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
A 21-year-old male patient presented to our dermatology clinic due to presternal papulopustular eruption, consistent with bacterial folliculitis. Dermatological examination revealed multiple café au lait macules along with a few asymptomatic subcutaneous soft papules on his shoulders and deltoid regions. Bilateral inguinal and axillary freckling were also present (Figure 1). Lisch nodules on both irides were seen in his ophthalmological examination. Based upon the presence of axillary and inguinal freckling, café au lait macules, and Lisch nodules, the patient was diagnosed with NF1. Further clinical examination and anamnesis did not reveal any other sign or symptom of NF1.
Dermatologic findings of patient 1. a) Numerous light brown colored patches-café au lait spots (thin arrows) on the back of the patient along with soft papules (bold arrow). b) Axillary freckling with an axillary café au lait macule. c) Close-up view of soft subcutaneous papules with a bluish hue (bold arrows).
After a few weeks, a 24-year-old female patient, the elder sister of the first case, presented at our clinic due to the recent diagnosis of her brother with NF1, although she did not have any specific complaints. Several asymptomatic light brown patches, café au lait spots, were visible on her abdomen, in the right lower quadrant, and on her right flank [Figure 2(a) and 2(b)]. The flexor surfaces of her right arm and forearm were covered with flesh-colored, painless non indurated continuous plaques [Figure 2(a)]. Her left arm was also hypertrichotic [Figure 2(c)]. A biopsy from the plaques revealed prominent immunohistochemical staining with S100, indicating a neural sheath tumor. Further opthalmological, neurological and orthopedic examinations revealed no additional pathology. The family medical history showed similar skin lesions in their paternal grandfather, father, uncle, aunt, cousins and brother. The pedigree is shown in Figure 3.
Dermatologic findings of patient 2. a, b) Numerous café au lait spots on the trunk and proximal part of the patient's thigh (black arrows), brown-colored soft plaques covered with terminal hair on the patient's left arm (white arrows). c) Close-up view of the arms showing hypertrichosis on the left arm.
Pedigree of the family, affected family members are indicated as black circles. Mutation analysis was performed only for III-6 and III-7 (proband).
Genomic DNA was isolated from peripheral blood samples using the QIAamp DNA Blood Mini kit (Qiagen GmbH, Hilden, Germany) according to the manufacturer's instructions. Next-generation sequencing (NGS) was performed on a MiSeq (Illumina Inc., San Diego, CA, USA), following the manufacturer's instructions for the
Electropherogram of the Sanger sequencing confirmed the mutation c.5392C>T, p.Gln1798Ter in exon 38 of the
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Here, we present two cases of NF1, a brother and a sister with c.5392C>T, p.Gln1798Ter mutation on the
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
To the best of our knowledge, this is the first case report with detailed clinical findings of NF1 with