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BLM heterozygosity and the risk of colorectal cancer. BRCA1 , a tumor suppressor gene at 17q21, is central to the maintenance of genome stability. It is a multifunction E3 ubiquitin ligase involved in DNA damage signaling, DNA repair homologous recombination repair of double-stranded DNA breaks , chromatin remodeling and transcription 1. It is not homologous to BRCA2 ; each has its own distinctive mechanisms of action. These genetic variants are relatively uncommon. Overall, BRCA1 and BRCA2 account for a small proportion of all breast cancers, a fraction that varies according to the population; most studies have been limited to early-onset cancer.
Among Australian women diagnosed with breast cancer before age 40 years, 3. Estimates of BRCA1 carrier frequencies have ranged from 0. Methods aimed at clarifying the cancer risks associated with sequence variants of unknown clinical significance are being developed Note, however, that in African American women diagnosed under age 35 years, BRCA1 mutations were particularly common This class of genetic lesion is missed by conventional sequencing technologies; the commercial BRCA testing algorithm was modified initially in and revised a second time in to include detection of some of these mutations.
BRCA -negative subjects who were tested before these modifications may benefit from additional testing. Larger numbers of early-onset breast cancer particularly, if bilateral and the presence of ovarian cancer increase the likelihood of finding a BRCA1 mutation. Genetic testing is required to confirm that an individual carries a BRCA mutation. A validation study comparing seven different models suggested that BRCAPRO had the best performance statistic, although all models were adequate for clinical use In small families, these models are less useful The US Preventive Services Task Force has published a systematic evidence review 34 , and there are formal recommendations for selecting individuals in whom genetic evaluation is warranted 35, Breast and ovarian cancer are the defining features of this syndrome.
Ductal carcinoma in situ is part of the spectrum of breast neoplasia in BRCA mutation carriers though mutations were somewhat less frequent than in comparable families with invasive cancer 37, Estimates of cancer penetrance by age vary considerably. In the US population, Chen et al. The risk of BRCA -related breast and ovarian cancer appears to be confined to epithelial malignancies of both organs. Recent data indicate that the dearth of estrogen receptors in BRCA1 -related breast cancer is a direct result of the mutation itself; BRCA1 regulates the expression of estrogen receptors Whereas the clinical features of BRCA2 -related breast cancer are indistinguishable from those of sporadic breast cancer, these two entities do appear to have distinctive molecular characteristics by mRNA expression profiles.
In general, the clinical differences between BRCA1 - and BRCA2 -related breast cancers are associated with differences in prognosis, such that the former but not the latter have a worse prognosis than their sporadic counterparts 45—47 , although outcome has been reported to be similar between these two breast cancer subgroups by some investigators The primary difference between BRCA -related ovarian cancer and sporadic ovarian cancer is the rarity of mucinous and borderline neoplasms in the former.
Although hereditary ovarian cancers tend to be of higher stage and grade than their sporadic counterparts, their clinical prognosis seems to be better 49, Fallopian tube carcinoma is now a well-established component of the BRCA -related cancer spectrum, with relative risks RRs as high as reported Carriers of BRCA1 mutations are at risk of primary papillary serous carcinoma of the peritoneum, a malignancy that is indistinguishable from serous epithelial ovarian carcinoma. The cumulative risk has been reported as 3.
Candidate morphological tubal intraepithelial carcinoma and molecular p53 overexpression colocalized with g-H2AX, a marker of DNA damage precursor lesions have been described in the tubal fimbriae, providing novel targets for early detection and prevention research It has been suggested that this risk of prostate cancer may vary substantially, depending on the location of the BRCA1 mutation A variety of other cancers have been inconsistently implicated as part of the BRCA1 cancer susceptibility syndromes The most convincing associations are increased risks of pancreatic cancer 60 and male breast cancer 61, The latter investigators report that the cumulative breast cancer risks to age 70 among male mutation carriers are 1.
Initial reports of increased colorectal cancer risk have generally not been replicated. The Breast Cancer Linkage Consortium reported statistically significantly elevated relative risks for cancers of the pancreas, uterine body, cervix, and prostate only in carriers younger than age 65 , with RRs of 2. The possibility that endometrial cancer might be a BRCA-related malignancy has been plausibly explained as related to tamoxifen exposure Cancer risks in BRCA1 mutation carriers have recently been reviewed Male mutation carriers are recommended to learn and perform BSE monthly ; undergo twice-yearly clinical breast examination; and consider baseline mammogram, with annual repeat in the presence of gynecomastia or glandular breast density on the baseline examination.
All patients should be advised regarding the genetic risk to relatives, urged to alert family members to the potential value of genetic risk assessment, and be educated regarding the signs and symptoms of BRCA-related cancers adapted from National Comprehensive Cancer Network The management of hereditary breast cancer has been reviewed In general, the data are inconsistent from study to study.
However, analyses from a large international cohort of mutation carriers have suggested that early age at first birth does not confer the same reduction in breast cancer risk among mutation carriers as that seen in the general population 69 , whereas parity associated with reduced ovarian cancer risk in the general population may be associated with an increased risk of hereditary ovarian cancer MRI of the breasts is substantially more sensitive as a breast cancer screening tool in young, high-risk women than mammography, ultrasound, or clinical breast examination, while maintaining high specificity as well There remains no proven benefit to any ovarian cancer screening strategy in either low- or high-risk women, and the very high false-positive rate inherent in standard screening techniques incurs substantial morbidity and economic cost.
However, a single study of women at high risk of hereditary ovarian cancer reported that both the absolute value and the serial change in CA tumor marker levels were statistically correlated with ovarian cancer, although the absolute differences in CA appeared to be quite small and of uncertain clinical utility 74 ; preliminary results using a panel of 6 biomarkers suggests that a more sensitive clinical tool will be available in the future Tamoxifen represents the first chemopreventive agent that might reduce the risk of breast cancer in BRCA mutation carriers.
The value of chemoprevention as an alternative to risk-reducing mastectomy is unclear, although a gonadotropin-releasing hormone agonist—based regimen has been shown to significantly reduce mammographic density a widely accepted breast cancer risk factor in BRCA1 mutation carriers This protective effect was observed in BRCA1 as well as BRCA2 carriers despite the predilection of the former to develop hormone receptor—negative breast cancer. As yet, there is no experience using raloxifene as a chemoprevention option in BRCA mutation carriers.
Although preliminary evidence suggested that this effect can be achieved without increasing the risk of breast cancer 78 , a subsequent analysis has demonstrated some increased risk of breast cancer in both BRCA1 and BRCA2 mutation carriers related to duration of oral contraceptive use, especially before the first full-term pregnancy This procedure must include removal of the fallopian tubes, given their increased cancer risk in this setting Preliminary evidence suggests that bilateral oophorectomy may improve both overall survival and cancer-specific survival among BRCA mutation carriers A report from the United Kingdom raised the disturbing possibility that mutation-negative women from BRCA mutation-positive families could be as much as five times more likely to develop breast cancer than women from the general population If correct, this observation raises major concerns regarding how to counsel women from high-risk families who are true negatives on genetic testing.
