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CHAPTER 7

Inherited Tumour Syndromes

The study of familial cancer syndromes has led to the discoveryof key genes that are important not only for the understandingof the mechanismsm of genetic susceptibility but also for giv-ing new insights into genetic and signaling pathways involvedin sporadic cancers. Investigations into the rare skin diseasexeroderma pigmentosum has led to the discovery of 7 DNArepair genes involved in the nucleotide excision repair path-way. Studies of these patients allowed us to understand themechanism of DNA repair in the general population. Eventually,the in-depth analysis of the activity of these repair genes mayallow us to define a subpopulation of individuals at higher riskof developing cancers in different organ sites. This chapter contains a detailed description of clinical, patho-logical and genetic data of some major, well characterizedinherited syndromes associated with skin cancer or other skindisorders.

278 Inherited tumour syndromes

OMIM Disease Inheritance Tumour Locus Gene Protein Functiontypes

Xeroderma Pigmentosum AR BCCSCCMM

278700 Complementation group A 9q22.3 XPA XPA Damaged DNA-binding interaction with TFIIH and XPF/XPG endonucleases

133510 Complementation group B 2q21 XPB/ERCC3 XPB 3’∆5’ helicase in TFHII 278720 Complementation group C 3p25.1 XPC XPC Damaged DNA-binding only involved in global

genomic repair. Heterodimer with HHR23B 126340 Complementation group D 19q13.2-3 XPD/ERCC2 XPD 5’∆3’ helicase in TFHII600045 Complementation group E 11q12-13 DDBI XPE P127 Damaged DNA-binding only involved in global

genomic repair. Heterodimer with DDB2 600811 Complementation group E 11p11-12 DDB2 XPE P48 Damaged DNA-binding only involved in global

genomic repair. Heterodimer with DDB1 278760 Complementation group F 16p13.3- XPF/ERCC4 XPF 5’ structure-specific endonuclease heterodimer

13.13 with ERCC1 133530 Complementation group G 13q32-33 XPG/ERCC5 XPG 3’ structure-specific endonuclease. Stabilization of

the open complex 603968 Xeroderma pigmentosum variant 6p21.1 POLh POL h Translesion DNA polymerase 600160 Familial melanoma MM 9p21 CDKN2A P16/INK4 Inhibits CDKs from phosphorylating Rb, thereby

freezing cell cycleP14ARF Stabilizes p53 by inhibiting MDM2, thereby

promoting apoptosis 123829 Familial melanoma MM 12q14 CDK4 CDK4 Activated protein kinase resistant to p16 inhibition ;

overphosphorylates Rb, thereby driving cell cycle 155600 Familial atypical mole- AD MM 1p36(?) unknown unknown CDKN2A and CDK4 genes have been excluded

malignant melanomasyndrome (FAMMM)/ Dysplastic naevus syndrome (DNS)

109400 Naevoid basal cell AD BCC 9q22.3 PTCH1 PTCH1 Development gene ; regulates the Sonic Hedgehog carcinoma syndrome signaling pathway

158350 Cowden disease b AD MH 10q23 PTEN/ PTEN/TEP1 Lipid/protein phosphatase MMAC1 /MMAC1

158320 Muir-Torre syndrome AD CSN 2p22 hMSH2 hMSH2 Involved in DNA mismatch repair 175100 Gardner syndrome a AD EC 5q21 APC APC Negatively regulates ß-catenin, a cytoskeletal and

growth-promoting protein, and the WNT signalingpathway

131100 Multiple endocrine neoplasia 1 AD MFA 11q13 MEN1 menin Inhibitor of Jun D-activated transcription171400 Multiple endocrine neoplasia 2 AD CLA 10q11.2 RET RET Tyrosine kinase receptor involved in signal transduction605284 Tuberous sclerosis 1 AD MSL 9q34 TSC1 hamartin Interacts with tuberin and exhibits growth-inhibitory

activity 191092 Tuberous sclerosis 2 AD MSL 16p13.3 TSC2 tuberin GTPase-activating protein for RAP1 and RAB5 ;

interacts with hamartin 162200 Neurofibromatosis 1 b AD FTK 17q11.2 NF1 neuro- Negatively regulates ras-family of signal molecules

(von Recklinghansen disease) fibromin through GAP function : Tumour suppressor activity 101000 Neurofibromatosis 2 b AD ST 22q12.2 NF2 merlin Integrates cytoskeletal signaling 210900 Bloom syndrome b AR ST 15q26.1 BLM/ BLM DNA helicase ; unwinds DNA at blocked

RECQL3 replication forks 175200 Peutz-Jeghers syndrome AD MML 19p13.3 STK11 STK11 Serine/threonine protein kinase : Tumour

suppressor activity 268400 Rothmund-Thomson syndromeb AR D 8q24.3 RECQL4 RECQL4 DNA helicase ; unwinds DNA at blocked replication

forks/recombination sites277700 Werner syndrome b AR SSC 8p12 WRN/ WRN DNA helicase ; unwinds DNA at blocked replication

RECQL2 forks/recombination sites 135150 Birt-Hogg Dubé Syndrome AD HFH 17p11.2 BHD folliculin Unknown 132700 Cylindromatosis familial AD C 16q12-13 CYLD1 CYLD1 Tumour suppressor gene. Protein with 3

cytoskeletal-associated-protein-glycine-conserved domains implicated in the attachment of organelles to microtubules

Table 7.1Inherited disorders associated with skin abnormalities

279Familial cutaneous melanoma

DefinitionFamilial melanoma is defined as theoccurrence in at least two affectedblood- relatives up to the third degree onone side of the family. This genetic sus-ceptibility is caused germline mutationsin the CDKN2A/p14ARF or CDK4 gene.

OMIM numbers

600160: Cyclin-dependant kinaseinhibitor 2A; CDKN2ASynonyms: CDK4 Inhibitor; multipletumour suppressor 1, MTS1; TP16;p16(INK4); p16(INK4A); p19(ARF);p14(ARF).

123829 Cyclin-dependant kinase 4;CDK4Synonyms: Cell Division Kinase 4; Cuta-neous malignant melanoma 3, CMM3.

155600 Melanoma, cutaneous malig-nant; CMM

Synonyms: Melanoma, malignant;Familial atypical mole-malignant melano-ma syndrome, FAMMM; Melanoma famil-ial, MLM; Dysplastic naevus syndrome,hereditary, DNS; Melanoma, cutaneousmalignant 1, CMM1; B-K Mole syndrome.

