Neurocutaneous manifestations of Neurofibromatosis type-1: Imaging findings and Review of literature

2015-05-14 17:04:00

Category: Neuroradiology, Region: Upper extremity-Nerves, Plane: Axial

ABSTRACT Neurofibromatosis type-1 or Von Recklinghausen disease is a multisystem neurocutaneous disorder and the most common phakomatosis. One of the main characteristics of this disease is systemic and progressive involvement with impaired neurological functions. It is characterised by predominantly neurocutaneous features such as cafe-au-lait spots, axillary freckling, skeletal dysplasias, benign and malignant neurofibromas. We report a case of an 18 yrs old male patient who came to department of radiodiagnosis for imaging evaluation of nodular lesions on both upper limbs and lower limbs associated with sensory and motor weakness. Imaging findings revealed multiple cutaneous and subcutaneous neurofibromas involving peripheral and autonomic nerves appearing as small soft tissue skin nodules clinically. We discuss the clinical, pathological and radiological appearances of neurofibromatosis and brief review of the available literatures in the present case report. CASE REPORT An 18 yrs old male patient presented with multiple hyperpigmented macules and small nodular lesions all over his body. He also complained of pain, motor and sensory weakness in bilateral lower limbs and was referred to the department of radiology for imaging evaluation. He had developed limp in his right leg one year back. There was no history of seizures or neurological deficit. He was well oriented with normal cognitive functions. On clinical examination: multiple soft to firm cutaneous nodules were seen more so in bilateral upper and lower limbs ranging from a few millimeters to several centimeters in diameter. (fig.1) Multiple cafe-au-lait spots with diameter > 1.5 cms were also noted. (fig.2) Bilateral foot drop was seen with zero motor power in extensor hallucis longus and tibialis anterior muscles. (fig.3) Ophthalmological evaluation revealed iris lischs nodules in both eyes without clinical visual involvement. (fig 4) Optic nerves were normal with no evidence of gliomas or retinal astrocytomas. ENT examination and nerve conduction study were unremarkable. He had positive family history with presence of cafe-au-lait spots and lischs nodules in his mother. • USG of upper limbs showed multiple well marginated discrete as well as conglomerated nodular soft tissue lesions giving target appearance i.e. central hyperechogenicity with hypoechoic periphery involving the ulnar, median nerves in the wrist (fig.5,6), intercostals nerves (fig.7 A&B), posterior tibial, peroneal nerves in the legs bilaterally (fig.8,9) and also in pelvis involving sacral plexus. The involved nerves were thickened and showed fusiform enlargement. • MRI both forearms with wrist, pelvis with both lower limbs showed multiple nodular lesions along the course of median nerves, ulnar nerves (fig. 10,11) and sacral plexus (fig. 13), common peroneal nerves, tibial nerves respectively suggestive of deep nodular neurofibromas. Lesions appeared as hypointense on T1 weighted and heterogeneously hyperintense on T2 weighted images giving ‘target sign’ i.e. central hypointensity surrounded by peripheral hyperintensity (fig.14). Post-contrast T1W sequences showed significant enhancement of the nodular lesions (fig.12). No significant abnormality was detected in MRI brain (fig.15,16). In addition to USG, MR of extremities, pelvis and thorax, skeletal survey including radiographs of chest, hands, spine and pelvis were done. X-ray thorax showed bilateral ribbon ribs (fig.17 A&B) and inferior rib notching (fig.7 B). Mild scoliosis of upper dorsal spine was also noted (fig.18). Radiographs of lumbar spine and limbs showed no significant abnormality. NCCT pelvis showed widening of bilateral sacral foramina (fig.19). Our patient fulfilled four diagnostic criterias i.e. Six or more cafe-au-lait macules, multiple neurofibromas, lisch nodules and positive family history of the disease (mother). Based on the clinical, radiological and histopathological findings (fig.21), the patient was diagnosed with Neurofibromatosis type -1. DISCUSSION Etiopathogenesis and demographics: The phakomatoses are a group of congenital disorders characterised by skeletal dysplasias and neoplasias of tissues arising from the embryonic ectodermal plate (involving skin, CNS, PNS and eyes) and to a lesser degree structures derived from the mesodermal layer (including bone, cartilage and blood vessels) and the endodermal layer. Due to predominant ectodermal involvement, these are also known as congenital neuroectodermal dysplasias or neurocutaneous syndromes [1]. Neurofibromatosis (NF) is a hereditary congenital disorder probably of neural crest origin that affects all 3 germinal layers. NF is not a single entity but a group of heterogenous neurocutaneous disorders involving neuroectodermal, endodermal and mesenchymal derivatives. Two types of neurofibromatosis are widely recognised: Type-1 (NF-1) and type 2 (NF-2). Commonest of these is NF-1 or Von Recklinghausen disease. Both types are inherited as autosomal dominant disorders with NF-1 having a penetrance of almost 100% and spontaneous mutation rate of about 50% [2]. With a prevalence of 1:3000-1:5000 individuals, NF-1 is over 10 times commoner than neurofibromatosis type-2. There is no ethnic or gender predilection. No specific risk factors for NF-1 have been reported. NF-1 is diagnosed on the basis of well established diagnostic criteria which is listed in Table I. • Six or more cafe-au-lait macules (diameter > 5 mm in prepubertal patients and > 15 mm in postpubertal patients) • Two or more neurofibromas or one plexiform neurofibroma • Axillary or inguinal freckling • Optic glioma • Two or more Lisch nodules (iris hamartomas) • A characteristic osseous lesion (sphenoid) dysplasia or cortical thinning