Von Recklinghausen’s Disneurofibromatosisease

Shagreen patch REF: Harrison’s 17^th ed chapter 374

“Shagreen patch is seen in tuberous sclerosis”

Autosomal recessive [Ref: Robbin’s 7^thle p. 1413]

• Neurofibromatosis is an inherited disorder
• It is of two types: ?
• Neurofibromatosis

– Neurofibromatois II

Genetics of Neurofibromatosis

• Both the neurofibromas are inherited in an autosomal dominant pattern.
• The genes for them are located on different chromosome 

         – NF-1—) Neurofibrin gene on chromosome 17
         – NF-2 —) Merlin gene on chromosome 22

NEUROFIBROMATOSIS TYPE I ?

• Neurofibromatosis is a comparatively common hereditary disorder in which the skin, nevous system, bone, endocrine glands and sometimes other organs are at the sites of a variety of congenital abnormalities often taking the fonn of benign tumours.

. The main feature of neurofibromatosis I is –

(i) Spots of hyperpigmentation

and

(ii)    Cutaneous and subcutaneous neurofibromatous tumours’.

Hyperpigmentation in Neurofibromatosis I takes two forms 😕

a) Cafe – au – lait spots’

.   These are patches of pigmentation and they appear shortly after birth’ and occur anywhere on the body.

.   They are light brown in colour (cafe – au – lait) and do not change in number as the patient ages but they increase in size during puberty.

.   Presence of more than six cafe – au – lait spots > 1.5 cm in size is considered diagnostic of Neurofibromatosis.

b) Freckles’

.   Neurofibromatosis I is also characterized by the presence of Freckles like or diffuse pigmentation of the axillae and other intertriginous areas (groin, under breast) and small round whitish spots. When coupled with cafe au lait patches they are virtually pathogtzomonic^e of the disease.

ii) Neurofibromas

a) Cutaneous tumours

.   They are situated in the dermis and form discrete soft or_, firm papules.

.   They are _,flesh coloured or violaceous and often topped with comedo. When pressed, the soft tumours tend to invaginate through a small opening in the skin giving the feeling of a seedless raisin or a scrotum without a testicle. This phenomenon is spoken of as “button holding”.

b) Subcutaneous tumours

.   They take two forms ?

a)   Firm discrete nodules attached to a nerve.

b) Plexiform neuromas^e (overgrowth of subcutaneous tissue sometimes reaching enormous size and occur most often in the face, scalp, neck and chest and may cause hideous disfigurement).

Lisch Nodule’?

• This is another unique _.finding of neurofibromatosiso.

.   It is a small whitish spot^e present in the iris.

Tumours associated with Neurofibromatosis I are

1) Tumours of the CNS

a)  Optic Nerve Gliomao

b)  Non-optic Gliomas (usually low grade astrocytomas)

c)   Nonneoplastic ‘ hamartomatous” lesion

Osborn writes –

“The common CNS tumor in NF-1 is optic nerve glioma occuring in 5 to 15% of casese”

2) Other tumours associated with NF-1

a)  Pheochromocytoma

b)  Rhabdomyosarcoma

c)   leukemia (myeloid leukemia)

d)     Wilms tumour

e) Juvenile Xanthogranuloma

Tumours associated with Neurofibromatosis I are

1) Tumours of the CNS

a) Optic Nerve Gliomao

b) Non-optic Gliomas (usually low grade astrocytomas)

c) Nonneoplastic ” hamartomatous” lesion

Osborn writes ?

“The common CNS tumor in NF-1 is optic nerve glioma occuring in 5 to 15% of cases’)”

2) Other tumours associated with NF-1

a) Pheochromocytoma

b) Rhabdomyosarcoma

c)  leukemia (myeloid leukemia)

d)  Wilms tumour

e)  Juvenile Xanthogranuloma

Neurofibromatosis type 1, or von Recklinghausen disease, is an autosomal dominant disorder with high penetrance, but variable expressivity. The disease has three major features:
(1) multiple neural tumors anywhere on or in the body
(2) numerous pigmented cutaneous lesions (café au lait spots); and
(3) pigmented iris hamartomas (Lisch nodules).

Electron micrographic studies show that the tumors are the result of the proliferation of fibroblasts or Schwann cells in the peripheral nerves, possibly due to ras inactivation.
There is no treatment, except for surgical resection of symptomatic tumors.

Children with neurofibromatosis type 1 have higher risk of developing juvenile myelomonocytic leukemia.
Ref: Essential pediatrics by O.P.Ghai 6th edn/page 545; Rook’s textbook of dermatology, Volume 1 By Arthur Rook, Tony Burns (FRCP.)page 2-32.

