2
`
`3 4 56
`
`7 8 9
`
`10
`
`Type of mutation:
`missense
`nonsense
`1:. deletion
`V insertion
`
`Fig. 5.17 MEN 1. Structure of the MEN! gene and examples of germline mutations spread over the coding
`sequence. From I. Lemmens et al. {1272}.
`
`total or total parathyroidectomy should
`reduce the risks of thymic carcinoid.
`Bronchial carcinoids are less common in
`MEN 1 and occur predominantly in
`women {1560). Most bronchial tumours
`in MEN 1 are typical carcinoids and treat(cid:173)
`ment requires curative resection with a
`risk of locoregional failure.
`
`Soft tissue tumours
`renal
`Oesophageal
`leiomyoma and
`angiomyolipoma have been described in
`rare MEN 1 cases 1 1466,2333). Mali(cid:173)
`gnant gastrointestinal stromal tumour
`(GIST) represents an atypical presenta(cid:173)
`tion of MEN 1 syndrome but has been
`considered as non-fortuitous {1680 ).
`
`Gastric ECLomas
`ECLomas are presumed to originate from
`proliferation of enterochromaffin-like
`(ECL) cells in gastric mucosa and such
`tumours are mainly recognized during
`gastric endoscopy for Zollinger-EIIison
`syndrome (ZES) in MEN 1 1228). These
`tumours are often small and multiple and
`they may be observed in about 10% of
`MEN 1 patients. ECLoma may be found
`in antra-pyloric and fundus mucosa and
`may be induced both by hypergastri(cid:173)
`naemic conditions and genetic predispo(cid:173)
`sition to MEN 1 1227}. Prognosis of
`ECLomas in patients with ZES-MEN 1 is
`good. Metastases are rare and tumour(cid:173)
`related deaths are exceptional. ECLo(cid:173)
`mas measuring less than 1 em should be
`treated by endoscopic polypectomy and
`survey {27 4} Considering
`the good
`prognosis of these tumours, aggressive
`surgery could be limited to selected
`patients.
`
`Central nervous system tumours
`been
`ependymomas
`have
`observed in rare MEN 1 patients and
`localize mostly in intratentorial cervical or
`lumbar regions {723, 1049) They are rap(cid:173)
`idly symptomatic and need surgery. One
`epidemiological study of a large series of
`MEN 1 patients has assessed that un(cid:173)
`common forms of meningioma and astra(cid:173)
`. cytoma may occur in
`the context of
`to MEN 1
`
`224
`
`Chromosomal location
`The MEN1 gene (GenBank acc.no.
`U93237) is
`localized on chromosome
`11 q 13 I 12341 This has mainly been
`shown by deletion mapping in tumours
`from MEN 1 patients {272}. Most tumours
`in MEN 1 affected patients, including
`less common lesions such as thoracic
`and gastric carcinoids, ECLomas and
`cutaneous tumours, show somatic loss of
`the wild-type allele (loss of heterozygosi(cid:173)
`ty (LOH) at 11q13 {558). This observation
`is consistent with the fact that MEN1 is a
`tumour suppressor gene with most path(cid:173)
`ogenic mutations corresponding to a
`loss of function.
`
`Gene structure
`The MEN1 gene consists of 10 exons,
`spanning -9 kb of genomic sequence,
`and encoding a protein of 610
`aminoacids, men in {351, 1272}. The first
`exon is noncoding and constitutes most
`of the 111 nt 5'-UTR. The sequence
`around the start codon (gccATGg) of the
`61 0-amino acid open reading
`frame
`(ORF) is identical to tr1e "Kozak consen(cid:173)
`sus". The 797 nt 3' UTR has an unusual
`(AATACA) located at -13.
`polyA
`The exon sizes range from 41 bp to 1296
`bp, and the introns range in s1ze from
`79nt to 1.5c3r:t Me:111' does ~>ot reveal
`
`homologies to any other known proteir
`The only motifs which have been reco1 ·
`nised in the menin sequence are tv
`leucine zippers, and two nuclear localiz
`lion sequences (NLS) in the carboxytc
`minal part of the protein {791}. Menin he:
`orthologs not only in mouse and rat, b·
`also in zebrafish and drosophila (98"
`97%, 75%, and 47% homology, respe1
`tively), but there is no homologue knov.
`in the yeast Saccharomyces cerevis1"
`1792,1072, 2130}.
`
`Gene expression
`The MEN1 transcript is 2.9 kb (GenBa1 .'