Of note, the methodologically most appropriate subset in this study, that is, mutation-negative women who had not developed breast cancer before study entry, and who were then followed prospectively for breast cancer development, showed only a twofold increase in breast cancer risk, which was not statistically significant. The data related to this important question have been reviewed The authors suggest that these women may, in fact, have a twofold increase in breast cancer risk and propose that being a mutation-negative member of a mutation-positive family may not exempt women from the usual risks associated with a positive family history of breast cancer.
However, the data to support a modification of breast cancer screening guidelines for such patients are not yet in hand. There is evidence that these women tend to overutilize both breast and ovarian screening procedures despite their mutation-negative status Kauff et al. The standardized incidence ratio of ovarian cancer in the proband was not increased relative to the Surveillance, Epidemiology, and End Results population, suggesting that women from such families are not at increased risk of ovarian cancer.
Further validation of this important observation is awaited. Boulton SJ. Cellular functions of the BRCA tumor-suppressor proteins. Biochem Soc Trans. Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell. Am J Hum Genetics. Breast Cancer Res Treat. Anglican Breast Cancer Study Group. BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer.
A genome-wide linkage search for breast cancer susceptibility genes. Ann Oncol. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. A preliminary validation of a family history assessment form to select women at risk of breast or ovarian for referral to a genetics center. Clin Genet. Breast Cancer Res. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.
Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Genetic testing for cancer susceptibility. BRCA mutations in women with ductal carcinoma in situ. Clin Cancer Res.
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history—a combined analysis of 22 studies. Chen S, Parmigiani G. The molecular pathology of hereditary breast cancer—genetic testing and therapeutic implications. Mol Pathol. Molecular basis for estrogen receptor a deficiency in BRCA1 -linked breast cancer.
Distant disease-free interval, site of first relapse and post-relapse survival in BRCA1 - and BRCA2 -associated compared with sporadic breast cancer patients [published online ahead of print October 19, ]. Surveillance for familial breast cancer: differences in outcome according to BRCA mutation status. Perspectives in pathology—hereditary ovarian cancer. Hum Pathol. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome.
Gynecol Oncol. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. Primary fallopian tube malignancies in BRCA -positive women undergoing surgery for ovarian cancer risk reduction. Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic. A twofold increase in BRCA -mutation-related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. BRCA1 mutations and prostate cancer risk in Poland. Eur J Cancer Prev.
Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. BRCA1 and pancreatic cancer—pedigree findings and their causal relationships. Cancer Genet Cytogenet. Male breast cancer. Thompson D, Easton DF. The breast cancer linkage consortium. Cancer incidence in BRCA1 mutation carriers.
Levy-Lahad E, Friedman E. J Natl Compr Canc Netw. Robson ME, Offit K. Management of an inherited predisposition to breast cancer. Narod SA. Modifiers of risk of hereditary breast cancer. A systematic review of the effectiveness of magnetic resonance imaging MRI as an addition to mammography and ultrasound in screening young women at high risk of breast cancer. Eur J Cancer. CA Cancer J Clin. Serum CA in relation to adnexal dysplasia and cancer in women at hereditary high risk of ovarian cancer.
Diagnostic markers for early detection of ovarian cancer. Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and non-carriers of BRCA1 mutations. Am J Epidemiol. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. Low prevalence of pre-malignant lesions in the breast and high prevalence in the ovary and fallopian tube in women at hereditary high risk of breast and ovarian cancer. SGO Committee Statement. Society of Gynecologic Oncologists Clinical Practice Committee statement on prophylactic salpingo-oophorectomy.
Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. BRCA2 , a tumor suppressor gene at 13q It is not genetically related to BRCA1 ; each has its own distinctive mechanisms of action. The central portion of the BRCA2 gene has been designated the Ovarian Cancer Cluster Region nucleotides — because mutations located here eg, the Ashkenazi founder mutation delT are twice as likely to be associated with ovarian cancer as are mutations at the 59 or 39 ends of the gene 2. The risk of breast cancer associated with mutations in this region is lower.
See BRCA1 chapter for additional details. Estimates of BRCA2 carrier frequencies include 0. Suspected on the basis of premenopausal breast cancer or a pedigree showing a constellation of BRCA2 -associated cancers with possible dominant inheritance. The presence of male breast cancer or pancreatic cancer may be a clue pointing toward the involvement of BRCA2.
Ovarian cancer is observed less frequently than in BRCA1 carriers. In small families, these models are less useful. Adenocarcinoma of the female breast generally estrogen receptor positive, moderately differentiated is the hallmark of BRCA2 -related cancer. The risk of a contralateral breast cancer by age 70 was The risk of ovarian cancer, although lower than that observed in BRCA1 mutation carriers, is still greatly increased compared with the rates in the general population.
Fallopian tube carcinoma has also been associated with BRCA2 mutations 16 , as has primary papillary serous carcinoma of the peritoneum, a malignancy that is indistinguishable from serous epithelial ovarian carcinoma; like ovarian cancer, this malignancy occurs less frequently among BRCA2 than BRCA1 carriers The latter is the lowest ovarian cancer penetrance estimate yet reported.
The presence of pancreatic cancer in a breast cancer family may be a statistically significant predictor of a BRCA2 mutation 20 , although BRCA1 carriers also have an increased risk. The latter three sites are inconsistently associated with BRCA2 22 , and initial reports of increased colorectal cancer risk have generally not been replicated.
Cancer risks in BRCA2 mutation carriers have recently been reviewed It is suggested that male mutation carriers learn and perform BSE monthly , undergo twice-yearly clinical breast examination, and consider baseline mammogram, with annual repeat in the presence of gynecomastia or glandular breast density on the baseline examination. All patients should be advised regarding the genetic risk to relatives, urged to alert family members to the potential value of genetic risk assessment, and be educated regarding the signs and symptoms of BRCA-related cancers [adapted from National Comprehensive Cancer Network 24 ].
The fact that BRCA2 carriers are substantially less common in most research studies has resulted in the evidence regarding the effectiveness of various intervention strategies eg, oral contraceptives, tubal ligation, tamoxifen, etc being substantially weaker than that for BRCA1. Affected individuals have extreme sensitivity to chemotherapy and therapeutic irradiation; full-dose treatment can be lethal. FANC-D1 patients have very high rates of spontaneous chromosomal instability and are at risk of Wilms tumor and medulloblastoma as well as the more typical acute leukemia [ 26 ; reviewed by 27,28].
Monoallelic truncating mutations in PALB2 appear to function as a low-penetrance breast cancer susceptibility allele, conferring a 2. There is strong evidence to suggest substantial increases in BRCA2 -related breast cancer penetrance over calendar time. This, and similar observations in BRCA1 carriers 32 , suggests that important environmental or lifestyle factors influence the underlying genetic predisposition to cancer.