Causes of Pseudarthrosis (In decreasing order of frequency) are:

• Neurofibromatosis (50% patients of pseudarthrosis have NF)
• Nonunion of fracture (including pathological fracture)
• Congenital (mostly in lower to middle third of tibia with cupping of proximal bone end and pointing of distal bone end)
• Idiopathic
• Osteogenesis imperfecta
• Fibrous dysplasia
• Cleidocranial dysplasia
• Ankylosing spondylitis (in fused bamboo spine)
• Post surgical e.g. triple arthrodesis, spinal fusion etc. as a complication. 

Neurofibromatoses are a group of clinically and genetically different autosomal dominant hereditary diseases that predispose to benign and malignant tumors of the nervous system. It is of two types NF 1 and NF2.
Cutaneous neurofibromas occur in NF1, and NF 2 is associated with posterior subcapsular cataract.

Ref: Harrison’s Internal Medicine, 18th Edition, Chapter 379; Color Atlas of Genetics By Eberhard Passarge, 3rd Edition, Page 338

Shagreen patch is highly characteristic of tuberous sclerosis and is seen in 80% of patients. It occurs in early childhood and may be the first sign of disease. They are soft, flesh colored to yellow plaques with an irregular surface. It is most commonly seen in the lumbosacral region. 

Features of Neurofibromatosis 1 are: cafe au lait spots, neurofibromas or plexiform neuroma, freckling, optic glioma and Lisch nodules.

Features of Neurofibromatosis 2 are: bilateral vestibular schwannomas, multiple meningioma, spinal ependymoma, astrocytoma, posterior subcapsular lens opacities and retinal hamartomas.

Neurofibromatosis Type II is characterized by bilateral tumors of the eighth cranial nerve (the vestibulocochlear nerve) and any of the following: meningiomas, schwannomas, gliomas, or juvenile subcapsular cataracts.

Ans. is ‘a’ i.e., Optic nerve glioma

Neurofibromatosis type I (Von-Recklinghewsen diseasel

o NF- 1 is diagnosed when any two of the following seven signs are present.

1. Six or more cafe-au-lait macules

o > 5 mm in prepupertal individuals

o > 15 mm in postpubertal individuals

• Cafe-au-lait spots are the hallmark of neurofibromatosis and are present in almost 100% of the patient.

1. Axillary or inguinal freckling
2. Two or more Lisch nodules.

• Lisch nodules are hamartomas located within the iris.

1. Two or more neurofibroma or one plexiform neurofibroma.

o Typically involve the skin, but may be situated along peripheral nerves and blood vessels. o They are small, rubbery lesions with a slight purplish discoloration of the overlying skin.

1. A distinctive osseous lesion.

• Sphenoid dysplasia or cortical thinning of long bones.

1. Optic glioma
2. A first degree relative with NF-1

o Other findings are : ‑

o Pseudoarthrosis of tibia.

• Scoliosis is the most common orthopaedic problem in NF-1, but is not specific enough to be included as a diagnostic criterian.
• Short stature

o Mental retardation, epilepsy

o Hypertension

o Aqueductal stenosis with hydrocephalus

o Meningiomas, ependynomas, Astrocytomas, pheochromocytomas.

o NF-1 is caused by mutation in NF-1 gene on chromosome 17 which encodes protein neurofibromin-1. Neurofibromatosis type -2

o NF-2 may be diagnosed when one of the following two features are present.

1. Bilateral ocoustic neuroma Most distinctive feature
2. A parent, sibling or child with NF-2 and either unilateral eighth nerve masses or any two of the following —> Neurofibroma, meningioma, glioma, Schwannoma or juvenile post subcapsular cataract.

o NF-2 is cause by mutation in NF-2 gene on chromosome 22 that encodes for protein neurofibromin 2, Schwannomin or merlin.

Ans. is ‘a’ i.e., Autosomal recessive

o Neurofibromatosis comprises of two distinct disorders –

• Neurofibromatosis I

 Neurofibromatosis II

o The genes for these are located on different chromosomes.

o Both are inherited in an autosomal dominant pattern.

o The classical form of the disease with multiple neuromas is called Neurofibromatosis I and is caused by a mutation of the gene neurofibromin on chromosome 17

Ans. is ‘a’ i.e., Optic nerve glioma

Neurofibromatosis type I (Von-Recklinghewsen disease)

o NF-1 is diagnosed when any two of the following seven signs are present.

1. Six or more cafe-au-lait macules

             > 5 mm in prepupertal individuals

             > 15 mm in postpubertal individuals

               Cafe-au-fait spots are the hallmark of neurofibromatosis and are present in almost 100% of the patient.

2. Axillary or inguinal freckling
3. Two or more Lisch nodules.

             Lisch nodules are hamartomas located within the iris.

