Clinical Aspects of Neurofibromatosis Type 1

#### **Chapter 2**

## Bone Lesions in Children with Neurofibromatosis

*Nikolaos Laliotis*

#### **Abstract**

Neurofibromatosis is often related with severe orthopaedic disorders in children. Bone lesions are rare but pose severe difficulties in management. It affects the spine and long bones. Lesions are associated either from enlargement of neurofibromas that affect the normal growth or from primary neurofibromatosis of long bones. Dystrophic scoliosis appears with short curves, with kyphosis and rotation of the apical vertebrae. Usually affect the thoracic spine, with penciling of the ribs. Surgical treatment is challenging in cases of rapid progression. Scoliosis may appear with curvatures similar to those in idiopathic scoliosis, without dysplastic changes of the vertebrae. Anterior bowing of the tibia is manifestation of NF and is distinguished from the benign posterolateral bowing. Evaluation of the medullary canal and presence of cystic lesions in the tibia is essential. Progression to pseudoarthrosis or pathologic fracture is common. Surgical management of tibial pseudoarthrosis remains a difficult procedure. Pseudoarthrosis may appear in fibula, radius or ulna but are extremely rare. Irregular eccentric bone cysts in long bones that are commonly diagnosed after a pathologic fracture, must be differentiated for NF. Malignant transformation of neurofibromas must be considered when there is rapid progression of the lesion.

**Keywords:** Scoliosis, dystrophic scoliosis, surgical management, spine in neurofibromatosis, spinal instrumentation, Congenital pseudoarthrosis tibia, fibula, radius, ulna, Idiopathic non-union tibia, fibula, radius, ulna, Neurofibromatosis tibia, fibula, radius, ulna

#### **1. Introduction**

Neurofibromatosis is a hereditary autosomal dominant disease associated with abnormal increase of neural cells, both from the central and peripheral nervous system. Children and adults are affected from the disease.

Orthopaedic manifestations of NF in children are found in the spine and the long bones. Alterations of the normal shape of the spine both in the frontal and sagittal plane appear, in the form of dystrophic and non-dystrophic scoliosis and kyphosis. It is unclear the exact mechanism for development of scoliosis is NF, as in general for scoliosis. Vertebral neurofibromas can erode the vertebrae either from the interior or the exterior, resembling congenital hemivertebra. Vascular and osteoblastic dysfunction may alter the shape of the vertebrae. Diagnosis of NF is based on the clinical criteria that include the dysplasia of long bones and spine lesions. Radiological evaluation both of x-rays and MRI and is important to properly follow the affected children. Management of dystrophic curves is a challenge for the pediatric spine surgeon.

Neurofibromatosis lesions of long bones are extremely rare, affecting usually the tibia and fibula in the lower limbs and radius and ulna in the upper limb. They appear with the form of congenital pseudoarthrosis. Treatment requires expertise since complications and relapse are not uncommon.

#### **2. Spine lesions in neurofibromatosis**

#### **2.1 Scoliosis**

Scoliosis is the most common osseous involvement in NF.

The incidence of scoliosis among children with NF is increased and it is referred that 10–60% of NF patients present with some type of spinal deformity. Approximately 3% of patients referred for scoliosis, have NF-1.

There are two patterns of scoliosis in neurofibromatosis: dysplastic and non-dysplastic.

Scoliosis appears early in life of children with NF, usually at the age of 5–8 years old. They belong to early onset scoliosis.

The dysplastic scoliotic curve is a short rigid curve with sharp angulation, usually located in the thoracic area. This is the primary curve. As the patient grow, scoliosis may involve the cervical or the thoracolumbar spine. Scoliosis in the lumbar spine is rare. The apical vertebra appears with wedging, there is scalloping of the vertebral bodies and pencilling of the apical ribs. This wedging is resembling an hemivertebra. The foramen is enlarged and neurofibroma may be found entering the canal. They present with simultaneous kyphosis, with a sharp angulation at the apex of the curvature. These curves have the tendency to progress rapidly and often require early fusion to prevent the progression of the scoliosis [1–5].

Bracing has limited success to prevent progression of the curvature. For dystrophic curves greater than 40o , posterior spinal fusion with segmental instrumentation is the procedure of choice. It is important to use autologous bone graft, to enhance solid fusion. Solid curves, with kyphosis less than 400 angle, can be managed with posterior fusion, while with the presence of severe kyphosis concomitant anterior fusion is required. Despite solid fusion, some curves continue to progress. In severe kyphoscoliosis curves, both anterior and posterior procedures are required to achieve stability. It is important to use intra operative neurophysiological monitoring for these patients.

Pedicle morphology of dystrophic curves have differences compared with those in idiopathic scoliosis. There are often abnormal pedicles that result in misplacement of pedicles screws. Using CT measurements, abnormal types of pedicles are significantly more common in NF-1 scoliosis. A 3 D navigation system was used for accurate placement of screws. In proximal thoracic pedicles, with small diameter, sublaminar hooks may be used [6–9].

Management of severe dystrophic curves is a challenge for the paediatric spine surgeon. Early fusion may interfere with the body development, lung and pulmonary function. The use of growing rods (GR) that can correct deformities, without fusion, become now the standard procedure for management of early onset scoliosis. They require periodically lengthening [10–12]. Carbone et al. [10] in a series of 7 children with dystrophic thoracic scoliosis, report the results from the use of GR. They achieved a scoliosis correction measuring the Cobb angle from 82,70 to 46,6<sup>0</sup> . Despite that they report 12 complications in 4 patients (47%), including rod breakage, their results are very promising for the management of the severe problem. They were lengthening the rods in a year basis program.

Yao et al. [13] compared the use of initial fusion in dystrophic curves, with the use of GR. Fusion achieved better correction and the complication rate reported was

#### *Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

lower in those treated with fusion. They report the technical difficulties to use fixation device because of the pedicle deformity. It is important to include all dystrophic vertebrae in the fusion area, to minimize complications.

High incidence of pseudoarthrosis in dystrophic curves have been reported, rising up to 60% in older reports [1]. Complication rate after surgery in children with dystrophic curves is expected to be higher than those surgically treated for idiopathic scoliosis [13, 14]. But recently, with the improvement of the procedures, Lyu et al. [15] report similar good results for both groups, with no fusion failure and similar rate of complications between the 2 groups.

Paraplegia may appear from the erosion of the vertebral bodies from neurofibromatosis tissue. It is of great importance to exclude the possibility of rib progression as a cause of paraplegia. CT scan and MRI are helpful to diagnose intraspinal rib progression. Resection of the rib as the first step, permit adequate correction of the curve with instrumentation, without risk for neurological deficit. In flexible curves, traction may result in reversal of the neurological deficit. Improvement of Frankel scores and rotatory thoracic subluxation using pre- operative halo traction has been reported. Traction (Halo traction) has no effect on rigid curves [12, 16, 17].

Non dysplastic scoliosis has similar natural history to idiopathic scoliosis that is seen in adolescents. They progress similarly to idiopathic scoliosis. We consider the balance of the body and the aesthetic shape of the body, as important parameters for management. Scoliosis with Cobb angle less than 200 is only observed. Curves between 20 and 35<sup>0</sup> may be managed with appropriate braces. Greater curves may require surgical correction and stabilization. It is important to regularly monitor these non-dysplastic curves, as they may become dysplastic with sudden increase of the curvature. This phenomenon of modulation, was first reported by Durrani [18]. Rib pencilling is an early sign for severe progression. MRI examination of the spine, every year is essential for the evaluation of the cord condition in NF scoliosis (**Figures 1**–**3**).

**Figure 1.** *Xray of non-dystrophic left thoracic scoliosis, in a boy with NF-1.*

#### **Figure 2.**

*Photo of the body (anterior and posterior) of a 13 years old boy with right thoracic scoliosis and skin manifestations of NF.*

#### **Figure 3.**

*Xray shows a non dystrophic right thoracic scoliosis. Brace treatment was ineffective to regress progression. He was advised for surgical correction.*

#### **2.2 Cervical spinal lesions in NF**

Cervical spine scoliosis is usually present with the sharp short kyphoscoliosis lesions of the thoracic spine. They may be found early in life.

Atlanto axial dislocations are reported in NF. Lesions of the upper cervical vertebrae, scalloping and erosion of the dens either from the eroding neurofibromas or from the pressure of the dural ectasia, are found. Children that had previously surgically treated for a neck mass, must be followed for recurrence and extension of the lesion in the upper cervical spine.

Patients may present neurological deficit. Prevention requires appropriate spinal instrumentation for stability and avoid of laminectomies. Patients with cervical spine involvement may present with torticollis or dysphagia. Manifestations of vertebral cervical involvement are found in radiological evaluation, with scalloping of the vertebrae, enlargement of the foramen due to neurofibroma. It is important to perform x-ray evaluation of the cervical spine for patients with NF that are scheduled for general anaesthesia.

#### **2.3 Spondylolisthesis**

Spondylolisthesis is a rare complication in NF, caused from erosion or elongation of the pedicles or the pars intraarticularis, from neurofibroma. It requires stabilization in case of progression (**Figure 4**).

#### **Figure 4.**

*Spondylolisthesis in a 12 yrs. old boy with NF-1, without signs of nerve compression. Observation and x-ray evaluation is recommended every year.*

#### **2.4 Case presentation**

We present an adolescent boy with intrathoracic and intrabdominal neurofibromas that presented with dystrophic scoliosis and kyphosis and signs of paraplegia (**Figures 5**–**11**).

**Figure 5.** *Initial x-ray evaluation of upper thoracic dystrophic kyphoscoliosis, lateral and posterior view.*

**Figure 6.** *MRI abdomen and front spinal with the presence of intrathoracic paraspinal neurofibromas.*

**Figure 7.** *MRI of the upper thoracic spine with neurofibromas.*

*Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

#### **Figure 8.**

*Frontal and lateral view of the child with enlarged neurofibroma.*

**Figure 9.** *CT evaluation with subluxation of the affected vertebrae.*

#### **Figure 10.**

*After a period of 2 weeks in halo traction, surgical treatment with rods and pedicular screws. Surgeon: Vasileios Lykomitros. Spine surgeon, PhD, General Clinic Thessaloniki, Greece.*

**Figure 11.** *Impressive correction of the shape of the body.*

#### **3. Osseous involvement of long bones**

#### **3.1 Tibia**

Lesions of long bones in NF patients are rare but create severe problems in their management.

The tibia is the most commonly affected long bone in NF. The incidence of congenital pseudoarthrosis of the tibia (CPT) is 1:250.000. It is most commonly associated with NF, but may appear with fibrous dysplasia or osteofibrous dysplasia.

The lesion appears with a characteristic anterior and lateral bowing, usually along with the presence of the skin manifestations of the disease. The lesion appears early in life; however, it must be distinguished from the congenital posteromedial bowing of the tibia. This has a benign course, with gradual improvement of the deformity, without underlying disease, usually leaving only problems of leg length discrepancy. Children affected with CPT have rarely simultaneously problems with scoliosis.