Cancer variation with the position of the mutation in the BRCA2 gene. Fam Cancer. Invited editorial. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.
BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. A genetic epidemiology study of carcinoma of the fallopian tube. Familial pancreatic cancer—where are we in ? Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour.
Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers — Younger birth cohort correlates with higher breast and ovarian cancer risk in European BRCA1 mutation carriers. Kirschner et al. Large deletions were recently reported. Stratakis et al. Diagnostic criteria for Carney complex 2 a. Testicular tumors occur in one-third of boys with CNC and nearly all adult males. In one series of 53 affected patients from 12 CNC families, two patients had thyroid carcinomas one papillary and one follicular , one had colorectal carcinoma, and one had pancreatic cancer 3.
Additional patients with CNC and pancreatic cancer have been identified since that report, so a syndrome-related predisposition to this malignancy now seems more likely. The pigmented lesions may be present at birth and typically increase in number around puberty. Spotty cutaneous pigmentation is common, especially involving the face, eyelids, vermillion border of lips, conjunctiva, sclera, vulva, glans penis, back of hands, and feet.
Buccal mucosa is uncommonly involved, unlike the pigmentation seen in Peutz—Jeghers syndrome. In CNC, the pigmented lesions include tiny black—brown macules, cafe-au-lait macules, blue nevi, and other pigmented lesions. In some individuals, pigmented lesions have been observed to fade with age. Myxoid uterine leiomyomas also occur. Prolactin may be secreted, but isolated prolactinomas are not reported 6. Breast duct adenomas, breast myxomas, and osteochondromyxomas of bone also occur.
Carney complex has been recently reviewed 7. For children with CNC, the following have been recommended: 1 echocardiography during the first 6 months of life and annually thereafter and 2 monitoring for aromatase excess resulting in increased estrogen levels among children with testicular calcification or known LCCSCT. For individuals with CNC after puberty, the following have been recommended: 1 annual echocardiogram; 2 annual determination of urinary free cortisol or overnight 1 mg dexamethasone suppression test; 3 annual measurement of plasma IGF-1; 4 baseline thyroid ultrasound, with repeat as needed this may be of less value in older individuals ; 5 baseline testicular ultrasound minute calcifications may be followed annually ; 6 ovarian ultrasound at baseline, with repeat not indicated unless abnormality detected, as risk of malignancy is judged to be low.
Additional biochemical studies and imaging studies may be needed to adequately evaluate adrenal and pituitary function and as an aid in establishing the diagnosis in the first place. The risks and benefits of screening in this disorder are unknown. It has been suggested recently that male infertility should be considered a component of CNC 8. Aidan Carney is also known for the identification of a clinical triad called Carney triad, which is unrelated to Carney complex.
It is characterized by gastrointestinal stromal tumor, functioning extra-adrenal paraganglioma, and pulmonary chondroma. Any two of these three findings are considered sufficient for diagnosis. No gene has yet been implicated in its etiology. In a series of 79 patients with Carney triad, only two had relatives with features of the triad.
These two had only paraganglioma and gastointestinal stromal tumors GIST. Mutations disrupting a phosphodiesterase gene called PDE11A were found in individuals with adrenal cortical hyperplasia and Cushing syndrome, as well as PPNAD; population studies suggest this is a low-penetrance predisposition gene. Mutations in PDE11 have not been associated with Carney complex Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas Carney Complex.
The lentiginoses: cutaneous markers of systemic disease and window to new aspects of tumorigenesis. Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity.
Mayo Clin Proc. Pituitary pathology in Carney complex patients. Carney complex—the first 20 years. Curr Opin Oncol. Male infertility as a component of Carney complex. Familial paraganglioma and gastric stromal sarcoma. Genetics of Carney triad—recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Stepanek et al.
Using the extended pedigree of this family, Kelley et al. This observation has been confirmed by Yang et al. Interphase fluorescent in situ hybridization studies have suggested that an as-yet-unidentified gene on chromosome 6p12 may be responsible for some instances of familial chordoma 4. Overall age-adjusted incidence of all chordomas is 0. Incidence of inherited disease is unknown.
Diagnosis is based on family and medical history. In the initial family, several clinically normal individuals in their 60s had lesions detected by magnetic resonance imaging MRI. Tumors may become symptomatic in the second decade of life or much later. Chordomas are very difficult to diagnose because they grow slowly and may present ambiguous symptoms eg, headaches and facial pain, dysphagia, extremity weakness, bowel or bladder symptoms as well as localizing symptoms [eg, diplopia, painful sacral mass, altered sacral sensation 6 ].
Because it arises from notochordal remnants, chordoma is found almost exclusively along the axial skeleton. Juliao et al. Rich et al. Chordomas; recently two cases with pilocytic astrocytoma one patient in each of two families have been presented at scientific meetings, suggesting that this rare tumor may be part of the familial chordoma syndrome. None has been defined.
Based on the reported family, we suggest that MRI of the entire craniospinal axis be performed at the time the familial aggregation is identified. A baseline examination is advised in childhood, with the frequency of repeated examinations uncertain perhaps every 3—5 years in asymptomatic individuals. Chordoma, presenting in infancy, is also part of the tuberous sclerosis complex see Tuberous Sclerosis chapter. Familial chordoma with probable autosomal dominant inheritance. Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q Corroboration of a familial chordoma locus on chromosome 7q and evidence of genetic heterogeneity using single nucleotide polymorphisms SNPs.
New candidate chromosomal regions for chordoma development. Surg Neurol. Chordoma: incidence and survival patterns in the United States, — Cancer Causes Control. Soo MY. Chordoma: review of clinicoradiological features and factors affecting survival. Australas Radiol. Galectin a biologic marker and diagnostic aid for chordoma.
Clin Orthop Relat Res. Clinical and pathologic review of 48 cases of chordoma. MLH1 at 3p The products of these genes participate in a multimeric DNA mismatch repair complex. In the largest population study in the United States, Hampel et al. Genetic modifiers of cancer risk in Lynch syndrome have been described. In the past, diagnosis was based on pedigree assessment. The Amsterdam I criteria AC-I were developed in to assist in defining a subset of families for research purposes 8.
Conversely, up to half the families that do fulfill the AC-I criteria do not have a detectable DNA mismatch repair defect and therefore do not have Lynch syndrome. Such families have been called familial CRC type X 9. AC-I criteria require all four of the following: 1 three or more cases of CRC, in which two of the affected individuals are first-degree relatives of the third; 2 CRCs occurring in two generations; 3 one CRC diagnosed before the age of 50 years; and 4 exclusion of familial adenomatous polyposis FAP.
