Neurofibromatosis

Author: Jason McKean

Topic updated on 02/08/13 10:12pm

Introduction

Neurofibromatosis is an autosomal dominant disorder of neural crest origin characterized by
- extremity deformities
  - congenital anterolateral bowing and pseudoarthrosis of tibia/ fibula and forearm
  - hemihypertrophy
- spine involvement
  - scoliosis & kyphosis
  - atlantoaxial instability
Epidemiology
- 1:3,000 births for NF1
Genetics
- autosomal dominant (AD)
- mutation in NF1 gene on chromosome 17q21
  - codes for neurofibromin protein
    - negatively regulates Ras signaling pathway
    - neurofibromin deficiency leads to increased Ras activity
    - affects Ras-dependent MAPK activity which is essential for osteoclast function and survival
- neurofibromatosis is the most common genetic disorder caused by a new mutation of a single gene
Associated conditions
- scoliosis (see below)
- anterolateral bowing of tibia
- neoplasias
Prognosis
- normal life expectancy
- high incidence of malignancy and hypertension
Diagnostic criteria
- according to the NIH Consensus Development Conference Statement (1987) the diagnostic criteria for NF-1 are met in an individual if two or more of the following are found
  - six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in postpubertal individuals.
  - two or more neurofibromas of any type or one plexiform neurofibroma.
  - freckling in the axillary or inguinal region.
  - optic glioma.
  - two or more Lisch nodules (iris hamartomas).
  - a distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis.
  - a first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria.is based on presence of both

Classification

NF1 (von Recklinghaussen disease)
- most common
NF2
- associated with bilateral vestibular schwannomas
Segmental NF
- features of NF1 but involving a single body segment

Presentation General

Presentation
- often presents with anterolateral bowing of tibia
- often presents with radial bowing
Physical exam
- verucous hyperplasia
- hemihypertrophy
- cafe-au-lait spots
- axillary freckling
- scoliosis
- anterolateral bowing or pseudoarthrosis of tibia
- dermal Plexiform-type neurofibroma may be seen
- Lisch nodules are benign pigmented hamartomas of the iris

Neoplasias (Neurofibromatosis)

Neurofibromas (plexiform-type)
- is pathognomonic for NF1
- present in 4% of NF1
- may be dermal or in deep tissues
- often associated with limb overgrowth
- can undergo malignant transformation to neurofibrosarcoma
Wilms Tumor

Scoliosis (Neurofibromatosis)

Introduction
- spine is most common site of skeletal involvement
- can take two forms
  - idiopathic-like form
    - longer curve and treatment resembles that for idiopathic scoliosis
  - dystrophic form
    - curve is typically thoracic kyphoscoliosis with a short segmented and sharp curve with distorted ribs and vertebrae
Imaging
- radiographs show
  - vertebral scalloping
  - penciling of ribs (penciling of 3 or more ribs is a poor prognositc finding and associated with rapid curve progression)
  - enlarged foramina
- MRI
  - always obtain preoperative MRI to identify dural ectasia and dumbell lesion (neurofibroma on nerve root)
  - paraspinal masses are useful to distinguish from idiopathic scoliosis
Treatment
- nonoperative
  - observation vs. bracing
    - bracing is not effective for dystrophic form
    - nondystrophic scoliosis in NF is treated like adolescent idiopathic scoliosis
- operative
  - decompression, ASF & PSF with instrumentation
    - indications
      - dystrophic scoliosis
        
        perform early in young children (< 7 yrs) with dystrophic curves
    - complications
      - high rate of pseudoarthrosis with PSF alone (40%)
        
        pseudoarthrosis rate still high with ASF&PSF (10%)
        
        some recommend augmenting the PSF with repeat iliac crest bone grafting 6 months after the primary surgery

Anterolateral Tibial Bowing (Neurofibromatosis)

Introduction
- epidemiology
  - anterolateral bowing is often associated with neurofibromatosis (NF1)
  - 50% with anterolateral bowing have NF1
  - 10% of NF1 have anterolateral bowing
- pathophysiology
  - may progress to pseudoarthrosis
- differentials for tibia bowing
  - anteromedial
    - associated with fibular hemimelia and congenital loss of lateral rays of the foot
  - posteromedial
    - usually congenital due to
      - abnormal intrauterine positioning
      - dorsiflexed foot pressed against anterior tibia
      - will develop leg length discrepancy
      - associated with calcaneovalgus deformity
Imaging
- radiographs
  - obtain AP and lateral of tib/fib