It may be associated with enlargement of the limb or with the presence of neurofibromas in the bone or in the surrounding tissue.

The posterior muscles of the calf are relaxed because of the anterior tibial bowing and the ankle is in a dorsiflexion position. The fibula is migrating proximally, leading in a valgus ankle position. Gradually leg length discrepancy (LLD) appears, due both to the tibial bowing and to altered function of the proximal and distal tibial growth plate. Hip alteration may appear in the form of coxa valga. This compensates the altered alignment of the tibia and there is overgrowth of the femur.

Radiological assessment of the tibia is the essential examination for evaluation of the severity of tibial involvement. The tibia is anteriorly and laterally bowed, most commonly in the distal third. The cortices present sclerosis with the presence of medullary canal, that may end without developing a fracture or pseudoarthrosis.

When cystic lesions appear with stenosis or loss of the medullary canal, the tibia becomes dysplastic and will present fracture or elements of pseudoarthrosis [19–26].

#### *Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

It is important to protect the limb since the anterior bowing is usually increasing gradually, leading either in fracture or forming the tibial pseudoarthrosis. Recently, guided growth of the bowed tibia with 8 plates, has been proposed, not only to prevent deformity and fracture but even to improve the axis of the tibia and fibula [27].

The fibula follows the bowing of the tibia but with smaller bowing, with increased thickness of the cortices as it carries more stress during walking. The ankle joint may be distorted, but the growth plate is not usually involved since the lesion is located in the diaphyseal lesion. There is alteration in the position of the growth plate that may be found in a recurvatum place. The distal part of the fibula is gradually migrating proximally [28].

Four radiologic types for CTP have been described from Crawford.

Type 1, non-dysplastic, with dense medullary canal. They have the best prognosis, that may end without a fracture.

Type 2 with an increased medullary canal and tubulation defect.

Type 3 with a cystic lesion. These patients require a surgical intervention before developing a fracture.

Type 4 Patients with fracture of the cyst that have developed pseudoarthrosis. Recently Paley classified CTP in 4 types, each one with subtypes, taking in consideration both tibia and fibula [25].

Type 1 with anterolateral bowing of both tibia and fibula, without fracture. Type 2 Fracture of the fibula, without tibial fracture, considering the possible fibular migration.

Type 3 Fracture of the tibia, without fibular fracture.

Type 4 Fracture both of tibia and fibula, considering 4 subtypes according to fibular migration and tibial bone defect.

The presence of neurofibromas in the area of the pseudoarthrosis are confirmed with MRI investigation, affecting the endosteal or periosteal area of the lesion.

The mechanism of development of pseudoarthrosis remains unknown. It may be the result of mechanical stress in the anterior bowing of the tibia, that has sclerotic cortices with eliminated canal. In the presence of neurofibroma in the endosteal, as it grows gradually, the cortices become thin and lead to fracture or pseudoarthrosis.

The periosteum is thickened, constricting the tibia and fibula, leading to atrophy. Resection of the thickened periosteum is part of treatment protocols used. Periosteal grafting has been used as a treatment option.

The osteoclastic activity of the periosteum is increased. The resorption of the bone graft is related to this increased osteoclastic activity. We have seen the delayed ossification of the proximal tibia, in the process of bone transport with the Ilizarov device. This can be explained by the generalised periosteum defect, for adequate bone formation [29, 30].

Treatment with bisphosphonates is now used to improve the bone formation in the pseudoarthrosis treatment. Stem cells harvested from the hamartoma tissue of CPT patients, have less osteogenic potential. We are using fibrin clot tissue, derived from the blood of the patients, to improve the union in surgically treated patients [31–33].

Neurofibromatosis lesions in the surrounding tissue interfere also with normal cortical development. In the histological specimen of the pseudoarthrosis tissue, removed at surgery, usually fibroblasts are found [19, 21].

Management of tibial pseudoarthrosis remains one of the most challenging issues, despite several methods that have been proposed. The strategy must target for the correction of the deformity, union of the pseudoarthrosis, restoration of the leg length discrepancy. Corrective osteotomies stabilized with plates and screws or

intramedullary devices present with a higher percentage of failure. The presence of neurofibromas in the surrounding tissues increase the surgical difficulties.

Microsurgery using the fibula for union of the pseudoarthrosis has been increasingly used in the last 20 years, improving the results of union [34, 35].

Early intervention, to prevent the development of pseudoarthrosis has better results. Prophylactic bypass grafting with an allograft fibula, has been reported in 10 patients, with no cases of tibial pseudoarthrosis [36].

Bone transport technique, after excision of the pathological bone specimen, can be used to restore the axis and the length discrepancy of the pseudoarthrotic tibia. The Ilizarov method has increased the rate of successful management of the tibial pseudoarthrosis [37, 38].

The use of Ilizarov external fixation can be combined with intramedullary rods to improve stability, with simultaneous iliac crest graft. Healing over the compression, with correction of LLD has been reported. The use of proliferative factors from stem cells are collaborative to achieve union [39–43].

Management of TCP with intramedullary rods alone in a cohort of 34 patients that reached skeletal maturity, was found to be functional in 82% of cases. Permanent IM rodding of the affected tibia is important factor for long term results [44].

Neurofibromas that are occasionally extending in large areas of the tibia, is difficult to be surgically removed. In these cases, amputation of the limb and use of prosthesis can be proposed [45, 46].

The cross-union concept initially presented from Choi et al. 2011 [47]. In children that both tibia and fibula were fractured, they converged the fibula ends to the tibia ends, creating a 4-in-1 bone osteosynthesis. They used cortical graft from the contralateral tibia and cortico-cancellous bone from the inner ilium table to form a layer posterior to the two bones, to complete the cross union of the tibia to the fibula. Paley [25] recently presented a 100% present union with this technique, combining the cross- union surgical technique with pharmacological agents. His protocol consists of presurgical administration of zoledronic acid. In surgery, removal of the hamartoma and the interosseous membrane. Rodding of both bones, the tibia with telescoping rods and fibula with wire. Application of a 3-layer graft from periosteum, cancellous bone and BMP2. Further stability provided initially with an Ilizarov device but recently with a locking plate.

#### *3.1.1 Case presentation*

We have treated a 15 years old adolescent with radical excision of the affected tibial pseudoarthrosis, with simultaneous bone transport from the proximal tibial.

We used the Ilizarov device to stabilize the bones and complete the bone transport. The affected tibia was extremely sclerotic. We removed 5 cm of bone, but the remaining ends were also sclerotic. There was an unexpected delay in the ossification process of the proximal part of the tibia, that was normal. After completing the docking of the transported bone, we removed the Ilizarov apparatus, performed an open procedure in the docking site, used bone graft and we performed plating of the docking site. We achieved the restoration of the LLD. Gradually the tibia appeared with bowing and x-ray examination revealed failure of union with loss of plating fixation. We repeated the osteosynthesis process with adequate reaming of the medullary canal, both proximal and distal, in very osteosclerotic cortices and inserted in the canal, the longitudinal half of the fibula. We augmented the graft that consisted from cortical and spongiosa from the ipsilateral fibula, with fibrin clot. We completed the operation with a revision of the plating. Fortunately, 2 years after the last operation the boy has signs of tibial union (**Figures 12**–**23**).

*Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

**Figure 12.** *Initial presentation antero medial bowing and sclerosis of the tibia in the x-ray.*

**Figure 13.** *The back of his mother, that has no osseous involvement.*

**Figure 14.** *X-ray of the tibia, with progression of the deformity and increased thickness of the fibula, with ankle malalignment.*

**Figure 15.** *CT scan of the cystic lesion of the tibia.*

#### **Figure 16.**

*MRI of the pseudoarthrosis, with the presence of a diffuse neurofibroma in the area of the pseudoarthrosis.*

#### **Figure 17.**

*Excision of the lesion, application of Ilizarov device with proximal osteotomy for bone transport. Simultaneous osteotomy of the fibula.*

*Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

**Figure 19.** *CT scan at the removal of the Ilizarov device.*

**Figure 20.** *CT scan with DELAYED OSSIFICATION at proximal osteotomy.*

**Figure 21.** *CT at the docking cite.*

**Figure 22.** *Mechanical failure of the plate, due to non-union of the tibial pseudoarthrosis.*

**Figure 23.**

*Revision of the pseudoarthrosis, using the fibula as a strut in the tibial diaphysis, augmenting the procedure with bone graft and use of fibrin clot.*

#### **3.2 Fibula**

Congenital pseudoarthrosis of the fibula (CPF), isolated, is extremely rare, with few cases reported in the literature. It is highly associated with NF. Patients early in life present a valgus deformity of the ankle joint and an anterior bowing of the leg. There are other manifestations of the NF, usually the skin findings and the positive family history of NF. It may initially present with ankle varus deformity but as the fibula becomes pseudoarthrotic, it does not provide stability to the ankle. The fibula with the anterior bowing, migrates proximally and the talus is shifted in valgus position.

Dooley and Menelaus have classified CPF in four types.

Type 1: fibular bowing without fibular pseudoarthrosis, Type 2 fibular pseudoarthrosis without ankle deformity, type 3 with ankle deformity, and type 4 fibular pseudoarthrosis with late development of pseudoarthrosis of the tibia. It is important that the tibia appears with sclerosis of the medullary canal and the last type is a case of tibial pseudoarthrosis with fibular involvement, type 3 or 4 of the Crawford classification.

In the radiological examination, the fibula presents with pencilling of the pseudoarthrosis ends, with possible cystic formation, with anterior bowing. Distortion of the ankle joint, with valgus deviation result [48–51].

Ankle braces may be initially used to protect the ankle, but surgical management should be attempted early to protect the ankle joint. Initially Langeskiold proposed the distal tibio-fibular fusion using bone graft. Treatment of the CPF aims to treat both the fibular pseudoarthrosis and the distortion of the ankle joint. Corrective osteotomies of the tibia and distal tibio fibular fusion, similar to Langeskiold procedure are used. The Ilizarov apparatus is also used for treatment of the valgus deformity with distraction of the fibula and treatment of the pseudoarthrosis [52–55].

The use of periosteal flap from the diaphysis of the fibula and coverage of the pseudoarthrotic area is reported to have satisfactory results. The authors have treated 6 patients, after resection of the affected bone, retaining the proximal pedicle of the periosteum and suturing it as a tube in the defect [56].