The Bethesda Guidelines [updated Umar et al. Patients meeting the Bethesda Guidelines were to be offered tumor testing for microsatellite instability MSI. The likelihood of detecting a germline mutation in MLH1 or MSH2 is low if the colorectal tumor does not have this tumor phenotype. Several mathematical models have now been published that predict the likelihood of carrying a mismatch repair gene mutation 11— In addition, a pathology-based model also demonstrated the usefulness of the histological features of MSI for selection of cases for further evaluation for possible Lynch syndrome The presence of an MSI-high phenotype can be suggested by the histological appearance of the CRCs in Lynch syndrome eg, poorly differentiated, presence of tumor-infiltrating lymphocytes, mucinous histology.
Most colorectal tumors due to hereditary mismatch repair deficiency show a high level of MSI. However, this tumor phenotype is not specific for germline mutations in the DNA mismatch repair genes because age-related methylation of MLH1 also leads to the MSI-high phenotype; in unselected series of CRC patients, the latter accounted for the majority of MSI-high tumors. Loss of MSH2 expression has high specificity for presence of a germline mutation in that gene, but loss of MLH1 is far less specific.
Muller et al. CRC, two-thirds of which are located in the right side of the colon, with average age at diagnosis in the mid 40s, is the hallmark of Lynch syndrome. The risk of colon cancer appears to be greater in carriers of MLH1 vs other MMR genes, but the overall risk of all cancers combined may be greatest with MSH2 mutations. Aarnio et al. Mean ages at diagnosis of gastric cancer and ovarian cancer are 56 and A trend toward increased risk of pancreatic cancer has been noted in some but not all studies.
Small bowel carcinoma is also a syndrome-related malignancy, having been reported in mutation carriers of each of the four susceptibility genes Small bowel cancer—associated MSH2 mutations clustered in codons — Describing the phenotype of germline PMS2 carriers has been hampered by its rarity and technical issues involving a pseudogene.
Recently, Senter et al. Mean ages at CRC diagnosis were 61 and 64 years for male and female carriers, respectively, in population-based registries, compared with 47 and 63 years in clinic-based registries. Sebaceous neoplasms of the skin are a feature in a subset of Lynch syndrome families. Benign or malignant carcinomas sebaceous skin tumors in combination with Lynch syndrome—related internal cancer have been called Muir—Torre syndrome; linkage and mutational analysis of MSH2 most common , MLH1 , and MSH6 have proven that Muir—Torre syndrome is a variant of Lynch syndrome.
Glioblastoma is also associated with Lynch syndrome. Brain tumor in combination with colorectal carcinoma is also called Turcot syndrome. Patients with Familial Adenomatous Polyposis have an increased risk of medulloblastoma, and this, confusingly, has also been called Turcot syndrome. Colonic adenomas, keratoacanthomas, sebaceous adenomas, Fordyce granules intraoral ectopic sebaceous glands , and epitheliomas. Consensus recommendations from experts 28—31 advise colonoscopy with removal of polyps every 1—2 years, beginning between ages 20—25, or 10 years before the earliest age of CRC diagnosis in the family, whichever is younger.
Periodic removal of polyps reduces the incidence of CRC in individuals with Lynch syndrome Prophylactic surgery has not been routinely recommended for individuals at risk of CRC because colonoscopy is an effective preventive measure. Patient preferences and likely compliance with medical recommendations are very important in decisions regarding the choice of prophylactic surgery vs screening.
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The nonsteroidal anti-inflammatory drug celecoxib has been shown to reduce the prevalence of adenomatous polyps in FAP and in patients who have undergone a prior polypectomy in the absence of cancer Small pilot studies have suggested that celecoxib 34 may reduce polyp prevalence in HNPCC, whereas sulindac does not Its use does not replace colonoscopic screening.
Both direct visualization of the endometrium and endometrial biopsy seemed superior to transvaginal ultrasound in these nonrandomized studies. Oral contraceptives are associated with substantial reductions in the risk of both endometrial and ovarian cancer risks in the general population, but this has not been demonstrated in Lynch syndrome. New evidence from a retrospective study of women documents that prophylactic removal of uterus and ovaries after childbearing is completed essentially eliminated the risk of cancer in these organs during the 10 years of follow-up and therefore is a reasonable option for women with Lynch syndrome to consider The value of screening for ovarian cancer in Lynch syndrome has not been proven.
Upper gastrointestinal endoscopy could be used to screen for gastric and ampullary neoplasms and has been advised by some experts, although one study reported no benefit because of the lack of precursor lesions Annual urinalysis and cytology for screening to detect cancer of the renal pelvis is inexpensive, noninvasive, and therefore generally advised, but evidence of efficacy is lacking. Presently, no specific screening for cancers of the pancreas, hepatobiliary tract, or brain is recommended. Small bowel carcinoma has been diagnosed in this setting with capsule endoscopy A careful examination of the skin should be included in the annual examination.
Reviews of Lynch syndrome and suggested management have recently been published 41,42,30, Peltomaki P, Vasen H. Dis Markers. Screening for the Lynch syndrome hereditary nonpolyposis colorectal cancer. A new variant database for mismatch repair genes associated with Lynch syndrome. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. Screening for Lynch syndrome hereditary nonpolyposis colorectal cancer among endometrial cancer patients.
IGF1 gene polymorphism and risk of hereditary nonpolyposis colorectal cancer. ArgGln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age-of-onset of hereditary non-polyposis colorectal cancer: a case-control study. Dis Colon Rect. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer Lynch syndrome and microsatellite instability.
J Nat Cancer Inst. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Eng J Med. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors.
Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study. In J Colorectal Dis.
Chapter The Esophagus | Concise Pathology, 3e | AccessPhysiotherapy | McGraw-Hill Medical
Cancer risk in mutation carriers of DNA-mismatch-repair genes. Germline mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer—International Society for Gastrointestinal Hereditary Tumors Collaborative Study. Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome. Familial endometrial cancer in female carriers of MSH6 germline mutations. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant.
Am J of Hum Genet. Risk of cancer in MSH6 mutation carriers: an international collaboration [abstract]. In press. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. Hereditary nonpolyposis colon cancer.
National Comprehensive Cancer Network. Colorectal cancer screening: clinical practice guidelines in oncology. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. Controlled year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Celecoxib for the prevention of colorectal adenomatous polyps.
Clinical management of adenomatous polyposis in patients with hereditary non-polyposis colorectal cancer and familial adenomatous polyposis [in Chinese]. Zhonghua Yi Xue Za Zhi. Sulindac treatment in hereditary non-polyposis colorectal cancer. Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome.
Prophylactic surgery to reduce the risk of gynecologic cancers in Lynch syndrome. No support for endoscopic cancer risk management for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol. Small bowel adenocarcinoma diagnosed via capsule endoscopy in a patient found to have hereditary nonpolyposis colorectal cancer. Gastrointest Endosc. Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, cancer risk management and management implications.
Diagnostic approach and management of Lynch syndrome hereditary nonpolyposis colorectal carcinoma : a guide for clinicians. Constitutive deficiency in DNA mismatch repair. HRAS at 11p The relationship between these complex disorders has recently been reviewed 3. In nine informative families, de novo mutations were inherited from the father in all cases, which were also associated with advanced paternal age 7. Prior studies have suggested a predominance of paternal origin of point mutations in numerous autosomal dominant disorders, presumably due to greater opportunity for mitotic errors in spermatogonia.