155755 Melanoma-astrocytoma syn-dromeSynonyms: Melanoma and neural systemtumour syndrome

606719 Melanoma-pancreatic cancersyndromeSynonyms: Familial atypical multiplemole melanoma pancreatic carcinomasyndrome (FAMMMPC)

EpidemiologyCutaneous melanoma is a typical exam-ple of a multifactorial disease, whereboth genetic and environmental factorsare involved and interact. Genetic factorswere first suspected through the exis-tence of familial aggregations of CM. Theproportion of familial cases varies from 4-15% across different studies. Withinlarge families, familial aggregation ofmelanoma was consistent with autoso-mal, dominant inheritance. In addition toCM family history, numerous epidemio-logical studies have demonstrated thatcutaneous and pigmentary characteris-tics (the presence of numerous naevi,naevi atypia, skin colour, red hair andfreckles), sun exposure (particularly dur-ing childhood) and reactions to sunexposure (inability to tan and propensityto develop sunburns) are major CM riskfactors. Some melanoma risk factors alsoshow familial aggregations independent-ly of melanoma, suggesting the exis-tence of genetic factors specific to thesephenotypes {309}. The various patternsof associations of these different pheno-types (phototype, naevus phenotypesand CM) across families are likely toresult from complex interactions ofgenetic and environmental factors under-lying these traits.

Clinical features and neoplasticdisease spectrumCutaneous melanoma (CM)Characteristics of familial melanomainclude multiple cases of CM amongblood-relatives on the same side of thefamily. Potential genetic predispositionmay be suspected also in sporadiccases such as multiple primary CM in thesame individual or early age of onset{1239}.

Pancreatic cancerThe existence of an increased risk ofpancreatic cancer in a subset ofCDKN2A families has been reported{286,859}.

Breast cancerAn excess of breast cancer has beendescribed in two sets of families, Italianand Swedish {286,822}.

Table 7.2: Inherited tumour syndromes Abbreviations

AR* Autosomal Recessive AD Autosomal Dominant BCC** Basal Cell Carcinoma SCC Squamous Cell Carcinoma MM Malignant Melanoma MH Multiple Hamartomatous CSN Cutaneous Sebaceous Neoplasms EC Epidermoid Cysts MFA Multiple Facial Angiofibromas CLA Cutaneous Lichen Amyloidosis MSL Multiple Skin Lesions FTK Fibromatous Tumours of the Skin ST Skin Tumours MML Melanocytic Macules of the Lip D Dermatosis SSL Scleroderma-like Skin Changes HFH Hair Follicle Hamartomas C Cyclindroma ...................................................................................a Already described in the WHO Classificationof Tumours of the Digestive System {944}b Already described in the WHO Classificationof Tumours of Soft Tissue and Bone {756}

B. Bressac-de PailleretsF. DemenaisFamilial cutaneous melanoma

Fig. 7.1 Interaction of environmental (sun exposure)and genetic factors in the evolution of cutaneousmelanoma (CM).

Fig. 7.2 Effect of great number of naevi (GNN), aty-pical naevi (AN) and sunburns (SB) on cutaneousmelanoma (CM) risk in CDKN2A mutation carriers.


Nervous system tumoursRare families have been described dis-playing melanoma and neural systemtumours (NSTs) over several generations{129,1230}. This has been termedmelanoma-astrocytoma syndrome due tothe presence of cerebral astrocytomas inthe first family described.

Uveal melanoma (UM)Certain melanoma-prone kindred havemembers affected by either uveal and/orcutaneous melanoma. The first CDKN2Agermline mutation was detected recentlyin a melanoma-prone family, where onecarrier was affected by UM and the otherby a CM (Kannengiesser C. et al., GeneChromosome and Cancer, pending).Naevus: total number (TN), clinicallyatypical (AN), histologically dysplastic(DN These naevus phenotypes are major riskfactors for CM but whether they repre-sent precursor lesions in the course oftumour development is still unclear.There are several lines of evidence sug-gesting that distinct genetic factors maybe involved in CM and number of naevi{309}. CDKN2A does not appear to be a“naevus” predisposing gene; this pheno-type was found in only half of the sub-jects with a CDKN2A gene mutation andwho had developed melanoma {2226}and a study of Australian twins hasreported that a CDKN2A-linked genemay influence flat moles but has no effecton raised or atypical moles {2601}.Naevus phenotypes (TN, AN and/or DN)have been shown to influence the pene-trance of CDKN2A in melanoma-proneNorth-American and French families

{860,452A} with a greater effect of DN innon-carriers than in carriers of CDKN2Amutations in the American sample.

Genetics Gene structure and mutationsTwo genes (encoding three proteins)conferring a high risk of developingmelanoma have been identified to date,CDKN2A/p14ARF and CDK4. In addi-tion, a low-risk melanoma susceptibilitygene has also been identified, themelanocortin-1 receptor gene (MC1R).

CDKN2A/p16INK4A geneLinkage analyses, cytogenetic studiesand loss of heterozygosity (LOH) studiesin tumour cells have led researchers tosuspect the existence of a CM suscepti-bility gene at 9p21 locus. The gene,p16INK4A/CDKN2A, was cloned in 1993{2140} and formally identified as amelanoma susceptibility gene in 1994{1088,1184}. The CDKN2A transcript includes exons1a, 2 and 3. It encodes the 156 amino-acid p16INK4A protein composed of fourankyrin repeats which are motifs involvedin protein-protein interactions. P16INK4Abinds to cyclin-dependent kinase 4(CDK4) and 6 (CDK6), therefore prevent-ing binding of cyclin D1 to the CDKs.Cyclin D1/CDK4/6 complexes participatein the phosphorylation of the retinoblas-toma protein (RB), allowing the cell toprogress beyond the G1 phase of thecell division cycle {2166}. The p16INK4Aprotein inhibits RB-dependant cell cycleand therefore acts as a tumour suppres-sor.The search for mutations of the CDKN2A

gene in numerous familial studies aroundthe world shows that the frequency ofCDKN2A mutations is about 20% onaverage but varies from 5-50% depend-ing on the criteria for family selection.Homozygotes for CDKN2A germlinemutation have been described in relationto a Dutch founder effect; they displaysimilar phenotypes than heterozygousindividuals {912}. Mutations of theCDKN2A gene are detected in approxi-mately 10% of sporadic multiple mela-noma cases, without any evidence of denovo mutations up to date but in relationto the existence of a founder effect forsome of them {115}. To date, no germline mutations have been found in casesof childhood melanoma (<18-20 years ofage) lacking a family CM context {2507}.Most CDKN2A mutations are missensemutations scattered throughout the cod-ing sequences of exons 1a and 2.Functional studies of mutant p16INK4Aproteins have been carried out usingseveral assays displaying various sensi-tivity: CDK-binding, kinase activity inhibi-tion, growth arrest and protein cellularlocalisation assays. Two more complexmutations have been also described: amutation located within CDKN2A 5’UTR,creating an aberrant initiation codon{1435} and a deep intronic mutation(IVS2-105A/G) of CDKN2A, leading toaberrant mRNA splicing {956}. Recurrentmutations described in melanoma-pronefamilies from different continents havebeen shown to be founder mutations{115,488}.Within the International MelanomaConsortium, CDKN2A mutation pene-trance was estimated to be, in a set of 80

Fig. 7.3 A. CDKN2A/p16INK4A germ-like mutations. B CDKN2A/p14ARF gene mutations.