#### *3.2.1 Fibula case presentation*

We have treated our patient with thorough cleaning of the pseudoarthrosis site of the fibula. The histological specimen of the removed tissue revealed fibrotic

#### **Figure 24.**

*Initial x-ray presentation of fibula pseudoarthrosis. The talus has a valgus position, with proximal migration of the distal end of the fibula.*

**Figure 25.** *Progression of the deformity, 2 years later.*

**Figure 26.**

*Further increased valgus position of the ankle and more proximal migration of the distal part of the fibula, as the child grows.*

**Figure 27.** *CT scan of fibular pseudoarthrosis.*

*Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

#### **Figure 28.**

*Clinical picture of the valgus ankle right leg and the photo of the back of the patient with multiple café au lait spots.*

**Figure 29.** *Intraoperative picture of pseudoarthrosis of fibula and application of fibrin clot.*

**Figure 30.** *X-ray 3 months after surgery.*

#### **Figure 31.**

*X-ray and CT scan, after failure of proximal screw and proximal fibular fracture. Pseudoarthrosis of the fibula is united.*

**Figure 32.** *X-ray, after revision of proximal fracture, with a longer plate. Pseudoarthrosis of the fibula is united.*

tissue. We stabilized the fibula using a semi tubular plate and adequate amount of bone graft with fibrin clot in order to enhance union. The fibula was extremely thin and despite that we use the fibular plate, the plate seems to be a little larger. In the latest examination, the patient is asymptomatic but despite that there was union of the pseudoarthrosis, the plate had failure in the proximal part and the fibula fractured in the area of the drill hole. We revised the plate, with a longer plate. We plan to improve the valgus position of the ankle, with 8 plate, as soon as the union will be complete (**Figures 24**–**32**).

#### **3.3 Radius and ulna**

Pseudoarthrosis of radius and ulna is an extremely rare condition, highly associated with NF. Patients present with a deformity of the arm, that is recognised early in life. It may present after an injury and failure to achieve union. The deformity is gradually increasing, despite that the function of the hand is not severely affected, children and parents are seeking for support. Radiological examination reveals the

#### *Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

presence of medullary sclerosis, cystic formation, obvious pseudoarthrosis, even type of agenesis of part of the affected bone.

Treatment of this condition is also very challenging. It requires the union of the pseudoarthrosis, restoration of the length of the affected bone and normal function of the wrist and elbow joint. As the child is growing, deformity is increasing, leading to distal radioulnar instability or to lesion of the radio capitellar joint. In ulnar pseudoarthrosis, with normal growth of the radius, the radial head will dislocate. All cases of untreated ulnar pseudoarthrosis ended with radial head dislocation.

Various surgical techniques have been used. Casting for treatment of pseudoarthrosis is not justified. Open reduction and stabilization with plate and screws with grafting has been reported to have a 23% success rate. The vascularized fibular graft with osteosynthesis has been referred to have the highest union rate [57–59]. The use of external fixator and Ilizarov technique is also reported. Either with excision of the affected part of the pseudoarthrotic bone, and bone transport, either with initial restoration of the length of the forearm and followed with vascularised fibular graft [60]. One bone arm treatment, with cross union of radius and ulna, has been proposed for the severe gap in the affected bones, having a high union rate but reducing the forearm function [61]. This is a salvage procedure.

Excision of the radius pseudoarthrosis, use of iliac crest graft, with shortening osteotomy of the ulna and stabilization of both forearm bones with intramedullary K wire was recently reported with sound union [62]. A double barrel vascularized fibular graft supplemented with k wires and external fixation, was used with success in a distal radius pseudoarthrosis [63].

#### *3.3.1 Case presentation*

We present our patient who had ulnar pseudoarthrosis with dislocation of the radial head. She had almost normal use of the arm and elbow. Her parents had decided to avoid early surgery. The radial head had been protruding from the

**Figure 33.** *Radiological presentation of ulnar pseudoarthrosis and progression to dislocation of the radial head.*

#### **Figure 34.**

*The clinical picture, with the deviated short forearm, with radial head prominence, with almost normal function of the elbow.*

**Figure 35.** *Radiological picture of the dislocated radial head with the ulnar pseudoarthrosis.*

elbow, requiring surgical excision. The child was lost from our department (**Figures 33**–**35**).

#### **3.4 Overgrowth**

The elephant man is the most known patient with neurofibromatosis. Overgrowth of the limb is usually associated with soft tissue enlargement, haemangiomatous lesions or plexiform neuromas. These severe lesions are unilateral and associated with retroperitoneal fibromas that may require repeated surgery and possible may develop sarcomas. Surgical procedures of debulking have usually very limited successful results. The use of epiphysiodesis is an alternative to reduce the increasing leg length discrepancy. Crawford has described a patient that required hip disarticulation because of the tremendous overgrowth of the limb (**Figure 36**).

*Bone Lesions in Children with Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.97802*

**Figure 36.** *Clinical picture of the overgrowth of the right leg, with café au lait spots in the leg and back of the child.*

#### **4. Conclusion**

Children affected from neurofibromatosis must be regularly followed for osseous involvement. Examination of the spine, at least in a year basis, is important for the early diagnosis of spine deformities. Dystrophic curves are difficult to be managed conservatively. Improvement of radiological evaluation with MRI and CT and development of modern instrumentation permit us to manage effectively the progression of scoliotic curves.

Long bone involvement is one of the major clinical criteria for the diagnosis of NF-1. Treatment of congenital pseudoarthrosis remains one of the most complicated problems in children. Recent advances in biology and new implants have greatly improved our results.

#### **Conflict of interest**

The author declare no conflict of interest.

### **Author details**

Nikolaos Laliotis Pediatric Orthopaedic Surgeon, Inter Balkan Medical Center, Thessaloniki, Greece

\*Address all correspondence to: nicklaliotis@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

## Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse Neurofibromatous Tissue

*Venkata Amruth Nadella, K. Joshi George and Calvin Soh*

#### **Abstract**

*Objectives*: To describe the prevalence, demographics and characteristics of a novel radiological entity in neurofibromatosis type 1: diffuse neurofibromatous tissue (DNFT) *Design*: Aretrospective, descriptive review of MDT and radiology notes. *Methods*: Of the 1049 patients from the NF1 adult radiology MDT minutes (2009– 2021), 77 patients with DNFT were identified and clinical data were collected. MRI scans from 20 DNFT cases were interpreted. *Results*: Although overall gender distribution of DNFT was roughly even, it was more prevalent in females (73.9%) at the sacroiliac joint—where this entity was most common (29.9%). DNFT often involves the fibrous part of the sacroiliac joint and is seen as diffuse, streaky infiltrating tissues that cause bone erosion without mass effect. The period prevalence of scoliosis and dural ectasia on corresponding spinal levels with spinal DNFT was 62.8 and 51.2%, respectively (n=43). *Conclusions*: This is the first reported descriptive study of DNFT in NF1 and the first to describe its MRI features in detail. The predilection for the sacroiliac joint and the possible associations with scoliosis and dural ectasia provide important insights that can form the basis for future studies whilst also suggesting the need for active surveillance of this tissue in NF1 patients.

**Keywords:** Neurofibromatosis type 1, diffuse neurofibromatous tissue (DNFT), scoliosis, Dural ectasia, Neurofibroma, sacroiliac joint

#### **1. Introduction**

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited genetic condition in which affected patients have a disposition to the development of benign neoplasms in peripheral nerve sheaths around the body – neurofibromas [1–4].

There are three main established types of neurofibroma: solitary, plexiform and diffuse neurofibromas [5]. Solitary neurofibroma is a benign, discrete neurofibroma involving a nerve root [6].

Plexiform neurofibromas are also benign tumours but they are diffuse and incorporate multiple, deeper nerve fascicles and corresponding branches. The involved large nerve trunks and nerve roots may form a thickened tortuous mass resembling 'a bag of worms' [5–7]. They are congenital but can also develop in later stages of life and are present in roughly half of all NF1 patients [5, 8]. Moreover, as they are not encapsulated, they can displace surrounding tissue and/ or cause bony deformities (e.g. scoliosis) resulting in pain [5, 7, 8]. This can make surgical resection of the tumour complex as the neoplasm is interspersed with its surrounding tissues [5]. The brachial and lumbosacral plexi are most commonly affected by plexiform neurofibromas as well as paraspinal tissues and the orbit [7]. There is a risk of malignant transformation into malignant peripheral nerve sheath tumour (MPNST) [9].

Meanwhile, diffuse neurofibromas are a rare subtype of neurofibroma that are found as a plaque-like mass in children and young adults [10]. They often have ill-defined borders and diffusely infiltrate the skin and subcutaneous tissues as a contiguous sheet. They infiltrate around other structures (rather than displacing them as in plexiform neurofibroma), thus enclosing subsequent neurovascular tissues [6, 10]. This diffuse infiltrating pattern makes surgical excision of the tumour challenging [6]. Moreover, it has been recently shown that diffuse neurofibromas are most prevalent in the subcutaneous regions of the head, neck, trunk and extremities and can grow deep into the fascia [10, 11]. However, as well as these three varieties, neurofibromas can also develop along the spinal nerve roots (spinal neurofibromas) in as much as 38% of the NF1 population [12].

In addition to neurofibromas, NF1 patients can also have many other clinical manifestations of the disease including short stature, cardiovascular disease, caféau-lait macules (CALMs), iris hamartomas and optic pathway gliomas [8, 13, 14]. Due to this wide variability in clinical features of NF1, a multidisciplinary approach to patient management is often required [13]. However, to provide the best patient care, we must first understand the disease in its entirety. Moreover, with an incidence of roughly 1 in 3000 people globally, NF1 is the most common neurofibromatosis, which conveys the importance of ongoing research in this area [13].

Over the past 10 years, a novel radiological finding – "diffuse neurofibromatous tissue" (DNFT) – has been noticed in many NF1 patients presenting to our NF1 centre. This tissue is a distinct entity from the more commonly reported neurofibromas in NF1, thus may represent an atypical form of the disease. Unlike diffuse neurofibroma which is plaque-like, this DNFT is streaky in appearance, diffusely infiltrating and does not have much mass effect but still erodes adjacent bone. From spinal imaging, this DNFT is often seen to involve the sacroiliac joint and the paraspinal locations.

Overall, there is a lack of significant literature on any such DNFT in NF1 patients. This paper aims to describe the period prevalence, demographics, characteristics and radiological appearance of DNFT. Moreover, this report will also attempt to identify the period prevalence of any lesions that occur with DNFT. Period prevalence refers to the proportion of individuals affected by a particular variable over a specified timeframe [15]. Any prevalence results from this paper will be referring to the period prevalence between October 2009 to April 2021. Finally, using this current research, this paper will endeavour to determine the effects, or lack thereof, that this novel entity will have on the clinical management of NF1.

#### **2. Material and methods**

#### **2.1 Study design and overview**

This is a retrospective, descriptive study of DNFT. We have identified this novel radiological entity that is similar to the well described diffuse neurofibroma but

*Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse… DOI: http://dx.doi.org/10.5772/intechopen.101102*

with some differences that will be discussed later in Section 4.2 of this paper. A descriptive approach to this study is favoured as this paper aims to characterise DNFT and identify any prevalent features.

This study was based in Manchester which is one of the two nationally commissioned complex NF1 centres in the UK. Hence, this centre is in a unique position wherein this type of large study can be undertaken due to the relative ease of access to NF1 patient records. Retrospective data from patients with DNFT was extracted from various sources at this centre: (1) NF1 adult radiology MDT minutes from October 2009 to April 2021, (2) NF1 adult neurology MDT minutes from February 2020 to March 2021 and (3) a piloted data collection proforma. Specific radiological data from 20 patients with DNFT was also collected by the interpretation of MRI scans of these patients. MRI was chosen as this is the most superior form of imaging for any NF1-related tumours.