Treatment
- nonoperative
  - bracing in total contactorthosis
    - indications
      - bowing without pseudoarthrosis or fracture (goal is to prevent further bowing and fractures)
      - spontaneous remodeling is not expected
      - osteotomy for bowing alone is contraindicated
- operative
  - bone grafting with surgical fixation
    - indications
      - in bowing with pseudoarthrosis or fracture
  - amputation with prosthesis fitting
    - indications
      - three failed surgical attempts
      - Syme's often superior to BKA due to atrophic and scarred calf muscle in these patients
Techniques
- intramedullary nailing with bone grafting
  - resect pseudoarthrosis
  - insert Charnley-Williams rod
  - antegrade through resection site, then retrograde through the heel
  - < 4yo than fix to calcaneus
  - 5-10yo than fix to talus
  - at 2y postop, 2nd surgery to push rod proximally to free the ankle joint
- free fibular graft
  - often need to take fibula from contralateral side because ilsilateral fibula is not normal
  - Illizarov's external fixation

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Qbank (7 Questions)

TAG

(OBQ10.142) All of the following are associated with neurofibromatosis except: Topic

Review Topic

1. Smooth bordered café-au-lait spots
2. Posterior-medial bowing of the tibia
3. Short, sharp dystrophic scoliosis
4. Cutaneous neuromas
5. Autosomal dominant transmission from mutated neurofibromin gene

PREFERRED RESPONSE ▶

DISCUSSION: Anterolateral bowing (which may be associated with a pseudarthrosis) of the tibia is characteristic of patients with neurofibromatosis while posterior-medial tibial bowing is associated with packaging problems during gestation. Café-au-lait spots show smooth "coast of California" borders as compared to the rough "coast of Maine" spots associated with McCune-Albright syndrome. Short, sharp dystrophic scoliosis, cutaneous neuromas, and autosomal dominant transmission are all associated with neurofibromatosis as well.

REFERENCES:

1. Dietz FR, Murray JC. Genetic basis of disorders with orthopaedic manifestations. In: Einhorn TA, O'Keefe RJ, Buckwalter JA (EDS). Orthopaedic Basic Science: Foundations of Clinical Practice, 3rd ed. American Academy of Orthopaedic Surgeons. Rosemont, IL. 2007:25-47

2. Lieberman JR (ED). Comprehensive Orthopaedic Review. American Academy of Orthopaedic Surgeons, Rosemont, IL. 2009:292-309

Question Authors:

Patrick O'Donnell MD/PhD, Eric Shirley MD,

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TAG

(OBQ08.25) A 3-year-old boy presents with a leg deformity and multiple skin lesions. Lisch nodules were found on ophthalmologic exam. A clinical photograph and radiographs are shown in Figure A and B. What is the inheritance pattern and mutation that encodes for this condition. Topic

Review Topic

FIGURES: A

1. autosomal dominant; mutation in NF1 gene that codes for neurofibromin protein
2. autosomal recessive; mutation in NF1 gene that codes for neurofibromin protein
3. autosomal dominant; mutation of FGFR3 (fibroblast growth factor recepter)
4. autosomal recessive; mutation of FGFR3 (fibroblast growth factor recepter)
5. autosomal dominant; mutation of GS alpha protein

PREFERRED RESPONSE ▶

DISCUSSION: Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant conditions affecting the nervous system, occurring with an estimated incidence of 1 in 2500 to 3000 individuals independent of ethnicity, race, and gender. Caused by a germ-line–inactivating mutation in the NF1 gene on chromosome 17 (neurofibromin), the disease is associated with increased morbidity and mortality. Currently, the diagnosis of NF1 is made in an individual with any 2 of the following clinical features: (1) cafe´-au-lait spots; (2) intertriginous freckling; (3) Lisch nodules; (4) neurofibromas; (5) optic pathway gliomas (OPGs); (6) distinctive bony lesions; and (7) a first-degree family relative with NF1. Long-bone dysplasia, such as congenital tibial dysplasia with pseudoarthrosis, is also seen with NF1. Identified in infancy, congenital tibial dysplasia presents as anterolateral bowing of a leg. The bone displays cortical thinning, which predisposes affected individuals to pathologic fractures on weight-bearing within the first year of life. Repeated fracture and failure to heal can result in a pseudoarthrosis

REFERENCES:

1. Alman BA, Goldberg MJ: Syndromes of orthopaedic importance, in Morrissy RT, Weinstein (eds) Lovell and Winters Pediatric Orthopaedics, ed 6. 2006, pp 251-313.

