Neurofibromatosis type 1
`
`D.G .R. Evans
`P Komm1noth
`B.W Scheithauer
`J. Peltonen
`
`Definition
`Type 1 neurofibromatosis (NFI) makes
`up 90% of the genetic disorders known
`clin ically as the neurofibromatoses NFI
`is inherited in an autosomal dominant
`manner and gene penetrance is such
`that almost all cases show sufficient evi(cid:173)
`dence of the disorder to allow diagnosis
`in childhood 1945) The condition is char(cid:173)
`acterised by tumour and pigmentary
`involvement of the neural crest and bony
`dysplasia. Neurofibromas occur widely
`throughout the body, but characteristical(cid:173)
`ly in the skin. Cafe au lait patches and
`axillary/g roin freckling are near constant.
`Other tumours include optic nerve and
`other brain stem gliomas, phaeochromo(cid:173)
`cytoma, carcinoid and malignant periph(cid:173)
`eral nerve sheath tumours.
`
`MIMNo.
`162200
`See: http//www.ncbi.nlm.nih.gov/omim
`11468)
`
`Synonyms
`Von Recklinghausen disease, peripheral
`neurofibromatosis, NFI
`
`Incidence/prevalence
`NF1 has a birth incidence of 1 in 2,500-
`3,300 1434,945) and a prevalence of 1 in
`4,150-4,950 1945). Several major studies
`have addressed this. A study in South
`Wales (UK) found the above frequency in
`a population of 280,000 people. A large
`US study by Crowe and colleagues esti-
`
`I
`
`Fig. 5.28 Cafe au lait spots and subcutaneous neu(cid:173)
`rofibromas in a 44 year old man with neurofibro(cid:173)
`matosis type 1 who had a benign adrenal
`phaeochromocytoma .
`
`mated incidence at 1 in 2,500 1434), but
`this was contaminated with NF2 patients.
`The highest frequency was reported in an
`Israeli study of military recruits with a pre(cid:173)
`valence of around I per thousand 1794).
`
`Diagnostic criteria
`The diagnostic criteria for NF1 (see table
`5.10) are unlikely to lead to misdiagnosis
`or confusion 12). They were originally laid
`out at the 1986 National Institutes of
`Health (N IH) consensus conference and
`have since been ratified by the National
`Neu rofibromatosis Foundation (NN FF)
`working party. Patients with segmental
`neurofibromatosis can fulfil these criteria
`and clinic ians should note any segmen(cid:173)
`tal involvement. Our own use of these cri(cid:173)
`teria in over 740 patients and in a large
`North American database has lent fur(cid:173)
`ther support for them 1474,1462).
`
`Skin lesions
`
`Age distribution and penetrance
`Skin lesions are critical in the diagnosis
`of NF1 , with cafe au lait patches being
`present from birth and nearly every
`affected child has 6 or more by 5 or 6
`years of age 1947,1462). Cafe au lait
`patches are usually the first feature of
`NF1 in most affected patients. They are
`usually seen in the first year of life and
`increase in number and size until the
`early teen s !94 7. 1462). Axillary and
`inguinal freckling usually follows some
`time afterwards although it may be pres(cid:173)
`ent as early as 3 years of age. Around
`90% of patients show freckling by adult(cid:173)
`hood (1 462). Plexiform tumours are often
`visible from birth with diffuse involvement
`of the skin and underlying structures.
`Externally v1sible plexiform neurofibro(cid:173)
`mas occur in approximately 25% of
`cases !947,1462). Cutaneous tumours
`typ1cally start to occur at puberty but
`may well be present before that, and are
`in >95% of adult patients.
`present
`Subcutaneous tumours are less frequent ,
`but show a similar age-dependent pro(cid:173)
`gression to their cutaneous counterparts.
`
`Clinical features
`In childhood , cafe au !ail patches are
`smaller, as reflected in the diagnostic cri(cid:173)
`teria, but they become larger and may
`merge with one another. They have a
`straight rather than ragged border, the so
`called "coast of California'' as opposed
`to "Coast of Maine" seen in McCune(cid:173)
`Albright syndrome. They often fade in
`later life against the generally darker
`"dirtier" looking skin and may be less
`easy to recognise. They are flat and not
`associated with hair or malignant trans(cid:173)
`formation. Freckling occurs in non-sun
`exposed skin typically in the axilla more
`frequently than the groin, and this usual(cid:173)
`ly appears later than the cafe au !ail
`spots. Neurofibromas on and under the
`skin are the characteristic feature of NF1 .