#### **2.2 Ethics approval**

Formal ethical approval was not needed as this was a descriptive study that used retrospective patient data from the Manchester NF1 adult centre.

#### **2.3 Study subjects and inclusion criteria**

Initially, source [1] – containing 1049 patients – was used to identify the 77 NF1 patients with DNFT according to radiological interpretation of MRI, computerised tomography (CT) scans and X-rays. The following search terms were applied: "diffuse neurofibromatous" and "neurofibromatous".

#### **2.4 Demographic data, outcome measures and procedures**

Following the extraction of the 77 patients with DNFT, patient demographics (including gender and age as of 28/05/2021) were collected using all three sources mentioned earlier. Data on these patients was collected regarding the location of DNFT, scoliotic deformity and dural ectasia using a combination of all three sources. Data on any scoliotic deformity of the spine and its location was chosen as it was the most common spinal deformity in NF1 patients in this complex centre, with a prevalence of 38.3% [4]. Meanwhile dural ectasia was chosen as it is a common spinal lesion with a prevalence of 28.4% in this centre [4].

This data was all inputted into a pre-piloted data collection proforma on "Microsoft Excel for Mac Version 16.48". Analysis was carried out using pivot tables (in the aforementioned version of Microsoft Excel) from which the desired correlations were selected in order to calculate the period prevalence of each feature with DNFT. Patients were grouped based on the location of their DNFT to assess gender distribution and other correlations in each subset of patients. Microsoft Excel was used to create relevant graphs on the data.

#### **3. Results**

#### **3.1 Patient demographics**

As mentioned in Section 2.3, 77 patients were found to have DNFT from the 1049 NF1 patients in source [1]. Thus, the period prevalence of DNFT in this NF1 centre (between October 2009 and April 2021) was 7.34%. Furthermore, the mean age of the patients was 39 years old with a roughly even gender distribution of 39 males to 38 females.

#### **3.2 Location of DNFT and gender distribution in each group**

DNFT was commonly found as a paravertebral lesion of the spine at varying levels and at the sacroiliac joint of the pelvis. The sacroiliac joint was the most common site for this tissue (n = 23/77, 29.9%), as shown by **Figure 1**.

There was a total of 19 miscellaneous cases in whom the DNFT was not located in any of the aforementioned regions. However, as DNFT was most prevalent at the sacroiliac joint, the presence of the tissue in this location has been studied in more depth in this paper.

#### **3.3 DNFT at the sacroiliac joint and it's radiological appearance on MRI scans**

#### *3.3.1 General findings of DNFT at the sacroiliac joint*

Of the 23 cases at the sacroiliac joint, 17 were females (73.9%) and 6 were males (26.1%) (**Figure 2**). These figures suggest a strong female correlation of DFNT at the sacroiliac joint.

Moreover, it was more common to have the tissue on the right side (n = 14/23, 60.9%) of the sacroiliac joint compared to the left side (n = 7/23, 30.4%). There were 2 out of the 23 cases where the patient displayed the tissue on both the left and right sacroiliac joint (8.70%).

#### *3.3.2 The radiological appearance of DNFT at the sacroiliac joint*

As DNFT is usually an incidental finding, not all sacroiliac joint cases had adequate MRI imaging for review. In our institution, our standard spinal MRI protocol includes sagittal and coronal post-contrast T1W and STIR sequences. As the comprehensive protocol includes brachial and lumbosacral plexal imaging, often

#### **Figure 1.**

*A graph that shows the prevalence of DNFT at each region of the spine and at the sacroiliac joint. For each data label, the first number is the percentage of patients with DNFT at that region out of the total 77 patients. The second number is the raw number of patients with the tissue at that region.*

*Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse… DOI: http://dx.doi.org/10.5772/intechopen.101102*

#### **Figure 2.**

*A pie chart showing the gender distribution of DNFT at the sacroiliac joint.*

including cranial and orbital imaging, pre-contrast T1W sequences are not routinely included in the spinal protocol.

In total, 20 out of the 23 patients had sufficient MRI imaging that could be studied. From the radiological review of these 20 patients, several patterns have been identified.

On imaging, this DNFT tends to appear as streaky, diffuse, infiltrating tissues with no real mass effect but seem to cause bone erosion and scalloping, resulting in a dysplastic joint. These bony changes can also be appreciated on available CT scans (**Figure 3**). This tissue is isointense with muscle on T1 but enhances on post-Gadolinium T1 with fat-saturation and appears hyperintense on STIR (**Figures 4** and **5**). However, on post-contrast STIR sequence, the lesion is inconspicuous – most likely due to the suppression of the Gadolinium contrast enhancement signal, as evident in the kidneys (**Figure 5**). Hence, the lesion is visible on STIR and post-contrast T1 with fat-saturation, but invisible on post-contrast STIR sequence.

Furthermore, the periosteum is presumed to be involved. Anatomically, the sacroiliac joint is a composite joint, the upper one-third is a syndesmosis, the lower two-thirds are lined by articular cartilage, although only the lower third is lined by synovium, while the middle third resembles a symphysis. This DFNT invariably

#### **Figure 3.**

*This CT imaging shows a 74-year-old female with DNFT eroding right sacroiliac joint (SIJ). CT scan shows streaky soft tissues on soft tissue windows, bone scalloping on bone windows, and an eroded fibrous part of the joint on 3D reformats.*

#### **Figure 4.**

*Sagittal MRI imaging of streaky tissues shows T1-isointensity, T2-slight hyperintensity, STIR-hyperintensity and enhancing with contrast on post-gad fat-saturated T1. There is some streaky residual fat interposed between the enhancing tissues.*

#### **Figure 5.**

*A 36-year-old female with DNFT on the right SIJ. Left: Post-contrast coronal STIR: Shows complete signal suppression, as in the kidneys. Right: Post-contrast coronal T1 with fat-saturation shows streaky enhancement.*

involves the upper third and in some cases extends down towards the lower part of the sacroiliac joint.

Moreover, this streaky DNFT was shown to commonly involve only the fibrous part of the sacroiliac joint (n = 18/20, 90%) (**Figures 3** and **6**). The remaining 2 cases involved both the fibrous and synovial part of the sacroiliac joint. In the few cases that had sufficiently comparable scans over time, the development of the tissue seemed to be relatively static.

#### **3.4 DNFT and its correlated lesions**

#### *3.4.1 Scoliosis and Dural ectasia*

It was calculated that a total of 43 patients had DNFT somewhere along the spine. Out of these 43 patients, 38 (88.4%) had a scoliotic deformity of the spine. A further

*Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse… DOI: http://dx.doi.org/10.5772/intechopen.101102*

#### **Figure 6.**

*This MRI shows a 57-year-old male with left SIJ DNFT. Streaky tissues eroding the fibrous part of the left SIJ, minimally hyperintense on T2, isointense on T1 with contrast enhancement.*

#### **Figure 7.**

*A graph showing the prevalence of DNFT on each location of a scoliotic deformity in the 27 patients with the tissue at the same level as their scoliosis.*

#### **Figure 8.**

*A graph showing the number of spinal DNFT patients with scoliosis and/or dural ectasia and the number of cases of each feature at the same spinal level. There are 2 values for each bar labelled: 1) the percentage (out of 43 spinal DNFT cases). 2) the raw number of cases.*

27 out of the 43 patients (62.8%) had the scoliotic deformity at the same level as the DNFT, suggesting a strong correlation between spinal DNFT and scoliosis.

Moreover, the most common location of DNFT on the scoliotic deformity was the concavity of the scoliosis (n = 21/27 cases, 77.8%) (**Figure 7**).

Out of the 43 patients with spinal DNFT, 27 (62.8%) also had dural ectasia. A further 22 out of 43 (51.2%) of these patient's had both the tissue and dural ectasia at the same spinal level.

In the spinal DNFT population of 43 patients, 22 (51.2%) cases had both scoliosis and dural ectasia. A further 20 of the 43 patients (46.5%) had both the scoliosis and dural ectasia at the same level as the spinal DNFT. Thus, it can be concluded that, out of the 22 cases with dural ectasia at the same spinal level as the tissue, 20 (90.1%) also had scoliosis at the same level. Overall, these results show a correlation between spinal DNFT, scoliosis and dural ectasia (**Figure 8**).

#### **4. Discussion**

The aims of this descriptive study were to describe the demographics, characteristics and radiological appearance of this novel, streaky tissue. Moreover, the prevalence of certain NF1 lesions such as dural ectasia and scoliosis was also investigated to find any correlated lesions. This section will discuss the principal results in relation to the objectives of this paper.

Although this report has been able to characterise this novel finding, the identification of past research on any similar tissue in NF1 proved challenging due to the lack of a standardised definition, characterisation, and terminology for DNFT. This scarcity of literature and existing knowledge on this entity is reflected in the few result comparisons that this paper can comment on with other similar studies. Moreover, DNFT is infrequently associated with specific clinical symptoms apart from the radiological deformity of the sacroiliac joint. As such, there is no justification for histological tissue diagnosis and DNFT is often accepted as an NF1-related lesion and loosely mislabelled plexiform neurofibroma. However, the results will be compared to the better studied plexiform and diffuse neurofibromas which should provide some insight into this novel tissue finding as a distinct entity from neurofibromas in NF1.

#### **4.1 DNFT is most prevalent at the sacroiliac joint and thoracic region of the spine**

Although neurofibromas can be found on skin and others areas of the body, they can also be found along the spinal nerve roots [5]. It has been identified in recent literature that spinal nerve root neurofibromas in NF1 patients are most common in the cervical – specifically C2 – and lumbar regions [4]. Following this finding, it was hypothesised that frequent movement of these mobile regions of the spine could be involved in the 'second hit' (of the Knudson's two-hit hypothesis) in NF1 leading to the development of spinal neurofibromas [4]. Meanwhile, the findings of this study suggest that this distinct entity – DNFT – has a predilection for immobile regions, the sacroiliac joint (29.9%) and thoracic spine (24.7%). The costovertebral and costotransverse joints of the thoracic vertebrae and the sacroiliac joint are all examples of synovial (diarthrodial) planar joints [16, 17]. This joint type contributes to the restricted movement at these areas. This could suggest that rather than repetitive movement, as in spinal neurofibromas, it is the lack of movement of these regions that could be a factor in the pathogenesis of DNFT. Moreover, as both the sacroiliac joint and the joints of the thoracic vertebrae are of the same classification, it could be possible that DNFT originates from the joints themselves.

*Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse… DOI: http://dx.doi.org/10.5772/intechopen.101102*

In comparison, although plexiform neurofibromas can also be found at paraspinal regions, they have a predilection for the lumbosacral and brachial plexi which is not seen in our study of DNFT [7]. Meanwhile, diffuse neurofibromas are commonly found in the head and neck where only 10.4% (n = 8/77) of DNFT was found in this study [10].