BA

281Familial cutaneous melanoma

families, 0.58 in Europe, 0.76 in theUnited States and 0.91 in Australia, byage 80 years {251}. This variation of pen-etrance by geographical location wasfound to be similar to the variation ofoverall population incidence ratesamong these countries. This suggeststhat the same risk factors mediate CMrisk to the same extent in CDKN2A muta-tion carriers as in non-carriers. Moreover,CM risk does not change according towhether or not the mutation can simulta-neously alter the p16INK4A and p14ARFproteins. Three MC1R variant alleles also act asmodifiers of melanoma risk in familiessegregating CDKN2A mutations:MC1Rvar/var genotypes increased themelanoma penetrance in CDKN2A carri-ers from 50-84% in Australia (sunnycountry) and from 18–55% in the Nether-lands (less sunny country) {291,2410}.

CDKN2A/p14ARF geneIn 1995, it was discovered that part ofCDKN2A gene was common to anothertranscript. This second transcript (exons1b, 2 and 3) encodes the human p14ARFprotein (ARF meaning “alternative read-ing frame”) composed of 132 amino-acid, encoded by exons 1b and 2.According to the current state of knowl-edge, p14ARF is involved in regulation ofthe cell cycle and apoptosis via the p53and RB pathways, by interacting withMDM2 (leading to p53 protein accumula-tion and to RB inactivation) and E2F1proteins {1437}. Mutations in exon 2 potentially affectp16INK4A and p14ARF proteins at thesame time. Despite this dual codingcapacity of the INK4A/ARF locus, recentdescription of three p14ARF germ-linealterations involving only exon 1b sug-gests a direct role for p14ARF haploin-sufficiency in melanoma predisposition :(1) a deletion restricted to exon 1b andsegregating with melanoma and neuralcell tumours within a family {1890}, (2) a16bp insertion in exon 1b in a sporadicmultiple melanoma case {1945}, (3) asplice mutation in exon 1b in a twomelanoma-cases family {1022}.

A role for both p14ARF andp16INK4A/CDKN2A genes?Germ-line alterations presumably alter-

ing both p16INK4A and p14ARF func-tions, have been described in three CMand NSTs families: two large deletionsinvolving the INK4A locus {128} and aCDKN2A splice point mutation, leadingto p16INK4A and p14ARF transcriptslacking exon2 {1818}. However, it cannotbe concluded that both p16INK4A andp14ARF inactivation are necessary formelanoma-astrocytoma syndrome as afourth such family has been alsodescribed with a germ line deletionapparently restricted to the p14ARF -specific exon 1b {1890}.

CDK4 geneThe CDK4 gene on chromosome 12q13is composed of 8 exons within a 5-kilo-bases (kb) segment. The initiation codonis located in exon 2, the stop codon inexon 8. This gene encodes the cyclin-dependant kinase 4 (CDK4), a 304amino-acid protein. It has been identifiedas a melanoma predisposing gene inthree families world-wide {2226.2607}.Germline mutations affect Arg-24 residuein exon 2, which plays a key role inp16INK4A binding. The mutation indu-ces the loss of the cell cycle down-regu-lation signal that p16INK4A exertsthrough RB phosphorylation. In a “knock-in” Cdk4R24C/R24C mouse model, con-stitutive Cdk4 activation is oncogenic{1891}.

Application of genetic testing in theclinical testingThere is some evidence that non-carrierof CDKN2A mutations in melanoma-prone families may have a higher inci-dence of melanoma than the generalpopulation, presumably due to co-inheri-tance of other low-risk susceptibilitygenes and common environmental riskamongst family members. Therefore,genetic testing for melanoma is of limitedclinical utility to date, mainly because anegative genetic test may give danger-ously false security. Testing should bedone in research protocols and first-degree relatives of high-risk individualsshould be engaged in the same pro-grams of melanoma prevention and sur-veillance, irrespective of the results ofany gene testing. However, in countriesof low melanoma incidence such as mostEuropean countries, DNA testing mayimprove compliance with sun protectionand surveillance in identified mutationcarriers. In such situations, CDKN2Atesting could be proposed after carefulgenetic counselling {1238}.

Fig. 7.4 p14ARF and p16INK4A signaling pathways and their role in apoptosis and proliferation ofmelanocytes.


Definition Xeroderma pigmentosum (XP) is an auto-somal recessive disease with sun sensi-tivity, photophobia, early onset of freck-ling, and subsequent neoplasticchanges on sun-exposed surfaces {284,778}. There is cellular hypersensitivity toUV radiation and to certain chemicals inassociation with abnormal DNA repair{2419}. Some of the patients have pro-gressive neurologic degeneration. TheXP syndrome is genetically heteroge-nous. Patients with defective DNAnucleotide excision repair (NER) havedefects in one of 7 NER genes, while XPvariant patients have normal NER and adefect in a polymerase gene {316,500}.

OMIM Numbers 278700 - XPA 133510 - XPB278720 - XPC278730 - XPD278740 - XPE278760 - XPF278780 - XPG278750 - XP variant

Synonyms De-Sanctis Cacchione syndrome, pig-mented xerodermoid, xeroderma pig-mentosum variant

EpidemiologyIncidence Xeroderma pigmentosum occurs with anestimated frequency of 1:1,000,000 inthe United States {1322}. It is more com-mon in Japan, the Middle East andNorth-Africa. Patients have been report-ed worldwide in all races includingWhites, Asians, Blacks, and NativeAmericans. Consanguinity is common.There is no significant differencebetween the sexes.

Clinical features Abnormalities may be present in the skin,eyes, or nervous system. There is agreatly increased frequency of cancer onsun-exposed sites.

SkinApproximately half of the patients with XPhave a history of acute sunburn reactionon minimal UV exposure {1322}. Theother patients give a history of normaltanning without excessive burning. In allpatients, numerous freckle-like hyperpig-mented macules appear on sun-exposed skin. The median age of onset of the cuta-neous symptoms is between 1 and 2years {1321}. Repeated sun exposureresults in dry and parchment-like skinwith increased pigmentation, hence thename xeroderma pigmentosum (“drypigmented skin”). Pre-malignant actinickeratoses may develop at an early age.

EyesOcular abnormalities are almost as com-mon as the cutaneous abnormalities{801,871,2424}. Clinical findings arestrikingly limited to the anterior, UV-exposed structures. Photophobia is oftenpresent and may be associated withprominent conjunctival injection.Continued UV exposure of the eye mayresult in severe keratitis leading tocorneal opacification and vasculariza-tion. The lids may develop loss of lashesand atrophy of the skin of the lids resultsin the lids turning out (ectropion), or in(entropion), or complete loss of the lids insevere cases. Benign conjunctivalinflammatory masses or papillomas of

Xeroderma pigmentosum K.H. KraemerA. Sarasin

DC

BA

Fig. 7.5 Xeroderma pigmentosum. A Face of a 16 year old patient showing dry skin with hyperpigmentation,atrophy and cheilitis. B Posterior view of the same patient showing absence of pigmentary changes onareas protected from sunlight. C Face of a 14 year old patient showing freckle-like lesions with differentamounts of pigmentation, an actinic keratoses, a basal cell carcinoma and a scar with telangiectasia at thesite of removal of another neoplasm. D Xeroderma pigmentosum. Eye of the 22 year old patient showingsecondary telangiectasia invading the cloudy cornea, and atrophy and loss of lashes of the lower lid.Figures from K.H. Kraemer {1319}.