The prenatal phenotype includes overgrowth, edema, and polyhydramnios. Postnatal features include mild-to-severe developmental delay, feeding difficulty often requiring feeding tubes, failure to thrive, hypotonia, hoarse voice, macrocephaly, coarse facies, prominent forehead, epicanthal folds, nystagmus, downslanting palpebral fissures, short nose with depressed nasal bridge, thick lips, low-set ears with thick helices, curly, sparse hair, soft loose skin, hyperkeratotic palms and soles with deep creases, and hyperpigmentation.
Cardiac findings may include structural defects especially pulmonic stenosis , hypertrophic cardiomyopathy, and conduction abnormalities. Musculoskeletal findings may include incomplete range of motion at the elbow, tight heel cords, ulnar deviation of the hands, small joint laxity, and broad distal phalanges. Warts in unusual locations are one of the defining features of the syndrome 8. Hennekam 9 reviewed all described cases through Costello syndrome has been recently reviewed Elevated catecholamine metabolites in serum and urine have been reported in a number of Costello patients in whom no tumor could be identified.
Thus, caution is needed in interpretation of catecholamine tests in this population Seventeen percent of known patients with Costello syndrome have had solid tumors Transitional cell carcinomas of the bladder are also reported in childhood often before puberty and are now accepted as part of the tumor predisposition spectrum. Among two adults with Costello syndrome, both had bladder tumors. No other cancers have been reported in affected adults Neuroblastoma, hepatoblastoma, ganglioneuroblastoma, and vestibular schwannoma have also been reported.
There is a mutational hotspot in HRAS involving codons 12 and 13 6. Papillomata develop throughout childhood in the perioral and perianal areas. Benign bladder tumors and multiple intraductal papillomas of the breast have been reported. The issues related to cancer surveillance in this rare syndrome have been reviewed Screening the abdomen and pelvis with ultrasound for rhabdomyosarcoma and abdominal neuroblastoma is suggested every 3—6 months from infancy until age 8—10 years; urine catecholamine metabolite analysis is indicated only if clinical symptoms or imaging studies suggest possible neuroblastoma because current evidence suggests a very high rate of false-positive tests in Costello syndrome.
Annual urinalysis to screen for bladder carcinoma after age 8 years is suggested, with aggressive follow-up of any abnormal finding. Urine fluorescent in situ hybridization for aneuploidy detection in exfoliated urothelial cells may also be considered for screening for urinary tract tumors. The efficacy of these screening strategies is unknown. Molecular and clinical characterization of cardio-facio-cutaneous CFC syndrome: overlapping clinical manifestations with Costello syndrome. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.
HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Denayer E, Legius E. What's new in the neuro-cardio-facial-cutaneous syndromes? Eur J Pediatr. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.
Diversity, parental germline origin and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hennekam RCM. Costello syndrome: an overview. Elevated catecholamine metabolites in patients with Costello syndrome. Gripp KW. Tumor predisposition in Costello syndrome. DeBaun MR. Screening for cancer in children with Costello syndrome.
Haplotype analysis suggests that mutation-negative patients may harbor deleterious PTEN mutations that are not detected by standard genetic testing methods 4. Nelen et al. CS is probably most often recognized clinically on the basis of skin lesions and intestinal hamartomas 7. Diagnostic criteria for Cowden syndrome 6 a. Operational diagnostic criteria are reviewed and revised on a continuous basis as new clinical and genetic information becomes available. Male breast cancer also can occur. Follicular histology predominates, but papillary carcinomas have been reported.
A much longer list of cancers has been reported in the context of CS, but the rarity of CS makes it difficult to prove that specific risks are different from those in the general population. The list includes glioblastoma, melanoma, Merkel cell cancer, lung cancer, retinal glioma, liposarcoma, and cancers of the colorectum, liver, pancreas, ovary, and bladder Single case reports also note ependymoma, medullary thyroid cancer, granulosa cell tumor of the ovary, and lipoblastoma 11— Verrucous skin lesions of the face and limbs and cobblestone-like hyperkeratotic papules of the gingiva and buccal mucosa.
In a series of patients with clinical diagnosis of CS, examination of more than half of biopsied skin lesions revealed facial trichilemmomas; all oral mucosal lesions were fibromas, and all hand and foot lesions were hyperkeratoses Sixty percent of affected individuals had hamartomatous polyps of the stomach, small bowel, and colon. The polyps resemble those found in juvenile polyposis but are dissimilar from those observed in Peutz—Jegher syndrome. Sweet et al.
Lipomas, cerebellar gangliocytomatosis, hemangiomas, and multiple early-onset uterine leiomyomas are common in CS. An intradural ganglioneuroma, inverted follicular keratosis, a pulmonary sclerosing hemangioma, multiple vertebral hemangiomas, and eccrine angiomatous hamartoma have each recently been reported. Tan et al. Cerebral developmental venous anomalies are quite common. Schrager et al. A common benign breast lesion in this series was a densely fibrotic hyalinized nodule, whereas the most frequent breast malignancy was ductal carcinoma.
The efficacy, risk, and benefits of cancer screening in CS are unknown. Monthly breast self-examination and annual clinical breast examination starting at age 18 years have been suggested. Annual mammography is recommended to begin at age 30 or 5 years younger than the earliest breast cancer in the family. No studies have assessed efficacy of breast magnetic resonance imaging MRI , chemoprevention eg, tamoxifen , or prophylactic mastectomy in CS. Nonetheless, based on expert consensus opinion, the American Cancer Society currently recommends annual MRI screening of the breasts as an adjunct to mammography in women with Cowden and Bannayan—Riley—Ruvalcaba syndromes and their first-degree relatives Careful palpation of the thyroid gland on an annual basis beginning in adolesence has been suggested.
The role of thyroid ultrasound is unclear, but a baseline examination in the early 20s may be considered, with periodic reexamination as guided by family history or physical examination. An annual urinalysis has been suggested, supplemented by cytology and renal ultrasound if there is a family history of renal cell cancer. At present, screening of other organs is advised as per standard American Cancer Society guidelines.
Marsh et al. Current data suggest that CS and BRR represent one condition with variable expression and age-related penetrance Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Molec Genet. Mutation-positive and mutation-negative patients with Cowden and Bannayan-Riley-Ruvalcaba syndromes are associated with distinct 10q haplotypes. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations.
Europ J Hum Genet. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol. Cowden syndrome. Genetic Predisposition to Cancer. London: Arnold Publishers; — Zbuk KM, Eng C.
Nat Rev Cancer. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. The spectrum of vascular anomalies in patients with PTEN Mutations: implications for the diagnosis and management. Intramedullary ependymoma associated with Lhermitte-Duclos disease and Cowden syndrome.