`acc.no. U93236) in all tissues, with z
`additional 4.2 kb transcript also bei1
`present in
`the pancreas and thyrn"
`I 1272). Western blot analysis show1
`strong expression of men in as a 68 kl;
`protein in all types of human cell lin1
`and tissues tested, and mostly in brn ·
`cortex, kidney, pituitary, testis, thym11
`adrenal glands with
`lower or unci<
`tectable levels in pancreas, liver, lur·
`and skin 12361}. Menin is a nuclear PI'
`tein whose expression is cell cycle reg'
`lated {1020/ln all cell lines tested, mer
`is found both in the nucleus and the cyl•
`plasm, but its localization depends c
`the phase of the cell-cycle during inlc ·
`phase, menin localizes in the nucleL1
`during and immediately after cell di
`sion, it migrates in the cytoplasm {93.
`Various transcripts of MEN1 vary in t: ·
`content of their 5'-untranslated region./
`transcript variants display upstrea(cid:173)
`exons correctly spliced to MEN1 exon
`Further identification of 5' promotii
`regions will be relevant to identify tissu
`specific promotion and the promoter(
`of the menin m1nor 4,2 Kb transcript
`pancreas and thymus
`{1 071}. Mou
`models of MEN 1 have produced
`inactivation of the mouse Men 1 ger
`through homologous
`recombinati'
`(knock-out mice) {425). Homozygor
`inactivation of the Men 1 gene is leth
`early during embryogenesis. Men 1~
`heterozygotes develop mostly hype
`plastic pancreatic
`islets and srnz
`tumours from 9 months of age Otr>
`tumours were also observed in ther
`mice, e.g. parathyroid hyperplasia ar •
`adenoma, pituitary adenoma. ar:
`adrenocortical adenoma/carcinoma.
`
`Gene function
`Menin is
`trot oatnways o1 eel\
`
`a role in
`and differc
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 055
`
`

`
`Glial fibrillarv acid
`protein (GFAP)
`lntennediate Filaments type
`Ill, acting in cytoplasmic
`Signalling and
`menin sequestering
`
`Vi men tin
`
`Smadl/5
`intracellular signaling
`molecules of
`transfonning growth factor-fl
`amily and
`
`Smadl/4
`Cofactors of the TGFfl
`receptor acting on the
`TGFfl-mediated signalling
`cascade
`
`NFkappa81-2- ReiA
`Transcription factors
`acting in concert with JunO,
`negatively regulated
`by menin
`
`TELOMERES interacts
`with menin and suggest
`an indirect role in mrtosis
`and chromosomal stability
`
`Jun0-AP1
`Negative regulator
`oftheAP1
`transcriptionnal
`complex
`
`Murine Pem
`Homeobox-containing
`factor involved in
`regulation of
`transcription
`
`nM23 (NDP kinase)
`Regulation of DNA replication
`and activation of menin to
`hydrolyse GTP such
`others Ras-relatedGTPase
`
`Fig. 5.18 MEN 1. Menin interacting proteins and putative function ofthe MEN I gene.
`
`i.iation during embryogenesis and post(cid:173)
`!l atal life. To date, menin has been shown
`to interact with a subset of proteins
`involved in regulation of transcription ,
`DNA
`replication , mitosis, apoptosis,
`genome integrity, growth factors sig(cid:173)
`nalling pathways and extracellular matri x
`organization. The first discovered was
`JunO , a transcription factor belonging to
`the AP1
`tran scription complex family
`[ 12). Wild-type men in represses tran(cid:173)
`scriptional activation mediated by JunO ,
`may be via a histone deacetylase(cid:173)
`dependent mechanism /733). There may
`be an antagonistic action of Menin
`towards JunO with its tumour suppres(cid:173)
`sive function. JunO has a reported effect
`in the inhibition of cell growth inside the
`AP1 complex. Menin
`represses
`the
`inducible activity of the c-fos promoter
`and inhibits Jun N-terminal kinase (JNK)(cid:173)
`mediated phosphorylation of both JunO
`and c-Jun /686) . This occurs through two
`independent mechanisms uncoupling
`ERK and JNK activation from phosphory(cid:173)
`lation of their nuclear targets Elk-1 , JunO
`and c-Jun, hence inhibiting accumula(cid:173)
`tion of active Fos/Jun heterodimers. This
`provides molecular insights
`into
`the
`tumour suppressor function of men in and
`suggests a mechanism by which menin
`may interfere with Ras-dependent cell
`transformation and oncogenesis. Menin
`
`interacts directly with three members of
`the NF-KappaB family of transcription
`regulators. NF-KappaB 1 (p50) , NF(cid:173)
`Kappa82 (p52) , and ReiA (p65) (868) .