4. Two or more neurofibroma or one plexiform neurofibroma.

             Typically involve the skin, but may be situated along peripheral nerves and blood vessels.

             They are small, rubbery lesions with a slight purplish discoloration of the overlying skin.

5. A distinctive osseous lesion.

             Sphenoid dysplasia or cortical thinning of long bones.

6. Optic glioma
7. A first degree relative with NF-1

Other findings are : –

             Pseudoarthrosis of tibia.

             Scoliosis is the most common orthopaedic problem in NF-1, but is not specific enough to be included as a diagnostic criterian.

             Short stature

A i.e. Neurofibromatosis

Neurofibromatosis type 1 is associated with widening (enlargement) of neural foraminaQ (mostly secondary to dumbbell neurofibroma along exiting spinal nerve root or less commonly d/t dural ectasia, arachnoid cyst or lateral menngocele)Q, scalloping of posterior vertebral bodies, enlargement of internal auditory canal (d/t dural dysplasia), enlargement of optic foramen (d/t optic glioma), enlargement of orbital margins & superior orbital fissure (d/t plexiform neurofibroma) and sclerosis of optic foramen (d/t optic nerve sheath meningioma).

NF1 causes empty orbitQ, Herlequin appearance of orbit and herniation of middle cranial fossa structures into orbit d/t sphenoid bone hypoplasia.

Both neurofibromas (common in NF1) and Schwannomas (common in NF2) are benign nerve sheath tumors mostly found in intradural extramedullary location. Both are derived from Schwann cells, however, neurofibromas also have colagen & fibroblasts. Vestibular or acoustic Schwannoma (or neurilemmoma or acoustic neuroma of 8^th cranial nerve) seen in NF2 1/t internal auditory canal (IAC) enlargement (erosion d/t mass centered on long axis of IAC forming acute angles with dural surface of petrous bone) and widening or obliteration of ipsilateral cerebello pontine angle cistern.

NF-2 is located on chromosome 22 and NF1 on chromosome 17(Mn 1 for 1 & 2 for 2). NF2 have propensity for developing MEN/MES i.e. meningioma, ependymoma (gliomas) and Schwannoma (neuromas). Nerves without Schwann cells are olfactory and optic nerve.

Schwannomas neurofibromas, on CT, appear as sharply marginated, unilateral, spherical, or lobular posterior mediastinal mass, with pressure erosion of adjacent rib or vertebral bodies or enlargment of neural foramen with occasional punctate intralesional calcifcation. Owing to their high lipid content, interstitial fluid and areas of cystic degeneration – Schwannomas are often of lower attenuation than skeleton muscle. Neurofibromas are often more homogenous & of higher attenuation than schwannomas (owing to fewer of above histological features). These may heterogenously enhance on contrast administration. On MRI both show variable intensity on T1WI but typically have similar signal intensity to the spinal cord. On T2WI these characteristically have high signal intensity peripherally and low signal intensity centrally (target sign) owing to collagen deposition. Both schwannoma & neurofibroma enhance on gadolinium administration.

A i.e. Neurofibromatosis; C i.e. Aortic aneurysm

A i.e. Autosomal recessive

B i.e. Axillary freckling

Neurofibromatosis is autosomal dominantQ disorder. Axillary freckling (crowe sign) is a pathognomic sign of von- Reckling hausen’s type 1 neurofibromatosisQ. Café – au – lait macules alone are not absolutely diagnostic of NF1, regardless of their size and number.

Ans. is ‘c’ i.e. Pheochromocytoma 

Ans. is ‘b’ i.e., Trigeminal nerve 

Ans. is `d’ i.e., All 

Ans. is ‘d’ i.e., Lymphadenovarix 

Ans is ‘a’ ie Never becomes malignant & ‘b’ i.e. is encapsulated

Malignant transformation of neurofibromas occurs in 5-10% of cases

Neurofibromatosis (or von Recklinghausens ds)

• is the MC hereditary neurocutaneous syndrome.
• There are two forms of neurotibromatosis, both Autosomal dominant*

• Schwannomas are encapsulated but neurofibromas are not Therefore Schwannomas can be resected surgically without sacrificing the nerve but in neurofibromas the nerve has to be resected along.

Difference b/w Schwannoma & Neurofibroma

• Schwannoma (or Neurilemmoma)
• are true encapsulated neoplasm composed of schwann cells.
• It compresses the nerve of origin.
• There is a plane of cleavage separating the nerve from the mass .
• Neurofibroma
• are unencapsulated benign neoplasm of schwann cells and fibroblasts.
• The tumor involves the nerve. Grossly it appears as expanded nerve.
• It is composed of mixture of schwann cell and fibroblast and contains axons within it.
• It can not be demarcated from the nerve therefore can not be removed without sacrificing the nerve.

