Case Report for Two Siblings Carrying Neurofibromatosis Type 1 with a Rare NF1: c.5392C>T Mutation

Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder with a well-established autosomal dominant inheritance pattern and characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, choroidal freckling and iris Lisch nodules. While osteopenia, osteoporosis and scoliosis are major skeletal features, dsyplasia of the long bones, especially tibia and fibula, is a rare but distinctive feature of NF1. Vascular system involvement of NF1 can cause renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with hypertension. Most NF1 patients have normal intellectual functioning but learning disabilities, behavioral problems, and features of autism spectrum disorder can be seen [1]. While NF1 has a high penetrance, it is characterized by highly variable clinical expressivity. In some patients, skeletal changes and benign tumors of the neurocutaneous system with malignant potential are the cause of morbidity and mortality, while other patients present only with café au lait spots. Its incidence is approximately 1/2600–3000 individuals [2,3]. Approximately half of the cases are familial. Although there is no clear genotype-phenotype correlation, the severity of the phenotype is thought to be correlated with the reading frame truncation degree [4]. Neurofibromatosis type 1 is caused by mutations on the NF1 gene, located at chromosome 17q11.2. Neurofibromin is widely expressed in a variety of tissues, including the brain, kidney, spleen, thymus, functioning as tumor suppressor by inhibiting the activity of the RAS gene [5], regulating cell proliferation, survival and growth.

The NF1 gene spans 287 kb of chromosome 17q11.2 and comprises 57 constitutive and four alternatively spliced exons (9a, 10a-2, 23a and 48a) [7]. To date, the Human Gene Mutation Database has documented more than 2450 disease-causing NF1 variants, of which 745 are missense/nonsense [8]. In the Varsome database (https://vas=rsome.com/gene/nf1), 26.1% of reported class 1 NF1 variants (328/1254) are nonsense mutations [9]. In our analysis, a C>T transition at nucleotide 5392 in exon 38, causing a premature termination codon at codon 1798 instead of a glutamine codon, was detected.

Recently, Zhu et al. [10] reported a study of NF1 germline variants in patients with congenital pseudoarthrosis of the tibia (CPT). Screening 55 NF1 patients with CPT they found 44 NF1 variants, of which 25 were novel. They described a c.5392C>T, p.(Gln1798Ter) inherited mutation in one patient, but they did not present the patient's clinical characteristics [10].

Here, we present two cases of NF1, a brother and a sister with c.5392C>T, p.Gln1798Ter mutation on the NF1 gene. Neurofibromatosis type 1 has great clinical variability even between affected individuals of the same family with the same mutation. Our represented cases of siblings also show inter-individual variation; they have different features of skin pigmentation, and the sister has an additional neural sheath tumor. The prominent lesions of the brother were relatively benign café au lait macules, but the sister also had a plexiform neurofibroma, estimated to have a lifetime risk of 5.0% for malignant transformation [11]. We speculate that modifier genes, as well as epigenetic and environmental changes, might be the cause of the clinical variability.

Although NF1 is a monogenic disorder, its clinical variability is similar to multifactorial disorders and may be affected by epigenetic and environmental changes, modifier genes as well as second somatic mutations during tumorigenesis. As NF1 is expressed in a large variety of tissues, possible modifier genes have variable effects, such as actin cytoskeleton remodeling, cell signaling, intracellular trafficking, ubiquitylation, membrane localization, cell adhesion and neural differentiation [12]. In twin studies, it has been shown that plexiform neurofibromas tended to be less concordant, and it is explained by the two-hit hypothesis as many NF1-related tumors necessitate a second mutation on the wild-type NF1 allele [13]. Consistent with this view, the major phenotypic difference is plexiform neurofibroma between our cases.

To the best of our knowledge, this is the first case report with detailed clinical findings of NF1 with NF1: c.5392C>T mutation. Although NF1: c.5392C>T is a nonsense mutation, predicted to cause premature termination and a truncated neurofibromin protein, the clinical course of NF1 in our patients and their family is benign. Even though there is great intra-familial and inter-familial variability in NF1 phenotypes, we can speculate that with the effect of epigenetic and environmental changes and modifier genes, the NF1: c.5392C>T mutation did not cause a severe NF1 phenotype in this family.