Updated: 6/15/2021

Neurofibromatosis

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  • summary
    • Neurofibromatosis is an autosomal dominant disorder caused by a mutation in the NF1 gene that codes for the neurofibromin protein that typically presents with skin lesions, lower and upper extremity deformities, and spinal involvement. 
    • Diagnosis is made with the NIH Consensus Development Conference Statement criteria with the presence of a combination of cafe-au-lait spots, neurofibromas, freckling in axillary/inguinal region, optic glioma, lisch nodules, and the presence of a 1st degree relative with NF-1.
    • Treatment depends on presence and severity of forearm, lower extremity or spinal deformity.  
  • Epidemiology
    • Incidence
      • 1:3,000 births for NF1
    • Anatomic location
      • extremity deformities
        • congenital anterolateral bowing and pseudoarthrosis of tibia/ fibula and forearm
      • spine involvement
        • scoliosis & kyphosis
        • atlantoaxial instability
  • Etiology
    • Genetics
      • autosomal dominant (AD)
      • mutation in NF1 gene on chromosome 17q11.2
        • 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 
      • anterolateral bowing of tibia
      • bowing of forearm bones with obliteration of medullary cavity
        • ulnar pseudoarthrosis
        • radius pseudoarthrosis
      • neoplasias
  • Diagnosis
    • 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
      • verrucous 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 in NF-1
        • scoliosis is NOT associated with NF-2
      • can take two forms
        • idiopathic-like form (nondystrophic)
          • 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
          • usually recognized earlier than nondystrophic form
          • generally characterized by a sharp angular curve involving 4 to 6 vertebrae
    • Imaging
      • radiographs show
        • vertebral scalloping
        • penciling of ribs (penciling of 3 or more ribs is a poor prognostic finding and associated with rapid curve progression)
        • enlarged foramina
      • MRI
        • always obtain preoperative MRI to identify dural ectasia and dumbbell 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, anterior spinal fusion (ASF) & posterior (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 contact orthosis
          • 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
        • < 4 y.o., extend fixation to calcaneus
        • 5-10 y.o., extend fixation to talus
          • 2 yrs. postop, typically a 2nd surgery to push rod proximally to free the ankle joint
      • free fibular graft
        • often need to take fibula from contralateral side because ilpsilateral fibula is not normal
        • Illizarov's external fixation
  • Prognosis
    • Studies show between 8-10 years of decreased life expectancy compared to general population
    • High incidence of malignancy and hypertension

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Questions (27)

(OBQ19.156) Figures A&B are the radiographs of a 5-year-old male who presents for evaluation of right lower leg pain. On examination, he is noted to have freckling in the axilla and optic examination is seen in Figure C. What is the pattern of inheritance of this most likely disease?

QID: 214058
FIGURES:

Autosomal dominant

84%

(795/943)

Autosomal recessive

10%

(96/943)

Non-inherited

1%

(8/943)

X-linked dominant

1%

(14/943)

X-linked recessive

3%

(27/943)

L 2 A

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(OBQ18.38) A child is found to have axillary and inguinal freckling, scoliosis, and hamartomas within his iris. Which of the following pairs the inheritance pattern of the condition with the leg abnormality found in the condition?

QID: 212934
FIGURES:

Autosomal dominant; Figure B

73%

(1279/1748)

Autosomal recessive; Figure B

12%

(207/1748)

X-linked recessive; Figure A

3%

(59/1748)

Autosomal dominant; Figure C

6%

(97/1748)

Autosomal recessive; Figure A

5%

(94/1748)

L 2 A

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(OBQ18.49) A 6-year-old boy with neurofibromatosis type 1 returns for follow-up of the condition shown in Figures A and B. The patient has attempted bracing with a knee-ankle-foot orthosis and long leg casting but has not had any radiographic improvement. What is the best next step in management?

QID: 212945
FIGURES:

Continued bracing

6%

(113/1905)

Bone stimulator

2%

(39/1905)

Intramedullary nailing

4%

(81/1905)

Resection of pseudoarthrosis , bone grafting, and intramedullary nailing

86%

(1643/1905)

Amputation

1%

(17/1905)

L 2 A

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(OBQ18.55) A 4-year-old refugee patient presents with multiple orthopedic complaints. To date, the patient has not seen any specialists or received any treatment with regards to their symptoms. Radiographs are shown in Figures A-C. Based on the diagnosis, what other manifestations may also be present?

QID: 212951
FIGURES:

Radial head subluxation

17%

(319/1919)

Excessive glenoid retroversion

3%

(62/1919)

Absence of the anterior cruciate ligament

13%

(257/1919)

Hemihypertrophy

33%

(639/1919)

Developmental dysplasia of the hip

33%

(637/1919)

L 5 A

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(SBQ13PE.55) A 4-year-old boy is referred to your office for evaluation of a progressive lower extremity deformity. AP radiographs are shown in Figure A. All of the following may also be found on physical examination EXCEPT:

QID: 5127
FIGURES:

Figure B

7%

(130/1748)

Figure C

5%

(85/1748)

Figure D

4%

(71/1748)

Figure E

76%

(1330/1748)

Figure F

7%

(125/1748)

N/A B

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(SBQ13PE.20) A patient presents with scoliosis associated with neurofibromatosis. In addition to intracanal neurofibromas, which of the following is commonly associated with this condition, and should be assessed by MRI of the spinal axis preoperatively?