#### **4.2 Radiological comparison of plexiform and diffuse Neurofibroma with DNFT**

To appreciate the differences between DNFT and the other common neurofibromas, one must first understand the MRI results – regarding the tissue composition. The MRI results of this study convey two principal findings. Firstly, as already mentioned, the streaky tissues are hyperintense on STIR imaging (another example of this is illustrated in **Figure 9**). As STIR imaging completely suppresses the fat signal of a T2-weighted image, this allowed for distinct identification of this tissue without it being obscured by the interposed fat that it is known to infiltrate. Moreover, the hyperintense nature of the tissue on STIR imaging, conveys that this entity has a notable amount of water content as seen in other tumours. Secondly, the streaky tissues were shown to enhance following the administration of Gadolinium contrast on T1-weighted images which suggests that this entity is solid in nature.

#### **Figure 9.**

*These MRI scans show a 22-year-old female with right sacroiliac joint DNFT. This figure reinforces the streaky changes which are T1-isointense and STIR-hyperintense, as mentioned earlier in section 3.3.2 of the results. Note that these STIR sequences are not post-contrast, hence the hyperintensity of the tissues and the kidneys.*

Distinguishing between plexiform neurofibromas and DNFT requires less focus on the aforementioned imaging techniques but rather more attention to their relevant growth patterns. Plexiform neurofibromas are seen to have a "bag of worms" appearance on MRI [18]. This is due to their diffuse, lobular growth along multiple nerves and their branches which creates a pattern of mass effect, whilst DNFT appears as streaky tissues without any real mass effect [19]. Although plexiform neurofibroma displays mass effect and DNFT does not, they both seem to be involved in bone erosion and thus, dysplasia of adjacent bony structures [7].

However, on review, we noticed that the radiological appearance of DNFT was more similar to that of diffuse neurofibromas but with some differences. Unlike a diffuse neurofibroma, which is a contiguous sheet of diffusely infiltrating soft tissue, this novel lesion is streaky. This streaky lesion erodes bone without actual mass effect whilst diffuse neurofibroma – like plexiform neurofibroma – also shows mass effect. Moreover, diffuse neurofibromas are more commonly found involving the skin and subcutaneous tissues of the head and neck whereas DNFT is more common in the sacroiliac joint and thoracic spine.

#### **4.3 Spinal DNFT and its correlation with other NF1 spinal lesions**

The study of a subset of NF1 patients with DNFT along the spine allowed for the identification of patterns of this tissue with other spinal lesions in NF1.

A notable finding of this study was the correlation between spinal DNFT and scoliosis. Scoliotic deformity had a prevalence of 88.4% in patients with spinal DNFT. Meanwhile, in a recent study of spinal lesions in NF1, conducted by Curtis-Lopez et al., it was found that only 38.3% of NF1 patients had a scoliotic deformity in their study [4]. The research by Curtis-Lopez was also carried out at Manchester's NF1 centre and as a result, also included some of the patients present in this study [4]. The prevalence of scoliosis in these two studies may suggest that scoliotic deformity is more common among the subset of patients with spinal DNFT. However, a comparison of the studies cannot be made directly as their study had a larger population size and did not include all the patients present in this study [4]. Moreover, the correlation of scoliosis with spinal DNFT at the same level (prevalence of 62.8%) could imply that the two lesions may be associated. However, this correlation will need to be tested in the future to confidently determine if the two factors have a true and significant association.

Another noteworthy finding of this study was the correlation found between spinal DNFT and dural ectasia. In a study conducted by Shah et al., it was identified that the prevalence of dural ectasia in the NF1 population was 10.05% [20]. Meanwhile, the prevalence of dural ectasia in the spinal DNFT subset in this study was 62.8% – with 51.2% at the same level as the spinal DNFT. These results convey a relationship between these two spinal lesions. Moreover, a study previously mentioned, by Curtis-Lopez et al., attempted to find significant associations between a range of spinal lesions as associations of DNFT with other lesions could be crucial in the discovery of possible inherited modifying factors of the disease process in NF1 [4]. Although their study did not find an association between spinal neurofibromas and dural ectasia, there could be an association between DNFT and dural ectasia [4]. Thus, in the future, studies should be carried out to establish whether there is a significant association between these two lesions.

Moreover, the prevalence of both scoliosis and dural ectasia with spinal DNFT was 51.2% (n = 22/43) – of which 46.5% (n = 20/43) of cases had all three lesions at the same spinal level. The significance of these figures relies on several factors based on the causal associations, if any, between these three lesions. Firstly, it has been shown that dural ectasia is significantly associated with spinal deformity such as scoliosis [4]. *Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse… DOI: http://dx.doi.org/10.5772/intechopen.101102*

Thus, the importance of finding scoliosis with this novel entity is subjective. A total of 27 out of the 43 spinal DNFT cases had scoliosis present. However, from **Figure 8** it can be calculated that only 7 patients had just scoliosis without dural ectasia at the same level as the DNFT. Thus, in the remaining 20 cases where scoliosis was found at the same level as the DNFT, dural ectasia was also present. As there is a 1.41 relative risk of spinal deformity (e.g. scoliosis) occurring with dural ectasia, the relevance of scoliotic deformity in the presence of DNFT needs more research [4]. However, as this study has shown that DNFT causes bone erosion leading to dysplasia and scalloping, it could be suggested that the tissue itself directly leads to scoliosis. Nonetheless, as the pathogenesis and pathophysiology of DNFT is not known, it cannot be confirmed that this novel entity has a causal association with either of these lesions. It may be that certain regions of the body in patients with NF1 are affected by a factor which then predisposes to the development of various unrelated lesions from a common progenitor. Thus, as mentioned previously in this section, more future research is needed in this area. Thus far, tissue diagnosis remains a challenge as there is no clinical justification yet which is needed to intervene and retrieve tissue samples. The histological differences of DNFT compared to diffuse neurofibroma remain to be seen.

#### **4.4 The significance of DNFT on the future Management of Forme Fruste NF1 patients**

Clinical management of NF1 aims to promptly recognise symptomatic complications of the disease (and hence treat them) through the use of active surveillance [21]. This allows a prophylactic solution for the deterioration of the quality of life of NF1 patients. Moreover, as already mentioned earlier in this paper, DNFT is an entity that has often been discovered as an incidental finding when imaging for other NF1-related pathology. Together with the lack of past knowledge and literature in this area, this has meant that this novel entity has often been ignored in the management of NF1 patients. However, as can be seen from this paper, DNFT may predispose to or be associated with other spinal lesions in NF1. These spinal lesions include dural ectasia and scoliosis and can lead to clinical outcomes such as pain and deformity [4]. Thus, we propose that dedicated monitoring of this tissue (once detected) should form a routine part of annual active surveillance in NF1 patients. Moreover, a prevalence of 7.34% in this study, further supports the need for active monitoring of this atypical radiological presentation in NF1.

#### **4.5 Future directions**

This study is a descriptive study including only patients with DNFT. Thus, the results of this study only show correlations between this DNFT and other lesions. As such, this study cannot ascertain significant associations between this tissue and the other lesions mentioned in this research. As explained previously in this paper, information on associations with other lesions is important as it could be vital in the discovery of possible inherited modifying factors of the disease process in NF1 [4]. Thus, future studies should aim to identify, if any, causal associations between DNFT and the other spinal NF1 lesions mentioned in this paper.

Moreover, future research focussing on the pathogenesis of DNFT may help in identifying the reasons for some results that this study was not able to comment on. Firstly, the reason for the involvement of the fibrous part of the sacroiliac joint and the periosteum of bone is still not known. Furthermore, the right sacroiliac joint is affected more than the left which this paper has not been able to comment on. It may be the case that, when a larger sample size is used, both the right and left sacroiliac joints are equally affected. This further supports the need for future studies with a larger sample

population. Thirdly, it remains perplexing that this streaky tissue, without significant mass effect, causes bone erosion and deformity, raising the possibility of indeterminate cytokine release. In addition to larger investigations, prospective studies may also prove useful in determining the development of DNFT over time. This will provide insight into the progression of this tissue and the ideal frequency for monitoring. Finally, tissue diagnosis and immunohistochemistry may reveal the true nature of this DNFT.

#### **4.6 Limitations**

Although the interpretation of the MRI scans was conducted by a senior neuroradiologist with a lot of expertise in this area, the imaging itself was in some cases, inconsistent and varied. This was because some cases were imported from other centres in the UK where they did not necessarily use the same imaging sequences or sometimes even in the same planes. Thus, comparing and identifying patterns between scans proved more challenging than initially thought. Moreover, of the 20 scans that could be studied, very few had comparable imaging over time. Thus, we have not been able to study whether there is progression of DNFT with time. Therefore, as previously mentioned, the progression of DNFT should be a focus in future studies. Finally, the lack of tissue diagnosis means that DNFT, for the time being, remains a radiological finding.

### **5. Conclusion**

This study at this complex NF1 centre has described the demographics, characteristics, and radiological appearance of DNFT in adult NF1 patients. To our knowledge, this is the largest descriptive study of DNFT and the first to describe its radiological appearance and its correlation with other NF1 lesions.

### **Author details**

Venkata Amruth Nadella1 , K. Joshi George2 \* and Calvin Soh3

1 University of Manchester, Manchester, UK

2 Manchester Centre for Clinical Neurosciences and University of Manchester, Manchester, UK

3 Manchester University Foundation Trust, Manchester, UK

\*Address all correspondence to: joshi.george@srft.nhs.uk

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Characterisation of a Novel Radiological Entity in Neurofibromatosis Type 1 - Diffuse… DOI: http://dx.doi.org/10.5772/intechopen.101102*

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#### **Chapter 4**

## Seizures in Adult with Neurofibromatosis Type 1

*Demet İlhan Algin and Oğuz Osman Erdinç*

#### **Abstract**

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder, with an estimated prevalence of 1 in 3000–4000 people. Seizures occur 4–7% of individuals with NF1, mostly due to associated brain tumors or cortical malformations. Seizures in NF1 are often relatively easy to control with one or more conventional antiseizure drugs; surgical resection of offending lesions is sometimes pursued. Surgery has been most successful for temporal lobe gliomas. However, if you faced the drug-resistant epilepsy you may consider the cortical malformations, tumors and hippocampal sclerosis. In this chapter, it is aimed to explain the types of seizures, EEG features and the properties of drug therapy in NF1.

**Keywords:** NF1, epilepsy, electroencephalogram (EEG)

#### **1. Introduction**

Neurofibromatosis (NF-1) type 1, which is the most common neurocutaneous disease, is autosomal dominant inherited, and its incidence has been reported as 1/3000 [1].

The NF-1 gene is located in the 17q11.2 region of chromosome 17, and this gene encodes a tumor suppressor protein called Neurofibromin. Neurofibromas are the most common tumors in NF1, often seen in adolescence and increasing in number and size with age. Most of them are benign and rarely undergo malignant transformation [2].

