Familial mediterranean fever (FMF) is characterized by recurrent fever, peritonitis , synovitis and pleuritis attacks sometimes associated with pericarditis and meningitis. Symptoms and severity varies between effected patients even in the same family. Amyloidosis is the most severe and life threatening complication.FMF type 2 is characterized by amyloidosis as the first symptom.

Both types are the result of mutations in MEFV gene and inherited by autosomal recessive transmission. It is frequent in Mediterranean countries, especially in North African Jews, Armenians, Turks, Arabs, Iraqi Jews, and Ashkenazi Jews. The carrier rate for FMF has been calculated to be as high as 1:3-1:7 in these populations.

The most common FMF mutations are M694V, M680I, E148Q, V726A, M694I, R408Q, P369S, K695R, A744S, R761H, 692delI and, R653H, which altogether constitute 95% of all MEFV mutations detected in North African Jews, 90% in Turkish, Armenian and Ashkenazi Jewish populations, 80% in Iraqi Jews, and 70% in Arabs.

Among these mutations, M694V is most commonly associated with amyloidosis. Prevalence of amyloidosis depends on ethnicity, genotype and sex. Periodic attacks and amyloidosis can be treated with colchicine. FMF Patients, especially the ones that carry homozygous or compound heterozygous M694V mutation,should be started on colchicine therapyas soon as the diagnosis is confirmed.

FMF is is a clinical diagnosis. However there are other disorders with periodic attacks that mimic FMF. Therefore, mutation testing confirms the final diagnosis.Parents of index patients with confirmed mutations are obligate carriers. All siblings have %25 risk of being affected and %50 risk of being carrier. Even though the carriers are asymptomatic, it is important to detect the carrier status for correct counseling . In populations with high carrier frequency and/or with high consanguineous marriage rates, the first degree relatives of an index patient may be at risk of being affected.
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  • Beta thalassemia occurs most frequently in people from Mediterranean countries and is a inherited blood disorder caused by reduced or absent synthesis of hemoglobin. Hemoglobin is a red pigment in red blood cells that can bind with oxygen and responsible for binding oxygen in the lung and transporting the oxygen throughout the body. Low levels of hemoglobin lead to a lack of oxygen and subsequently cause shortage of red blood cells (anemia) of which the two most common symptoms are fatigue and weakness.

    Mutations in the HBB gene, which is located on chromosome 11p15.5, cause beta thalassemia. There are three forms of beta thalassemia. Thalassemia minor occurs if an individual receives a defective HBB gene from only one parent. The individuals with thalassemia minor have mild anemia that does not require any treatment. Mutations in the both copies of HBB gene result in thalassemia major or intermedia. Individuals with thalassemia intermedia have milder anemia that only rarely requires transfusion. Thalassemia major is suspected in an infant or child younger than age two years with severe microcytic anemia and hepatosplenomegaly. Untreated, affected children usually manifest failure to thrive and expansion of the bone marrow to compensate for ineffective erythropoiesis. Lack of oxygen and iron overload as a result of therapy may cause damage in the organs.

    Thalassemia major and thalassemia intermedia are inherited in an autosomal recessive pattern. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. Consanguineous marriages increase the risk of having an affected offspring and the frequency of this disease in a population. Carriers can be identified by testing relies on hematologic analysis. When the hematologic analysis indicates a β-thalassemia carrier state, molecular genetic testing of HBB can be performed to identify a disease-causing mutation(s).
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  • Bradai M, Abad MT, Pissard S, Lamraoui F, Skopinski L, de Montalembert M. Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia. Blood. 2003;102:1529–30.

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  • Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev. 2008;22 Suppl 2:S35–41.

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  • Freson K, Matthijs G, Thys C, Marien P, Hoylaerts MF, Vermylen J, Van Geet C. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum Mol Genet. 2002;11:147–52.

  • Galanello R, Agus A, Campus S, Danjou F, Giardina PJ, Grady RW. Combined Iron Chelation Therapy. NYASCI. In press

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  • Galanello R, Melis MA, Ruggeri R, Addis M, Scalas MT, Maccioni L, Furbetta M, Angius A, Tuveri T, Cao A. Beta 0 thalassemia trait in Sardinia. Hemoglobin. 1979;3:33–46.

  • Galanello R, Sanna S, Perseu L, Sollaino MC, Satta S, Lai ME, Barella S, Uda M, Usala G, Abecasis GR, Cao A. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood. 2009;114(18):3935–7.

  • Gaziev J, Lucarelli G. Stem cell transplantation for hemoglobinopathies. Curr Opin Pediatr. 2003;15:24–31.

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  • Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J, Wu D, Taylor J, Westwood MA, Anderson LJ, Pennell DJ. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009;120(20):1961–8.