Clin Neurol Neurosurg. Thyroid medullary carcinoma in a teenager with Cowden syndrome. The dermatopathology of Cowden's syndrome. Br J Dermatol. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. Clinical and pathological features of breast disease in Cowden's syndrome: an under-recognized syndrome with an increased risk of breast cancer. Mucocutaneous neuromas: an under-recognized manifestation of PTEN hamartoma-tumor syndrome. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers.
Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. Cowden Syndrome.
Semin Oncol. Biallelic mutations in TERT have been associated with an autosomal recessive or apparently sporadic pattern of DC 1,2. TINF2 , chromosome 14q In families with X-linked DC, the majority of mutations in DKC1 result in single amino acid substitutions in the dyskerin protein. No genotype—phenotype correlations have been observed with specific mutations.
Mutations in TERC include large intragenic and terminal deletions, a small frameshift mutation, and point mutations often resulting in haploinsufficiency for functional telomerase. These mutations do not account for all autosomal dominant DC. TERC deletions are associated with progressive telomere shortening, resulting in clinical anticipation with more severe disease presenting at an earlier age in successive generations 5—7.
A single kindred with clinical DC and a germline mutation in TERT in an affected mother and her identical twin sons has recently been reported 8. DC is a multisystem disorder characterized by the classic triad of nail dystrophy, lacey reticular skin hyperpigmentation or generalized hyperpigmentation, and mucosal leukoplakia.
Bone marrow failure is frequent and is the principal cause of death. Other abnormalities include short stature, premature loss of hair and teeth, hyperhidrosis of palms and soles, telangiectasiae, hair tufts with hyperkeratotic plugs, keratinized basal cell papillomas, pulmonary fibrosis, esophageal stricture, urethral stricture, liver disease, gastrointestinal abnormalities, and increased predisposition to cancer, particularly squamous cell carcinomas of the head and neck and acute myelogenous leukemia [recently reviewed by Kirwan and Dokal 9 ].
Because most of the affected tissues are characterized by rapidly dividing cells, DC shares features with premature aging syndromes eg, Werner syndrome and other bone marrow failure syndromes eg, Fanconi anemia [FA]. In fact, DC may be mistaken for FA Diagnosis may be difficult because of the clinical and genetic heterogeneity of DC [reviewed by Handley et al.
ISBN 13: 9780757002106
Age at onset and severity of the cutaneous and noncutaneous features are highly variable; in some cases, patients may present with noncutaneous manifestations, including aplastic anemia or solid tumors, before developing the characteristic integumental features. The diagnosis of squamous cell carcinoma of the head and neck in a young, nonsmoking, nondrinking adult warrants seeking the presence of an unrecognized cancer susceptibility disorder such as DC or FA. Autosomal dominant DC appears to have milder manifestations compared with the X-linked and autosomal recessive forms, which may present with more frequent physical anomalies and earlier onset of aplastic anemia.
Identification of skewed X-chromosome inactivation patterns in peripheral blood cells of women from DC families can differentiate X-linked from autosomal forms of the disease, distinguish inherited mutations from de novo events in sporadic male DC cases, and establish carrier status for the purpose of risk counseling Mutations in DKC1 and homozygous TERT mutations have been detected in patients with the Hoyeraal—Hreidarsson syndrome OMIM , a severe variant of DC characterized by severe growth failure, cerebellar hypoplasia, aplastic anemia, and progressive immunodeficiency.
Mutations in TERC as well as TERT have been described in cases of familial aplastic anemia without other features suggestive of DC and also are reported in families with autosomal dominant idiopathic pulmonary fibrosis with no features of DC The latter is characterized by bone marrow failure and exudative retinopathy and has long been suspected to be part of the DC disease spectrum. White cells from DC patients have very short telomeres 5,7 , and a clinical assay Flow-FISH for this parameter has recently become available Very short telomere length ie, below the first percentile for age has been proposed as a diagnostic screening test, analogous to the chromosome breakage test in FA, to identify DC patients in families without detectable mutations in one of the three genes and to distinguish DC from other hereditary bone marrow failure disorders These are predominantly acute myelogenous leukemia AML and carcinomas of the upper aerodigestive tract, particularly squamous cell cancers of the head and neck and esophagus.
Case reports of gastric, pancreatic, and rectal carcinoma, as well as malignant lymphoma, are of uncertain significance.
Myelodysplasia occurs in DC patients with bone marrow failure; it may precede the development of AML. Art history is the academic study of objects of art in their historical development and stylistic contexts and involves a study of genre, design, format, and look. Therefore, an art historian uses the historical method to answer foundational questions, such as how did the artist come to create the work, who were his or her teachers, who was the audience, who were the patrons, what historical forces fashioned the artist's work and in turn how did it affect the course of artistic, political or social events.
Studies by art historians often involve close scrutiny of individual objects. Using them, they attempt to answer in historically specific ways, questions such as what are the key features of its style, what symbols are involved, to which period can the object be dated, what meaning did this object convey, how does it function visually, and so on.
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One of the best examples from the Qur'anic manuscripts studied using the art-historical method is DAM The fine geometric, architectural and vegetal patterns calligraphed on this manuscript bear a striking resemblance and share certain stylistic idiosyncrasies pointing towards a similar timeframe of production. It is thus argued the date assigned to a given manuscript using this method is the same time frame from where comparative material is normally adduced. In recent years, a highly promising scientific method of dating Qur'an manuscripts has been utilised, namely, radiocarbon dating.
One of the great benefits and advantages of this method of dating is that scholarly prejudice and pre-suppositions about the genesis of Arabic scripts and Qur'anic manuscripts are not factored into the calculation. Nevertheless, one of the downsides is the large time intervals which do not prove very useful in dating manuscripts very precisely. Some examples are manuscript St. They both have large ranges of and years, respectively. Such is not always the case. The Radiocarbon dating has been put to the test by comparing its results with art historical methods with regard to the dating of Roman and Coptic textiles; the authors conclude that radiocarbon dating can assist the art-historical method and is not something to be frowned upon or feared.
Eight of them form part of the table below. George says,. The oldest manuscripts of the Qur'an - called 'Hijazi' in modern scholarship, even though many of them were probably not made in the Hijaz - are key witnesses in the genesis of Arabic calligraphy. Their date has been a subject of controversy in modern scholarship, but thanks to the discovery of new documents from the first decades of Islam and to our better understanding of the transformation of Arabic script under the Umayyads, it is becoming increasingly clear that the vast majority of these Qur'ans were written in the first century of Islam.
It is of course entirely possible, even probable, that some of the manuscripts listed below may extend to the early second century of hijra. This list is certainly not authoritative and omits manuscripts which are known to be present in collections but their accession number, folios and content are not known. The table entries are not ordered chronologically; instead, manuscripts that are written in a similar script style have been grouped together for ease of navigation.