`Plexiform tumours are often vi sible from
`birth with diffuse involvement of the ski n
`and underlying structures. About 2-3% of
`patients have
`unsightly plexiform
`tumours affecting the head and neck.
`The overlying skin is often hyperpigment(cid:173)
`ed and loses its elasticity. Cutaneous
`tumours usually start as soft. often pur(cid:173)
`plish coloured areas on the skin, but can
`
`Table 5.10
`Diagnostic criteria lor NF1. Two or more must be
`present.
`
`1. Six or more cafe au fait macules, the great(cid:173)
`est diameter of which is more than 5 mm in pre(cid:173)
`pubertal patients and more than 15 mm in post·
`pubertal patients.
`
`2. Two or more neurofibromas of any type, or
`one plexiform neurofibroma.
`
`3. Axillary or inguinal freckling.
`
`4. Optic glioma.
`
`5. Two or more Lisch nodules.
`
`6. A distinctive osseous lesion such as sphe·
`noid dysplasia or pseudarthrosis.
`
`7. A first-degree relative with NFI according to
`the preceding criteria.
`
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`Fig. 5.29 Type 1 neurofibromatosis. A Somatostatinoma in a patient with neurofibromatosis type 1. Note the glandular structure of the tumour and the psammoma
`like bodies (arrows). PAS stain. B Same tumour as illustrated in A stained for somatostatin.
`
`evolve into unsightly warty outgrowths.
`Subcutaneous tumours occur as fusiform
`swellings on more major nerve routes
`and can be painful to touch. The deeper
`fusiform subcutaneous and plexiform
`tumours may undergo malignant change
`to malignant peripheral nerve sheath
`tumour (MPNST). Lifetime risk could be
`as high as 10% 11360. 1462) About 5%
`of patients develop xanthogranulomas
`aged 2-5 years, and these are associat(cid:173)
`increased risk of juvenile
`ed with an
`chronic myeloid leukaemia. Although the
`risk of malignant change in visible cuta(cid:173)
`neous tumours is probably small, it likely
`warrants monitoring of skin
`lesions.
`Although not strictly skin
`lesions, ins
`Li sc h nodules (benign hamartomas )
`occur early in childhood and usually pre(cid:173)
`cede the appearance of cutaneous neu(cid:173)
`rofibromas 15871 Ophthalmic slit lamp
`examination is therefore a useful diag(cid:173)
`nostic aid in equivocal cases.
`
`Pathology
`Cafe au fait macule
`Macroscopically, cafe au fait macules
`vary greatly in size, millimetres to many
`centimetres. Flat and smooth bordered ,
`they vary in colour from light to dark
`brown . Cafe au fait macules spots are not
`dragnostic of neurofibromatosis. Solitary
`examples are common in normal individ(cid:173)
`uals. Histologically. they feature basilar
`hyperpigmentation with or without super(cid:173)
`basilar melanosis. A minor degree of
`melanocytic hyperplasia may be seen.
`The macules are characterized by the
`presence of giant (2-6 micron) mela(cid:173)
`nosomes within the melanocytes and at
`trmes m ke ratrnocytes as well. Such
`
`melanosomes are not limited to neurofi(cid:173)
`bromatosis but may also be seen in
`Albright syndrome, in occasional exam(cid:173)
`ples of lentigo simplex and nevus spilus
`as well as
`in dysplastic nevi. Micro(cid:173)
`scopically, they appear as markedly pig(cid:173)
`mented, rounded cytoplasmic bodies
`derived by fusion of primary mela(cid:173)
`nosomes or secondary lysosomal resid (cid:173)
`ual bodies 11 005)
`
`Neurofibroma
`Neurofi bromas are benign nerve sheath
`tumours composed largely of Schwann
`cells in the various neurofibroma types .
`All can be seen in NF1 including local(cid:173)
`ized cutaneous, diffuse cutaneous, local(cid:173)
`ized intraneural , plexiform, massive soft
`tis sue. and visceral examples. Their clin(cid:173)
`icopathologic features have recently
`been summarized 11968)
`Localised cutaneous neurofibromas are
`common in NF1 and affect the dermis
`and subcutis and show no site predilec(cid:173)
`tion. Nodular or polypoid and unencap(cid:173)
`sulated. they infrequently exceed 2 em.