`These proteins are known to play a cen(cid:173)
`tral
`role
`in oncogenesis of various
`organs, as they modulate the expression
`of numerous genes NF-KappaB and
`JunO cooperate - and interact directly -
`to activate transcription in rat hepato(cid:173)
`cytes (1789) Menin interferes with the
`TGFf3 signaling pathway at the level of
`Smad3 (1021) and probably with Smad1
`and Smad5 (2103) The latter interac(cid:173)
`tions have been implicated in menin-spe(cid:173)
`cific inactivation of the commitment of
`pluripotent mesenchymal stem cells to
`the osteoblast lineage. Through TGFI)
`pathways, menin is important for both
`early differentiation of osteoblasts and
`inhibition of their later differentiation, and
`it might be crucial for intramembranous
`ossification . Smad-mediated TGFB sig(cid:173)
`naling and Ras phosphorylation pathway
`may be related and lead for instance to
`activation of AP-1 complexes in which
`JunO is a primary component This may
`be a relevant core action of menin action
`which has been shown to share an intrin(cid:173)
`sic GTPase activity /2436) Last in this
`series . the rodent protein Pem has been
`shown to bind Menin directly /1 273)
`Pem is a homeobox-containing protein,
`
`expressed mostly in testis. which plays a
`role in the regulation of transcription .
`However. Pem has no known homolog in
`the human genome Menin may also be
`present in the cytoplasm and interact
`with two intermediate filaments proteins ,
`glial fibrillary acidic protein (GFAP) and
`vimentin 11353). These interactions sug(cid:173)
`gest that intermediate filament network
`may serve as a cytoplasmic sequester(cid:173)
`ing network for menin. The binding of
`menin to GFAP raises the issue of a puta(cid:173)
`tive role of this tumour suppressor in glial
`cell oncogenesis such as ependymoma.
`Interestingly, menin interacts with Nm23,
`a nucleoside diphosphate kinase f3 iso(cid:173)
`form 1 which was first isolated as a
`metastasis suppressor /1639). Nm23
`associated to GFAP-containing interme(cid:173)
`diate filaments and enables menin to
`hydrolyze GTP, hence linking menin to
`Ras-related GTPases . This suggest
`again atypical GTPase activity of Menin
`may play a central role through multiple
`factors in the cell with specific actions
`depending the cellular type and physio(cid:173)
`logical context. Menin may play a role in
`synapse formation and plasticity during
`embryonical organization. Lastly, menin
`might control genome stability through
`interaction with Nm23 which isoform 1 is
`associated to the centrosomes in divid(cid:173)
`ing cells . Centrosomes regulate chromo(cid:173)
`some integrity and orchestrate the forma(cid:173)
`tion of GFAP and vimentin containing fil(cid:173)
`aments through protein phosphorylations
`regulated by GTPases . The direct or indi(cid:173)
`rect role of menin in maintaining genome
`stability and DNA integrity has been
`assessed by numerous reports which
`show evidence that normal cells from
`MEN 1 patients present with an elevated
`level of chromosome alterations [975,
`2251 ). These aberrations might be relat(cid:173)
`ed to the increase of premature cen(cid:173)
`tromere division observed in cell lines
`from patients with a heterozygous MEN 1
`gene mutation when compared to normal
`controls (1906). Recently, another molec(cid:173)
`ular link between the MEN 1 pathogenic
`context and cellular DNA replication has
`been found through the demonstration
`that menin was found to interact with the
`32-kDa subunit (RPA2) of replication pro(cid:173)
`tein A (RPA), a heterotrimeric protein
`required for DNA replication , recombina(cid:173)
`tion and repair 12161 ). In vitro and in vivo
`biological assays have shown that stable
`overexpre ssion of Menin partially sup(cid:173)
`presses the RAS-mediated tumour phe-
`
`' 1. ,
`
`225
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 056
`
`

`
`Clinical/ familial
`
`criteria suggesting MEN1
`
`+
`
`Multiple lesions
`
`No familial history
`
`I
`
`+
`
`Unique lesion
`
`pHPT
`
`d-PET
`
`llJ 1
`l 1
`
`Pituitary
`
`Adrenal
`
`b/c NET
`
`MENl gene sequence
`
`analysis
`
`Identification of gene-carriers
`
`and clinical follow-up
`
`...
`
`pHPT (<50yr)
`
`d-PET (<fi()yr)
`
`Pituitary
`Adrenal
`other NET
`Intestinal NE
`
`No genetic analysis
`
`1
`
`Further clinical and
`
`familial evaluation
`
`Fig. 5.19 MEN 1. A schematic view of MEN I gene testing in clinical practice.
