We thank Hannah-Shmouni and Stratakis1 for their comment on our clinical practice resource on the care of adults with neurofibromatosis type 1 (NF1)2. We agree that growth hormone excess resulting in subclinical gigantism or acromegaly is generally underrecognized by clinicians. We also agree that many of the published accounts of growth hormone excess and clinical consequences in NF1 have been reported in children. As noted in the Methods of our clinical practice resource, we focused on common and emerging NF1-related clinical problems and emphasized studies that investigated populations, multi-institution clinic cohorts, and large case series. We could not address all potential comorbidities, such as growth hormone excess in NF1 adults, so we focused on those with a large published reference base and that in our clinical experience are more common.
As the authors note, growth hormone excess in NF1 is particularly intriguing from an endocrine perspective because it can arise from a pituitary or an optic tract tumor. In the latter situation, growth hormone excess may stem from a hypothalamic regulatory defect.3 In children with NF1, growth hormone excess has been reported to be a transient phenomenon and thus may not need treatment.4,5 Although gigantism and acromegaly in NF1 are rare, childhood overgrowth secondary to NF1 microdeletion has been recognized for many years.6,7 Its pathogenesis may involve other genes (such as RNF135 or SUZ12) at the NF1 locus and not NF1 itself.8,9 As noted in our clinical practice resource,2 people with an NF1 deletion are also at increased risk for malignant peripheral nerve sheath tumor and intellectual disability.
The role of growth hormone itself in the etiology of NF1 microdeletion–associated overgrowth, if any, is unknown. Similarly, the reporting of NF1 genotype (or deletion) in published reports of NF1-associated growth hormone excess, acromegaly, or gigantism is uncommon.10 In this respect, the report of germline NF1 genotypes (one missense, one truncating) by Hannah-Shmouni et al. of two patients with NF1 and growth hormone excess is useful, even in abstract form.11
In summary, Hannah-Shmouni and Stratakis are correct that growth hormone excess in NF1 is rare, easily overlooked, and merits additional phenotype and genotype investigations.
References
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Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:671–82.
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Douglas J, Cilliers D, Coleman K, et al. Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat Genet. 2007;39:963–5.
Ferrari L, Scuvera G, Tucci A, et al. Identification of an atypical microdeletion generating the RNF135-SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth. Hum Genet. 2017;136:1329–39.
Martini AE, Zolton JR, DeCherney AH. Isolated absent thelarche in a patient with neurofibromatosis type 1 and acromegaly. Obstet Gynecol. 2018;131:96–99.
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D.A.S. has been a consultant for and received compensation from Lineagen, Alexion, and GLG. B.R.K. has been a consultant for Novartis and received a travel grant from AstraZeneca. The other authors declare no conflicts of interest.
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Stewart, D.R., Korf, B.R., Nathanson, K.L. et al. Response to Hannah-Shmouni and Stratakis. Genet Med 21, 1256 (2019). https://doi.org/10.1038/s41436-018-0313-0
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DOI: https://doi.org/10.1038/s41436-018-0313-0