283Xeroderma pigmentosum

the lids may be present. Basal andsquamous cell carcinoma, and mela-noma of UV-exposed portions of the eyeare common.

Nervous systemNeurologic abnormalities have beenreported in approximately 30 percent ofthe patients. The onset may be early ininfancy (the De-Sanctis Cacchione syn-drome) or delayed until the seconddecade. The neurologic abnormalitiesmay be mild (e.g., isolated hyporeflexia)or severe, with progressive mental retar-dation, sensorineural deafness (begin-ning with high-frequency hearing loss),spasticity, or seizures. In clinical prac-tice, deep tendon reflex testing and rou-tine audiometry can usually serve as ascreen for the presence of XP-associatedneurologic abnormalities. The predomi-nant neuropathologic abnormality foundat autopsy in patients with neurologicsymptoms was loss (or absence) of neu-rons, particularly in the cerebrum andcerebellum {1894}.

CancerPatients with XP under 20 years of agehave a greater than 1000-fold increasedrisk of skin cancer (basal cell or squa-mous cell carcinoma or melanoma){1321}. Multiple primary skin cancers arecommon. The median age of onset ofnon-melanoma skin cancer reported inpatients with XP was 8 years. This 50-

year reduction in comparison to the gen-eral population is an indication of theimportance of DNA repair in protectionfrom skin cancer in normal individuals.There is a greatly increased frequency ofcancer of the anterior portion of the eyeand of the oral cavity, particularly squa-mous cell carcinoma of the tip of thetongue. These are presumed sun-exposed sites. Brain (sarcoma and medulloblastoma),central nervous system (astrocytoma ofthe spinal cord), lung, uterine, breast,pancreatic, gastric, renal, and testiculartumours and leukaemias have beenreported in a small number of XPpatients. Overall, these reports suggestan approximate ten to twenty-fold in-crease in internal neoplasms {1321}.

Diagnosis There have been no consistent routineclinical laboratory abnormalities inpatients with XP. Diagnosis is based onclinical features and confirmed by testsof cellular hypersensitivity to UV damagealong with a defect in nucleotide excisionrepair for classical XP {778}.

Cellular hypersensitivityCultured cells from patients with XP gen-erally grow normally when not exposedto damaging agents. The populationgrowth rate or single-cell colony-formingability is reduced to a greater extent thannormal, however, following exposure to

UV radiation. A range of post-UV colony-forming abilities has been found withfibroblasts from patients, some havingextremely low post-UV colony-formingability and others having nearly normalsurvival. XP fibroblasts are also deficientin their ability to repair some UV-dam-aged viruses or plasmids to a functional-ly active state. XP variant cells are specif-ically sensitive killing by UV-irradiation inthe presence of caffeine.

DNA repairCells from most XP patients have adefect in one of 7 genes (XPA throughXPG) involved in the nucleotide excisionrepair (NER) system {500}. The NERpathway is described in Figure 7.6{2253}. The DNA repair defect can bemeasured by post-UV unscheduled DNAsynthesis. Host cell reactivation assayscan be used to determine the comple-mentation group by use of a panel ofcloned DNA repair genes. Cells from XPvariant patients have normal NER buthave a defect in an error-prone poly-merase (pol eta) {316}.Prenatal diagnosis can be performed byuse of unscheduled DNA synthesisassays on cultured amniotic fluid cellsand by molecular analysis of trophoblastbiopsies {52,1309}. Most XP cells have a normal response totreatment with x-rays, indicating thespecificity of the DNA repair defect.

Genetics The seven complementation groupsfound for the classical XP correspond to

Fig. 7.6 General scheme for nucleotide excisionrepair (NER). The "classical" XP patients carrymutations in one of the seven XP genes indicated..Adapted from A. Stary and A. Sarasin {2253}.

Fig. 7.7 DNA repair diseases. Correlation between clinical disorder (yellow letters) and molecular defects(black letters).

seven genes involved in NER {2253,2419}; XPC, XPE and XPA code for pro-teins able to recognize DNA lesions pro-duced by various DNA damagingagents, including UV-radiation. XPB andXPD are two helicases necessary toopen the double helix at the site of thelesion. XPF and XPG are two endonucle-ases able to cut the damaged strand atthe 5’ and 3’ sites, respectively. Numerous other enzymes are necessaryto complete the error-free repair butdefects have not yet been identified inthese genes in association with humandiseases. There is marked clinical and molecularheterogeneity in XP. Patients in XP com-plementation groups A, B, D, and G mayhave neurological abnormalities in addi-tion to skin involvement. Patients withdefects in XP complementation group Dmay have one of at least 5 different clini-cal phenotypes: XP with skin disease, XPwith neurological disease, the XP/Cockayne syndrome complex {1894}, tri-chothiodystrophy (TTD - a disorder withsulphur deficient brittle hair) {1113} orXP/TTD {315}.

Treatment Management of patients with XP is basedon early diagnosis, life-long protectionfrom UV radiation exposure, and earlydetection and treatment of neoplasms{778}.


285Naevoid basal cell carcinoma (Gorlin) synrome

DefinitionThe naevoid basal cell carcinoma syn-drome (NBCCS) is a genodermatosiscaused by germline mutations of thePTCH gene. It is characterized bynumerous basal cell cancers and epider-mal cysts of skin, odontogenic kerato-cysts of jaws, palmar and plantar pits,calcified dural folds, various neoplasmsor hamartomas (ovarian fibromas, me-dulloblastoma, lymphomesenteric cysts,fetal rhabdomyomas, etc.) and variousstigmata of maldevelopment (rib and ver-tebral abnormalities, Sprengel anomaly,enlarged head circumference, cleft lipand/or palate, cortical defects of bonesand other lesions.

OMIM number 109400

SynonymsNaevoid basal cell carcinoma syndrome,Gorlin syndrome, Gorlin-Goltz syndrome,basal cell naevus syndrome.

EpidemiologyThe frequency of NBCCS has been vari-

ously estimated. It constitutes about0.4% of all cases of basal cell carcino-mas. Evans et al {698} suggested thatthe minimal prevalence was 1 per57,000.

Clinical featuresAlthough the syndrome is remarkablyvariable in sites of involvement, the mostpersistent problems are the odontogenickeratocysts and the inordinate number ofbasal cell carcinomas, only a fraction ofwhich become aggressive {867,868,1273}.