`
`notype directly supporting MEN1 gene
`function as a tumour suppressor gene
`(1078)
`In pancreatic islet cells, menin
`inhibits insulin promoter activity, hormon(cid:173)
`al secretion and cell proliferation through
`a mechanism which might involve sup(cid:173)
`pression of AP-1 activation by menin
`either by direct inhibition on AP-1-medi~
`ated transcription and suppression of c~
`Fos induction (1954,2470).
`
`Mutation spectrum
`Germline and somatic mutations in the
`MEN1 gene do not appear to cluster in
`hot spots and are spread over the entire
`coding and intronic sequences (23621
`More than 400 different mutations have
`now been described. Approximatively
`60% are truncating mutations, either
`frameshift
`or nonsense
`mutat;ons. 20% are missense mutations.
`1 0% are in frame deletions or insertio;;s
`and about 10% are ;ntronic and
`s;te mutat;ons.
`dele:;ons
`e'lcompass:r:g
`
`226
`
`exons making any correlation study eve
`more difficult. However, the findings
`predominantly missense mutations
`familial
`isolated hyperparathyroidisr,
`especially in large families, may be tl
`exception. For example. in two
`autosomal dominant
`familial
`isolatr
`hyperparathyroidism
`(FIHP)
`familie
`which are characterized by multigland,,
`lar disease (one with 7 affected and H
`other 14 affected), two distinct missem
`mutations in close proximity in exon
`E255K and 0260P were identified /1 OLI .
`2206). Nevertheless, even if speci1,.
`point mutations might be related to mi:
`phenotype, this has no accurate inr
`dence in clinical follow-up of MEN
`patients. In the same family. expressiv"
`of MEN 1-related lesions is h;ghly vanab .
`(322,7231. Specific mutations have be(
`conversely related to uncommon expre~
`sion of the disease, such as the Bur;•
`variant of MEN 1, characterized by t!
`absence of pancreatic tumours (164 ~
`Nevertheless, this correlation may L:
`related to founder effects in related larr ,
`lies living in the same region. More the.
`10% of the mutations arise de novo ( 13f
`and despite typical expression of the d:
`ease, about 5-10% of MEN 1 patients rJ
`not share germline mutations in the co
`ing region or intronic borders of the MEr
`gene, suggesting that some of the mul
`lions occur in unknown parts or
`ry regions of the MEN1 gene.
`
`Genetic counselling
`MEN 1 is inherited in an autosomal dor
`inant manner with an age related per,
`trance and vanable expression. Clinic
`primary hyperparathyroidism is presr
`in at least 50% of the patients by age
`years (130,1989) Penetrance is mo•·
`than 80% by age 50 years, althouf:
`blood and urine tests could detect 90'
`by this age /130,322,14211 Most indivi
`uals with MEN 1 will have an aflectr
`parent (90%) although onset of syn•
`toms can be quite variable. even witl'
`the same family /350, 1421) DNA-bas(
`is
`recommended
`lor
`ind·
`patients and their relatives to establ;·
`the diagnosis
`for medical
`
`have also been shown (278, 1096). The
`frequencies of mutations detected in dif(cid:173)
`ferent studies vary. and range from 75~
`95% of the MEN 1 kindreds analyzed.
`Non-familial presentations of at least one
`or two MEN 1-related endocrine lesions
`have germline MEN1 mutations in 5-10%
`of cases. Taken together, it has been
`shown that genetic analysis of the MEN1
`gene may be helpful in 8% of all-comers
`in
`with primary hyperparathyroidism,
`those younger than 50 years and in about
`6% of subjects affected by duodenal
`and/or pancreatic endocrine tumours.
`
`Genotype vs phenotype
`Penetrance of ME~~ 1 at age 50 years is
`about 85%
`in gene-carriers. To date,
`there IS no clear-cut genotype-phenotype
`. The
`correlation in MEN 1
`clinical presentat;on. age of onset and
`of the d1sease have been
`natural
`even among
`The muta-
`
`t;ons
`
`the 9
`
`tions
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 057
`
`

`
`is useful for individuals and lami(cid:173)
`as who have some of the components of
`1EN 1 but are not classic /319,14231.
`11e appropriate age for offering MEN 1
`remains controversial,
`owever, given the significant early mor(cid:173)
`,;dity that can occur, testing of at-risk
`.hildren should be strongly considered
`c'41, 13081 Prenatal testing is possible
`/hen a MEN1 mutation has been identl(cid:173)
`ed in an affected family member.