QID: 4987

Syrinx

26%

(1119/4309)

Hemivertebra

4%

(181/4309)

Dural ectasia

56%

(2393/4309)

Diastematomyelia

7%

(315/4309)

Spina bifida occulta

7%

(286/4309)

L 4 B

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

QID: 3230

Smooth bordered café-au-lait spots

3%

(86/2616)

Posterior-medial bowing of the tibia

81%

(2132/2616)

Short, sharp dystrophic scoliosis

10%

(267/2616)

Cutaneous neuromas

2%

(57/2616)

Autosomal dominant transmission from mutated neurofibromin gene

3%

(69/2616)

L 2 C

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(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.

QID: 411
FIGURES:

autosomal dominant; mutation in NF1 gene that codes for neurofibromin protein

85%

(2473/2925)

autosomal recessive; mutation in NF1 gene that codes for neurofibromin protein

12%

(339/2925)

autosomal dominant; mutation of FGFR3 (fibroblast growth factor recepter)

1%

(41/2925)

autosomal recessive; mutation of FGFR3 (fibroblast growth factor recepter)

1%

(31/2925)

autosomal dominant; mutation of GS alpha protein

1%

(20/2925)

L 1 C

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(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?

QID: 612
FIGURES:

COMP

3%

(43/1236)

Fibrillin

10%

(118/1236)

Neurofibromin

78%

(961/1236)

COL2A1

6%

(68/1236)

RUNX2/CBFA1

3%

(37/1236)

L 2 C

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(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?

QID: 423
FIGURES:

Achondroplasia

0%

(3/1590)

Fibrous dysplasia

2%

(27/1590)

Osteogenesis imperfecta

8%

(130/1590)

Neurofibromatosis Type 1

86%

(1375/1590)

Ollier's disease

3%

(45/1590)

L 1 C

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(SAE07PE.91) What is the most important sign of impending modulation with rapid progression of a spinal deformity in neurofibromatosis?

QID: 6151

Apical curve rotation

13%

(53/400)

Anterior vertebral body erosions

6%

(26/400)

Cervical spine involvement

5%

(20/400)

Penciling of three or more ribs

43%

(171/400)

Curve magnitude of more than 50 degrees

32%

(130/400)

L 4 E

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(SAE07PE.34) A 10-year-old girl who is Risser stage 0 has back deformity associated with neurofibromatosis type 1 (NF1). She has no back pain. Examination shows multiple cafe-au-lait nevi with normal lower extremity neurologic function and reflexes. Standing radiographs of the spine show a short 50-degree right thoracic scoliosis with a kyphotic deformity of 55 degrees (apex T8). A 10-degree progression in scoliosis has occurred during the past 1 year. There is no cervical deformity. MRI shows mild dural ectasia, primarily in the upper lumbar region. Management should consist of

QID: 6094

observation with repeat radiographs in 6 months.

4%

(23/549)

a thoracolumbosacral orthosis (TLSO).

17%

(92/549)

in situ posterior spinal fusion without instrumentation, followed by full-time TLSO bracing.

8%

(45/549)

anterior spinal convex hemiepiphysiodesis.

3%

(19/549)

combined anterior and posterior spinal arthrodesis with instrumentation.

66%

(365/549)

L 2 E

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(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?

QID: 213
FIGURES:

observation

21%

(605/2833)

bracing in total contact orthosis

72%

(2052/2833)

intramedullary nailing with bone grafting

3%

(76/2833)

free fibular graft from contralateral side

0%

(12/2833)

external fixation using Illizarov techniques

3%

(71/2833)

L 2 C

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

QID: 79

2 or more neurofibromas

1%

(17/1311)

6 or more cafe-au-lait macules

2%

(20/1311)

2 or more Lisch nodules

3%

(35/1311)

freckling on the plantar surface of the feet

82%

(1074/1311)

optic glioma

12%

(162/1311)

L 2 C

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(SBQ04PE.41) A 3-year-old male is evaluated in your office. On examination he is found to have several pigmented cutaneous lesions and hamartomas of the iris. His right leg was previously treated with both a knee-ankle-foot orthotic and long-leg casting for approximately 9 months. His most recent radiographs are seen in Figures A and B. What is the next best treatment?

QID: 2226
FIGURES:

Bone stimulator

2%

(37/1844)

Continue bracing

8%

(154/1844)

Syme amputation

1%

(11/1844)

Resection of pseudoarthrosis with bone grafting and surgical fixation

87%

(1611/1844)

Below knee amputation

1%

(24/1844)

L 2 C

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

QID: 1179

freckling in the axillae

3%

(29/854)

optic glioma

10%

(85/854)

2 or more Lisch nodules

2%

(18/854)

talipes equinus

83%

(712/854)

cafe' au lait spots

1%

(8/854)

L 2 D

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