`Whether sporadic or syndrome-associat(cid:173)
`ed, the microscopic features are srmilar.
`They consist mainly of uniform , spindle(cid:173)
`shaped Schwann cells with barely dis(cid:173)
`cernible processes and delicate elongate
`or sinuous nuclei. Such neurofibroma
`show no tendency to malignant change.
`
`Diffuse cutaneous neurofibroma.
`Thr s uncommon variant presents in chil(cid:173)
`dren, and 10% are NF1 associated. They
`consist of sizable . diffuse plaque-like
`thrckenings of dermis and subcutaneous
`tissu e often of the head and neck region.
`They tend to nondestructively infiltrate
`
`the dermis with extention into subcuta
`neous tissue. Pseudo-Meissnerian cor
`puscles are commonly seen as are mincH
`plexiform components. Such tumo ur~ .
`rarely undergo malignant change.
`Localized intraneural neurofibroma infre(cid:173)
`quently involve skin. They affect spina:.
`cranial, or autonomic nerves. The neu
`rofibroma cells grow within the nerve.
`transforming it into a fusiform mass. Sue r.
`neurofibromas
`infrequently undergc
`malignant change.
`
`Plexiform neurofibroma.
`This characteristic tumour occurs almo:c.:
`exclusively in NF1 and generally affect:
`sizable nerves. Cutaneous lesions ar·
`often part of diffuse neurofibromas , bu
`they may occur in pure form. Occasrona'
`usually small, tumours lack an NF1 assc•
`ciation; these presumably result from <
`local mutation . Involvement of branchin ~
`nerves often form worm-like tangl e~
`Approximately 2-5% of plexiform neurof ,
`bromas undergo malignant change.
`Neurofibromas vary in cellularity and ir
`content of stromal mucin_ The cells lea
`ture ovoid to elongate, often curvec:
`nuclei , scant cytopla sm and
`indis·
`cernible processes. Accompanying rna~:·
`cells are commonly seen. Melanin-con
`taining cells are rare . Variations in the cer·
`pattern incl ude structures resemblirw
`Wagner-Meissner corpuscles or Paciniar
`corpuscles. Nodules of pure Schwam
`cells may be seen in plexiform tumours
`Neurofibroma s are generall y diploil :
`11912) All neurofibromas are S-100 pre>
`tein immunoreactive. Leu-7 and collage:
`IV or laminin staining is frequent.
`/'<.s
`rul e. MIB-1 labelling
`indices are lm·
`
`244
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`

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`often less than 1% !1087) Ultrastru(cid:173)
`cturally, the neoplastiC Schwann cells are
`well-differentiated 15781
`
`Malignant peripheral nerve sheath
`tumour
`Malignant peripheral nerve sheath
`tumours (MPNST) are uncommon tu(cid:173)
`mours vary1ng greatly in clinicopatholog(cid:173)
`ic features 119681, about 50% are NF 1-
`associated. Cutaneous MPNST is very
`rare /444,698,15101; skin involvement is
`usually secondary to larger underlying
`tumours Grossly, MPNST as a whole
`form globoid or fusiform masses, not all
`of which are nerve-associated. Ap(cid:173)
`proximately half of the tumours originate
`in neurofibromas of intraneural or plexi(cid:173)
`form type. Pathologically. they show a
`broad spectrum. Most are high grade,
`poorly differentiated and aneuploid Only
`half can be shown to exhibit schwannian
`differentiation by immunohistochemical
`methods. The minority show perineurial
`features 18931 The epithelioid subtype
`shows no NF1 association. Particularly
`associated with NF1, however, are
`tumours exhibiting mesenchymal prima(cid:173)
`rily rhabdomyosarcomatous differentia(cid:173)
`tion ("Triton tumour") 124161 or differenti(cid:173)
`ation toward mucinous, squamous, or
`neuroendocrine epithelium ("glandular
`MPNST") /2416). As a rule, MPNSTs are
`highly aggressive tumours with a poor
`prognosis.
`
`Prognosis and prognostic factors
`Life expectancy in I\JF1 is reduced by an
`average of around 15 years partly due to
`excess deaths due to MPNST 11798,
`21021 Early detection and complete
`excision of MPNST is essential. They
`usually present with rapid growth or pain.
`The vast majority of skin tumours remain
`benign and usually become dormant
`after a period of fairly rapid evolution.