Diagnostic criteria for NF1 include cutaneous/subcutaneous or plexiform neurofibromas, "cafe au lait" spots, axillary or inguinal freckles, Lisch nodules, optic glioma, and skeletal dysplasia. Cranial magnetic resonance imaging (MRI) can show focus areas of high T2-weighted signals known as neurofibromatosis bright objects (NBOS).

Other findings that may accompany NF1 include vasculopathy, short stature, malignancy tendency, macrocephaly, learning disability, and epilepsy. Other symptoms include cognitive dysfunction, pain in specific nerve distribution (usually due to the presence of neurofibroma), seizures, visual changes that may be associated with optic gliomas, stenosis of the major intracranial arteries leading to the Moyamoya phenomenon, headaches. The prevalence of epilepsy in NF1 is 4–5 times the prevalence defined in the general population and is reported to be 4–7% [3, 4].

#### **2. Epilepsy mechanism at NF1**

The exact mechanism of epilepsy in NF1 is not clear. Identifying the features associated with epilepsy can provide clues about its pathogenesis [5].

Neurofibromin plays important roles in many aspects of cortical development, including synaptic plasticity, learning and memory, neurotransmitter phenotype, and synapse formation [6]. However, it is not clear why the brains of individuals with NF1 can be overstimulated and prone to seizures, and this issue is rarely discussed in the literature [7].

#### **Figure 1.**

*Potential mechanisms of increased epileptogenesis in NF1 [17]. Potential mechanisms of increased epileptogenesis in neurofibromatosis type 1. Protein neurofibromin is the NF1 gene product and functions as a negative regulator of Ras activity. In neurofibromatosis type 1, decreased neurofibromin levels lead to increased Ras activation and higher RAF/MEK/ERK and PI3K/AKT/mTOR signaling levels. Although the mechanism of increased seizures and epilepsy in patients with neurofibromatosis is unknown, changes in these signaling pathways may increase epileptogenesis, possibly through changes in GABAergic signaling, changes in ion channels, or altered synaptic plasticity.*

*Seizures in Adult with Neurofibromatosis Type 1 DOI: http://dx.doi.org/10.5772/intechopen.98660*

The possibilities are undoubtedly speculative and include the pathophysiological spectrum that disrupts the excitation and inhibition balance [8]. Possibly related to seizure mechanisms, GABA release and levels were found to increase in NF1 +/− mice, resulting in unlimited Extracellular Signal Regulated Kinase (ERK) signal and increased synaptic GABA release as a result of neurofibromin loss [9]. This finding explains the impaired cognition, learning, and Long-term potentiation (LTP) of NF1 +/− mice. However, decreasing rather than increasing GABA levels will be more consistent with susceptibility to epilepsy. However, the increased GABA release strategically limited to local inhibitory circuits could theoretically increase excitability [10].

In NF1 +/− mice, calcium channel opening increases in hippocampal neurons and calcium currents increase, which increases excitability and neurotransmitter release [11]. Dysfunction of various ion channels (e.g. sodium, potassium, cyclic nucleotide-gated, activated by hyperpolarization) has been reported in different brain regions and NF models, but no consistent model emerged to suggest a unified hypothesis about cortical hyper-excitability or seizures. Several sodium channel isoforms (NaV1.1, NaV1.7, NaV1.8) have increased expression and activity in NF1 +/− mice, leading to hyper-excitability [12, 13].

These findings may be related to central neurons and circuits, a subject that needs to be investigated in terms of epilepsy mechanisms in NF. There is no published information on whether NF1 +/− mice alter the sensitivity to seizures induced by standard experimental methods (eg bicuculline, kindling) [14].

Stafstrom et al. stated that impaired excitation/inhibition balance and dysfunction of ion channels may be possible mechanisms of epilepsy in NF1 [15].

Neurofibromin deficiency leads to increased Ras activity, which is the mechanical target of rapamycin activation, and GABAergic signaling in the inhibitory circuit, which may contribute to neuronal hyperpolarization. Neurofibromin also plays a role in cortical development including synaptogenesis and synaptic plasticity; therefore, its deficiency may be associated with abnormal cortical development and seizure development (**Figure 1**) [15–17].

The high rate of learning disability in the epileptic group (without epilepsy;8,2 with epilepsy; 64%) without any negative factors such as resistant epilepsy, multiple drugs or epileptic encephalopathy suggests that it is probably not caused by learning disability, but due to a GABA-mediated pathogenesis [17].

The mutation site in the NF1 locus may also be associated with epilepsy: replication of the NF1 locus has been shown to cause mental disability and epilepsy without any physical imprint of NF1. The duplication site also contains many genes that can cause epilepsy when the microdeletion site is deleted or mutated in some cases of NF1, explaining why only a small percentage of patients with NF1 experience seizures. Comparison of genotypes between NF1 patients with and without epilepsy may clarify this possibility [18].

#### **3. Seizures in NF1**

Neoplastic or non-neoplastic central nervous system symptoms occur in 15–20% of patients with NF-1. Brain lesions in NF1 have been reported as neoplastic, non-neoplastic structural changes, vasculopathy, cerebral and cerebellar cortical malformations [19].

Neoplastic lesions are classified as optic gliomas, brainstem gliomas, and other brain gliomas. Non-neoplastic structural lesions are NBOs, macrocephaly, corpus callosum pathologies, dural ectasia and encephalocele. In NF1, cortical malformations have been reported as transmantled cortical dysplasia, periventricular band

consisting of heterotopic gray matter with cerebral cortex pachygyria, and perisylvian polymichrogyria [20, 21].

Describing five adult patients with epilepsy associated with aqueductal stenosis, subdural hematoma, cerebral hamartoma, and meningioma, Hsieh HY. et al. reported several NF1 patients with seizures caused by various tumor types. Most of these patients continued their follow-up without seizures after lesionectomy [22, 23].

It has been reported that the seizures of patients with hemimegalencephaly and NF1 are well controlled [24]. MRI lesions of other cortical developmental malformations such as focal cortical dysplasia and polymicrogyria are often accompanied by drug-resistant epilepsy [22, 25].

However, about half of NF1 patients with epilepsy do not have a structural abnormality on MRI [4] and it has been reported that MRI lesions in NF1 are not always localized with epileptiform discharges on EEG [16]. In this case, they raised the question of whether the genetic condition itself contributes to overstimulation of the brain, susceptibility to seizures, and other chronic changes that lead to epilepsy. Seizures in NF1 are usually secondary to brain lesions such as tumors or cortical dysplasia [4, 26], but neurofibromatosis, a typical MRI lesion, has not been associated with bright nodes (NBOs) [4, 26].

NBOs (neurofibromatosis bright objects) were detected in 16 (69.6%) epilepsy patients and 108 (72.5%) patients without epilepsy in a study in which the MRI of 172 (23 with and 149 without epilepsy) NF1 patients were examined. The location or number of these intracranial lesions do not correlate significantly with the occurrence of epilepsy in our cohort. Among the 11 NF1 patients with intracranial tumors, 4 patients (36.36%) had seizures, whereas 19 (11.80%) of 161 NF1 patients without tumor were found to have seizures. In conclusion, in this article, epileptic seizure formation in NF1 patients was interpreted as associated with intracranial tumors, but not with NBOs [23].

Different seizure types and syndromes have been described in NF1. Most seizures in NF1 tend to be focal-onset seizures and are generally secondary generalized [22, 27, 28]. The seizures in NF1 are thought to be caused by numerous focal lesions that make up the disorder, namely, tumors and malformations of cortical development. The prevalence of West syndrome (infantile spasms) and febrile seizures is higher in NF1 patients compared to the general population.

EEGs are abnormal in about 25% of patients with NF1. EEG findings may include normal to focal or multifocal spike waves, spike and slow spike wave complexes at 2 Hz compatible with Lennox–Gastaut syndrome. The most common abnormality in EEG is focal disorders [27].

Therefore, seizure formation requires neuroimaging even if previous neuroimaging was normal. The relationship of NBOs to seizures is controversial, but most studies have concluded that NBOs are not associated with seizures [22, 28]. Seizures in NF1 are generally relatively easy to control with one or more conventional antiepileptic drugs (AED); Sometimes, those ending lesions are surgically resected. Surgery is the most successful for temporal lobe gliomas [3].

#### **4. Epilepsy surgery in NF1**

In the review of 43 studies, structural causes were found in half of the patients with NF1. Low-grade gliomas were the most common, followed by mesial temporal sclerosis, cortical growth malformation, dysembryoplastic neuroepithelial tumor, and cerebrovascular lesions. Surgical method was the best approach for the treatment of epilepsy in patients with NF1 with structural lesions [29].

*Seizures in Adult with Neurofibromatosis Type 1 DOI: http://dx.doi.org/10.5772/intechopen.98660*

Eighteen patients with mesial temporal sclerosis (MTS) who were followed up with a diagnosis of NF1 and epilepsy have been reported in the literature. Ten of the 18 patients were women and 8 were men, 10 patients had right MTS, 6 patients had left MTS and 1 patient had bilateral MTS [30].

Vivarelli et al. [22] described 9 patients with NF1 and brain lesions. 5 patients had cerebral tumor, 3 patients had cortical malformation and 1 patient had MTS. Responded to medication in 1 case with MTS [16].

Carmen Barba et al. [31] reported 12 resistant epilepsy patients with cortical development or malformations of glioneuronal tumors on NF1 and MRI. Four of 12 patients had MTS. Four patients with MTS were women, and 3 had left MTS and 1 had right MTS. Three of the 4 patients were seizure-free after temporal lobectomy.

In the study by Ostendorf AP. et al. [3] 9.5% of individuals with NF1 had a history of at least one unprovoked seizure and 6.5% were diagnosed with epilepsy. Individuals who had seizures were more likely to have inherited NF1 from their mothers. Focal seizures were the most common seizure type occurring in 57% of individuals [21]. It has been reported in the literature that 60% of individuals with NF1 have good seizure control with only one AED or without AED treatment [5, 16]. Epilepsy in NF1 can be associated with more than one type of epilepsy and syndromes, and when relevant to localization, it is often drug resistant [31, 32].

#### **5. Conclusion**

As a result, epilepsy is more common in NF1 patients than in the general population. Although the clinical features of epilepsy in NF1 are heterogeneous, most patients have focal seizures and have a good response to treatment. In at least half of cases, epilepsy is mainly caused by central nervous system structural lesions represented by brain tumors. However, other brain changes such as MTS, DNETs, cortical abnormalities, cerebrovascular disease, and other complications cannot be ruled out. In addition, epilepsy in NF1 is associated with a history of epilepsy and learning disabilities in a family that contributes to a genetic mechanism that may be associated with cellular or synaptic changes in the brain and epileptogenesis in the NF1 pan.

Given the heterogeneity of structural causes in NF1-, correlation of relevant epilepsy, clinical-video EEG and neuroimaging should always be performed, especially before surgery.

#### **Author details**

Demet İlhan Algin\* and Oğuz Osman Erdinç Faculty of Medicine, Department of Neurology, Eskişehir Osmangazi University, Eskişehir, Turkey

\*Address all correspondence to: ilhandemet@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[2] Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease. Dev Period Med 2014;18:297-306.