SkullThe head appears large (>60 cm inadults). Relative macrocephaly (occip-itofrontal circumference greater than 95thcentile for height) is found in 50%. Mildmandibular prognathism, noted as “pout-ing lower lip”, is seen in 35%.

Basal cell carcinomasThese may appear as early as 2 years ofage, especially on the nape, most oftenproliferate between puberty and 35

years. There appears to be a relationshipto increased sun exposure. The basalcell cancers, which vary in number froma few to literally thousands, range in sizefrom 1-10 mm in diameter. They arepearly to flesh coloured to pale brownand may be mistaken for skin tags ornaevi. The basal cell carcinomas whichmost often involve the face and upperchest may become aggressive andinvade locally. Increase in size, ulcera-tion, bleeding and crusting indicate inva-sion. Radiation therapy causes prolifera-tion of basal cell carcinomas and inva-sion several years later.

MiliaSmall keratin-filled cysts (milia) are foundintermixed with basal cell carcinomas in30-50%. Larger, often multiple, epider-mal cysts arise on the limbs and trunk inabout 35-50% of whites. Multiple cystsare located on the palpebral conjunctivain about 40%.

PitsPalmar and, somewhat less often, plantar

Naevoid basal cell carcinoma (Gorlin)syndrome

R.J. GorlinJ.C. Ehrhart

Fig. 7.8 A Multiple naevoid basal cell carcinomas scattered over neck and shoulder. B Multiple bifid ribs. C Desmoplastic medulloblastoma. The pale, reticulin-freenodules often show focal astrocytic differentiation. GFAP immunohistochemitry. From {1287}. NBCCS is typically associated with this variant.

BA C


pits (1-2 mm) are asymmetrically presentin 65-80%.

Keratocystic odontogenic tumoursCharacteristically, multiple (average-6;range 1-30) odontogenic keratocysts,now termed keratocystic odontogenictumours {153}, of both the upper andmore often lower jaws appear after theseventh year of life with an overall fre-quency of 65%. They effect marked toothdisplacement but only rarely cause frac-ture. There is marked tendency (over60%) for these cysts to recur followingsurgery.

MedulloblastomaThis embryonal neoplasm is present in 3-5% of NBCCS patients and characteristi-cally presents during the first 2 years oflife as opposed to 7-8 years in the gen-eral population {698}. Because medul-loblastoma presents early (mean 2.5years) in patients with NBCCS, childrenwho present with the tumour, especiallythose less than 5 years, should be care-

fully examined for signs of the syndrome.Radiation therapy of medulloblastomaresults in profuse numbers of invasivebasal cell carcinomas appearing in theradiation field (from nape to base ofspine).

FibromasCardiac fibromas occur in 3% {698}.Conversely, about 5% of patients withcardiac fibromas have NBCCS. Pre-sentation time has varied from birth to 60years. Most have been found incidental-ly. Ovarian fibromas are noted in 25%{698}. The ovarian fibromas associatedwith NBCCS are most often bilateral(75%).Minor kidney anomalies and hypogona-trophic hypogonadism are found inroughly 5%. Gorlin {868} reviewed exam-ples of fetal rhabdomyoma.

Imaging Lamellar calcification of the falx cerebri isfound in 55-95% (normal-5%). Calci-fication of the tentorium cerebelli hasbeen noted in 20-40%, the petroclinoidligament in 20%, and the diaphragmasellae in 60-80%. Radiographically, thisappears as if the sella turcica is bridged,i.e., as if there were fusion of the anteriorand posterior clinoid processes{1897,1898}.Odontogenic keratocysts first appear atabout 7-8 years of age and increase innumber from puberty onward. They peakduring the second and third decades.The cysts cause marked tooth displace-ment. They may invade the paranasalsinuses and, in the mandible, mayextend from the molar-ramus area to thecoronoid processes.Fused, splayed, hypoplastic or bifid ribshave been documented in 45-60%.Kyphoscoliosis with or without pectus isfound in 25-40% with spina bifida occul-ta of the cervical or thoracic vertebrae in60%. Sprengel deformity and/or unusualnarrow sloping shoulders have beendescribed in 10-40%. Other anomaliesseen in about 40% include cervical orupper thoracic vertebral fusion, hemiver-tebra, and lumbarization of the sacrum.Pectus occurs in about 15-25%{1897,1898}.Small pseudocystic bone lesions (flame-shaped lucencies) have been identifiedin the phalanges, metapodial bones,carpal and tarsal bones, long bones,pelvis and calvaria in 30%. Calvarial

Fig. 7.9 Panoramic radiograph (panorex) showingmultiple keratocystic odontogenic tumours / odon-togenic keratocysts.

50% or greater frequencyEnlarged occipitofrontal circumference

(macrocephaly, frontal-parietal bossing)Multiple basal cell carcinomasOdontogenic keratocysts of jawsEpidermal cysts of skinHigh-arched palatePalmar and/or plantar pitsRib anomalies (splayed, fused, partially

missing, bifid, etc.)Spina bifida occulta of cervical or thoracic

vertebraeCalcified falx cerebriCalcified diaphragma sellae (bridged sella,

fused clinoids)Hyperpneumatization of paranasal sinuses

49-15% frequencyBrain ventricle asymmetryCalcification of tentorium cerebelli and

petroclinoid ligamentCalcified ovarian fibromasShort fourth metacarpalsKyphoscoliosis or other vertebral anomaliesLumbarization of sacrumNarrow sloping shouldersPrognathismPectus excavatum or carinatumPseudocystic lytic lesion of bones

(hamartomas)Strabismus (exotropia)SyndactylySynophrys

14% or less but not randomMedulloblastomaTrue ocular hypertelorismMeningiomaLymphomesenteric cystsCardiac fibromasFetal rhabdomyomaOvarian fibrosarcomaMarfanoid buildAnosmiaAgenesis of corpus callosumCyst of septum pellucidumCleft lip and/or palateLow-pitched female voicePolydactyly, postaxial - hands or feetSprengel deformity of scapulaVertebral body fusionCongenital cataract, glaucoma, coloboma of

iris, retina, optic nerve, medullated retinal nerve fibers

Subcutaneous calcifications of skin (possibly underestimated frequency)

Minor kidney malformationsHypogonadism in malesMental retardation

Table 7.3Diagnostic findings in adults with naevoid basalcell carcinoma syndrome. Modified, from R.J. Gorlin {868}.

Major criteria1. More than 2 BCCs or one under age of 20 yrs2. Odontogenic keratocyst3. Three or more palmar pits4. Bilamellar calcification of falx cerebri5. Bifid, fused or splayed ribs6. First degree relative with NBCCS

Minor criteria1. Macrocephaly adjusted for height2. Frontal bossing, cleft lip/palate,

hypertelorism3. Sprengel deformity, pectus, syndactyly

of digits4. Bridging of sella turcica, hemivertebrae,

flame-shaped radiolucencies5. Ovarian fibroma6. Medulloblastoma...................................................................................Based on V.E. Kimonis et al {1273}.