`Excision of tumours is often undertaken
`for cosmetic reasons, but is particularly
`problematic for plexiform tumours due to
`the indistinct borders and poor heal1ng of
`the involved skin.
`
`Duodenal endocrine lesions
`
`Age distribution and penetrance
`Carcinoid tumours occur in NF1 with a
`frequency of around 1% (9471. A series
`with NF1 and duodenal
`of 27
`
`inc:dence in
`carcinoids showed a
`the fourth and fifth decades 17771 Many
`with carc:no1d and NF1 have a
`co-existent phaeochromocytoma.
`
`Clinical features
`Carcinoid tumours while predominantly
`occurring in the duodenum in NF1 very
`rarely also occur in other organs derived
`from the embryonic foregut such as the
`stomach. pancreas, thyro1d and bron(cid:173)
`chus as well as elsewhere in the small
`intestine. Carcinoid or ·'somatostatino(cid:173)
`ma" syndromes are extremely rare.
`Duodenal tumours may present with
`obstructive jaundice, intestinal obstruc(cid:173)
`tion and or bleeding. As many as 50% of
`all duodenal somatostatinomas occur in
`the context of NF1 /4641 and an associa(cid:173)
`is especially observed
`tion with NF1
`is
`located
`in
`the
`when
`the
`tumour
`ampullary region.
`
`Pathology
`Neuroendocrine tumours of the duode(cid:173)
`num in NF1 patients are usually solitary
`the periampullary
`and are located in
`region. They may display a polypoid
`growth but infiltration of the sphincter of
`Oddi, the duodenal wall or head of the
`pancreas may also occur /464,21151
`The tumours have a mean diameter of 2
`em.
`Histologically, they typically exhibit well(cid:173)
`formed tubulo-glandular structures with
`some evidence of luminal secretion 17761
`and contain characteristic PAS-positive
`psammoma bodies composed of calci(cid:173)
`um apatite crystals in 66% of cases (341.
`lmmunohistochemically,
`they express
`neuroendocrine markers (but in 50% are
`negative for chromogranin A), cytoker(cid:173)
`atins and label strongly with somatostatin
`"pure"
`(representing non-functioning
`somatostatinomas) with rare single cells
`expressing other hormones (e.g. calci(cid:173)
`tonin, pancreatic polypeptide, ACTH,
`insulin) (21151 This IS in contrast to spo(cid:173)
`radically occurring somatostatinomas,
`which frequently display a multihormonal
`expression pattern 12641
`By electron microscopy, the neoplastic
`cells show signs of intestinal differentia(cid:173)
`tion (microvilli, glycocalyceal bodies, fila(cid:173)
`mentous core rootlets) as well as of neu(cid:173)
`roendocrine differentiation (0-type secre-
`torv
`whorls of
`These tumours are seldom associated
`with a
`"somatostatin syn(cid:173)
`drome··
`diarrhoea and b11iary
`
`!:thias1s) (768/. but often present w:th
`obstructive
`duodenal obstruc(cid:173)
`tion. weight
`loss or gastrointestinal
`
`A genomic examination of a
`resected somatostatinoma of a NF1
`patient showed ne1ther KRAS nor TP53
`gene mutations (1 0191.
`Other tumours wh1ch may be encoun(cid:173)
`tered in the duodenum of NF1 patients
`include gastrointestinal stromal tumours,
`gangliocytic paragangliomas and am(cid:173)
`pullary adenocarcinomas (329,400, 421,
`1039,1900,21241.
`
`Prognosis and prognostic factors
`The endocrine tumours in the duodenum
`mostly remain localised but do metasta(cid:173)
`SIZe in 27% of cases mainly to lymph
`nodes (88%) or the liver. However, they
`appear to be less aggressive than their
`pancreatic and sporadically occurring
`duodenal counterpart tumours which fre(cid:173)
`quently exhibit a malignant clinical
`behaviour (813.20911. The risk of metas(cid:173)
`tasis significantly increases with tumours
`larger than 2.0 em (21901
`
`Phaeochromocytoma
`
`Age distribution and penetrance
`Phaeochromocytomas occur in < 1% of
`NF1 patients, predominantly in the fourth
`and fifth decades, similar to carcinoids.
`About 5% of phaeochromocytoma pa(cid:173)
`tients have NF1 and inherited forms of
`these tumours are more frequently asso(cid:173)
`ciated with MEN type 2 or VHL disease.