`
`Preventive measures
`lithough early pre-symptomatic bio(cid:173)
`rlemical screening for MEN 1 does sig(cid:173)
`'lficantly improve diagnosis, decrease
`qorbidity. and is considered standard of
`~are by most practising clinical cancer
`Jeneticists, there is no general consen(cid:173)
`:us as to what management protocol is
`nost beneficial and cost-effective. There
`agreement that regular biochemical
`.creenirg for high-risk individuals should
`Je every 6-12 months, selected imaging
`;tudies less often (every 3-5 years), and
`his should continue for life (241, 758,
`1421,23581.
`
`for primary hyperparathy(cid:173)
`
`Screening
`roidism
`l31ood tests measuring ionized calcium
`1nd intact parathyroid hormone (IPTH)
`:evels should be done at 6-12 month
`.ntervals, beginning by 8-10 years of
`age. Elevated ionized calcium and/or
`
`elevated parathyroid hormone levels
`confirm the presence of hyperparathy(cid:173)
`roidism, at wh1ch point surgical resection
`should be discussed. As parathyroid
`tumours are multiple in MEN 1 some
`groups practice complete parathyroidec(cid:173)
`tomy with fresh parathyroid auto-trans(cid:173)
`plantation to the forearm, or cryopreser(cid:173)
`vation of a portion of a parathyroid gland.
`Others try to leave a parathyroid remnant
`although the possibility of recurrence
`remains high. All agree that transcervical
`thymectomy should be done as part of
`the initial parathyroidectomy.
`
`Screening for islet cell tumour
`Although primary hyperparathyroidism is
`the usual first presenting sign, this is not
`always so. Moreover, MEN 1-related islet
`cell tumours typically present with symp(cid:173)
`toms of hormone release rather than bulk
`disease. Thus annual pre-symptomatic
`screening should include, at a minimum,
`fasting and secretin-stimulated gastrin
`levels beginning at age 20. Many practi(cid:173)
`tioners also do fasting glucose, insulin
`and glucagon, as well as albumin, pro(cid:173)
`lactin and chromogranin-A. Given that
`one fourth of tumours are non-functional,
`abdominal imaging studies (CT. MRI or
`Octreotide scan) should be done every
`3-5 years. In general, surgery in MEN 1 is
`indicated for most symptomatic MEN 1
`related islet cell tumours. as these are
`usually benign. The exception is gastri-
`
`noma, wh1ch in MEN 1 is usually multiple
`and/or metastatic, and the role of surgi(cid:173)
`cal versus non-surgical management
`remains controversial.
`
`Screening for pituitary tumour
`The management of pituitary tumour in
`MEN 1 involves annual screening for
`fasting prolactin levels
`although
`some advocate monitoring insulin-like
`growth factor (IGF-1) as well. Most begin
`regular biochemical screening by age 8-
`10; some wait until early adulthood. CT
`scan or gadolinium-enhanced MRI of the
`pituitary gland is usually not routinely
`done in the United States. but some
`physicians will do them every 3 years
`
`Other screening
`Gastroduodenal, thymic and bronchial
`carcinoid tumours can occur in patients
`with MEN 1, and are usually more
`aggressive than sporadic cases. Thus
`some groups have advocated baseline
`CT or MRI scan with follow-up imaging
`studies every 3 years.
`
`227
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 058
`
`

`
`Hyperparathyroidism-Jaw tumour
`syndrome
`
`B.l Teh
`K.M. Sweet
`CD. Morrison
`
`Definition
`Hyperparathyroidism-jaw tumour syn (cid:173)
`drome (HPT-JT) is an autosomal domi(cid:173)
`nant disorder characterised by parathy(cid:173)
`roid adenoma or carcinoma ,
`libra(cid:173)
`osseous lesions (ossifying fibroma) of the
`mandible and maxilla, and renal cysts
`and tumours .
`
`MIM No. 145001
`
`Synonyms
`Familial
`isolated hyperparathyoridism;
`familial cystic parathyroid adenomatosis
`
`Incidence or prevalence
`It is a relatively recently described entity
`is
`an d
`its
`incidence or prevalence
`unknown .