Question Authors:

Guillem Lomas MD,

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TAG

(OBQ08.37) A 3-year-old boy presents with a forearm deformity. Radiographs are shown in Figure A. Ophthalmologic exam shows the lesion seen in Figure B. These finding are most consistent with which of the following conditions? Topic

Review Topic

FIGURES: A

1. Achondroplasia
2. Fibrous dysplasia
3. Osteogenesis imperfecta
4. Neurofibromatosis Type 1
5. Ollier's disease

PREFERRED RESPONSE ▶

DISCUSSION: The radiographs in Figure A show radial bowing. Image B shows a Lisch nodules. These findings are consistent with neurofibromatosis. Neurofibromatosis is an autosomal dominant condition that has multiple cutaneous and musculoskeletal manifestations including café au lait spots, neurofibromas on the skin, lisch nodules in the eye, scoliosis, and long bone bowing & pseudoarthrosis. It is caused by a mutation in NF1 gene that codes for neurofibromin protein. The reference by Bell et al is a case series of 6 patients with congenital pseudoarthrosis of the forearm. They found promising results utilizing a free vascularized fibular transfer, and present it as an alternative to existing treatment options. The reference by Feldman et al reviews the different orthopaedic manifestations of neurofibromatosis type I. They emphasize a multidisciplinary treatment approach as NF-1 affects multiple organ systems. Anterolateral tibial bowing is a common presenting condition, and is more common than forearm bowing.

REFERENCES:

1. Bell DF. Congenital forearm pseudarthrosis: report of six cases and review of the literature. J Pediatr Orthop. 1989 Jul-Aug;9(4):438-43. PMID:2659623 (Link to Abstract)

2. Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010 Jun;18(6):346-57. PMID:20511440 (Link to Abstract)

Question Authors:

Derek Moore, Eric Shirley MD,

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TAG

(OBQ08.226) A 60-year-old man presents with the hand condition shown in Figure A. The mass is resected with gross pathology and histopathology representations displayed in Figures B and C, respectively. What is the altered genetic etiology of this condition? Topic

Review Topic

FIGURES: A

1. COMP
2. Fibrillin
3. Neurofibromin
4. COL2A1
5. RUNX2/CBFA1

PREFERRED RESPONSE ▶

DISCUSSION: The clinical presentation is consistent with Neurofibromatosis type 1 (NF1), a condition caused by a NF1 gene mutation on chromosome 17 that codes for neurofibromin.

NF1 is an autosomal dominant disorder and affects approximately 1 in 4000 individuals. The orthopedic complications of neurofibromatosis, which usually appear early, include spinal deformities such as scoliosis and kyphoscoliosis, congenital anterolateral bowing and pseudoarthrosis of the tibia, bowing of the forearm, overgrowth phenomenon of an extremity, and soft tissue tumors.

Figure A shows a hand with multiple cutaneous neurofibromas. Figure B shows the gross pathology of a a plexiform neurofibroma, which the characteristc "bag of worms" appearance. Figure C shows spindle cell stroma containing wavy eosinophilic fibrillar material consistent with a peripheral nerve tumor .

Incorrect Answers:
Answer 1. COMP is associated with MED - Type I
Answer 2. Fibrillin is associated with Marfan's syndrome
Answer 4. COL2A1 is associated with SED tarda and SED congenita
Answer 5. RUNX2/CBFA1 is associated with Cleidocranial dysplasia

REFERENCES:

1. Weiss SW, Goldblum JR: Benign tumors of peripheral nerves, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors. St Louis, MO, Mosby, 2001, pp 1111-1207.

2. Schwartz HS (ed): Orthopaedic Knowledge Update: Musculoskeletal Tumors 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 273-275.