`
`Clinical features
`Headache is the most common present(cid:173)
`ing
`feature of phaeochromocytoma
`occurring in about 60% of patients. The
`headaches are usually frontal or occipital
`start suddenly and usually last about 15
`minutes. Associated nausea, vomiting
`and neck ache are common if there is
`associated paroxysmal hypertension.
`Blurred vision and other visual features
`such as homonymous hemianopia occur
`in about 10% of
`Visual sco(cid:173)
`tomata scintillating in time with the heart(cid:173)
`beat may also occur. Seizures and tran(cid:173)
`sient loss of consciousness due to cere(cid:173)
`bral ischaemia are later features. About a
`third of
`suffer frorn
`attacks, tremor and a
`of impend-
`doom. Cardiac complications due to
`catecholamine cardiomyopathy are the
`
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`
`most serious complication and account
`for 58% of deaths ! 18681 Palpitations
`due to arrythmias and chest pain due to
`cardiac ischaemia are manifestations of
`this. Night or constant sweats often con(cid:173)
`fined to the upper body occur in around
`50% of patients and weight loss is a less
`common accompanying sign
`(6191
`Other vascular effects include claudica(cid:173)
`tion and gangrene of limbs. Unusual
`sites of phaeochromocytoma may cause
`unusual symptoms such as haematuria
`from bladder neck tumours. Clinically
`sustained or paroxysmal hypertension
`may be detectable with actively secret(cid:173)
`ing tumours, but this is not a totally reli(cid:173)
`able sign. Any NF1 patient with persist(cid:173)
`ent r1ypertension refractive to treatment,
`especially if there is a narrow pulse pres(cid:173)
`sure or where beta- blockers actually
`increase blood pressure should be
`actively assessed for phaeochromocy(cid:173)
`toma (18681. Most NF1 specialists do not
`screen their patients with regular abdom(cid:173)
`inal ultrasound and 24-hour urine cate(cid:173)
`cholamines due to the very low yield
`annually. However, an annual check of
`blood pressure and suggestive symp(cid:173)
`toms should prompt a more complete
`search including MRI or CT (6191.
`
`Pathology
`There is no evidence that NF1 related
`phaeochromocytoma differs significantly
`from other sporadic or syndrome related
`tumours from a histologic point of view
`
`Prognosis and prognostic factors
`Hypertensive crisis especially during
`pregnancy is a life-threatening complica(cid:173)
`tion in NF1 patients with phaeochromo(cid:173)
`cytomas. The majority of phaeochromo(cid:173)
`cytomas are benign (3921 Malignant
`tumours have been described in single
`case reports (1782,21811 including com(cid:173)
`posite tumours (1573, 19491 Compiled
`data
`indicate a malignancy rate of
`11.5%, which is somewat higher than in
`sporadically occurring phaeochrornocy(cid:173)
`tornas (23451 As for sporadic tumours it
`is difficult to predict rnai1gnant behaviour
`by histology when no gross invas1on or
`metastases are present (22291.
`
`Age distribution and penetrance
`stud1es where children with NF1
`have been screened With MRI or CT
`
`246
`
`scans indicate that around 15% have at
`least a unilateral optic glioma (898, 1310)
`It is unclear how many children who have
`a scan-detected glioma will ever develop
`symptoms as studies which have not
`specifically screened with imaging find
`much lower rates of between 0.7-5%
`(947,2062) Tumours usually present
`between birth and 6 years of age peak(cid:173)
`ing at around 3-4 years, but adult onset
`of symptoms does occur. Other brain
`stern gliomas are less frequent, affecting
`around 1-2% of patients, but are more
`those with optic gliomas
`frequent in
`!9291 Other CNS lesions include macro(cid:173)
`cephaly (45% above 97th centile), aque(cid:173)
`duct stenosis ( < 1%) and "Unidentified
`Bright Objects" (UBOs) on T2-weighted
`MRI (33%) About 3% of NF1 patients
`have epilepsy.
`
`Clinical features
`Perhaps the most worrysorne complica(cid:173)
`tion in NF1 is that of CNS tumours and
`malignancy. The area over which there is
`most current controversy is in the occur(cid:173)
`rence rate of optic gliomas and how or
`whether they should be screened for. The
`tumours themselves are often benign
`and vision may not deteriorate at all from
`presentation. Other features of optic
`glioma include precocious puberty with a
`rapid growth spurt or appearance of sec(cid:173)
`ondary sexual characteristics and ocular
`proptosis. It is also unclear whether treat(cid:173)
`ment of even symptomatic cases is war(cid:173)
`ranted /1311, 1736), although radiothera(cid:173)
`py and chemotherapy have been shown
`to be beneficial in several series !1736).