  • Kolialexi A, Vrettou C, Traeger-Synodinos J, Burgemeister R, Papantoniou N, Kanavakis E, Antsaklis A, Mavrou A. Noninvasive prenatal diagnosis of beta-thalassaemia using individual fetal erythroblasts isolated from maternal blood after enrichment. Prenat Diagn. 2007;27(13):1228–32.

  • La Nasa G, Argiolu F, Giardini C, Pession A, Fagioli F, Caocci G, Vacca A, De Stefano P, Piras E, Ledda A, Piroddi A, Littera R, Nesci S, Locatelli F. Unrelated bone marrow transplantation for beta-thalassemia patients: The experience of the Italian Bone Marrow Transplant Group. Ann N Y Acad Sci. 2005;1054:186–95.

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  • Patients typically present with proximal muscle weakness, manifested as increased level of serum creatine phosphokinase (CK), difficulty getting up from the floor (arms and hands are used to walk up the thighs; Gower’s maneuver) and large calves. The mean age of diagnosis of DMD is 4 to 5 years. Affected males may also have developmental delay and toe walking.

    DMD and BMD are allelic forms of an X­linked disorder due to mutations in the DMD gene, which encodes dystrophin. DMD is the severe form and rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and cardiomyopathy being common causes of death. BMD is generally milder than DMD and characterized by later-onset skeletal muscle weakness. Dilated cardiomyopathy is the common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the beginning of the fifth decade. Two-third of mothers having affected son(s) are carrier. One-third of the cases are attributed to de novo mutations in the DMD gene.
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  • Males with Fragile X syndrome demonstrate mental retardation ranging from moderate learning difficulties to more severe intellectual disabilities. Mental retardation is always accompanied with some characteristic physical features, which include large ears, long face, soft skin and large testicles (macroorchidism) and hyper-flexible joints, and some behaviours such as social anxiety, hand-biting and/or flapping, poor eye contact. Fragile X syndrome may very rarely be diagnosed in females with mild mental retardation/intellectual disability. Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.

    Approximately 99% of all cases with Fragile X syndrome are caused by the expansion of CGG triplet repeats in the first intron of FMR1 gene loated on chromosome X. In normal individuals, the number of these CGG repeats range from 5 to 54 repeats. 55-200 repeats are considered as pre-mutation while >200 repeats, so called full-mutations, are associated with the disease. There are also cases that were reported to have somatic mosaicism which means that the different repeat numbers were observed in different tissues.

    The mothers of the affected individuals with >200 CGG repeats are carriers for pre-mutations. The frequency of the pre-mutation carrier females is about 1:260 in the population. The fathers of the carrier females may also be pre-mutation carriers. Male pre-mutation carrier frequency was reported to be 1:800.

    During oogenesis of female pre-mutation carriers, the number of CGG repeats tend to increase. Therefore, the children of such women are at risk of inheriting full-mutation alleles. The intermediate alleles with 41 to 58 CGG repeats, also termed as gary zone or borderline alleles, show slightly increased risk of being transmitted as full-mutations.

    Individuals with pre-mutation alleles do not have any risk of having intellectual disability but Fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian failure (POF).

    FXTAS is characterized by late-onset progressive cerebellar ataxia and intention tremor in persons who have an FMR1 premutation. Both males and females with a premutation are at increased risk for FXTAS but the penetrance is lower in females than in males. Other neurologic findings include short-term memory loss, executive function deficits, cognitive decline, dementia, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction. The prevalence of FXTAS is estimated at approximately 40% to 45% overall for males with premutations who are older than age 50 years.

    POF, defined as cessation of menses before age 40 years, has been observed in ~20% of female pre-mutation carriers. A significant increase of alleles in the 35 to 54 range was found in women with POF. Larger pre-mutations (>80 CGG repeats) were reported to carry lower risk for POF. Women with full mutation alleles are not at increased risk for POF.
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  • Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple anomaly syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. Deficiency of 7-DHC reductase is aassociated with the mutations in DHCR7 gene located on chromosome 11q13. SLOS is inherited in autosomal recessive manner.

    It is characterized by prenatal and postnatal growth retardation, microcephaly, moderate to severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide and individuals have been described with normal development and only minor malformations.

    Low unconjugated estriol (uE3) detected during 2nd trimester maternal serum screening may be associated with SLOS. Beside low uE3, some antenatal ultrasonographic features such as microcephaly, cleft lip-palate, polydactyly, renal and genital anomalies may be considered as risk factors for SLOS.
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    Normally, the CAG triplets are repeated less than 27 times within the gene. CAG repeats in the range 27 to 36 are not associated with HD but having risk of expansion while transmitting to the offspring. Therefore, an offspring of such an individual has 50% risk of being affected with HD. People with 36 or more CAG almost always develop the disorder.