`
`Diagnostic criteria
`Unlike the MEN 1 patients who invariably
`develop multiglandular disease, the HPT(cid:173)
`JT patients present with hereditary soli(cid:173)
`tary (occasionally double) adenoma or
`carcinoma. The latter is a rare entity and
`is not associated with other forms of
`hereditary endocrine neoplasia syn(cid:173)
`dromes and should lead to strong su spi(cid:173)
`cion of this syndrome. About 30% of
`patients also develop
`fibro-osseous
`lesions, primarily in the mandible and
`
`maxilla. Kidney lesions have been report(cid:173)
`ed including bilateral cysts , renal adeno(cid:173)
`ma, hamartomas and papillary renal cell
`carcinoma . It is important to be aware
`that in some families , only parathyroid
`lesions are present. As more families are
`currently being tested genetically, it is
`expected that the incidence and spec(cid:173)
`trum of its associ ated clinical features will
`be better known in due course.
`
`Hyperparathyroidism
`
`Age distribution/penetrance
`About 80 % of patients present with
`hyperparathyroidism , that may develop
`in late adolescence, similar to the pres(cid:173)
`entation in MEN 1. There is a reduced
`in
`females 12207), and
`penetra nce
`parathyroid carcinoma occurs in approx(cid:173)
`imately 10-15% of affected individuals
`j319l.
`
`higher incidence of parathyroid carcinc
`ma than in other endocrine related diso
`ders.
`
`Pathology
`Primary hyperparathyroidism in HPT-.J
`syndrome is more often one or two glar ,,,
`involvement (adenoma or double adent
`ma) that may or may not present sy: .·
`chronously 1985l One unique feature c
`the parathyroid neoplasia is the high inc
`dence of cystic change \1396), but sue
`changes also occur in sporadic paratlr
`roid adenoma or hyperplasia . The dia 1 ~
`nosis of parathyroid carcinoma remains ,
`challenge, and the only indisputab:
`proof
`for parathyroid malignancy
`i
`extensive local invasion and/or metast:.
`sis. The finding of parathyroid carcinom.,
`in the small number of reported tamilie
`with HPT-JT syndrome is significant co ~ ·
`sidering the rarity of parathyroid carcinc
`ma in sporadic parathyroid tumours.
`
`Clinical features
`Compared with MEN 1-related hyper(cid:173)
`parathyroidi sm,
`HTP-JT
`syndrome
`ru n a more agg ressive
`appears
`to
`course: the patients tend to have more
`severe hypercalcemia and some actually
`In
`present with hypercalcemic crisis.
`addition. there appears to be a much
`
`Prognosis and prognostic factors
`The majority patients with adenoma c2.·
`be cured by surgery and recurrence :
`not as common as in MEN 1 patient
`Prognosis is guarded once parathyror
`carci noma is confirmed , but it is un cle ~·
`whether the prognosis is any differe:
`from sporadic parathyroid carcinoma .
`
`. .
`: \\:~:-~ .. ~i
`
`' ; : ~I • '
`\' -t
`,
`
`'
`
`•;I k):·::·-:·.
`- ~ ;· • _ _ .;
`-~-:·.·:: . ·.:.:. ;~>~:.;~~~ ~~-
`· , -'!(· ~i ..
`:1 .l~, l;i -:'\.,:_~f'~,:, \ 4 "
`-c ·
`·.·""-.
`..... #~'<."> .... . ·!~~: . A" ·'1\ ~~ ... . ._
`.·, ·- ~ \t.:. .
`:
`--
`... -.
`Fig. 5.20 Hyperparathyroidi sm - jaw tumour syndrome (HPT-JT). ACT showing a well demarcated fibroosseus lesion in the maxillary antrum . B Typical jaw le sio1·
`from a patient with HPT-JT syndrome with a dense. relatively avascular fibroblast-rich stroma and irregu lar spic ules of woven bone, some of which show at leas
`a focal rim of osteoblasts
`
`-
`
`·
`
`228
`
`.• \1 l
`.
`·;)~_.·)·~:\.-. .:.:~!,:::{h:. : -~ r
`
`' ·'
`
`•
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 059
`
`

`
`aw tumours
`
`Table 5.04
`Tumours and cysts reported in association with HPT-JT syndrome.
`
`Lesions
`Renal cysts, polycystic kidney disease, renal hamartoma
`Wilms tumour
`Renal cysts
`Renal cysts, papillary renal cell carcinoma,
`multiple renal cortical adenomas, Hurthle cell adenoma,
`clear cell pancreatic adenocarcinoma
`Adenomyomatous polyps of endometrium
`Papillary thyroid carcinoma, uterine leiomyoma
`Cellular neurofibroma
`
`Reference
`{2207}
`{1022,2166}
`{331}
`
`{845}
`{669}
`{965}
`{1396}
`
`;iinical features
`)me cases are fast growing while some
`,nsidious and slow growmg. Ra-
`features
`show a
`ell-demarcated osseous lesion of the
`andible or maxrlla.