[3] Ostendorf AP, Gutmann DH, Weisenberg JL. Epilepsy in individuals with neuro- fibromatosis type 1. Epilepsia 2013;54:1810-4.

[4] Santoro C, Bernardo P, Coppola A, Pugliese U, Cirillo M, Giugliano T, et al. Seizures in children with neurofibromatosis type 1: is neurofibromatosis type 1 enough? Ital J Pediatr 2018;44(41)

[5] Nix JS, Blakeley J, Rodriguez FJ. An update on the central nervous system manifesta- tions of neurofibromatosis type 1. Acta Neuropathol 2020;139: 625-641.

[6] Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia 2012; 53:1119-30.

[7] Gutmann DH, Parada LF, Silva AJ, Ratner N. Neuro bromatosis type 1: modeling CNS dysfunction. J Neurosci 2012; 32:14087-93.

[8] Diggs-Andrews KA, Gutmann DH. Modeling cognitive dysfunction in neuro bromatosis-1. Trends Neurosci 2013; 36:237-47.

[9] Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y, Gutmann DH, et al. Neurofi bromin regulation of ERK signaling modulates GABA release and learning. Cell 2008; 135:549-60.

[10] Moutal A, Dustrude ET, Khanna R. Sensitization of ion channels contributes to central and peripheral dysfunction in neurofibromatosis type 1. Mol Neurobiol 2016;54:3342-3349.

[11] Wang Y, Brittain JM, Wilson SM, Hingtgen CM, Khanna R. Altered calcium currents and axonal growth in Nf1 haploinsufficient mice. Transl Neurosci 2010; 1:106-14.

[12] Omrani A, van der Vaart T, Mientjes E, van Woerden GM, Hojjati MR, Li KW, et al. HCN channels are a novel therapeutic target for cognitive dysfunction in neurofib romatosis type 1. Mol Psychiatry 2015; 20:1311-21.

[13] Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Primers 2017;23: 17004

[14] Wang Y, Duan JH, Hingtgen CM, Nicol GD. Augmented sodium currents contribute to the enhanced excitability of small diameter capsaicin- sensitive sensory neurons isolated from Nf1+/– mice. J Neurophysiol 2010;2085-94.

[15] Stafstrom CE, Staedtke V, Comi AM. Epilepsy mechanisms in neurocutaneous disorders: tuberous sclerosis complex, neurofibromatosis type 1, and Sturge-Weber syndrome. Front Neurol 2017;8: 87.

[16] Serdaroglu E, Konuskan B, Karli Oguz K, Gurler G, Yalnizoglu D, Anlar B. Epilepsy in neurofibromatosis type 1: Diffuse cerebral dysfunction ?. Epilepsy Behav 2019;98:6-9.

[17] Sabetghadam A, Wu C, Liu J, Zhang L, Reid AY. Increased epileptogenicity in a Mouse model of neurofibromatosis type 1. Exp Neurol. 2020;331:113373.

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[18] Moles KJ, Gowans GC, Gedela S, Beversdorf D, Yu A, Seaver LH, et al. NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype. Genet Med 2012;14:508-14.

[19] Abdel A, Razek KA. MR imaging of neoplastic and non-neoplastic lesions of the brain and spine in neurofibromatosis type I. Neurol Sci 2018;39:821-8.

[20] Abdel Razek AA, Kandell AY, Elsorogy LG, Elmongy A, Basett AA. Disorders of cortical formation: MR imaging features. AJNR Am J Neuroradiol 2009;30:4-11

[21] Balestri P, Vivarelli R, Grosso S, Santori L, Farnetani MA, Galluzzi P, Vatti GP, Calabrese F, Morgese G. Malformations of cortical development in neurofibromatosis type 1. Neurology 2003; 61: 1799-1801

[22] Vivarelli R, Grosso S, Calabrese F, Farnetani M, Di Bartolo R, Morgese G, et al. Epilepsy in neurofibromatosis 1. J Child Neurol 2003;18:338-42.

[23] Hsieh HY, Fung HC, Wang CJ, Chin SC, Wu T. Epileptic seizures in neurofibroma- tosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure 2011;20:606-11.

[24] Flores-Sarnat L. Hemimegalence phaly: Part 1. Genetic, Clinical, and Imaging Aspects. J Child Neurol 2002;17:373-384.

[25] Gales J, Prayson RA. Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I. J Clin Neurosci 2017;37:15-19

[26] Pecoraro A, Arehart E, Gallentine W, Radtke R, Smith E, Pizoli C, et al. Epilepsy in neuro fibromatosis type 1. Epilepsy Behav 2017;73:137-41.

[27] Korf BR, Carrazana E, Holmes GL. Patterns of seizures observed in association with neuro bromatosis 1. Epilepsia 1993; 34:616-20.

[28] Caraballo RH, Portuondo E, Fortini PS. Neurofibromatosis and epilepsy. J Pediatr Epilepsy 2016;5: 59-63.

[29] Pia Bernardo, Cinalli G, Santoro C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst 2020;36:2333-2350.

[30] Algın Dİ, Tezer FI, Oguz KK, Bilginer B, Soylemezoglu F, Saygi S. Pharmacoresistant seizures in neurofibromatosis type 1 related to hippocampal sclerosis: three case presentation and review. J Clin Neurosci 2019; 64:14-17.

[31] Barba C, Jacques T, Kahane P, Polster T, Isnard J, Leijten FS, et al. Epilepsy surgery in Neurofibromatosis Type 1. Epilepsy Res 2013; 105: 384-95.

[32] Kullkantrakom K, Geller TJ. Seizures in neurofibromatosis 1. Pediatr Neurol 1998; 19: 347-50.

#### **Chapter 5**

## Endocrine Conditions in Neurofibromatosis 1

*Shilpa Mehta and Resmy Palliyil Gopi*

#### **Abstract**

Neurofibromatosis 1 (NF1) is an autosomal-dominant multisystemic neurocutaneous disorder primarily affecting the skin, bone and the nervous system. It has been long appreciated that NF1 is often associated with endocrine disorders. In this chapter, we will discuss the endocrine disorders associated with NF1. The most common endocrinological disorders in NF1 are short stature with or without growth hormone deficiency, central precocious puberty, growth hormone excess. Less common endocrine-related conditions in NF1 include gynecomastia, diencephalic syndrome and the presence of endocrine tumors like pheochromocytoma.

**Keywords:** NF1, endocrine conditions, short stature, GHD, growth hormone excess, central precocious puberty, endocrine tumors

#### **1. Introduction**

Neurofibromatosis 1 (NF1) is an autosomal-dominant multisystemic neurocutaneous disorder primarily affecting the skin, bone and the nervous system. The incidence has been described to be around 1 in 2500–3500 live births, and the estimated prevalence is 1 in 4000–5000. The penetrance is complete, but the severity of the clinical manifestations is variable and unpredictable, even within affected families [1]. Approximately one-half of the cases are familial and the remainder arise from a *de novo NF1* mutation. The diagnosis of NF1 relies primarily on the clinical grounds, which is based on the National Institutes of Health (NIH) diagnostic criteria [2], as described in the other chapter.

In this chapter, we will discuss endocrine disorders associated with NF1. The association of NF1 with endocrinopathies has been reported since 1920 [3]. The data on the incidence and prevalence of endocrine disorders in NF1 are scarce [4]. The most common endocrine disorders in NF1 are short stature with or without growth hormone deficiency (GHD), central precocious puberty, growth hormone excess (GHE). Less common endocrine-related conditions in NF1 include gynecomastia, diencephalic syndrome and the presence of endocrine tumors like pheochromocytoma. The most endocrine disorders in NF1 are thought to be related to central nervous system tumors compromising the hypothalamic and pituitary function [1]. In a recent retrospective study, endocrine disorders were found in approximately one-third of patients with NF1 and optic pathway glioma [4].

#### **2. Pathophysiology**

The protein product of the NF1 gene is a large cytoplasmic protein, neurofibromin. The neurofibromin coding sequence comprises a 300-amino acid sequence, with the GTPase-activating protein domain. Loss of neurofibromin function results in hyperactivation of the proto-oncogene RAS, as well as enhanced activity of RAS downstream effectors. In animal studies with a mouse model, loss of neurofibromin alone is insufficient to cause nervous system tumor formation and that additional genetic or environmental changes are probably necessary for tumor formation [5].

Neurofibromin also regulates intracellular cAMP generation in the brain. Cyclic AMP and the transcription factor called cAMP response element-binding protein (CREB) represent key regulators of hypothalamic-pituitary axis development. In animal models, brain-specific loss of CREB is known to cause hypopituitarism and poor growth [5, 6]. During embryonic differentiation, neurofibromin regulates the proliferation and maturation of both glial and neuronal progenitor cells [7]. The animal studies with a mouse model (*Nf1BLBPCKO* mice) with NF1 gene inactivation in neuroglial progenitor cells showed significantly reduced body weight and a small anterior pituitary gland with normal posterior pituitary. The anterior pituitary hypoplasia reflects a loss of neurofibromin expression in the hypothalamus, leading to reduced growth hormone-releasing hormone (GHRH), growth hormone (GH) and insulin-like growth factor-1 (IGF1) production. GHRH gene expression analysis by immunohistochemistry in hypothalamic-pituitary tissue from these mice has shown a significant reduction in GHRH staining within the median eminence. About 40–60% reduction in the GHRH mRNA was evident in the hypothalamic cells of *Nf1BLBPCKO* mice, compared with wild-type controls.

#### **3. Endocrine disorders in NF1**

#### **3.1 Short stature**

Short stature is a well-recognized clinical feature of NF1. The risk factors for short statue in NF1 include suprasellar lesion, surgery or radiation for such lesions causing GHD and scoliosis or other skeletal abnormalities. Short stature has been reported in 13–33% of children with NF1 [8, 9]. After exclusion of risk factors, the short stature has been reported in 8% of children with NF1 [10]. Short stature in NF1 has been associated both with and without GHD.

The population with NF1 as a whole is significantly shorter than the general population and specific growth charts are available for children with NF1. Clementi et al. analyzed the growth profile of 528 children with NF1 based on the data collected through a population-based registry from three contiguous regions of North-East Italy, and created growth charts of height, weight and head circumference (HC) for children with NF1 [11]. There was no difference in height between children with NF1 and normal children up to 7 years in girls and 12 years in boys. Beyond that age, the 50th centile of children with NF1 overlapped with the 25th centile of normal children and the 3rd centile of children with NF1 was significantly lower than the normal children. The height growth velocity was normal for both sexes in children with NF1 during childhood, but pubertal spurt was reduced in NF1 boys. Children with NF1 and normal children showed a similar median weight during the whole growth period. The 3rd centile for weight was consistently lower in children with NF1 during adolescence, and the 97th centile was higher during adulthood. The HC was larger in children with NF1 during the whole childhood and adulthood.