    The expanded CAG repeat generates an elongated polyglutamine tail on the huntingtin protein, which leads to cleavage and the generation of toxic fragments of this abnormal protein. The polyglutamine composition of the toxic fragments predisposes them to cross-link, forming aggregates that resist degradation and interfere with a variety of normal cellular functions, particularly mitochondrial energy metabolism which especially leads to neuonal cell death.
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  • Myotonic Dystrophy Type 1
    Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings have been categorized into three phenotypes: mild, classic, and congenital. Mild DM1 is characterized by cataract and mild myotonia (sustained muscle contraction) and life span is normal. Classic DM1 is characterized by muscle weakness, myotonia, cataract and cardiac conduction abnormalities. adults may become physically disabled and may have a shortened life span. Congenital DM1 is characterized by hypotonia and severe generalized weakness at birth that are often accompanied with respiratory insufficiency. Intellectual disability and early death are frequently observed.

    DM1 is inherited in autosomal dominant manner and caused by the expansions of CTG trinucleotide repeats in DMPK gene located on chromosome 19q13. Normally, the CTG triplets are repeated less than 35 times within the gene. CTG repeats in the range 35 to 49 are not associated with DM1 but having risk of expansion while transmitting to the offspring. Therefore, an offspring of such an individual has 50% risk of being affected with DM1. People with 50 or more CTG almost always develop the disorder. Individuals with milder form of DM1 have alleles with approximately 50 to 150 repeats whereas classic DM1 is associated with alleles in the range from approximately 150 to 1000 repeats. Alleles with over 2000 CTG repeats always cause congenital type.

    Myotonic Dystrophy Type 2
    Myotonic dystrophy type 2 (DM2) is characterized by myotonia (90% of affected individuals) and muscle dysfunction (weakness, pain, and stiffness) (82%), and less commonly by cardiac conduction defects, iridescent posterior subcapsular cataracts, insulin insensitive type 2 diabetes mellitus, and testicular failure. Although myotonia has been reported during the first decade, onset is typically in the third decade. DM2 related-myotonia rarely causes severe symptoms.

    DM2 is inherited in autosomal dominant manner and caused by the expansions of CCTG tetranucleotide repeats within a complex repeat motif [(TG)n(TCTG)n(CCTG)n] in CNBP (ZNF9) gene located on chromosome 3q21. Normally, the lenght of this complex motif is in the range from 104 to 176 base pairs. Alleles that are 177 to 372 base pairs in lenght are considered as borderline and have risk of further expansion while transmitting to the offspring. Therefore, an offspring of an individual with a CNBP allele longer than 176 base pairs has 50% risk of being affected with DM2. People with alleles longer than 372 base pairs always develop DM2.

    CCTG repeat size increases with age. More than 25% of affected individuals have two or more CCTG expansion sizes detectable in peripheral blood (somatic mosaicism).
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  • MRX: X-linked Mental Retardation
    Mutations in ARX gene are responsbile more than 10% of MRX cases. The most common mutation is the duplication of 24 bp long DNA strech located in exon 2. This mutation accounts for approximately 40% of all ARX gene mutation-positive cases described to date.

    XLAG: X-linked Lissencephaly with Ambiguous Genitalia
    This disorder is characterized by nearly infantile epileptic encephalopathy, hypotonia, severe growth and phsycomotor retardation, ambiguous genitalia, small testis/penis, lissencephaly, hydranencephaly, agenesis of the corpus callosum, mental retardation and poor feeding in affected males. Although head measurements are normal at birth, microcephaly becomes prominent as the child grows older. Lissencephaly can be seen on an MRI as moderately thickened cerebral cortices. Total agenesis of the corpus callosum may be accompanied by the presence of mild-to-moderate ventricular dilatation and abnormal basal ganglia. In female carriers, mental retardation, epilepsy and agenesis of the corpus callosum were reported. This genetic disorder is associated with the loss-of-function mutations in ARX gene.

    Proud Syndrome
    The clinical features of this X-linked dominant disorder includes mental retardation, agenesis of the corpus callosum and ambiguous genitalia. Males are severely affected and may die within the infantile period of their life. In living male patients, microcephaly, contractures, scoliosis, hyperconvex nails, facial dysmorphism, optic atrophy, broad alveolar ridge, cryptorchidism, hypospadias, epilepsy and renal failure were reported. Although being variable, phenotypes observed in female patients are similar to male patients.

    Partington Syndrome
    Partington syndrome İs characterized by mild to moderate mental retardation and foca hand dystonia which is also known as “Partington Sign”. Mild facial dysmorphism, EEG abnormalities with seizures and lower limb spasticity/foot dystonia may be observed.

    Infantile Spasm Syndrome (West Syndrome)
    Infantile spasm syndrome is a severe form of epilepsy which is characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns. Majority of patients with infantile spasm progress to West syndrome which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. In affected males, corpus callosum hypoplasia and cerebellar atrophy may accompany ,nfantile spasm.

    XMESID: X-linked Myoclonic Epilepsy/Spasticity/Intellectual Disability
    Myocolonic epilepsy, severe growth retardation and spasticity were reported in affected males. Female carriers may develop hyperreflexia and spastic ataxia.
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  • Brooks-Kayal A. Epilepsy and autism spectrum disorders: are there common developmental mechanisms? Brain Dev. 2010 Oct;32(9):731-8.