Table 7.4Diagnostic criteria for NBCCS Diagnosis based on two major or one major andtwo minor criteria.

287Naevoid basal cell carcinoma (Gorlin) synrome

involvement may give the impression thatmedulloblastoma has spread to bone.Histologically, the flame-like lesions arehamartomas consisting of fibrous con-nective tissue, nerves and blood vessels.Subcutaneous calcification of fingersand scalp has been rare. Sclerotic bonelesions have been reported occasionally.Ovarian fibromas are found in about 25%of females. They are bilateral and oftencalcified, at times overlapping medially.Prenatal diagnosis by sonography hasbeen accomplished {235}.

Genetics The first link between the SONICHEDGEHOG (SHH) signalling pathwayand tumour formation in humans was in

familial cancers, as 30-40% of NBCCSpatients harbour loss-of-function muta-tions in the PATCHED1 (PTCH1) gene{514,939,1992}. That disruption of theSHH signalling pathway is a major deter-minant of tumour formation, particularlyfor BCCs, was established from the dis-covery that PTCH1 is mutated in 10-38%of sporadic BCCs {514,1992}. Inactivation of both PTCH1 alleles alsoresults in the formation of cysts {1408}.Consistent with its pivotal role in embry-onic development, aberrant SHH sig-nalling is associated with a range ofhuman developmental anomalies {2434}.In NBCCS, tumours (BCCs, keratocysts,meningiomas, ovarian fibromas, odonto-genic keratocysts) exhibit loss of het-

erozygosity (LOH) in the PTCH1 locus(9q22.3) {514}. Various physical anom-alies (bifid rib, macrocephaly, cleft lip,etc.) apparently need but one-hit {1407}.LOH in the PTCH1 locus was observed in89% of hereditary BCCs. The majority(61-71%) of germline PTCH1 mutationsare rearrangements. Most mutations(>80%) are likely to represent null muta-tions since they are predicted to result intruncation of the PTCH1 protein {133,514,1408,1992}.The PTCH1 tumour suppressor genecomprises 23 exons which encode 12putative transmembrane domains andtwo large extracellular loops. The func-tion of PTCH1 is to silence the SHH sig-nalling pathway in absence of activeSHH ligand {2308}. In presence of SHH,the pathway acts in at least two ways toregulate target genes. One is to activateGLI 1/2 transcription factors and theother is to inhibit the formation of GLIrepressors, mostly from GLI3, to dere-press target genes {1992}.

Prognosis and predictive factorsNew keratocystic odontogenic tumours(odontogenic keratocysts) and basal cellcarcinomas continue for life. Limitation ofsun exposure reduces the appearance ofthe skin cancers. The medulloblastomaappears before the age of 4 years, theovarian fibromas after puberty.Therapeutic radiation should be avoidedwhenever possible due to the highoccurrence of basal cell carcinomas inthe radiation field.

Fig. 7.10 Model of Sonic Hedgehog (SHH) signaling pathway. The function of the pathway is to stimulatecellular proliferation and inhibit apoptosis. The PTCH-1 gene is predicted to encode a 12-transmembranereceptor with high affinity for the SHH secreted 19 kDa protein ligand. In presence of SHH, the pathwayreleases the 7-transmembrane protein. Smoothened (SMO) from its inhibition by PTCH-1, thus activatingtarget genes through the glioma (GLI) family of zinc-finger transcription factors (GLI1 is the most studied ofthe three GLI factors). GLI1 may control the G1/S transition checkpoint through activation of the transcrip-tion of Cyclin D2 and E genes, and apoptosis through activation of BCL2 expression. PTCH-1 may also beinvolved in a G2/M transition checkpoint via Cyclin B1 which localizes to the nucleus upon SHH binding{152}. PTCH-1 transcription is induced by GLI1, thus generating a negative feedback loop. Abbreviations : Cyc, cyclin ; CDK, cyclin-dependent kinase.


DefinitionCowden syndrome (CS) is an autosomal-dominant disorder with age-relatedpenetrance and variable expression,characterized by multiple hamartomasarising in tissues derived from all threeembryonic germ cell layers and with ahigh risk of developing benign andmalignant neoplasms in many organ sys-tems, especially in the skin, breast, andthyroid gland. The condition wasdescribed in 1963 by Lloyd and Dennis{1439}. It is caused by germline muta-tions in the tumour suppressor genePTEN located on chromosome 10q23{1424}.

OMIM number 158350

SynonymsMultiple hamartoma syndrome, Cowdendisease

EpidemiologyIncidenceThe incidence of CS, after PTEN wasidentified as the gene, was found to be 1in 200 000 {1693}. The latter may be anunderestimate, since CS has variableexpression and often manifests itself onlywith subtle skin changes, so that thiscondition may be difficult to recognize{688}. Although the exact proportion ofisolated and familial cases is not known,previous and on-going observations sug-gest that 40-60% are familial {1521,2448,688A}.

Clinical featuresCS is classically characterized as a mul-tiple hamartoma syndrome with a highrisk of breast and thyroid cancers.Although the reported age at onsetvaries from 4–75 years {1451}, CS usual-ly manifests in the second or thirddecade. More than 90% of individualsaffected with CS are likely to manifest aphenotype by the age of 20 years, and99% develop at least mucocutaneouslesions by the age of 30 years{1694,2448}. CS is characterized by thedevelopment of hamartomas, benignand malignant tumours in multiple organsystems including the skin, soft tissues,breast, thyroid gland, gastrointestinaltract, genitourinary tract, and centralnervous system. The most commonlesions are trichilemmomas (90-100%),breast fibroadenomas (70%), thyroidadenomas (40-60%), multinodular goiter(40–60%), and multiple gastrointestinalpolyps (35–40%) {688,1451}. Macro-cephaly is seen in 35-40% of cases.Malignant neoplasms develop in thebreast in 25–50% of CS females, in thethyroid gland in 3–10% (usually follicularadenocarcinoma) and in the uterus in 3-6%. The most common malignant neo-plasm in the breast is ductal adenocarci-noma, which is bilateral in one third ofcases {2098}. The average age of CSpatients at diagnosis of breast cancer is10 years younger than in those with spo-radic disease {2252}. Male breast can-cers also occur, but with unknown fre-

quency {704,1519}. A feature that distin-guishes CS from other breast cancersusceptibility syndromes is the occur-rence of benign breast disease prior tothe development of breast cancer{2098,2099}. Many other internal malignancies havebeen reported to occur in individualsaffected with CS. There are no data tostate whether they are true componentsof this syndrome or merely coincidental.

Bannayan–Riley–Ruvalcaba syndrome(BRRS)This pediatric disorder characterized bycongenital macrocephaly, multiple lipo-matosis and angiomatosis involving theskin and visceral tissues, intestinalhamartomatous polyposis, and pigment-ed penile lesions, shows a partial clinicaloverlap with CS {711,1519}.