`The situation is made more confused by
`the appearance of focal hyperintensity or
`unidentified bright objects (UBOs) in
`many asymptomatic individuals on MRI
`scanning (249) The full significance of
`these is not yet known, as even their
`is
`learning disorde1·s
`association with
`controversial. Other CNS gliomas do
`occur but their frequency is probably
`below 5% even in neurological-based
`(225). Symptoms
`from
`these
`series
`tumours will depend on their position in
`the brain stern or cerebellum, but signs
`of increased intracranial pressure may
`be the first manifestation. Meningiomas
`and vestibular Schwannomas probably
`do not occur in excess frequency in NF1
`(474,947). However, the old literature is
`littered with NF2 cases included in series
`with NF1. Spinal neurofibromas may
`paraes-
`cause weakness ar1d
`
`but sympto
`thesia or nerve root
`malic tumours occur in only 1-2% (474
`947) Nonetheless, MRI scans reveal evi(cid:173)
`dence of spinal nerve root involvement in
`up to 60% of patients A significant pro
`portion of children with NF1 have learn(cid:173)
`ing difficulties particularly with reading
`and or minimal intellectual handicap
`Although some studies have shown ci
`large proportion (8-11%) with an 10< 7C•
`indicating mental handicap (620,946
`18191, population-based studies sugges:
`that fewer children have moderate or
`severe handicap (3%) or need specia
`/620). Learning difficultiec
`schooling
`improve with extra education and 10 i1
`adulthood is better (620,9461.
`
`Pathology
`literature
`The medical
`gliomas in NF1 does so largely in topo
`graphic (optic nerve. chiasma! or visu<:
`pathway glioma, cerebellar astrocytom<:•
`brainstern glioma) and radiologic, rathe1
`than histologic terms. Many reports u
`optic glioma are of small series and, as
`the case of brainstem tumours, drav
`conclusions without the benefit of biops)
`Thus. it is difficult to critically discuss the
`pathology of NF1 associated CN~
`tumours and to meaningfully contra:
`them with sporadic
`lesions. Neve·
`theless, certain distinguishing feature
`emerge.
`the comrno
`Pilocytic astrocytoma,
`glioma in NF1, occurs in 15% of cases I
`arises at any of the typical loci for th,
`tumour type, but is especially prone
`affect the optic nerve as a diffu~­
`enlargement without cystic
`typical. Opt;.
`Bilateral mvolvement is
`pathway pilocyt1c astrocytomas in nc
`NF1 patients, on the other hand, a:
`more likely to be cystic and situate
`more posteriorly, i.e. in the chiasm
`While it has been claimed that the NF(cid:173)
`associated optic nerve gliomas are rno1
`prone to massive leptomeningeal exte
`sion (21251, this has not been the gene
`al
`Pilocytic astrocytomas
`the optic nerves in NF1 are notoriow
`indolent. At this location and others. N'
`and even sporadic pilocytic astroc
`lomas sometimes regress 116941
`Gliomas of the brain stern in NF1 incluc
`focal contrast-enhancing masses cons:
`astrocytorn·
`tent with classic
`but also radiologically diffuse les1c>~
`whose
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`r1on form of bra1n stem glioma. 1nf11trat1ng
`:r
`'diffuse astrocytoma. th1s NF1-asso(cid:173)
`::ated process IS unusually llidolent
`1527.17571
`Nith respect to cerebellar astrocytomas
`:1 NF1. it has been
`they may
`than those occumng
`Whether th1s is due to
`:ability to clearly distinguish pilocytic
`rom diffuse astrocytomas in all cases is
`mclear. but some NF-1 associated astro(cid:173)
`:ytic tumours do show indeterminate his(cid:173)
`ologic features.
`1are among other astrocytic tumours
`;ccurring in NF1
`is pleomorphic xan(cid:173)
`:hoastrocytoma 116421.