of long bone, with or without pseudoarthrosis • First-degree relative (parent, sibling or child) with NF-1 Table I : Criteria for NF-1 (two or more of the following) Neurofibromin, the NF-1 gene protein product, located on the long arm of chromosome 17, is a tumor suppressor gene [3]. It is a regulator of Ras GTPase activity [4]. The loss of its function leads to uncontrolled cell proliferation. Schwann cells and melanocytes have a mutation in both NF-1 alleles, thus are abnormally proliferated in this condition. Clinical findings: In an affected individual of NF-1, the criteria set by the NIH Consensus Conference are met [5]. (Table-1) Prominent oculocutaneous manifestations are cafe-au-lait spots, cutaneous and subcutaneous neurofibromas, iris hamartomas, axillary or inguinal freckling and optic gliomas. NF-1 has a much early age of onset with approximately 50% of patients meeting the diagnostic criteria for NF-1 by the age of 1 year and approximately 97% meeting the criteria by the age of 8 years [6]. Signs and symptoms of NF-1 can vary widely from patient to patient. The earliest clinical finding usually seen in children with NF-1 is multiple cafe-au-lait spots. Cafe-au-lait spots are oval/round smooth bordered hyperpigmented flat macules. Hamartomas of the iris (lisch nodules) appear as reddish brown spots in blue or green coloured eyes and hypopigmented spots in brown eyes. Neurofibromas are benign NSTs appearing as discrete swellings arising from peripheral nerves [7]. Generally, the cutaneous/dermal tumors are dome-shaped, soft, fleshy and skin-coloured to slightly hyperpigmented while subcutaneous ones are firm and nodular. Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents and adults. When the neurofibromas develop in the subcutaneous nerves, they may lead to chronic disabling pain and may degenerate into MPNSTs. Spinal neurofibromas are a source of neural or spinal cord compression. These may cause radicular symptoms including pain, sensorymotor weakness and mononeuropathies [8]. Despite a considerable range of complications related to PNSTs in NF-1, the prevalence of peripheral nerve involvement in NF-1 is considered rather low in large clinical studies, ranging from 0 to 4.3%. There is an association between peripheral neuropathy and subcutaneous neurofibromas. A study depicted the potentially poor prognosis of patients with NF-1 associated neuropathy and subcutaneous neurofibromas [9]. Other CNS manifestations of NF-1 are optic nerve glioma, UBOs, hydrocephalus and meningocoele. All these features were not present in our case. Osseous lesions like thoracic scoliosis, posterior vertebral scalloping, tibial bowing, pseudoarthrosis and ribbon ribs have been described. Vascular lesions may occur resulting in arterial hypertension and aneurysm formation. Imaging findings: Ultrasound, CT and MRI can be useful in the noninvasive diagnosis and characterization of neurofibromatosis. Plain radiographs may detect a variety of subtle as well as obvious bony abnormalities like neural foraminal widening, thoracic scoliosis, posterior vertebral scalloping, tibial bowing, pseudoarthrosis and ribbon ribs associated with NF-1. On ultrasound, most PNSTs are hypoechoic, sometimes mimicking cystic lesions. However peripheral nerve continuity is diagnostic [10]. CT has a role in the investigation of thoracic, abdominal and pelvic complications of NF-1. CT scans demonstrate neurofibromas as hypodense solid fusiform masses in the distribution of nerves, with central areas of low attenuation and calcification. Low attenuation is due to myelin lipid content, fat entrapment and high water content in endoneurial myxoid tissue. These masses may present in the paravertebral, mediastinal, abdominal, pelvic/ischiorectal fossae and limbs. Paraspinal neurofibromas are commonly dumbbell shaped /fusiform/spherical soft-tissue masses which may enlarge the exiting foramina. MRI is the most useful imaging modality to characterize tumour extent and suggest neurogenic origin due to its high contrast resolution and multiplanar capabilities [11]. PNSTs typically show T1 hypointensity & homogenous T2 hyperintensity or characteristic target sign with a central hypointensity surrounded by peripheral hyperintensity, oriented longitudinally along the nerve [12]. This sign is due to a dense central area of collagenous stroma. On post contrast images, they show heterogenous intense enhancement. T2 high-signal intensities within the brain (globus pallidus and cerebellum) are recognized as UBOs on MRI, a common finding in children with NF-1. Treatment and prognosis: Patients should be routinely monitored for complications because of the possibility for generalized involvement of other organs. Usually, there is no need for treatment of cafe-au-lait spots, which are common in NF-1. Neurofibromas that press on vital structures, obstruct vision or grow rapidly deserve immediate attention. Small neurofibromas can be treated using laser surgery. Chemotherapy, radiation therapy or both may be used to treat malignant tumors but with the avoidance of radiation therapy when possible, due to the increased risk of secondary malignancies. Surgery may be required for severe cases of scoliosis and pseudoarthrosis to realign the bones of the spine. Life expectancy in NF-1 is approximately 8 years lower than the general population. [13]. Lifetime risks for both benign and malignant tumors are increased in NF-1 affected individuals. Conclusion: The patient described here is a typical case of NF-1, which presents a considerable interest because of the high generalization of the skin lesions. The proper clinical and genealogic analysis is important for the determination of the genetic risk and prognosis for the relatives of the proband. Although there is a paucity of available medical treatments but ongoing trials hold promise in treating both cutaneous and non-cutaneous manifestations of NF-1.