`
`5athology
`t;e usual case is described as having a
`latively avascular cellular fibroblast-
`ch stroma, sometimes with a storiform
`attern, admixed with bone trabeculae
`nd/or cementum-like spherules. Some
`f the bone trabeculae generally show at
`:ast focal osteoblastic rimming It is dis(cid:173)
`the classical
`net histologically from
`one
`lesion of hyperparathyroidism,
`•steltis fibrosa cystica, which tends to
`JSolve slowly after correction of the
`yperparathyroidism, albeit over a
`ourse of months to years /1993). In con(cid:173)
`. a st. the fibroosseous lesions of HPT-JT
`lo not resolve with correction of the
`yperparathyroidism. While most of
`•lese lesions involve either the mandible
`,r maxilla of one side, bilateral or multifo(cid:173)
`al lesions have been described !331,
`
`Prognosis and prognostic factors
`.Vhile none of the described Jaw tumours
`•ave behaved in a malignant fashion,
`! 1864,22071
`ome
`have
`recurred
`dthough it is difficult to discern if this is
`Jue
`to
`incomplete initial resection or
`Jevelopment of a new lesion.
`
`Other features
`
`2166), which has been reported in three
`separate rndividuals from three separate
`families.
`
`Genetics
`
`Chromosomal location
`The HRPT2 gene is mapped to 1 q25-q31
`(2166/.
`
`Gene structure
`The HRPT2 gene contains 17 exons
`spanning 18.5 kb of genomic distance
`and predicted to express a 2 7kb tran(cid:173)
`script. It encodes a protein of 531 amino
`acids /3191
`
`Gene expression
`The gene is ubiquitously expressed
`including kidney, heart, liver, pancreas,
`skeletal muscles, brain and lung /319).
`
`Gene function
`The function remains unknown although
`the gene has moderate (32%) identity to
`a yeast protein Cdc73p, which is an
`accessory factor associated with an
`alternative Rf\JA
`II (3191
`
`lr1 addition to cystic adenomatosis and
`•aw lesions, a wide spectrum of tumours
`:las been associated wrth HPT-JT syn(cid:173)
`drome but most notable is the associa(cid:173)
`tion of various renal
`lesions, which
`occurs in approximately 20% of patients
`(319.1022,2166,2207)1n the two families
`reported, 5 individuals in one kindred
`and 2 in the other had renal lesions. In
`I he latter kindred, polycystic kidney dis(cid:173)
`ease was the predominant finding, while
`in the other kindred in addition to renal
`cysts there were several individuals with
`renal hamartomas described as cystic
`tumours with mesenchymal, blastema!. Genetic counseling
`and
`elements. Another renal
`with HPT- When HPT-JT
`tumour that has been
`JT syndrome is Wilms tumour (1022.
`Df\JA-based
`
`Mutation spectrum
`The vast maJority of mutations are
`frameshift and nonsense loss-of-function
`mutations found in several exons. The
`most common exon involved is exon 1
`/319).
`
`Genotype vs phenotype
`To date, it remains unknown if there is a
`genotype-phenotype correlation.
`
`index patients and their relatives to
`establish the diagnosis and for medical
`management. As the HRPT2 gene was
`recently identified, testing for each of the
`complex syndromes associated with
`hereditary primary hyperparathyroidism
`has become possible (319).
`
`for primary hyperparathy(cid:173)
`
`Screening
`roidism
`Annual blood tests measuring ionized
`calcium and intact parathyroid hormone
`(iPTH) levels should begin by 15 years of
`age. Surgical intervention should occur
`once serum levels confirm the presence
`of HPT Parathyroid disease in HPT-JT is
`typically represented by asynchronous
`adenomas although the potential for
`malignancy needs to be considered
`(2055,23561. While some groups advo(cid:173)
`cate removal only of
`the enlarged
`parathyroid gland with continued regular
`monitoring /1423.20551, the alternative
`approach would be complete parathy(cid:173)
`roidectomy with fresh parathyroid auto(cid:173)
`transplantation to the forearm (or stern(cid:173)
`ocleidomastoid), or cryopreservation of a
`portion of a parathyroid gland.
`
`Screening for jaw manifestations
`Orthopentography of the jaw every three
`years.
