proved in the fourth child. Precocious puberty occurred in 3% of our entire population of children with NF-1, markedly greater than its incidence in the general population of about 0.06%. 15, 16 Preco-

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cious puberty developed in 39% of the children with NF-1 who had tumors of the optic chiasm; this may underrepresent the true incidence, because many of the children in whom precocious puberty may develop are still very young. W e believe that these figures are generalizable and that our children with N F - 1 are representative of the N F - 1 population at large, because most were referred because of the presence of multiple caf6 au lair spots rather than for the more serious complications. In addition, 76% of the OPTs were discovered by screening neuroimaging rather than by the presence of symptoms), 10 These data indicate that such children should be followed very closely for the early signs of puberty, such as linear growth acceleration. We were able to identify one subject with precocious puberty before the development of obvious clinical signs. Conversely, we previously described two children with NF-1 in whom such signs led to the discovery of tumors of the optic chiasm. 17 The relationship of precocious puberty to the exact location of the tumor is unknown and has not been commented on in previous studies. All the children with clinical precocious puberty in our study had tumors involving the optic chiasm. Although almost half of our patients with optic pathway gliomas had tumors confined to the optic nerves, precocious puberty developed in none of them. This observation is consistent with the currently accepted theory that lesions located near the hypothalamus interfere with tonic central nervous system inhibition of the hypothalamicpituitary-gonadal axis, resulting in the premature onset of puberty.~8, 19 However, one of the two patients with a pubertal L H - R H test was a 9-year-old boy with a glioma confined to the intraorbital optic nerve; puberty developed shortly after study completion. Although his age- and sexmatched control subject did not have a pubertal response to L H - R H , this boy's relatively early entrance into puberty may have been physiologic rather than the result of the tumor. Previous studies of precocious puberty have involved children who already had clinical manifestations of puberty. The earliest hormonal manifestations of precocious puberty have never been studied. W e identified two children in whom the development of precocious puberty was a risk because of the presence of OPTs; before obvious pubertal signs developed, these children had pubertal L H responses to L H - R H , elevated basal L H - I C M A concentrations, and elevated levels of testosterone. In contrast, none of the control children had abnormal L H - R H tests. Thus the preponderance of evidence is that the precocious onset of puberty is due to the presence of OPTs rather than to NF-1 itself. W e conclude that precocious puberty is found exclusively in children with NF-1 who have OPTS involving the optic chiasm. Precocious puberty will develop in at least 39% of such children. With the use of a highly sensitive L H assay, biochemical evidence of premature activation of the hypo-

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thalamic-pituitary-gonadal axis may be found before overt signs of puberty, without the need for provocative testing with L H - R H . Children with NF-1 who have OPTs should be followed closely for signs of premature sexual development. We thank Mark Stene, PhD, of Endocrine Sciences, for the LH-ICMA measurements. REFERENCES

1. Listernick R, Charrow J. Neurofibromatosis type 1 in childhood. J PEDIATR 1990;116:845-53. 2. Riccardi VM. Type 1 neurofibromatosis and the pediatric patient. Curt Probl Pediatr 1992;22:66-106. 3. Saxena KM. Endocrine manifestations of neurofibromatosis in children. Am J Dis Child 1970;120:265-71. 4. Laue L, Comite F, Hench K, Loriaux L, Cutler GB, Pescovitz OH. Precocious puberty associated with neurofibromatosis and optic gliomas. Am J Dis Child 1985;139:1097-100. 5. Tertsch D, Schoen R, Ulrich FE, et al. Pubertas praecox in neurofibromatosis of the optic chiasm. Acta Neurochir Suppl (Wien) 1979;28(suppl):413-5. 6. Brauner R, Malandry F, Rappaport R, et al. Growth and endocrine disorders in optic glioma. Eur J Pediatr 1990; 149:825-8. 7. Iraci G, Gerosa M, Scanarini M, et al. Anterior optic gliomas with precocious or pseudoprecocious puberty. Childs Brain 1980;7:314-24. 8. Listernick R, Charrow J, Greenwald M, Mets M. The national history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J PEDIATR1994; 125: 63-6. 9. National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Bethesda, Maryland: The Institute, 1987:6. 10. Listernick R, Charrow J, Greenwald M J, Esterly NA. Optic gliomas in children with neurofibromatosis type 1. J PEDIATR 1989;114:788-92. 11. Tanner JM. Growth at adolescence. Oxford: Blackwell, 1962. 12. CDC anthropometric software package, edition 3.0. Atlanta, Georgia: Centers for Disease Control, 1987. 13. Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy M JR, Goldstein H. Assessment of skeletal maturity and prediction of adult height (TW2 method). 2rid ed. London: Academic Press, 1983. 14. Stene MA, Mayes D, Neely EK, Wilson DM. Usefulness of highly sensitive chemiluminescent gonadotropin assays in the diagnosis and treatment of central precocious puberty [Abstract]. Endocrinology 1993;132(suppl):92A. 15. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291-303. 16. Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13-23. 17. Listernick R, Charrow J, Greenwald M. Emergence of optic pathway gliomas in children with neurofibromatosis type 1 after normal neuroimaging results. J PEDIATR 1992;121: 584-7. 18. Grumbach MM, Kaplan SL. The neuroendocrinology of human puberty: an ontogenetic perspective. In: Grumhach MM, Sizonenko PC, Aubert ML, eds. Control of the onset of puberty. Baltimore: Williams & Wilkins, 1990:1-68. 19. Stein DT. Southwestern Internal Medicine Conference. New developments in the diagnosis and treatment of sexual precocity. Am J Med Sci 1992;303:53-71.