Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis type 1: a longitudinal study.

OBJECTIVE: This study prospectively evaluates parameters of growth, puberty, and attained adult height in children with sporadic or familial occurrence of neurofibromatosis type 1 (NF-1), followed up longitudinally, to define the most important factors affecting these parameters.

PATIENTS AND METHODS: The study was made up of 89 patients (55 boys, 34 girls) with sporadic (n = 45) or familial NF-1 (13 affected fathers and 31 affected mothers). The average age at referral was 8.9 years (range 8.5-15 years), and the average follow-up period was 8.5 years (6-15 years). A total of 28 patients attained adult height at the time of the report. Anthropometric measurements and bone age determinations were performed at 6- to 12-month intervals. As indicated, central nervous system (CNS) imaging was performed on 60 patients. Serum levels of thyroid stimulating hormone, free T4, lutheinizing hormone, follicle stimulating hormone, testosterone or estradiol, cortisol, and prolactin were measured in all patients periodically, and the pituitary growth hormone reserve was assessed in 32 short patients.

RESULTS: CNS pathology was found in 23 of the 89 patients. A total of 6 patients required neurosurgery, and 2 patients had cranial irradiation. Of these patients, 3 were receiving recombinant growth hormone and thyroxin replacement therapy and 5 patients with precocious puberty were treated with a gonadotropin-releasing hormone analog. All other patients had normal endocrine tests. Precocious puberty was recorded in 5 patients and was more common among the familial cases. The 5 patients with precocious puberty also had CNS pathology. Short stature (<10th percentile) was observed in 25.5% of the patients during the prepubertal period with a significant gradual reduction of their relative height for age (standard scores) during puberty. Short adult height was noted in 12 (43%) of 28 patients, and only 50% of the 28 patients attained an adult height that was appropriate for their respective target height. Short stature was more common among patients with familial NF-1, particularly if the father was affected, and among those patients with CNS pathology. Parental short stature was observed in 39% of the mothers and in 33% of the fathers (59% and 54% among the affected parents, respectively). Tall stature (>90th percentile) was observed in 4 of 89 patients (4.5%), who all had CNS tumors. A highly significant correlation was found among all adult height-predicting parameters (r =.79), and attained adult height was best correlated with the target height (r =.7; n = 28).

CONCLUSIONS: Short adult height is an important characteristic of NF-1 and deserves to be emphasized in the evaluation and follow-up of these patients during childhood. Short adult height is strongly linked with familial background of NF-1, in particular if the affected parent is the father, and is affected adversely by the relatively poor pubertal growth. Despite normal pituitary gland and thyroid function tests in most children and adolescents with NF-1, increased incidence of precocious puberty was observed. As the clinical expression in the second generation is more pronounced, the underlying mechanism seems to be mediated by genetic factors that are yet undefined.