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  • Nabbout R, Depienne C, Chipaux M, Girard B, Souville I, Trouillard O, Dulac O, Chelly J, Afenjar A, Héron D, Leguern E, Beldjord C, Bienvenu T, Bahi-Buisson N. CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy. Epilepsy Res. 2009 Nov;87(1):25-30.

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  • Kitamura K, Itou Y, Yanazawa M, Ohsawa M, Suzuki-Migishima R, Umeki Y, Hohjoh H, Yanagawa Y, Shinba T, Itoh M, Nakamura K, Goto Y. Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. Hum Mol Genet. 2009 Oct 1;18(19):3708-24.

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  • Stafstrom CE. Infantile spasms: a critical review of emerging animal models. Epilepsy Curr. 2009 May-Jun;9(3):75-81.

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  • Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, Evans J, Clarke A, Pelka GJ, Tam PP, Watson C, Lahooti H, Ellaway CJ, Bennetts B, Leonard H, Gécz J. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004 Dec;75(6):1079-93.

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  • Hemochromatosis is caused by the mutations in HFE gene located on chromosome 6p21.3 and is a disorder of iron metabolism characterized by increased iron absorption. Iron is progressively deposited in various tissues, particularly the liver, pancreas, heart, joints, and pituitary gland. Early symptoms of the disease include abdominal pain, fatigue, wight loss and letargy. When left untreated, the symptoms of hemochromatosis become apparent at age 40-60 years in affected males and in post-menapausal period in affected females. Untreated patients over 40 years of age may develop liver fibrosis or cirrhosis. Other sypmtoms, that untreated patients may demonstrate, may include increased skin pigmentation, diabetes mellitus, congestive heart failure and/or arrhythmias, arthritis and hypogonadism.

    Hemochromatosis is inherited in autosomal recessive manner. However, high carrier frequency (11%, 1/9 persons) has been reported in the general population of European origin. Therefore, hemochromatosis exhibits so- called pseudo-autosomal dominant inheritance which may mean that the risk for a sib of an individual affected with hemochromatosis can reach 50% instead of 25% regarding normal autosomal recessive inheritance.

    Vast majority of the hemochromatosis patients have one or both of C282Y and H63D mutations in HFE gene. 60-90% of the patients are homozygous for C282Y mutation while 3-8% are compound heterozygous for C282Y and H63D mutations and ~1% are homozygous for H63D mutation. The other HFE gene mutations associated with hemochromatosis, that include S65C, V53M, V59M, Q127H, R330M, I105T, G93R, Q283P, E168X and p.W169X, are very rare in the population.
  • Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P. Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators; Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352:1769–78.

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  • Crawford DH, Fletcher LM, Hubscher SG, Stuart KA, Gane E, Angus PW, Jeffrey GP, McCaughan GW, Kerlin P, Powell LW, Elias EE. Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis. Hepatology. 2004;39:1655–62.

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  • Fleming RE, Britton RS, Waheed A, Sly WS, Bacon BR. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis. 2004;8:755–73.

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  • About 5% to 10% of breast cancer cases are thought to be hereditary. About 12% of women in the general population will develop breast cancer sometime during their lives compared with about 60% women who have a mutation in BRCA1 or BRCA2 genes.Among women in the general population, 1.4% will be diagnosed with ovarian cancer compared with 15-40% of women who have BRCA1 or BRCA2 mutation. The mutations in TP53 gene encoding tumor surpressor p53 are also associated with breast cancer (<1% of all cases). Women that are diagnosed with breast cancer before the age of 30 years and negative for BRCA1 and BRCA2 gene mutation have 2%-7% risk of carrying a mutation in TP53 gene.

    In men, mutations in BRCA1 and BRCA2 genes are reported to be associated with prostate cancer. Men with BRCA2 gene mutation are also at the rish of developing breast cancer. Therefore, genetic testing for the male relatives of BRCA1/BRCA2 related breast cancer cases is appropriate.
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  • Antoniou AC, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL. et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005;42:602–603.

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  • Shattuck-Eidens D, McClure M, Simard J, Labrie F, Narod S, Couch F, Hoskins K, Weber B, Castilla L, Erdos M. et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995;273:535–41.

  • Stratton MR, Ford D, Neuhasen S, Seal S, Wooster R, Friedman LS, King MC, Egilsson V, Devilee P, McManus R. et al. Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet. 1994;7:103–7.

  • Struewing JP, Brody LC, Erdos MR, Kase RG, Giambarresi TR, Smith SA, Collins FS, Tucker MA. Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer. Am J Hum Genet. 1995;57:1–7.

  • Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R, Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP. Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 1997;57:1222–7.

  • Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 2004;95:866–71.

  • Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Da Rocha JC, Vettore AL, Hainaut P. The TP53 mutations, R337Y, is associated with Li-Fraumeni and Li-Fraumeni-like syndrome in Brazilian families. Cancer Lett. 2007;245:96–102.

  • Avigad S, Peleg D, Barel D, Benyaminy H, Ben-Baruch N, Taub E, Shohat M, Goshen Y, Cohen IJ, Yaniv I, Zalzov R. Prenatal diagnosis in Li-Fraumeni syndrome. J Pediatr Hematol Oncol. 2004;26:541–5.

  • Bachinski LL, Olufemi SE, Zhou X, Wu CC, Yip L, Shete S, Lozano G, Amos CI, Strong LC, Krahe R. Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res. 2005;65:427–31.

  • Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2258–31.

  • Birch JM, Hartley AL, Tricker K, Prosser J, Condie A, Kelsey A, Harries M, Jones P, Binchy A, Crowther D, Craft A, Eden O, Evans D, Thompson E, Mann J, Martin J, Mitchell E, Santibanez-Koref M. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298–304.

  • Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, Eden OB, Varley JM. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001;20:4621–8.

  • Bond GL, Hu W, Bone EE, Robins H, Lutzker S, Arva N, Bargonetti J. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602.

  • Bougeard G, Brugieres L, Chompret A, Gesta P, Charbonnier F, Valent A, Martin C, Raux G, Feunteun J, Bressac-de Paillerets B, Frebourg T. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene. 2003;22:840–6.

  • Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L, Chompret A, Bressac-de Paillerets B, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T. Impact of the MDM2 SNP309 and p53 arg72-to-pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet. 2006;43:531–3.

  • Bourdon JC. p53 and its isoforms in cancer. Brit J Cancer. 2007;97:277–82.

  • Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet. 2005;118:489–98.

  • Chao MM, Levine JE, Ruiz RE, Kohlmann WK, Bower MA, Petty EM, Mody RJ. Malignant triton tumor in a patient with Li-Fraumeni syndrome and a novel TP53 mutation. Pediatr Blood Cancer. 2007;49:1000–4.

  • Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, Bonaiti-Pellie C. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001;38:43–7.

  • Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, Frebourg T, Lemerle J, Bonaiti-Pellie C, Feunteun J. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82:1932–7.

  • Chompret A. The Li-Fraumeni syndrome. Biochimie. 2002;84:75–82.

  • Cohen R, Curtis R, Inskip P, Fraumeni JF. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer. 2005;103:2391–6.

  • Eeles R. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101–24.

  • Evans D, Birch J, Narod S. Is CHEK2 a cause of the Li-Fraumeni syndrome? J Med Genet. 2008;45:63–4.

  • Evans D, Birch J, Ramsden RT, Sharif S, Baser ME. Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006;43:289–94.

  • Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009a;46:689–93.

  • Gonzalez K, Noltner K, Buzin C, Gu D, Wen-Fong C, Nguyen V, Han J, Lowstuter K, Longmate J, Sommer S, Weitzel J. Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009b;27:1250–6.

  • Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998;90:606–11.

  • Hwang SJ, Cheng LS, Lozano G, Amos CI, Gu X, Strong LC. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum Genet. 2003;113:238–43.

  • Krutilkova V, Trkova M, Fleitz J, Gregor V, Novotna K, Krepelova A, Sumerauer D, Kodet R, Siruckova S, Plevova P, Bendova S, Hedvicakova P, Foreman NK, Sedlacek Z. Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. Eur J Cancer. 2005;41:1597–603.

  • Lalloo F, Varley J, Moran A, Ellis D. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer. 2006;42:1143–50.

  • Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358–62.

  • Libé R, Bertherat J. Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol. 2005;153:477–87.

  • Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer. 2001;96:238–42.

  • Lindor NM, McMaster ML, Lindor CJ, Greene MH. Li-Fraumeni syndrome. In Concise Handbook of Familial Cancer Susceptibility Syndromes – Second Edition. J Natl Cancer Inst Monogr. 2008;38:80–5.

  • Lustbader ED, Williams WR, Bondy ML, Strom S, Strong LC. Segregation analysis of cancer in families of childhood soft tissue sarcoma patients. Am J Hum Genet. 1992;51:344–56.

  • Masciari S, Van den Abbeele A, Diller L, Rastarhuyeva I, Yap J, Schneier K, Digianni L. F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed tomography screening in Li-Fraumeni syndrome. JAMA. 2008;299:1315–1319.

  • Meulmeester E, Jochemsen AG. p53: a guide to apoptosis. Curr Cancer Drug Targets. 2008;8:87–97.

  • NCCN (2008) The NCCN Clinical Practice Guidelines in Oncology™ Li-Fraumeni syndrome (Version 1.2008). © 2009 National Comprehensive Cancer Network, Inc. www.nccn.org. Accessed March 15, 2009. To view the most recent and complete version of the NCCN Guidelines, login to http://www.nccn.org.

