Atypical hematologic and renal manifestations in neurofibromatosis type I: coincidence or pathophysiological link?

Eur J Med Genet. 2014 Nov-Dec;57(11-12):639-42. doi: 10.1016/j.ejmg.2014.09.001. Epub 2014 Sep 16.


Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors with a birth incidence rate of 1 in 2500-3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as café-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots café-au -lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C > A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.

Keywords: Acute myeloid leukemia; Blood disease; Nephrotic syndrome; Neurofibromatosis type 1; Proto-oncogene protein ras; Von Recklinghausen disease; mTOR serine threonine kinases.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Cafe-au-Lait Spots / diagnosis
  • Cafe-au-Lait Spots / genetics
  • Child
  • Humans
  • Male
  • Mutation, Missense
  • Nephrotic Syndrome / diagnosis*
  • Nephrotic Syndrome / genetics
  • Neurofibromatosis 1 / diagnosis*
  • Neurofibromatosis 1 / genetics
  • Neurofibromin 1 / genetics
  • Pedigree
  • Proto-Oncogene Mas


  • MAS1 protein, human
  • Neurofibromin 1
  • Proto-Oncogene Mas