Diagnostic criteriaThe International Cowden Consortiumoriginally proposed a set of operationaldiagnostic criteria in 1996 {1694}.Because of new data, the Consortiumrevised the criteria in 2000 {688}, which

Cowden syndrome D. V. KazakovG. BurgC. Eng

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Fig. 7.11 Acral hyperkeratotic papules.

Fig. 7.12 Cowden disease (PTEN). A Multiple confluent papules on the upper lip. B Multiple wart-likelesions on the gingivae.

289Cowden syndrome

have also been adopted by the UnitedStates’ National Comprehensive CancerCenter (NCCN) Practice GuidelinesPanel.

Cutaneous and mucosal lesionsCutaneous lesions are the most impor-tant hallmarks for CS, since they arepresent in almost every patient and fre-quently appear prior to the developmentof any internal disease {1030}. Facialpapules are the most frequent lesions(85-90%). They are mainly located inperiorificial regions, sometimes extend-ing into the nostrils. Histopathologically,the papules frequently show non-specificverrucous acanthomas, trichilemmomas,perifollicular fibromas or may reveallesions with features intermediatebetween trichilemmomas, inverted follic-ular keratosis, and tumour of follicular

infundibulum {322,2249-2251}. Althoughhuman papilloma virus has not beenconsistently found in these lesions, someexperts believe that trichilemmomas inCS represent verrucae vulgaris withtrichilemmal differentiation {28}. Acralverrucous hyperkeratosis on the exten-sor sides of the extremities and palmo-plantar translucent keratoses are seen inapproximately 20-30% of cases. Histopathologically, they show wart-likechanges, with prominent compact ortho-keratosis, hypergranulosis, and acantho-sis, in some cases with trichilemmal dif-ferentiation. Involvement of the oralmucosa is present in over 80% of cases.Coalescent lesions produce the charac-teristic cobblestone-like pattern in 40%of patients. Histopathologically, theselesions are composed of acellular colla-gen fibres, with a predominantly whorl-

like arrangement {2251}. Mucosalpapules and nodules with trichilemmo-ma-like histopathological features arealso common. A scrotal tongue is anoth-er common finding. Usually mucocuta-neous lesions are present in multiplelocations, and extension to the orophar-ynx, larynx, tongue, and nasal mucosamay occur. Other cutaneous lesions reported tooccur in individuals affected with CSinclude lipoma, angiolipoma, multiplesclerotic fibromas, squamous cell carci-noma, melanoma, basal cell carcinoma,Merkel cell carcinoma, haemangiomas,xanthoma, vitiligo, neuroma, apocrinehidrocystoma, café au lait spots, periori-ficial and acral lentigines and acanthosisnigricans (reviewed in {748,1030})

GeneticsPTEN/MMAC1/TEP1 on 10q23.3, is thesusceptibility gene for CS {1424,1694}.

Gene structure and functionPTEN comprises 9 exons spanning 120-150 kb of genomic distance. It encodesa 1.2 kb transcript and a 403 amino acidlipid dual-specificity phosphatase (itdephosphorylates both protein and lipidsubstrates) {1419,1421,2256,2448}. Aclassic phosphatase core motif is encod-ed within exon 5, which is the largestexon, constituting 20% of the codingregion {1419,1421,1519,2256}. PTEN is the major 3-phosphatase actingin the phosphatidylinositol-3-kinase(PI3K)/Akt pathway {1478,2241}. To date,virtually all naturally occurring missensemutations tested abrogate both lipid andprotein phosphatase activity, and onemutant, G129E, affects only lipid phos-phatase activity. Overexpression of PTENresults, for the most part, in phos-phatase-dependent cell cycle arrest atG1 and/or apoptosis, depending on celltype (reviewed in {687,2448}). There isalso growing evidence that PTEN canmediate growth arrest independent of thePI3K/Akt pathway and perhaps inde-pendent of the lipid phosphatase activity{460,1564,2448,2495,2496}.

Mutation spectrumApproximately 70-85% of CS cases, asstrictly defined by the ConsortiumCriteria, have a germline PTEN mutation{1424,1519,2599}. If the diagnostic crite-ria are relaxed, then mutation frequen-cies drop to 10-50% {1464,1695,2382}. A

Pathognomonic criteriaMucocutaneous lesions

Trichilemmomas, facial Acral keratoses Papillomatous papules Mucosal lesions

Major criteria Breast carcinoma Thyroid carcinoma (nonmedullary), especially follicular thyroid carcinoma Macrocephaly (megalencephaly) (~95th percentile or more) Lhermitte-Duclos diseaseEndometrial carcinoma

Minor criteria Other thyroid lesions (eg, adenoma or multinodular goitre) Mental retardation (IQ~75 or less) Gastrointestinal hamartomas Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumours (eg, renal cell carcinoma, uterine fibroids) or malformation

Operational diagnosis in an individual1. Mucocutaneous lesions alone if there are:

(a) 6 or more facial papules, of which 3 or more are trichilemmoma, or(b) cutaneous facial papules and oral mucosal papillomatosis, or(c) oral mucosal papillomatosis and acral keratoses, or(d) 6 or more palmoplantar keratoses,

2. Two major criteria, one of which is macrocephaly or Lhermitte-Duclos disease 3. One major and three minor criteria4. Four minor criteria

Operational diagnosis in a family where one individual is diagnosed with Cowden syndrome1. The pathognomonic criterion or criteria 2. Any one major criterion with or without minor criteria 3. Two minor criteria

Table 7.5International Cowden Consortium operational criteria for the diagnosis of Cowden syndrome 2000 {688}.


formal study which ascertained 64 unre-lated CS-like cases revealed a mutationfrequency of 2% if the criteria are notmet, even if the diagnosis is made shortof one criterion {1519}. A single researchcentre study involving 37 unrelated CSfamilies, ascertained according to thestrict diagnostic criteria of the Con-sortium, revealed a mutation frequencyof 80% {1519}.As with most other tumour suppressorgenes, the mutations found in PTEN arescattered throughout all 9 exons. Theycomprise loss-of-function mutationsincluding missense, nonsense, frame-shift and splice-site mutations {1519,1521,2448}. Approximately 30-40% ofgermline PTEN mutations are found inexon 5. Further, approximately 65% of allmutations can be found in one of exons5, 7 or 8 {1519,1521}.

Although PTEN is the major susceptibilitygene for CS, one CS family, without PTENmutations, was found to have a germlinemutation in the bone morphogenic pro-tein receptor type 1A gene (BMPR1A,MIM 601299), which is one of the sus-ceptibility genes for juvenile polyposissyndrome {1066,2600}. Whether BMPR1A is a minor CS suscep-tibility gene or whether this family with CSfeatures actually has occult juvenile poly-posis is yet unknown.