  • Nemunaitis JM, Nemunaitis J. Potential of Advexin: a p53 gene-replacement therapy in Li-Fraumeni syndrome. Future Oncol. 2008;4:759–68.

  • Nichols KE, Malkin D, Garber JE, Fraumeni JF, Li FP. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001;10:83–7.

  • Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63:6643–50.

  • Patenaude AF, Schneider KA, Kieffer SA. et al. Acceptance of invitations for TP53 and BRCA1 predisposition testing: factors influencing potential utilization of cancer genetic testing. Psycho-oncol. 1996;5:241–50.

  • Peterson SK, Pentz RD, Marani SK, Ward PA, Blanco AM, LaRue D, Vogel K, Solomon T, Strong LC. Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome. Psychooncology. 2008;17:783–9.

  • Prochazkova K, Pavlikova K, Minarik M, Sumerauer D, Kodet R, Sedlacek Z. Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome. Am J Med Genet A. 2009;149A:206–11.

  • Rechitsky S, Verlinsky O, Chistokhina A, Sharapova T, Ozen S, Masciangelo C, Kuliev A, Verlinsky Y. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online. 2002;5:148–55.

  • Ribeiro RC, Rodriguez-Galindo C, Figueiredo BC, Mastellaro MJ, West AN, Kriwacki R, Zambetti GP. Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni like syndrome. Cancer Lett. 2007;247:353–5.

  • Ruijs MW, Broeks A, Menko F, Ausems M, Wagner A, Oldenburg R, Meijers-Heijboer H, Van’t Veer LJ, Verhoef S. The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype. Hered Cancer Clin Pract. 2009;7:4–11.

  • Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomaki K, Pruntel R, Verhoef S, van’t Veer LJ. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet. 2007;14:110–4.

  • Schneider KA, DiGianni LM, Patenaude AF, Klar N, Stopfer JE, Calzone KA, Li FP, Weber BL, Garber JE. Accuracy of cancer family histories: Comparison of two breast cancer syndromes. Genetic Testing. 2004;8:222–8.

  • Senzer N, Nemunaitis J, Nemunaitis M, Lamont J, Gore M, Gabra H, Eeles R, Sodha N, Lynch FJ, Zumstein LA, Menander KB, Sobol RE, Chada S. p53 therapy in a patient with Li-Fraumeni syndrome. Mol Cancer Ther. 2007;6:1478–82.

  • Sidransky D, Tokino T, Helzlsouer K, Zehnbauer B, Rausch G, Shelton B, Prestigiacomo L, Vogelstein B, Davidson N. Inherited p53 gene mutations in breast cancer. Cancer Res. 1992;52:2984–6.

  • Simpson J, Carson S, Cisneros P. Preimplantation genetic diagnosis (PGD) for heritable neoplasia. J Natl Cancer Inst Monographs. 2005;34:87–90.

  • Tabori U, Nanda S, Druker H, Lees J, Malkin D. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. 2007;67:1415–8.

  • Tan T, Orme L, Lynch E, Croxford M, Dow C, Dewan P, Lipton L. Biallelic PMS2 mutations and a distinctive childhood cancer syndrome. J Pediatr Hematol Oncol. 2008;30:254–7.

  • Thull DL, Vogel VG. Recognition and management of hereditary breast cancer syndromes. Oncologist. 2004;9:13–24.

  • Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaiti-Pellie C, Stoppa-Lyonnet D. 2009 Version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009;27:1–2.

  • Tomkova K, Tomka M, Zajac V. Contributation of p53, p63, and p73 to the developmental diseases and cancer. Neoplasma. 2008;55:177–81.

  • Trkova M, Prochazkova K, Krutilkova V, Sumerauer D, Sedlacek Z. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007;110:694–702.

  • Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Aaltonen LA, Blomqvist C, Aittomaki K, Nevanlinna H. p53, CHK2 and CHK1 genes in Finnish Families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001;61:5718–22.

  • Varley JM, Evans G, Birch JM. Li-Fraumeni syndrome: a molecular and cinical review. BR J Cancer. 1997;76:1–14.

  • Varley JM, McGown G, Thorncroft M, James LA, Margison GP, Forster G, Evans DG, Harris M, Kelsey AM, Birch JM. Are there low-penetrance TP53 Alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65:995–1006.

  • Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003;21:313–20.

  • Walsh T, Casadei S, Coats K, Swisher E. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295:1379–88.

  • Wang QE, Xhu Q, Wani MA, Wani G, Chen J, Wani AA. Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. DNA Repair. 2003;2:483–99.

  • Wong P, Verselis SJ, Garber JE, Schneider K, DiGianni L, Stockwell DH, Li FP, Syngal S. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology. 2006;130:73–9.

  • Wu CC, Shete S, Amos CI, Strong LC. Joint Effects of Germ-Line p53 Mutation and Sex on Cancer Risk in Li-Fraumeni Syndrome. Cancer Res. 2006;66:8287–92.