These growth charts can be used in neurofibromatosis clinics for the identification of secondary growth disorders, for growth prognosis and the evaluation of the effects of various treatments in children with NF1 [11].

#### **3.2 Growth hormone deficiency (GHD)**

The GHD is more common in children with NF1 compared to the general population. Cnossen et al. found a prevalence of 2.5% among patients with NF-1, which is higher than the 0.03% observed in the general pediatric population [12]. The cause of GH deficiency in NF1 is not clear, but it is much more common in the presence of an intracranial tumor and in some cases, it is clearly related to the treatment of these tumors with surgery and radiotherapy [13, 14]. GHD is also seen in children with NF-1 without suprasellar abnormalities, which suggests an association with NF-1 independent of organic pituitary damage [9].

As children with NF1 have a greatly increased risk of malignancy, there has been concern about the safety of GH treatment in children with NF1. Howell et al. reviewed the safety and efficacy of growth hormone therapy in a cohort of 102 children with both NF and biochemical evidence of GHD who had received GH replacement therapy at a mean dose of 0.18 mg/kg/week. During the 1st year, the median height velocity increased significantly from 4.2 cm/year before treatment to 7.1 cm/year, and the median height standard deviation score increased from −2.4 to −1.9. Children with NF1 and GHD respond favorably to treatment with GH, but not as good as that seen in patients with idiopathic GHD. Most of the adverse events reported in this cohort during GH therapy were either relatively minor or unlikely to be directly attributable to GH therapy. Five GH-treated patients had either a recurrence of an intracranial tumor or a second intracranial tumor. This incidence of tumor occurrence was comparable to that previously reported in similar NF1 patients not treated with GH. GH therapy did not influence the progression of any of the features of NF1, including intracranial tumors, and was not associated with an excess of other adverse events. Though controversial, GH treatment in NF1 patient is beneficial in terms of growth rate [15]. There is a need for prospective and randomized studies to test the efficacy, risk and safety of GH therapy in this population.

#### **3.3 Central precocious puberty (CPP)**

Central precocious puberty is the most common endocrine disorder in children with NF1. The prevalence of this disorder in patients with NF1 is 3%, which is markedly higher than the prevalence of about 0.6% reported in the general pediatric population [1]. Central precocious puberty is reported more often in girls than in boys, while precocious puberty in NF1 is observed more in boys [12, 16].

Precocious puberty in NF1 almost occurred invariably in association with optic pathway tumors, especially when optic chiasm is involved [16]. This supports the theory that lesions located near the hypothalamus interfere with the tonic Central nervous system inhibitions of the hypothalamic-pituitary-gonadal axis, resulting in the premature onset of puberty [17]. However precocious puberty in NF1 has also been reported in the absence of optic glioma [12]. Saxena reported two cases of precocious puberty in patients with NF1 without tumors of the optic chiasm, but no imaging was available at that time, which leaves open the possibility of undetected tumors [3]. In the study reported by Cnossen et al., CPP was diagnosed in 3 of 122 children but only 1 child had an OPG at MRI showing that optic chiasm glioma is not a prerequisite for CPP [12]. This could possibly be due to some cerebral abnormality undetected by neuroimaging or due to abnormalities at the cellular level involving neurofibromin. Other tumors like hypothalamic hamartoma that causes

precocious puberty in the general population have also been reported to cause precocious puberty in patients with NF1 [18].

Treatment of NF1 children with CPP is similar to those approved for children with idiopathic or organic CPP not related to NF1. Pubertal progression in CPP is treated by administration of a gonadotropin-releasing hormone (GnRH) agonist. These agents act by causing continuous stimulation of the pituitary gonadotrophs, instead of physiologic pulsatile stimulation from hypothalamic GnRH and this continuous stimulation leads to desensitization of the gonadotroph cells and suppression of gonadotropins, resulting in decreased sex steroid production. These treatments are mostly effective in children with younger age at the onset of puberty or with a progressive decline in predicted adult height.

In contrast to precocious pubertal development, a very high incidence of delayed menarche among NF1 girls has been reported [19].

#### **3.4 GH excess**

GH excess is generally a rare disease in children and adults but affects patients with NF1 at higher rates. It is mostly observed in the presence of OPG located inside the hypothalamic area or close to it. The prevalence of GH excess in patients with NF1 is unknown. Cambiaso et al. noted that 10% of the population with NF1 had abnormalities in the GH axis consistent with GH excess. All the affected patients studied by Cambiaso et al. had a tumor involving the optic chiasm, without pituitary involvement [20].

The mechanism underlying GH excess in NF1 is unknown. It has been postulated that the presence of OPT, particularly those involving the hypothalamic and sellar regions, inhibits somatostatin tone allowing for the unregulated release of GH. Some authors proposed the presence of overactive GH-releasing hormone in OPTs, although immunostaining for GHRH and GH were negative in some reported cases [21].

The diagnosis of GH excess in NF1 should be suspected in children with accelerated linear growth and clinical features of gigantism such as enlargement of the hands and feet, soft tissue thickening, coarse facial features, prognathism or worsening of clinical features such as neurofibromas, pain or endocrinopathies. Screening for GH excess in NF1 should be based on the existing guidelines for the diagnosis of gigantism and acromegaly. Initial screening includes the measurement of serum IGF-1 and GH levels that can be paired in a random sample. In patients with suspected GH excess with normal IGF1 and GH levels, a serial overnight GH sampling may be performed in specialized centers. GH excess is confirmed with elevated IGF-1 and lack of GH suppression to levels <1 ng/mL after the oral glucose tolerance test. Once confirmed, brain imaging is recommended to evaluate for OPT and to assess for lesions in the pituitary and hypothalamus [21].

Growth hormone excess in children with NF1 has been reported to be a transient phenomenon in some children and thus may not need treatment [22, 23]. In children requiring treatment, somatostatin analogs and GH receptor antagonist have been used to reduce tumor growth and the long-term systemic effects related to uncontrolled GH excess. The outcome of the medical treatment has been reported only in a few cases [24] and there are limited data on the longitudinal course of patients treated with somatostatin analogs or GHR antagonists.

#### **3.5 Diencephalic syndrome**

Diencephalic syndrome (DS) is a rare endocrine disorder reported in children with NF1 and OPG. It is a clinical condition present in early infancy and is characterized by failure to thrive despite adequate or slightly decreased food intake, severe

#### *Endocrine Conditions in Neurofibromatosis 1 DOI: http://dx.doi.org/10.5772/intechopen.100371*

emaciation and hyper-alertness, associated with supratentorial midline spaceoccupying lesions involving the hypothalamus.

DS is commonly reported within the first 2 years of life. But the median age of children diagnosed with DS associated with NF1 is slightly advanced, with only one case reported at age less than 12 months [25]. DS in an infant or a child with NF1 usually indicates the presence of an undiagnosed OPG. Less often, it may become evident later with the progression of an already known OPG due to the enlargement of the tumor, which causes compression of the hypothalamus.

#### **3.6 Gynecomastia**

Gynecomastia is the growth of glandular breast tissue in males. Gynecomastia seen during puberty is physiologic, but gynecomastia with prepubertal-onset is very uncommon and suggests a different etiology such as gonadal steroid-secreting tumors, congenital adrenal hyperplasia, aromatase excess [26]. An increased frequency of unilateral and bilateral prepubertal gynecomastia has been described in NF1 patients [27]. Endocrine workup was found normal in all the described cases, ruling out other etiologies of prepubertal gynecomastia. The exact etiology and pathogenesis of gynecomastia in NF1 are not clearly understood. It is thought to be due to pseudoangiomatous stromal hyperplasia of breast tissue secondary to a mutation in neurofibromin [28]. Distinct histopathologic features seem to be associated with gynecomastia related to NF1. Standard pubertal gynecomastia is characterized by hypocellular fibrous stroma, with proliferative multilayered ductal epithelium, while NF-1-related gynecomastia is characterized by hypercellular fibrous stroma and a single layer of ductal epithelium [27]. A few cases of neurofibroma, hamartoma, lipomatous hyperplasia and pseudoangiomatous hyperplasia of the breast, mimicking gynecomastia (usually unilateral), have also been described in children with prepubertal NF1 [29–31]. Surgery is indicated in cases of progressive breast enlargement.

#### **4. Endocrine tumors in NF1**

Patients with NF1 are at an approximately 2–4-fold higher risk of developing tumors than the general population. The gastrointestinal tract may be involved in NF-1 and includes gastrointestinal stromal tumors (GIST), carcinoids, pheochromocytomas, paragangliomas and pancreatic neuroendocrine tumors. Gastrinomas, insulinomas and nonfunctioning pancreatic endocrine tumors have also been reported in patients with NF-1.

#### **4.1 Pheochromocytoma**

The incidence of pheochromocytoma among patients with NF1 is estimated to be 0.1–5.7% [32]. It is usually seen in adult patients with NF1. NF-1-associated pheochromocytomas are predominantly epinephrine-producing, and thus, patients present with paroxysmal symptoms. Approximately 60% of patients with pheochromocytoma in the setting of NF-1 have sustained hypertension. Metabolites of epinephrine, such as metanephrines, can be measured in plasma by high-performance liquid chromatography with electrochemical detection. Biochemical screening *via* serum fractionated metanephrines is recommended in patients with NF1 in case of development of hypertension or other suggestive symptoms to exclude or confirm pheochromocytoma. If biochemical testing is positive, other imaging modalities such as CT, MRI and functional imaging with I123 metaiodobenzylguanidine (MIBG) scintigraphy may be utilized to further characterize the tumor.

#### **4.2 Optic pathway gliomas**

The Optic Pathyway Gliomas occurs in 15-20% of children with NF1. These can involve the hypothalamus and lead to endocrine disorders [33]. A retrospective study by Sani et al. (*n* = 40) reported endocrinopathies in 55% of children with NF1 and OPG by the mean age of 7.4 years. This study reported GHD in 36%, CPP in 33% and GH excess in 5%. This study also reported that GHD was transient in patients who were retested. A recent multicenter retrospective study in children with NF1 and OPG (*n* = 116) showed 27% of children had endocrine dysfunction by age 7.8 years including CPP (72%) and GHD (10%), GHE (6%) and DS (12.5%) [4].

There are no specific recommendations for surveillance of patients with NF-1 for endocrine tumors. However, due to the association of NF-1 with endocrine tumors, physicians should have a high index of suspicion in patients with symptoms suggestive of a neuroendocrine tumor and appropriate screening tests should be performed.

#### **5. Conclusion**

Children with NF1 are at risk for developing endocrinopathies such as CPP, GHD, GHE and DS. A close follow-up is crucial in NF1 patients especially in children with OPG, for early identification of endocrinopathies.

#### **Author details**

Shilpa Mehta\* and Resmy Palliyil Gopi Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, New York Medical College, New York, NY, USA

\*Address all correspondence to: shilpanarpat@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Endocrine Conditions in Neurofibromatosis 1 DOI: http://dx.doi.org/10.5772/intechopen.100371*

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Section 3
