Neurofibromatosis, though not discussed in depth, is not at all a clinical rarity. The condition has been reported in all races and does not exhibit specific clinical manifestations and features for occurrence. The hereditary nature has been recognized for long, though the depth of mutations is still a long way in short of understanding. It has got a chance occurrence of 50% mutation rate. It occurs with a frequency of 1 case in approximately 3000 births. Malignant transformation has been reported in a few cases, which underlines the importance of in depth analysis of this condition.
Neurofibromatosis is one of the most common hereditary neurocutaneous disorders with an incidence of 1:3000. It is autosomal dominant and shows no race or sex predilection.1 30 to 50% are de-novo cases occurring due to spontaneous mutations.2The condition first documented in 1882 by the German pathologist Frederich Von Recklinghausen presents with protean clinical manifestations.3This case is reported due to the severe facial hemi hypertrophy associated with neurofibromatosis.
A 12 year old female patient presented with swelling of left side of face since infancy. Swelling was first noted at one year of age after which it increased steadily and reached the present size. Speech was slurred. No family history of such a condition was observed. On extra oral examination severe hemi hypertrophy of the maxilla was noted with subsequent disfigurement of the face on account of deviation of the nose and mouth to the right (Fig 1). There was a soft painless mass on the left forehead measuring four centimeters in length and two centimeters in breadth. There was overgrowth of coarse, stiff hair on the mass. The skin showed patchy pigmentation. Left eye is pushed downwards and remained closed due to the pressure exerted by the mass (Fig 2&3). On palpation the mass was soft to firm with diffuse borders. No fixity to underlying tissue was noted. There was no associated regional lymphadenopathy. Cafe au lait spots (CALS) of size one to two centimeters and blue black in color were distributed over the trunk and palms of hands (Fig 4). There was a large CALS of size 10 X 15 centimeters in the back of trunk which was irregular with diffuse borders (Fig 5).
Intraoral examination showed a firm mass extending from right maxillary lateral incisor to left maxillary first premolar. The mass measured 3 X 2 centimeters in size and was firm and non – tender on palpation. Maxillary left central incisor was found embedded and the lateral incisor and canine were partially exposed. CALS were noted on the mass. Nodular masses were seen on the palate adjacent to right maxillary premolars, on the mass adjacent to right central incisor and on the left upper lip. There was hemi hypertrophy of the tongue and spacing of teeth on the left side resulting in malocclusion (Fig 6).
CT scan shows the lesion extended well in to the brain- cerebrum, frontal sinus, and eye, nasal and maxillary sinus (Fig 7). Preliminary hematological investigations including serum calcium and alkaline phosphatase were carried out and values were found within normal limits.
Incisional biopsy was performed from the anterior palate. Histopathological examination of H & E stained sections showed cells with elongated, bent nuclei separated by abundant, fine and sinuous collagen fibers. There is presence of nerve bundles, mild vascularity and areas of hemorrhage. Overlying epithelium is orthokeratinized stratified squamous epithelium of normal thickness (Fig 8&9). Diagnosis of neurofibroma was made. Patient was referred to the department of oral surgery for further treatment.
Present knowledge shows that neurofibromatosis consists of at least two diseases which show distinct clinical and genetic features, the peripheral form or neurofibromatosis 1 (NF1) and the central form or neurofibromatosis 2 (NF2). The more common one is the NF1. 4 This is autosomal dominant and 50% of cases are new mutations, 80% of which are of paternal origin. The NF1 gene, one of the largest in the human genome is a tumor suppressor gene located in the pericentromeric region of chromosome 17. It encodes the neurofibromin protein which consists of 2800 amino acids. Due to the large size of the gene and numerous mutations that may occur genetic testing is not a viable option in diagnosis. A protein truncation assay is used to detect stop mutations but this confirms the disease only in two thirds of cases and cannot predict the severity. 5,6 Diagnosis is confirmed if two or more of the diagnostic criteria are present. (Table 1) Hence clinical findings are imperative.
Accurate correlations between the genotype and phenotype have not been possible because of the large size of the gene. Still it has been found that the severity of the condition increases with complete gene deletions with occurrence of large numbers of neurofibromas and a significantly higher lifetime risk for malignant peripheral nerve sheath tumors. Familial spinal neurofibromatosis corresponds with mutations at the 3’ end of the gene. Somatic mosaicism may account for the segmental forms of neurofibromatosis.5
The clinical manifestations are first seen in childhood as small macules resembling freckles which slowly increase in size and deepen in color. Microscopically melanin pigment is seen in macromelanosomes. The number of cafe au lait spots indicates the severity of the disease. In mild forms with fewer spots the neurofibromas occur late in life and may also be restricted to one part of the body. Secondary symptoms may arise due to occurrence of neurofibromas. An abrupt increase in size may indicate malignancy or may be due to pregnancy or onset of puberty.7The central nervous system may be affected with neurofibromas example the optic nerve glioma.8 The skeleton may be affected due to primary defects and also pressure effect from the tumors. Cystic lesions are noted within the bones histologically resembling non-ossifying fibroma.9 Renovascular hypertension occurs due to vascular stenosis. The varied symptoms of neurofibroma include growth disorders, abnormal sexual development and lung abnormalities. Certain forms of neurofibroma shows atypical or incomplete features compared to the classic form. These variants are segmental neurofibroma, gastrointestinal neurofibroma, familial spinal neurofibroma and familial cafe au lait spots.8
Neurofibroma is a disease with diverse characteristics. Early diagnosis aids in proper monitoring of patient. Genetic counseling is also required in familial cases. Frequent reviews are needed as there is possibility of development of malignant peripheral nerve sheath tumor (MPNST) in a subset of NF1. Proper histologic evaluation is essential as it is difficult to differentiate a neurofibroma with atypical histologic features from a low grade MPNST.
Germ-line mutations in genes encoding RAS-ERK signaling pathway components cause a set of related, autosomal dominant developmental disorders, termed “RASopathies” , which include Noonan syndrome . Noonan syndrome with multiple lentigenes (NS-ML; formerly known as LEOPARD syndrome), cardio-facio-cutaneous syndrome (CFCS), Costello syndrome (CS), and neurofibromatosis type 1 (NF-1). RASopathy patients typically display short stature, facial dysmorphia, cardiac defects, developmental delay, and other variably penetrant features. 10
Neurofibormatosis and concomitant symptoms are always associated with numerous manifestations. The condition including von Recklinghausen disease has to be understood in depth for proper diagnostic criteria and treatment protocols. Though, significant steps has been taken for analyzing the molecular pathway and genetic mutations involving the conditions, the finer details are still out of light as far as molecular origin and pathway is concerned. An extensive discussion and deliberation is needed in this regard so that debility and mortality rate