Khalili Collection of Islamic Art, London. Bonham's , Lot 19 . Christies , Lot 20 . Marcel 15 . Arabe c . Leiden Or. Marcel 17 . Arabe d . In the designation field, if the manuscript has been separated and in the process given different accession numbers, all of them will be listed here, the primary holding institution being mentioned first.
Only the maximum preserved size of the surviving folios of the manuscript are mentioned in the dimensions field.
If dimensions are given in brackets this is the estimated original size of the folio. The minimum and maximum number of lines are taken only from intact folios; a damaged or incomplete folio has not been used to supply the minimum number of lines in manuscripts which contain one or more non-partial folios. The folios field supplies the number of folios that have been mentioned in the literature.
Where available, bibliographic references are provided that were used to populate the columns with information — this is not intended as a comprehensive bibliography for every manuscript, instead a selection of the primary references. For sake of convenience, all verse numbering is according to the kufan system as found in the modern printed edition of the Qur'an first published in Egypt in Given the nature of this list, we welcome any comments, additions or corrections to the information contained in the respective columns. Lastly, the information contained in the columns is based on those folios which have been published or mentioned in the literature.
Amongst them, one could name the following codices from Tunisia: Ms. R 38 ,  Ms. R ,  and Ms. P  ; from Yemen: DAM Perg , and Mixt. Garrett Coll. A hitherto largely unknown Qur'anic manuscript, Kodex Wetzstein II located at the Staatsbibliothek in Berlin,  must rank as one of the most significant manuscripts of the Qur'an in a Western institution that still awaits detailed study.
The importance of this manuscript is guaranteed by the remarkably large number of extant folios; in total there are extant folios meaning some pages of examinable text. Apart from a brief mention by Gerd-R. Puin  and some Moroccan scholars,  this manuscript has barely managed a notice. Dating manuscripts is not based on conservatism or liberalism, it is simply trying to assign an accurate date as possible to its production.
Therefore, a Qur'anic manuscript assigned a 4th century date instead of a 1st century date, can do just as much damage to the chronology of the Arabic script as can a manuscript dated to the 1st century that belongs to the 4th. Both dates are inaccurate and injure the chronological time frame resulting in the faulty dating of other manuscripts also.
For example, both a palaeographic and radiocarbon analysis give a 1st century hijra date for Mingana Islamic Arabic a. One could put their hands up in the air and say there is no absolute method to determine that this is the case and it would be quite true. But one should realise that certainty in the field of history in rarely akin to certainty in mathematics, where a conclusion can be demonstrated as an inevitable result of the premises applied.
One could not demonstrate with the same degree of certainty the existence of this manuscript in the 1st century of hijra as one could demonstrate the truth of the Pythagoras theorem. Indeed, if such unjustified epistemological scepticism is advanced to its logical conclusion, centuries of Western Qur'anic scholarship would fall by the wayside with no prospect of a replacement.
Let us consider a somewhat comparable situation in numismatics. The study of Arab-Byzantine coinage from the 7th century, especially the first half of the 1st century of hijra , has been riddled with a certain amount of confusion. Scholars knew the coinage normally associated with this period was very early, but had no secure means by which to attach a specific date to them.
This has all changed as very recently early Islamic numismatics has seen a methodological breakthrough, whereby secure dates can be attributed to identifiable series of early Arab-Byzantine issues in Syria. If the breakthrough in the numismatic realm is anything to go by, it shows that promising new research can provide rewarding results.
If one considers the location of these manuscripts, it will become apparent many of them are located in Western institutions. During the nineteenth and twentieth century, Western imperialist and colonial powers had politically, economically, militarily, and culturally dominated the Muslim lands. Many of the most precious artefacts of these countries were appropriated by officials working in or alongside government and by travelling scholars representing their respective countries' higher institutions — as the collections of any oriental studies department in the West will attest.
None of these images were shared with their Muslim hosts. After the untimely death of both men, Anton Spitaler came to inherit these valuable films, lied about their existence and hid them for more than 50 years before secretly passing them on to his student Angelika Neuwirth who now heads the project Corpus Coranicum. It is said that history is bound to repeat itself. Puin attempted to leave the country with some 35, images and was subsequently prevented from doing so. Only once Puin succeeded in enlisting the help of the German Government via local German diplomats was the initial resolve of the Yemenis broken, who finally granted the microfilms passage out of the country.
In spite of the fact a significant quantity are sold at auction,  it goes without saying none of the Qur'anic manuscripts listed above, that are now located in the West, are indigenous there. One will also notice some surprising omissions. The most obvious is modern day Saudi Arabia. It would seem inconceivable the birth place of Islam and the Qur'an would not have any early Qur'an manuscripts, despite the fact many of its manuscripts would have moved to different parts of the Muslim community as the spheres of power and influence became progressively spread out. This surprising omission can probably be attributed to a lack of searching and cataloguing, an endemic problem in the vast majority of Muslim countries.
What are the major manuscript discoveries of the Qur'an in modern times? In a fire broke out at the Great Mosque of Damascus Umayyad Mosque during which a forgotten storeroom containing a huge quantity of used Qur'anic manuscripts was discovered. During this time a forgotten storeroom with no access door and a single window was discovered to contain a substantial cache of used Arabic manuscripts, almost all being ancient manuscripts of the Qur'an spanning the first few Islamic centuries.
Over time the curator of the library sold off the contents of the sacks unlawfully with some of the manuscripts ending up in Western libraries. In in order to consolidate the north-west corner of the external wall to the mosque, it was necessary to remove part of the roof to allow progress to be made in the restoration and renovation works.
As the storeroom was also located in this area the remaining manuscripts were permanently removed consisting of some twenty sacks and placed in the National Museum. The assessment of the value of the Qur'anic manuscripts from 1st century hijra requires tabulation and assessment of their contents, both individually and collectively. These contents can be evaluated as number of verses or the percentage of the actual text these verses represent.
This printing complex is a , sq. The popularity of this edition is such that the arrangement of the text is also emulated by editions of the Qur'an printed in Beirut and Damascus. At the printing complex, the Qur'an in the reading of Warsh is also produced but its usage is largely confined to the North Africa. Therefore, what would have been a page book i.
This interesting information, though not very obvious, will be very useful when we analyze the data from the Qur'anic manuscripts. Highly fragmented text such as that found in P. For instance, although it is clear DAM There are two important properties required by any mathematical calculation to ensure its viability.
The calculation must be a verifiable and, b repeatable. As such, all the proceeding calculations have been independently summed and reproduced so the interested reader can establish for himself whether what is being presented faithfully represents what is being claimed. DAM Arabe a Arabe g Marcel 17 Marcel 3 M. Arabe a Ms. Arabe g Ms. AMAS Ms. Arabe P. Highly fragmented texts are represented inside brackets. This graph is plotted using the information presented in Table II. Highly fragmented texts are not considered for calculating the percentages.
Despite being based on an incomplete data set, this is a significant observation. Sadeghi and Goudarzi observed these changeovers somewhat resembled the ordering of the codex of Ubayy b. Thus one must carefully consider to what extent the manuscript in question was originally a full or partial copy. There are a few interesting points to note. Figure 4: Bar graph of the percentage of text of the Qur'an in the 1st century AH manuscripts of the Qur'an.