`\!though there is little literature on the
`.oubject, diffuse astrocytomas. in some
`=ases high grade. also occur in the set-
`of NF1 .The same is true of rare
`.~ases of gliomatosis 116481
`fhe genetic underpinnings of NF1 sug(cid:173)
`:jest that abnormalities in the NF1 tumour
`;uppressor gene are likely to be critical
`n the genesis of pilocytic astrocytomas
`chat arise within the syndrome, and pos-
`31bly in the much more common counter(cid:173)
`Darts that arise sporadically in the non(cid:173)
`NF1 patient. Loss of NF1 alleles occurs
`in
`the syndrome-associated astrocy(cid:173)
`tomas, although not the pilocytic neo(cid:173)
`plasms arising in patients without NF1
`11119) Loss of staining for the product of
`the NF1 gene, neurofibrornin, has been
`in an NF1 associated pilocytic
`found
`astrocytoma, but not in surrounding
`112441.
`Unidentified Bright Objects (UBO) are a
`frequent abnormality in ~~F1 patients in
`the brain stern, as well as in the cerebel(cid:173)
`lum and deep cerebral grey matter. They
`are often multiple, bilateral, foci on MRI.
`While they are often referred to as hamar(cid:173)
`tomas,
`they are evanescent in some
`patients. Little is known about their histo(cid:173)
`logical features. One study suggested a
`form of spongiosis, whose water content
`in T2-weighted
`explains the
`images 15001
`
`Prognosis and prognostic factors
`Prognosis of CNS lesions depends on
`age of onset and location.
`megalencephaly is common and usually
`harmless but can lead to increased skull
`circumference. Hydrocephalus with or
`without associated tumours may present
`at any age and can become sympto(cid:173)
`matic. Nerve root and spinal cord neu(cid:173)
`rofibromas can lead to deficits
`
`on
`
`locat1on Gliomas and menln-
`may
`surround1ng
`structures or nerves
`neurologi-
`cal symptoms. Optic nerve gliomas may
`loss. Pilocytic astrocy(cid:173)
`lead to v1sual
`tomas are relatively benign while half of
`fibrillary astrocytomas exhibit malignant
`behaviour. Some gliomas may progress
`to
`tumours which have a poor
`prognosis.
`Overall, the prognosis of CNS tumours in
`NF1 patients appears to be slightly better
`than those of sporadic tumours 123221, In
`a retrospective study on 104 NF1 pa(cid:173)
`tients w1th CNS tumours, the overall sur(cid:173)
`vival rate was 90% at 5 years Extra-optic
`location, tumour diagnosis in adulthood
`and symptomatic tumours are independ(cid:173)
`ent factors associated with shorter sur(cid:173)
`vival time (786) UBOs which commonly
`occur in children usually regress with
`however,
`age and seem to be
`young children with a large number and
`volume of UBO should be followed close(cid:173)
`ly with regular MR examinations because
`of an
`increased risk of proliferative
`change (778)
`
`Bone and other
`
`Age distribution and penetrance
`Bony abnormalities are frequently pres(cid:173)
`ent from birth. While scoliosis typically
`advances at puberty,
`there are often
`congenital bony abnormali(cid:173)
`ties of the vertebrae. Scoliosis occurs in
`about 5-9% of cases, with about half
`requiring surgery /947). Pseudoarthrosis
`of the t1bia/fibula occurs congenitally in
`around 1-2%
`Sphenoid wing
`dysplasia and lamboid suture defects
`occur in about 1%. Less common non(cid:173)
`bony lesions include gastrointestinal
`neurofibromas (2%), renal artery stenosis
`(1%) and congenital glaucoma in <1%
`/947,1462)
`
`Clinical features
`Pseudoarthrosis is the development of a
`false joint in a long bone or the failure of
`a fracture to unite after 6 months to a
`year. It typically occurs in the upper tibia
`or fibula where 50-90% of such cases are
`due to NF1 (1541, 1561). However. it may
`occur in all other long bones. The tibial
`condition often presents with anterior
`bowing, and an hourglass appearance
`may be present at b1rth. Spontaneous
`fracture or fracture with minor trauma
`
`often occurs by 2 years of age. Pseu(cid:173)
`doarthrosis may occur rn relat1on to a
`lJu11e cyst. sclerotic bone or even rarely,
`an 1ntamedullary neurofibroma. Pseudo(cid:173)
`arthrosis can be managed with brace
`treatment 11768), electrical stimulation
`or free vascularised bone
`(2461. The spine may be affected w1th
`scalloping of the
`or
`dysplasia of vertebral bodies, enlarge(cid:173)
`ment of foramina, and defective pedi(cid:173)
`cles. The above abnormalities give rise
`to a dystrophic scol1osis although idio(cid:173)
`pathic scoliosis is probably more com(cid:173)
`mon. Dystrophic scoliosis is relentlessly
`progressive 1nvolving a sequence of 4-6
`vertebrae and cannot be managed by
`brac1ng. Surgical treatment with spinal
`fusion has a risk of paraplegia and
`pseudoarthrosis. Idiopathic scoliosis can
`its sporadic
`be managed similarly to
`counterpart. However, even in th1s form
`pseudoarthrosis may occur after surgery
`(2370) Sphenoid wing dysplasia often
`presents with proptosis and can be asso(cid:173)
`ciated with an orbital plexiform tumour.
