Neurofibromatosis type 1 (NF1) is a relatively common inherited disorder. It is a genetic disorder representing one of the most common forms of Von Recklinghausen’s disease. The neurofibromatoses comprise a trio of diverse disorders known as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. It is an autosomal dominant disease with the development of «café-au-lait» skin macules, benign tumors affecting the skin, peripheral nerves, optic pathway, and can involve the brain, bones, and vessels. It is characterized by a large clinical polymorphism. Previous studies reported that almost all patients with multiple «café-au-lait» macules will eventually develop NF1 based on clinical criteria, recent studies and clinical observations suggest that a significant percentage of them do not have NF1. The severity of the disease is related either to the malignant transformation or to the internal locations, in particular intracerebral, optic, and medullary pathways with the risk of neurological disorders, blindness, or spinal cord compression. A multidisciplinary approach is necessary to its management, with a team of specialists throughout the lifetime of the patient

We report the case of an 8-year-old child. He presented with a left supraclavicular mass of progressive evolution for more than two years. The medical history does not find any family history of the condition. The skin assessment found multiple «café-au-lait» spots and skin nodules (Figure 1) which appeared on ultrasound examination as heterogeneous mass with echogenic formations (Figure 2).

A cervicothoracic computed tomography (CT) scan was ordered to investigate the mass. The scan revealed multiple dense nodular formations above the clavicle, extending into the subscapular and left axillary regions. There was an anterior mediastinal and right paravertebral extension without intramedullary extension (Figure 3 and Figure 4).

We then completed the examination with cervicothoracic magnetic resonance imaging (MRI) that showed: the same mass in low signal intensity at T1, hyperintense on T2, T2 Spair and non-enhancing after gadolinium administration, with no further foraminal extension or spinal cord compression. A target sign pathognomonic for plexiform neurofibroma is visible as central low intensity surrounded by a rim of high intensity (yellow arrows in Figure 5). The child had no eye disorders or other associated abnormalities. No abnormality of brain MRI identified. A biopsy of the supraclavicular mass was performed. Histological analysis showed neurofibromatosis with no evidence of degeneration. The rest of the examinations (ophthalmological and neurological) did not reveal any significant abnormalities.

Given the association of «café-au-lait» skin spots, the presence of nodular lesions of the neurofibroma type, and histological confirmation, the diagnosis of neurofibromatosis type 1 was retained. The child was referred for multidisciplinary management.

Neurofibromatosis type 1 (NF1) is the most common phakomatosis. It is an autosomal dominant genetic disease caused by a mutation in the gene coding for neurofibromin synthesis which is a tumor suppressor gene on chromosome 17. Its incidence is approximately 1 in 2500 births and its prevalence 1 in 2000–4000 births [1]. It was recognized as a multisystem clinical entity in 1882 by Friedrich von Recklinghausen who gave his eponymous name to the disease (von Recklinghausen disease or NF1) [2]. There is no difference in the involvement of races or gender.

There are clear diagnostic criteria according to a consensus (two or more criteria for diagnosis) [3],[4]:

An individual who lacks a parent with an NF1 diagnosis can meet the diagnostic criteria for NF1 if two or more of the following conditions are fulfilled:

1. Prepubertal individuals with six or more caféau-lait macules, each measuring over 5 mm in greatest diameter, and postpubertal individuals with those measuring over 15 mm in greatest diameter.
2. Freckling observed in the axillary or inguinal regions.
3. Presence of two or more neurofibromas of any type, or a single plexiform neurofibroma.
4. Identification of an optic pathway glioma.
5. Identification of either two or more iris Lisch nodules through slit lamp examination, or the presence of two or more choroidal abnormalities (CAs), characterized as bright, patchy nodules visualized by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging.
6. Occurrence of a distinct osseous lesion, such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone.
7. Identification of a heterozygous pathogenic NF1 variant, with a variant allele fraction of 50% in apparently normal tissue, such as white blood cells.

If one or more of the criteria listed in paragraph below are present, a child of a parent who satisfies the specified diagnostic criteria qualifies for an NF1 diagnosis.

Neurofibromatosis type 1 is characterized by polymorphic and multisystem involvement. These abnormalities are varied [3],[5]:

- Benign abnormalities are pigmentation abnormalities including «café-au-lait» spots that develop during the first two years of life. It is associated with axillary and inguinal freckles and Lisch nodules (benign melanocytic hamartoma of the iris).

Also mentioned are neurofibromas, a benign Schwann cell tumor of variable composition, and plexiform neurofibromas (which may begin at birth and develop into adulthood).

- Bone anomalies (congenital bone dysplasia, pseudoarthrosis, scoliosis).

- Cardiovascular anomalies (congenital heart disease, valvulopathy and hypertension).

- Nervous system tumors (gliomas of the optic tract and brain stem, neurocognitive deficits, glioblastomas, malignant tumors of the peripheral nerve sheath).