Genotype-phenotype associationsClinically useful genotype–phenotypecorrelations are being intensively investi-gated. Exploratory genotype-phenotypeanalyses revealed that the presence of agermline mutation was associated with afamilial risk of developing a malignantbreast disease. Further, missense muta-

tions and/or mutations 5’ of the phos-phatase core motif seem to be associat-ed with a surrogate for disease severity(multiorgan involvement) {1519}. Previously thought to be clinically dis-tinct, BRRS is likely allelic to CS {1519}.Approximately 65% of BRRS families andisolated cases combined carry a germ-line PTEN mutation {420,1520,1521,2599}. Interestingly, there were 11 casesclassified as true CS-BRR overlap fami-lies in this cohort, and 10 of the 11 had aPTEN mutation. The overlapping muta-tion spectrum, the existence of true over-lap families and the genotype-phenotypeassociations which suggest that thepresence of germline PTEN mutation isassociated with cancer, strongly indicatethat CS and BRR are allelic and are alonga single spectrum at the molecular level.The aggregate term “PTEN hamartomatumour syndrome” (PHTS) has thereforebeen proposed {688,1521}. The clinicalspectrum of PHTS has recently beenexpanded to include also subsets ofProteus syndrome and Proteus-like (non-CS, non-BRR) syndromes {2203,2598}. Genetics of Cowden syndrome is alsoreviewed in detail in the WHO Classi-fication of the Tumours of the NervousSystem, Tumours of the DigestiveSystem, as well as in the WHO Classi-fication of Tumours of the Breast andFemale Genital Organs.

Fig. 7.13 Histopathological appearance of trichilemmoma in a patient with Cowden syndrome (Courtesy ofCarl D. Morrison, MD, Ohio State University, USA).

291Carney complex

DefinitionCarney complex (CNC) is a lentiginosis-multiple endocrine neoplasia syndromecaused by at least two distinct mutationsand characterized by multiple oftenunique tumours including myxomas andschwannomas, endocrine abnormalities,and cutaneous pigmentary lesions {397}.

OMIM numbersCNC1 160980; CNC2 605244

SynonymsNAME syndrome {111}, LAMB syndrome{1926}.

Epidemiology Carney complex is an uncommon disor-der, inherited in an autosomal dominantfashion. More than 350 cases are knowninvolving more than 65 families. The penetrance is high but the expres-sivity is highly variable. Patients maypresent with cutaneous, cardiac, orendocrine lesions; often the diagnosis isdelayed until multiple manifestations arepresent.

LocalizationThe most commonly involved organs arethe skin (75%), heart (50%) and adrenalglands (25%).

Clinical featuresThe cutaneous findings in CNC are oftenmost dramatic. Patients may have multi-ple flat pigmented lesions that have beendescribed both as ephelides (freckles)with an increased amount of melanin{111} and as lentigines with an increasednumber of melanocytes {1926}. Bluenaevi are another marker of the syn-drome; many exhibit epithelioid featureson microscopic examination {396}.Pigmented lesions are also common onmucosal surfaces, such as the lips,mouth, conjunctiva and genital mucosa{1244}. Some patients have no pigmen-tary changes. Another highly specificcutaneous finding is myxomas, especial-ly when they affect the eyelids and theexternal ear canal {734}. Histologically,these benign tumours often featurestrands of lacy epithelium {398}. The most dramatic systemic finding iscardiac myxoma(s). The CNC-associat-ed myxomas have important differencesfrom sporadic cardiac myxomas; theyare more likely to be familial, multiple,occur at a younger age, involve the ven-tricles and recur {2433}. Recurrent car-diac myxoma(s) may require multiplesurgical resections that may result inpostoperative arrhythmias and increasedmortality.

The most common endocrine finding isprimary pigmented nodular adrenal dis-ease, a very rare ACTH-independentcause of Cushing syndrome (25%){2164}. The adrenal glands show bilater-al small, pigmented nodules with intern-odular cortical atrophy {881,2571}. Oneof Cushing’s first patients, Minnie G., maywell have had CNC {395}. Acromegalyand thyroid tumours {2275} are eachseen in around 10% of patients. Aboutone-third of male patients have large-cellcalcifying Sertoli cell tumours of thetestes, often bilateral and sometimesleading to precocious puberty {1734}.Two other uncommon tumours whichshould suggest the presence of CNC arepsammomatous melanotic schwanno-mas (20%) of the GI tract, sympatheticchain and skin {394}, and myxoid mam-mary fibroadenomas (25% of women){400}.

Diagnostic proceduresBoth epithelioid blue naevi and myxomas(the latter sometimes with a characteris-tic epithelial component) may be identi-fied on skin biopsies and suggest thediagnosis of CNC. When investigation forCushing syndrome reveals low or unde-tectable ACTH levels and no adrenaltumour, a diagnosis of primary pigment-

Carney complex W.H.C. BurgdorfJ.A. Carney

Fig. 7.14 A Spotty pigmentation and blue naevus in CNC. Courtesy of Dr. David J. Atherton, London, UK, and reference {111}. B Histological specimen of blue nae-vus showing large epithelioid melanocytes. Courtesy of Dr. Luis Requena, Madrid, Spain.

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ed nodular adrenal disease should beconsidered and the patient evaluated forCNC, particularly if the patient is youngor has multiple pigmented skin spots orlumps. Echocardiography is particularlyimportant {2276}.

Differential diagnosisWhen multiple pigmented lesions arepresent, LEOPARD syndrome should beconsidered but myxomas are absent inthis condition and the systemic manifes-tations more protean. Mucosal pigmenta-tion strongly resembles that of Peutz-Jeghers syndrome, but intestinal polypsare not part of the usual spectrum ofCarney complex.

Genetics Carney complex is inherited in an auto-somal dominant fashion. The gene forCNC1, known as PRKAR1A, normallyencodes the protein kinase A regulatorysubunit R1a {408,1284}. When the mutat-

ed gene is present, the regulatory sub-unit is no longer produced. The patientsare heterozygous for the mutation: thetumours tend to have LOH of the wildtype allele for this regulatory gene. TheCNC2 gene is less well characterized butappears to be involved in regulatinggenomic stability, perhaps via the telom-eres.

Prognosis and predictive factorsThe prognosis depends on detectingcardiac myxoma, the most serious com-plex of CNC. The average age of 22patients who died as the result of cardiaccauses (cardiac failure from myxoma,cardiac myxoma emboli or cardiacarrhythmia) was 31 years. Timely diagno-sis of the neoplasms requires an aware-ness of the possible significance of thepigmented skin spots, skin tumours, pri-mary pigmented nodular adrenal dis-ease and psammomatous melanoticschwannoma. Patients with lesions sug-

gestive of CNC should be advised tohave a general medical evaluation andan echocardiogram. Primary relatives ofCNC patients should be similarlyadvised.

Fig. 7.15 A Eyelid myxoma in a young man with CNC and no cutaneous pigmentary changes. B Microscopic view of the same lesion, showing lacy epithelial strandsamidst deposits of mucin.

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0 b skin pages1-8 - iarc.fr · xeroderma pigmentosum has led to the discovery of 7 dna repair genes...

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