Question Authors:

Michael Hughes MD, Eric Shirley MD,

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TAG

(OBQ06.202) A 3-year-old boy presents with the skin lesion seen in Figure A and a leg deformity. Radiographs are shown in Figure B. What is the most appropriate first step in treatment? Topic

Review Topic

FIGURES: A

1. observation
2. bracing in total contact orthosis
3. intramedullary nailing with bone grafting
4. free fibular graft from contralateral side
5. external fixation using Illizarov techniques

PREFERRED RESPONSE ▶

DISCUSSION: The clinical presentation is consistent with neurofibromatosis with associated anterolateral tibial bowing. Neurofibromatosis is the most common cause of anterolateral tibial bowing and congenital pseudoarthrosis of the tibia, two conditions which represent a continuum of the same disease process. Because there is no fracture or pseudoarthrosis the treatment in this case is bracing in a total contact orthosis, otherwise known as a clamshell orthosis. If the patient had a fracture or a pseudoarthrosis, then you would treat him with surgery. The reference by Crawford et al is a review article that describes the incidence and treatment of orthopaedic conditions seen with neurofibromatosis. In their database of 588 patients they found the incidence of spinal deformity in children with NF-1 to be 21%; pectus deformity, 4.3%; limb-length inequality, 7.1%; congenital tibial dysplasia, 5%; hemihypertrophy, 1.4%; and plexiform neurofibromas, 25%. The cited reference by Feldman et al is a more recent review articles that also discusses the orthopaedic manifestations of neurofibromatosis. There are various tibial bowing conditions found in children and one should be faimilar with the differential diagnosis and associated conditions. Bowing of the tibia that is present at birth typically occurs either anteriorly (in association with fibular hemimelia), anterolaterally (in association with congenital pseudoarthrosis), or posteromedially (in association with calcaneovalgus foot deformity).

REFERENCES:

1. Schonecker PL, Rich MM: The lower extremity, in Morrissy RT, Weisntein SL (eds): Lovell and Winter’s Pediatric Orthopaedics, ed 5. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1059-1104.

2. Crawford AH, Schorry EK. Neurofibromatosis update. J Pediatr Orthop. 2006 May-Jun;26(3):413-23. PMID:16670560 (Link to Abstract)

3. Crawford AH Jr, Bagamery N. Osseous manifestations of neurofibromatosis inchildhood. J Pediatr Orthop. 1986 Jan-Feb;6(1):72-88. PMID:3079778 (Link to Abstract)

4. Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010 Jun;18(6):346-57. PMID:20511440 (Link to Abstract)

Question Authors:

Derek Moore, Eric Shirley MD,

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TAG

(OBQ05.43) The diagnostic criteria for neurofibromatosis type I includes all of the following EXCEPT: Topic

Review Topic

1. 2 or more neurofibromas
2. 6 or more cafe-au-lait macules
3. 2 or more Lisch nodules
4. freckling on the plantar surface of the feet
5. optic glioma

PREFERRED RESPONSE ▶

DISCUSSION: First described by Frederick von Recklinghausen and subsequently mapped to chromosome 17, NF1 is one of the most common tumor predisposition syndromes involving the nervous system. The diagnosis of NF1 is made according to established diagnostic criteria, such that an individual with any two of the following criteria is diagnosed with NF1:
1) Six or more café-au-lait macules measuring at least 0.5 cm in diameter (before puberty) or at least 1.5 mm in diameter (after puberty).
2) Two or more neurofibromas of any type OR one plexiform neurofibroma.
3) Freckling in the axillary or inguinal regions (skinfolds).
4) Optic pathway glioma.
5) Two or more Lisch nodules (iris hamartomas).
6) Dysplasia of the sphenoid bone, or dysplasia or thinning of the cortex of the long bones (e.g., tibia).
7) First-degree relative with NF.
The cited reference by Ward et al reviews the clinical and molecular features of neurofibromatosis type 1 and discusses a mouse model that is being used to develop experimental treatment. The review article by Feldman et al reviews the orthopaedic management of NF-1 and emphasizes the importance of a multidisciplinary approach to treatment as NF-1 affects multiple organ systems.