  • Yamada H, Shinmura K, Yamamura Y. et al. Identification and characterization of a novel germline p53 mutation in a patient with glioblastoma and colon cancer. Int J Cancer. 2009;125:973–6.

  • Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL) are inherited cancer syndromes characterized by autosomal dominant inheritance and early onset of tumors, multiple tumors within an individual, and multiple affected family members. The most common types of tumors are soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma.

    Classic LFS is defined by the following criteria:
    - A proband with a sarcoma diagnosed before age 45 years and
    - A first-degree relative with any cancer before age 45 years and
    - A first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age

    LFL is defined as
    - A proband with any childhood cancer, or a sarcoma, brain tumor, or adrenocortical tumor before the age of 45 years, plus
    - A first- or second-degree relative in the same lineage with a typical LFS tumor at any age, and
    - An additional first- or second-degree relative in the same lineage with any cancer before the age of 60 years

    Approximately 70% of LFS cases and 40% of LFL cases contain germline mutations in TP53 gene, which is located on chromosome 17p and codes for p53 protein. p53 is a tumor suppressor protein that regulates cell cycle and, thus, is involved in preventing cancer. Mutations in p53 geneare frequently associated with in a number of different human cancers.
  • Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Da Rocha JC, Vettore AL, Hainaut P. The TP53 mutations, R337Y, is associated with Li-Fraumeni and Li-Fraumeni-like syndrome in Brazilian families. Cancer Lett. 2007;245:96–102.

  • Avigad S, Peleg D, Barel D, Benyaminy H, Ben-Baruch N, Taub E, Shohat M, Goshen Y, Cohen IJ, Yaniv I, Zalzov R. Prenatal diagnosis in Li-Fraumeni syndrome. J Pediatr Hematol Oncol. 2004;26:541–5.

  • Bachinski LL, Olufemi SE, Zhou X, Wu CC, Yip L, Shete S, Lozano G, Amos CI, Strong LC, Krahe R. Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res. 2005;65:427–31.

  • Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2258–31.

  • Birch JM, Hartley AL, Tricker K, Prosser J, Condie A, Kelsey A, Harries M, Jones P, Binchy A, Crowther D, Craft A, Eden O, Evans D, Thompson E, Mann J, Martin J, Mitchell E, Santibanez-Koref M. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298–304.

  • Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, Eden OB, Varley JM. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001;20:4621–8.

  • Bond GL, Hu W, Bone EE, Robins H, Lutzker S, Arva N, Bargonetti J. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602.

  • Bougeard G, Brugieres L, Chompret A, Gesta P, Charbonnier F, Valent A, Martin C, Raux G, Feunteun J, Bressac-de Paillerets B, Frebourg T. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene. 2003;22:840–6.

  • Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L, Chompret A, Bressac-de Paillerets B, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T. Impact of the MDM2 SNP309 and p53 arg72-to-pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet. 2006;43:531–3.

  • Bourdon JC. p53 and its isoforms in cancer. Brit J Cancer. 2007;97:277–82.

  • Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet. 2005;118:489–98.

  • Chao MM, Levine JE, Ruiz RE, Kohlmann WK, Bower MA, Petty EM, Mody RJ. Malignant triton tumor in a patient with Li-Fraumeni syndrome and a novel TP53 mutation. Pediatr Blood Cancer. 2007;49:1000–4.

  • Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, Bonaiti-Pellie C. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001;38:43–7.

  • Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, Frebourg T, Lemerle J, Bonaiti-Pellie C, Feunteun J. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82:1932–7.

  • Chompret A. The Li-Fraumeni syndrome. Biochimie. 2002;84:75–82.

  • Cohen R, Curtis R, Inskip P, Fraumeni JF. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer. 2005;103:2391–6.

  • Eeles R. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101–24.

  • Evans D, Birch J, Narod S. Is CHEK2 a cause of the Li-Fraumeni syndrome? J Med Genet. 2008;45:63–4.

  • Evans D, Birch J, Ramsden RT, Sharif S, Baser ME. Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006;43:289–94.

  • Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009a;46:689–93.

  • Gonzalez K, Noltner K, Buzin C, Gu D, Wen-Fong C, Nguyen V, Han J, Lowstuter K, Longmate J, Sommer S, Weitzel J. Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009b;27:1250–6.

  • Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998;90:606–11.

  • Hwang SJ, Cheng LS, Lozano G, Amos CI, Gu X, Strong LC. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum Genet. 2003;113:238–43.

  • Krutilkova V, Trkova M, Fleitz J, Gregor V, Novotna K, Krepelova A, Sumerauer D, Kodet R, Siruckova S, Plevova P, Bendova S, Hedvicakova P, Foreman NK, Sedlacek Z. Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. Eur J Cancer. 2005;41:1597–603.

  • Lalloo F, Varley J, Moran A, Ellis D. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer. 2006;42:1143–50.

  • Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358–62.

  • Libé R, Bertherat J. Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol. 2005;153:477–87.

  • Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer. 2001;96:238–42.

  • Lindor NM, McMaster ML, Lindor CJ, Greene MH. Li-Fraumeni syndrome. In Concise Handbook of Familial Cancer Susceptibility Syndromes – Second Edition. J Natl Cancer Inst Monogr. 2008;38:80–5.

  • Lustbader ED, Williams WR, Bondy ML, Strom S, Strong LC. Segregation analysis of cancer in families of childhood soft tissue sarcoma patients. Am J Hum Genet. 1992;51:344–56.

  • Masciari S, Van den Abbeele A, Diller L, Rastarhuyeva I, Yap J, Schneier K, Digianni L. F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed tomography screening in Li-Fraumeni syndrome. JAMA. 2008;299:1315–1319.

  • Meulmeester E, Jochemsen AG. p53: a guide to apoptosis. Curr Cancer Drug Targets. 2008;8:87–97.

  • NCCN (2008) The NCCN Clinical Practice Guidelines in Oncology™ Li-Fraumeni syndrome (Version 1.2008). © 2009 National Comprehensive Cancer Network, Inc. www.nccn.org. Accessed March 15, 2009. To view the most recent and complete version of the NCCN Guidelines, login to http://www.nccn.org.

  • Nemunaitis JM, Nemunaitis J. Potential of Advexin: a p53 gene-replacement therapy in Li-Fraumeni syndrome. Future Oncol. 2008;4:759–68.

  • Nichols KE, Malkin D, Garber JE, Fraumeni JF, Li FP. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001;10:83–7.

  • Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63:6643–50.

  • Patenaude AF, Schneider KA, Kieffer SA. et al. Acceptance of invitations for TP53 and BRCA1 predisposition testing: factors influencing potential utilization of cancer genetic testing. Psycho-oncol. 1996;5:241–50.

  • Peterson SK, Pentz RD, Marani SK, Ward PA, Blanco AM, LaRue D, Vogel K, Solomon T, Strong LC. Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome. Psychooncology. 2008;17:783–9.

  • Prochazkova K, Pavlikova K, Minarik M, Sumerauer D, Kodet R, Sedlacek Z. Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome. Am J Med Genet A. 2009;149A:206–11.

  • Rechitsky S, Verlinsky O, Chistokhina A, Sharapova T, Ozen S, Masciangelo C, Kuliev A, Verlinsky Y. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online. 2002;5:148–55.

  • Ribeiro RC, Rodriguez-Galindo C, Figueiredo BC, Mastellaro MJ, West AN, Kriwacki R, Zambetti GP. Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni like syndrome. Cancer Lett. 2007;247:353–5.

  • Ruijs MW, Broeks A, Menko F, Ausems M, Wagner A, Oldenburg R, Meijers-Heijboer H, Van’t Veer LJ, Verhoef S. The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype. Hered Cancer Clin Pract. 2009;7:4–11.

  • Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomaki K, Pruntel R, Verhoef S, van’t Veer LJ. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet. 2007;14:110–4.

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  • Congenital adrenal hyperplasia (CAH) is related with 21-hydroxylase deficiency and charaterized with hyperplasia of adrenal glandes located on top of the kidneys. CAH is inherited in autosomal recessive manner and caused by the mutations in CYP21A2 gene located on chromosome 6p21.3. 21-hyroxylase is an enzyme involved in producing hormones cortisol and aldosterone. Cortisol maintains blood sugar levels, protects the body from stress and suppresses inflammation. Aldosterone is regulates the amount of salt retained by the kidneys. The retention of salt affects fluid levels in the body and blood pressure. When 21-hydroxylase is deficient, the adrenal glands produce excess androgens, which are male sex hormones, while levels of cortisol and aldosterone decrease. The hormonal imbalance due 21-hydroxylase deficiency may result in three different types of CAH:

    1. Simple virilizing form: Excessive prenatal production of androgens in affected females results in masculinization of the reproductive tract to a point that the sex of the newborn is not clear ("ambiguous genitalia") or appears male-like. Affected males are usually normal at birth. In both sexes, linear growth in childhood is accelerated, but the epiphyses fuse early, leading to short stature. The simple virilizing form of CAH is seen in approximately 25% of those with 21-hydroxylase deficiency.
    2. Salt wasting type: Roughly 75% patients are unable to synthesize adequate amounts of aldosterone, which is essential for sodium homeostasis. Such individuals lose large amounts of sodium in urine, which leads to potentially fatal electrolyte and water imbalance. Individuals with severe deficiency usually present with "adrenal crisis" in the first month of age; signs are often non-specific, but can include poor appetite, vomiting and failure to grow. Replacement therapy is mandatory in such patients.
    3. Non-classical form: This form of the disease is mild and usually manifest as some type of androgen excess later in life. Aldosterone deficiency is not usually observed.
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