B/L acoustic neuromas are a hallmark of Neurofibromatosis 2

• Neurofibromatosis Type 2 is an autosomal dominant highly penetrant condition
• Gene for NF-2 is located on chromosome 22q.
• Patients with NF2 present in second and third decade of life, rarely after the age of 60.
• M/C symptom/Presenting symptom = Hearing loss
• Skin tumors are present in nearly two thirds of patients of NF-2

-Current Otolaryngology 3/e

Answer is A (Autosomal Recessive inheritance):
Neurofibromatosis is inherited as an autosomal dominant condition

Neurofibromatosis

Oculoneurocutaneous syndrome characterized by multisystem involvement

Answer is A (Optic Nerve Glioma):
The commonest tumor in neurofibromatosis I is optic nerve gliomna. Optic gliomas are present in approximately 15% of patients with NFI and its presence is included as one of the criteria in establishing its diagnosis.

Neoplasms associated with NF-I include:

Answer is B (Optic Nerve Glioma):

Optic Gliomas are present in about 15 to 25% of patient with NF-I and its presence is included as one of the criteria in establishing its diagnosis (Diagnostic criteria in NFl)

Optic Gliomas are the most common intracranial tumors of Neurofibromatosis 1- Child Neurology

Ans. B i.e. Neurofibromatosis

Lisch nodule

• It is a pigmented hamartomatous nodular aggregate of dendritic melanocytes affecting the iris
• These nodules are found in neurofibromatosis type 1, and are present in greater than 94% of patients over the age of six.
• They are clear, yellow-brown, oval to round, dome-shaped papules that project from the surface of the iris.
• These nodules typically do not affect vision, but are very useful in diagnosis.
• They are detected by slit lamp examination. lmmunohistochemistry stains positive against vimentin and S-100, and points to an ectodermal origin.
• They are not found in neurofibromatosis type 2.

Ans. C: Neurofibromatosis

Pheochromocytoma is also associated with neurofibromatosis

Ans. B: Neurofibromatosis

Ans. A i.e. Ash leaf spots

Dermatological conditions and important findings

Tuberous sclerosis:

– Ash leaf spot,

– Adenoma sebaceum

– Shagreen patches

• Urticaria pigmentosa: Darrier’s sign
• Amyloidosis: Pinch purpura
• Lichen planus:

– Wickham’s striae,

– Civatte bodies

• Atopic dermatitis: Dennie Morgan folds
• Pityriasis rosacea:

– Herald patch, Mother patch

– Annular collratte of scales

Ans. is ‘a’ i.e., Neurotibromatosis type I

Optic nerve glioma

Optic nerve glioma (astrocytoma) is the most common intrinsic tumor of the optic nerve. Most common type of optic nerve glioma is juvenile pilocytic astrocytoma. The majority of optic nerve gliomas are of astrocytic origin. However, a few rare optic nerve gliomas arise from oligodendrocytes. 70% of optic gliomas occur during first decade of life. Optic nerve gliomas are associated with Neurofibromatosis-1 (Von Recklinghausen’s disease) in 55% of cases. 75% of optic gliomas arise from optic chiasma and adjacent optic nerve. 25% are confined to optic nerve alone (orbital optic nerve glioma).

Patients present with some degree of unilateral visual dysfunction, visual field loss, afferent pupillary defect, decreased ocular motility, optic atrophy, pain headache and nystagmus. Proptosis is often the chief complaint of an orbital glioma. Nystagmus may also occur. Other late features of optic nerve glioma are neovascular glaucoma, anterior segment ischemia and hemorrhagic glaucoma from retinal vascular occlusion.

In chiasmal gliomas there may be visual field defects, raised ICT, papilloedema and endocrine abnormalities like diabetes insipidus, hypopituitarism, dwarfism and precocious puberty.

Ans. is ‘b’ i.e., Neurofibromatosis
Lisch nodules are the most common type of ocular involvement in NF-1. These nodules are melanocytic hamartomas, usually clear yellow to brown, that appear as well-defined, dome-shaped elevations projecting from the surface of the iris.

Ans. is `a’ i.e., Autosomal recessive

Ans. is ‘a’ i.e., AD

Neurofibromatosis shows autosomal dominant inheritance pattern

• Single gene disorders (Mendelian disorders) typically follow one of the three patterns of inharitance ‑

1. Autosomal dominance
2. Autosomal recessive
3. X-linked

Autosomal dominant disorders

• Normally a gene pair has two alleles.
• When one allele becomes abnormal due to mutation it is called heterozygous state.
• When both the alleles become abnormal due to mutation it is called homozygous state.
• Autosomal dominant disorders are manifested in heterozygous state, i.e. only if one allel is abnormal the disease will be manifested.