- Other tumors (gastrointestinal stromal tumors, breast cancer, leukemia and lymphoma, pheochromocytoma, duodenal carcinoids, rhabdomyosarcoma).

Different radiological means are used for diagnosis, in particular the CT scan for the detection of neurofibromas and cerebral lesions, the MRI which has a better accuracy in the detection of intramedullary extensions, cerebral lesions and optic tracts, the standard radiography for the detection of bone lesions, the NIR spectroscopy (near-infrared reflectance spectroscopy) for the visualization of intraocular lesions.

Genetic testing for NF1 diagnosis, searching for inactivating mutations in the NF1 gene is essential for the diagnosis. It allows making the differential diagnosis with the Legius syndrome by the detection of the gene SPRED1.

The role of imaging is important and threefold: firstly, to confirm the diagnosis, secondly, to delineate extent of disease (extent of involvement and effect on adjacent structures), and thirdly, suggests the type of the tumors in the affected patient. Three modalities can be used: ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI).

The significant contribution of sonography to the assessment of soft tissue tumors, particularly plexiform neurofibromas, tends to be inadequately emphasized in radiology literature [6] .

The characteristic CT characteristics of plexiform neurofibroma are often associated with low attenuation, attributed to the presence of myelin lipids, trapped fat, and the high water content within the endoneurial myxoid tissue. Evaluating potential bony involvement (osseous remodeling) is crucial in these cases [6],[7].

Magnetic resonance imaging (MRI) stands as the gold standard imaging technique for both assessing neural tissues and outlining the parent nerve in instances of tumors with neural origins. The tumor has been described as being characteristically lobulated with a hyperintense signal on T2W imaging. The presence of a “target sign” has been identified as a distinctive marker for plexiform neurofibromas, where each individual “target” area is thought to represent an involved nerve fascicle. Within the lesion, there exists a central region of reduced intensity, encircled by a zone of heightened intensity, particularly when aligned along the nerve’s longitudinal axis. The central low intensity is attributed to the fibrous constituents, while the encompassing myxoid components contribute to the intensified signal [6],[7].

The differential diagnosis is mainly with other types of neurofibromatosis type 2 and other pathologies such as schwannomatosis, Legius syndrome, Noonan syndrome, constitutional mismatch repair deficiency syndrome [1]. Legius syndrome or NF1-like is characterized by the presence of «café-au-lait» spots and lentigines, which may be associated with macrocephaly, facial dysmorphia, and cognitive disorders. It is autosomal dominant and therefore shares a number of diagnostic criteria with neurofibromatosis type 1. On the other hand, neurofibromas, Lisch nodules, and gliomas are absent, thus significantly reducing the risk of tumors. The gene involved (SPRED1) is located at 15q13.2 and consists of 7 exons [4].

Treatment requires a multidisciplinary team based primarily on the severity of the symptoms and the different organ involvement. Surgical treatment of neurofibromas is difficult due to infiltration, with therapeutic trials with Imatinib chemotherapy, interferons. Surgical treatment is recommended for optic tract gliomas with severe visual loss, disfiguring proptosis. Other combinations of carboplatin-based chemotherapy with vincristine remain the gold standard in the treatment of low-grade gliomas [5]. As per Gross et al., in April 2020, selumetinib was approved for the treatment of children with NF1-related symptomatic plexiform neurofibroma in the United States [8].

The evolution of NF1 associated with the optic tract glioma after chemotherapy is approximately one-third and the patient will regain vision after treatment. These visual impairments in NF1 reduce life experience by 10–15 years [5].

The most common cause of death in NF1 is cancer. Patients with NF1 have a 5-fold increased risk of cancer and a 2000-fold increased risk of neurogenic malignancy compared to the general population [9].

Neurofibromatosis type 1 remains a disease with multiple and variable visceral involvement. Ocular involvement results in uni- or bilateral visual loss. Early diagnosis is essential for good management and to avoid irreversible complications in order to improve patients’ quality of life.

It requires multidisciplinary management and close collaboration between radiologists and clinicians in order to reduce the morbidity and mortality associated with NF1.

Neurofibromatosis type 1 is the most common autosomal dominant genetic disease. It is a pathology with multiple and variable visceral damage. The presence of characteristic cutaneous features and certain types of tumors should raise suspicion for the possibility of NF1 and prompt clinicians to refer patients to the appropriate specialists. A notable proportion of patients who initially present with solitary «café-au-lait» macules may not necessarily have NF1. Genetic testing could offer valuable insights to steer the subsequent care for these patients, but additional evidence is necessary to formulate concrete recommendations. Genetic counseling to families could also be greatly improved by the knowledge of the true presence or absence of NF1 in a child. Early detection is crucial for quality care and reduction of disability, enhancing the importance of diagnostic criteria. Strong collaboration between radiologists and clinicians of different subspecialties from making an early diagnosis and multidisciplinary management up to the follow-up is valuable to offer a quality of care and therefore improve morbidity and mortality.