Growth in neurofibromatosis 1 microdeletion patients

Abstract

Microdeletions of the entire NF1 gene and surrounding genomic region occur in about 5% of patients with neurofibromatosis 1 (NF1). NF1 microdeletion patients usually have more cutaneous and plexiform neurofibromas and a higher risk of developing malignant peripheral nerve sheath tumors than other people with NF1. Somatic overgrowth has also been observed in NF1 microdeletion patients, an observation that is remarkable because most NF1 patients are smaller than average for age and sex. We studied longitudinal measurements of height, weight, and head circumference in 56 patients with NF1 microdeletions and 226 NF1 patients with other kinds of mutations. Although children with NF1 microdeletions were much taller than non-deletion NF1 patients at all ages after 2 years, the lengths of deletion and nondeletion NF1 patients were similar in early infancy. NF1 microdeletion patients tended to be heavier than other NF1 patients, but height or weight more than 3 standard deviations above the mean for age and sex was infrequent in children with NF1 microdeletions. Head circumference and age of puberty were similar in deletion and non-deletion NF1 patients. The pattern of growth differs substantially in deletion and non-deletion NF1 patients, but the pathogenic basis for this difference is unknown.

Emerging genotype–phenotype relationships in patients with large NF1 deletions

“…In a study of 21 patients with type-1 NF1 microdeletions, overgrowth was most evident in preschool children (2–6 years, n  = 10) (Spiegel et al 2005). These findings were confirmed by Ning et al (2016) who performed longitudinal growth measurements in 56 NF patients with NF1 microdeletions and 226 NF1 patients with intragenic NF1 mutations. Most height measurements in 2–18-year-old boys and girls with NF1 microdeletions were greater than the median observed in non-deletion NF1 patients.…”

“…More appropriate would have been a methodical comparative analysis of a large number of age-matched patients with and without germline type-1 NF1 deletions investigated by standardised analytical tools. Although such comparative analyses have been attempted to assess differences in height (Ning et al 2016), cognitive capability (Descheemaeker et al 2004) or the frequency of cardiovascular anomalies (Nguyen et al 2013), they have not as yet been performed methodically in the context of the number of neurofibromas and other NF1 microdeletion-associated clinical features.…”

“…Most height measurements in 2–18-year-old boys and girls with NF1 microdeletions were greater than the median observed in non-deletion NF1 patients. However, extreme body height (more than three standard deviations above the mean) was still unusual among patients with NF1 microdeletions (Ning et al 2016). These authors also showed that children with NF1 microdeletions were usually much taller than non-deletion NF1 patients after the age of 2 years.…”

“…These authors also showed that children with NF1 microdeletions were usually much taller than non-deletion NF1 patients after the age of 2 years. In early infancy, before the age of 2, the body length of microdeletion and non-deletion NF1 patients was found to be similar (Ning et al 2016). The reasons for these differences in growth pattern are currently unknown.…”

Growth hormone excess in children with neurofibromatosis type‐1 and optic glioma

“…A prevalence of GH deficiency of 2.5% has been reported (Cnossen et al, ) and the loss of a critical role of neurofibromin in hypothalamic‐pituitary axis function was hypothesized as the pathogenic basis of this phenomenon (Hegedus et al, ). By contrast, mild somatic overgrowth has been observed in some NF1 microdeletion patients (Ning et al, ). In children with NF1 and OPG, central precocious puberty (CPP), leading to transient rapid growth with reduced final height, is considered the most common endocrinopathy (Habiby, Silverman, Listernick, & Charrow, 1995) and only few cases of GH excess (GHE), mainly associated to CPP, have been reported (Costin, Fefferman, & Kogut, ; Crawford & Buckler, ; Duchowny, Katz, & Bejar, ; Manski, Haworth, Duval‐Arnould, & Rushing, ; Fuqua & Berkovitz, ; Drimmie et al, ; Drake, Lowis, Bouffet, & Crowne, ; Main, Sehested, & Feldt‐Rasmussen, ; Josefson, Listernick, Fangusaro, Charrow, & Habiby, ; Bruzzi, Sani, & Albanese, ).…”