`
`Screening for renal manifestations
`At-risk individuals should receive annual
`abdominal ultrasound or CT scan with
`and without contrast at least every other
`year to screen for polycystic disease,
`Wilms tumour or carcinoma, and renal
`hamartomas 119931
`
`229
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 060
`
`

`
`Von Hippei-Lindau syndrome (VHL)
`
`E.R. Maher
`K. Nathanson
`P Komm inoth
`HP.H. Neumann
`
`K.H. Plcl'
`T Bohli1
`K. Schneid
`
`Definition
`Von Hippei-Lindau (VHL) disease is a
`dominantly inherited familial cancer syn(cid:173)
`drome caused by germline mutations in
`the VHL tumou r suppressor gene. VHL
`disease demonstrates marked phenotyp(cid:173)
`ic variability and age-dependent pene(cid:173)
`trance. The most frequent tumours are
`retinal and central nervous system hae(cid:173)
`mangioblastomas , renal cell carcinoma .
`phaeochromocytoma and pancreatic
`endocri ne tumours. Families with VHL
`disease may be subdivided according to
`clinical phenotype, and this subdivision
`forms the basis for genotype-phenotype
`correlations (see later) .
`
`MIM No . 193300 (18621
`
`Synonyms
`Von Hippei-Lindau syndrome
`
`Incidence/prevalence
`VHL disease was estimated to have an
`incidence of 1/36000
`live births
`in
`Eastern England (13831 and a preva(cid:173)
`lence of 1/39000 in South-West Germany
`(15901.
`
`Diagnostic criteria
`If there is a confirmed fami ly history of
`VHL disease, a clinical diagnosis can be
`made in a relative with a single typical
`VHL tumour (e.g . retinal or central nerv(cid:173)
`ous system haemangioblastoma, clear
`cell renal cell carcinoma, phaeochromo-
`
`cytoma, pancreatic endocrine tumour or
`endolymphatic sac tumour). In isolated
`family hi story, two
`cases without a
`tumours (e.g. two haemangioblastomas
`or a haemangioblastoma and a visceral
`tumour) are required for the diagnosis.
`Genetic studies allow a molecular-based
`diagnosis of VHL in atypical cases and
`early diagnosis in patients who do not
`satisfy cl inical diagnostic criteria.
`
`Phaeochromocytoma
`
`Age distribution and penetrance
`The association of phaeochromocytoma
`with VHL is strongly dependant upon
`genotype (Table 5.06). More than 95% of
`patients with truncating or null mutations
`have VHL type 1 (low risk of phaeochro(cid:173)
`mocytoma) (358 ,4331 Patients with VHL
`type 2 (high risk of phaeochromocytoma)
`have primarily missense mutation s. The
`penetrance of phaeochromocytoma in
`those with missense mutations of VHL is
`high one large series estimated a 59%
`nsk by age 50 years ( 138 11 . Risks for
`specific missense mutations vary, with
`risks of 82% for type 28 codon 167 muta(cid:173)
`tions and 50% for the "Black Forest"
`c.505 type 2A mutation at 50 years bein g
`re ported ( 163,138 11.
`In series of VHL
`patients with phaeochromocytomas, the
`age range of diagnosis is from 5-64
`years, starting notably younger and with
`a younger average at diagnosis than in
`
`syndromes w·
`hereditary
`other
`phaeochromocytoma (MEN 2, SOH : ·
`(119 ,244,565 ,962, 1585 ,15i
`SDHB)
`2291 ,23481 .
`
`Clinical features
`Patients with VHL and phaeochromoc
`toma common ly have multi-focal ci
`ease, both adrenal and extra-adren
`Extra-adrenal disease has been parti ' .
`larly associated with a mutati on
`nucleotide 505 (23481 . As noted abo .
`early age at diagnosis of phaeochron
`cytoma is a predominant feature, how.
`er, there is some genotype-phenoty: ·
`correlation with
`individuals with mu: .
`lions at nucleotides 595 and 695 pr.
`senting with phaeochromocytomas a:
`younger age than those with other mui ·
`tions (p<0.025) (23481 As mutatiom.
`VHL can lead to phaeochromocyto1·
`alone , it is difficult to define the trequ c
`cy of phaeochromocytoma as th e t•
`sign of VHL. However, depending on '
`mode of ascertainment, VHL mutatw
`have been identified from 2-50% of t
`patients with sporadic or
`isola;.
`phaeochromocytoma in hospital ba ~;·
`seri es (119,244 ,565 , 1587,22911 . In 1
`recent study of 271 sporadic phaeoc l1•
`mocytomas in a population-based '··
`ries, mutations in VHL were found in 1 '
`of cases and accounted tor almost ha::
`the germline mutations identified (30ft. ·
`(15851 . The biochemical findings fOll'
`in phaeochromocytomas due to V: '