REFERENCES:

1. Ward BA, Gutmann DH. Neurofibromatosis 1: From lab bench to clinic. Pediatric Neurology; (32); pp 221-228 PMID:15797177 (Link to Abstract)

2. Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010 Jun;18(6):346-57. Review PMID:20511440 (Link to Abstract)

Question Authors:

Greg Galano MD, Derek Moore, Eric Shirley MD,

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TAG

(OBQ04.74) All of the following are clinical features of neurofibromatosis type I (NF-I) EXCEPT? Topic

Review Topic

1. freckling in the axillae
2. optic glioma
3. 2 or more Lisch nodules
4. talipes equinus
5. cafe' au lait spots

PREFERRED RESPONSE ▶

DISCUSSION: NF-1 is an autosomal dominant disorder, with approximately 50% of cases due to a new mutation. It is the most common genetic disorder caused by a new mutation of a single gene. The entity is quite common, affecting 1 in 4000, and is one of the most common dominantly inherited gene disorders in humans. According to the NIH Consensus Development Conference Statement (1987) the diagnostic criteria for NF-1 are met in an individual if two or more of the following are found: 1) Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals. 2) Two or more neurofibromas of any type or one plexiform neurofibroma. 3) Freckling in the axillary or inguinal region. 4) Optic glioma. 5) Two or more Lisch nodules (iris hamartomas). 6)
A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis. 7) A first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria. According to the Crawford article, common orthopaedic manifestations are "spinal deformity, congenital tibial dysplasia (congenital anterolateral tibia bowing and pseudarthrosis), and disorders of excessive bone and soft-tissue growth".

REFERENCES:

1. Crawford AH, Schorry EK. Neurofibromatosis in children: the role of the orthopaedist. J Am Acad Orthop Surg. 1999 Jul-Aug;7(4):217-30. PMID:10434076 (Link to Abstract)

2. National Institutes of Health Consensus Development Conference Statement:neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis.1988;1(3):172-8. PMID:3152465 (Link to Abstract)

Question Authors:

Paul D. Kim MD, Derek Moore, Eric Shirley MD,

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Evidence & References Show References

Level of Evidence 4 (Case Series)

Bell DF. Congenital forearm pseudarthrosis: report of six cases and review of the literature. J Pediatr Orthop. 1989 Jul-Aug;9(4):438-43. PMID:2659623 (Link to Abstract)

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

National Institutes of Health Consensus Development Conference Statement:neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis.1988;1(3):172-8. PMID:3152465 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Dietz FR, Murray JC. Genetic basis of disorders with orthopaedic manifestations. In: Einhorn TA, O'Keefe RJ, Buckwalter JA (EDS). Orthopaedic Basic Science: Foundations of Clinical Practice, 3rd ed. American Academy of Orthopaedic Surgeons. Rosemont, IL. 2007:25-47
Lieberman JR (ED). Comprehensive Orthopaedic Review. American Academy of Orthopaedic Surgeons, Rosemont, IL. 2009:292-309
Schwartz HS (ed): Orthopaedic Knowledge Update: Musculoskeletal Tumors 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 273-275.
Weiss SW, Goldblum JR: Benign tumors of peripheral nerves, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors. St Louis, MO, Mosby, 2001, pp 1111-1207.

Undefined

Alman BA, Goldberg MJ: Syndromes of orthopaedic importance, in Morrissy RT, Weinstein (eds) Lovell and Winters Pediatric Orthopaedics, ed 6. 2006, pp 251-313.
Crawford AH Jr, Bagamery N. Osseous manifestations of neurofibromatosis inchildhood. J Pediatr Orthop. 1986 Jan-Feb;6(1):72-88. PMID:3079778 (Link to Abstract)
Crawford AH, Schorry EK. Neurofibromatosis in children: the role of the orthopaedist. J Am Acad Orthop Surg. 1999 Jul-Aug;7(4):217-30. PMID:10434076 (Link to Abstract)
Crawford AH, Schorry EK. Neurofibromatosis update. J Pediatr Orthop. 2006 May-Jun;26(3):413-23. PMID:16670560 (Link to Abstract)
Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010 Jun;18(6):346-57. PMID:20511440 (Link to Abstract)
Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010 Jun;18(6):346-57. Review PMID:20511440 (Link to Abstract)
Orthopaedic Knowledge Update: Pediatrics 3. Editor Mark F., M.D. Abel. American Academy of Orthopaedic Surgeons. Copyright 2006
Schonecker PL, Rich MM: The lower extremity, in Morrissy RT, Weisntein SL (eds): Lovell and Winter’s Pediatric Orthopaedics, ed 5. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1059-1104.
Ward BA, Gutmann DH. Neurofibromatosis 1: From lab bench to clinic. Pediatric Neurology; (32); pp 221-228 PMID:15797177 (Link to Abstract)

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Neurofibromatosis

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