`
`Pathology
`Although bony les1ons are common in
`NF1, they show non-specific changes.
`
`Prognosis and prognostic factors
`Bony abnormalities may be clinically
`silent and only evident on x-ray. Con(cid:173)
`genital pseudarthrosis may be present at
`birth. with bowing of the tibia being the
`most typical presentation. Long bone
`abnormalities may be treated with limb(cid:173)
`sparing procedures but sometimes
`necessitate amputation. Scoliosis in NF1
`is often mild, but a subset of children
`younger than 10 years (especially young
`g1rls) develop a more rapidly progressive
`form of (kypho) scoliosis that requires
`aggressive intervention to prevent para(cid:173)
`paresis. Scoliosis detected during ado(cid:173)
`lescence is much less likely to require
`orthopedic intervention (428). Sphenoid
`bone dysplasia is usually asymptomatic
`but occasionally can be associated with
`herniation
`through
`the bony defect.
`Massive osseous and soft tissue over(cid:173)
`growth may lead to facial deformity and
`
`Stenosis of the renal artery (secondary to
`fibromuscular dysplasia) or coarctation
`of the aorta :llay lead to arteria!
`tension. Vascular disease and cardiac
`involvement can cause
`and sudden
`death.
`
`247
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 078
`
`

`
`ed with a greater neurofibroma burdr
`as well as dysmorphic features and me
`mental retardation /1059, 1352). There ,
`also emerging evidence for an eleva!
`risk of MPNST in those patients with N
`deletions 12425). No clear correlat;c ·
`exists for other mutation type or
`although segmental disease has nc
`been shown to be due to somatic mtr
`lion (403)
`
`Genetic counselling and preventive·
`measures
`NF1 can nearly always be diagnos(
`clinically using the NIH criteria. An inz '·
`vidual fulfilling these criteria will havE
`50% risk of transmitting the disease
`their offspring, unless they show SE
`mental involvement /403), in which ca•(cid:173)
`offspring risks may be substantic::
`below this. D1sease severity varie~
`great deal within families and it is '' ·
`possible to predict the disease course
`an affected offspring unless they have
`large deletion. It is likely that there
`significant genetic modifiers for ~~~
`/538). There are unfortunately no rt
`preventive measures that can be taker
`NF1. but early detection of
`by regular blood pressure checks m::
`detect complications such as renal art;
`stenosis and phaeochromocytoma ar
`regular skin checks could detect
`in a
`malignant
`
`Chromosomal location
`The NF1 gene was mapped to 17 q 11.2
`by family linkage studies (20031 and the
`gene was eventually cloned by the iden(cid:173)
`tification of 2 patients with balanced
`translocations involving the 17q locus.
`
`Gene structure
`The NF1 gene was cloned in 1990
`12325/
`It is a mass1ve gene containing
`over 300 kilobases of DNA divided into
`more than 50 exons. The gene tran(cid:173)
`scribes for a 327 kd GAP protein con(cid:173)
`taining 2818 amino acids. It is unusual in
`having 3 embedded genes in one intron,
`which transcribe in the reverse direction.
`
`Gene expression
`The NF1 gene is ubiquitously expressed
`in almost all tissues but most intensely in
`central and peripheral nervous systems
`(461 ,2421 ). Mutations of the NF1 gene
`lead to reduced levels of functional pro(cid:173)
`tein, which may not be sufficient for the
`proper funct1on of the cell. Regulation of
`the NF1 gene takes place at multiple lev(cid:173)
`els transcription. mRNA and protein sta(cid:173)
`bility, and mRNA targeting. The levels of
`NF1 mRNA and protein, neurofibromin,
`can undergo rapid changes. and m