The filled diamonds shows the cumulative percentage of the unique text in each of the manuscripts starting from the top i. A study of the manuscripts discussed in Table I and the percentage of the Qur'anic text they contain show that Ms. After this comes Arabe a and DAM It can also be noted from Figure 1 that although some manuscripts may contain a decent amount of Qur'anic text, their net contribution towards the unique text is nil.
Thus only a few manuscripts are required to collate substantial portions of the unique text of the Qur'an. From the above discussion it is clear that Noseda's conclusions are in need of some modification. These, therefore, cannot be considered deficiencies per se on Noseda's part as they were never designed to be part of his table in the first place.
With regard to Noseda's observation, instead of seeing the cup more than eight-tenths full, Keith Small sees it less than two-tenths empty. Ancient codices that are frequently handled over time tend to be acephalous and apodal. It also clearly shows that a non-standard text of the Qur'an could be recognised as such in the mid-1st century of hijra. This shows the strict standardisation of the Qur'anic text in this period. One must be careful not to make an over-simplification in the progression of the Arabic script where a strict linear chronological development is envisaged that does not allow for regional variation and the simultaneous existence of different styles.
This is indisputable. Such artificial limitations imposed on this style of writing are unjustified and produce a skewed picture of the development of the Arabic script. Many scholars have properly questioned Christoph Luxenberg's tendency to intentionally ignore the extant documentary evidence in relation to the Arabic language and the Qur'an, without focusing on the underlying reasons. Garshuni alt. Karshuni in a strict sense is a term for manuscripts or printed works in Arabic language in Syriac script. In other words, Garshuni refers to the practice of writing Arabic texts in Syriac script.
This practice did not require the modification of Syriac script and thus it did not require a development of separate ductus for writing Arabic. Therefore, it is not surprising that in many manuscripts written in Syriac script, a text in Syriac is often followed by a Garshuni text written by the same hand. As recently reiterated by Mengozzi, from a theoretical and practical standpoint there was no need for Garshuni due to the high level of competence required in Arabic, including comprehensive knowledge of its grammar and lexicon.
On the other hand, Garshuni scribes need only be conversant with the calligraphic techniques associated with their scribal traditions. An initial text typology given by Mengozzi helps to simplify and classify the diversity of manuscripts containing Garshuni texts. The first important distinction to be made is between short texts e. The short texts seem to be a good deal earlier than complete literary texts, the earliest of which hail from the 14th century.
When one looks sideways at dated Garshuni texts we find ourselves in a comparable situation. One of the very earliest dated samples of Garshuni text known is from CE and is one of a number of short notes contained in the famous Rabbula codex. How does Luxenberg's hypothesis fare when viewed alongside the extant documentary evidence? Firstly, as we have mentioned, he has failed to adduce a single piece of documentary evidence , be it a manuscript or inscription, showing the Qur'an was originally written in Garshuni.
Secondly, he fails to appreciate the fact that the Garshuni writing tradition appears much later on than Arabic. Such an evidence on the cover page of the book would have befittingly matched the title. In the last few decades a controversy has arisen over the period in which the text of the Qur'an became codified. Hawting  and, recently, the Qur'an is a product of Syriac Christianity and was first written in Garshuni pace Christoph Luxenberg. Should one ponder over this list, one will come to the appreciation that scholars involved in this field of study suffer from an embarrassment of riches.
Quite simply, there is no other work from Late Antiquity that comes close to the Qur'an in terms of the number of their earliest manuscripts including textual content. This is reflected in the fact that we have obtained a slightly higher percentage of the text of the Qur'an. It must be added that the current paper is a working document. But let us not anticipate.
Les manuscrits de style hijazi. Volume 2. Tome I. Le manuscrit Or. The term Textus Receptus was first coined from the second edition of the Greek New Testament published by the famous Dutch printers the Elzevier's in who enlisted Daniel Heinsius, a Greek and Latin classics professor at the University of Leiden, to write a brief preface for the text. Based on a few manuscripts from the Byzantine textual tradition , the Textus Receptus exhibited additional words, phrases, sentences and even whole pericopes compared to the earlier Alexandrian textual tradition. For example, consider I John , the Comma Johanneum ,  the only explicit reference to the Trinity in the New Testament that first appears as a verse proper in a 16th century Greek New Testament manuscript.
The question is posed thus — What does a marketing soundbite from a Latin preface to a Greek New Testament written by a Dutch professor from the Renaissance have to do with the text of the Qur'an? Not a great deal at all. We must ask ourselves then why is it that this term is used? There is a reason subtlety assumed and very seldom explained. Some Western scholars are implying the modern printed Qur'anic text is an uncritical text which, like the Textus Receptus , was initially received as flawless but over time will soon come to be discovered as corrupted with the application of modern scholarly tools such as textual criticism.
Is such a conclusion supported by the earliest extant manuscripts of the Qur'an, some of which have been listed above? On the basis of the published manuscripts listed in the table above, none of them shows the full type, spectrum and extent of textual corruption exhibited by the Textus Receptus. The transmission of the Arabic Qur'an is very different from that of the Greek New Testament, rendering a comparison between them one of apples and oranges. The New Testament reflects multiple archetypes and its transmission was uncontrolled from the outset.
In any case, such phrases have no application to the Qur'an, either the modern printed texts or its earliest handwritten manuscripts, and should probably remain in the sphere from where it originated. None of the persons mentioned are associated with Islamic Awareness , neither are the views expressed in this article necessarily their own. In any case there is still no basis for comparison as this manuscript has never been published.
Franke Ed. August Bis 4. In the latter article, Grohmann also includes Arabic Pal. Plate 43 , which is a severely mutilated papyrus manuscript of the Qur'an presently lost containing a few dozen letters. The image which was reproduced by Moritz is of such poor quality it is practically unreadable rendering it unhelpful for comparative purposes. Noseda Eds. The earliest Christian manuscripts are analysed in much the same fashion.
See B. Dodge Trans. Arthur Jeffery dismisses the statement of al-Nadim by saying that it belongs to "4th Islamic century" and claims it to be "suspicious" see A. Jeffery, " Book Review Of N. Nabia Abbott, on the other hand, agrees with the statement of al-Nadim and she provides the manuscript evidence to support his statement. She pointed out that Jeffery misread and misrepresented the statements of al-Nadim N.
Blair, Islamic Calligraphy , , op. See N. Neuwirth, N. Marx Eds. Abul Quasem Trans. Translation taken from M. A fairly comprehensive system of diacritical marks was already in place in the early 20's AH, roughly contemporaneous with Uthman's collection of the Qur'an. Ghabban Trans. Also see A. For another recent study on the ordered use of diacritical marks in early Arabic texts see, A. Kropp Ed. Read in conjunction with idem.
George's explanation has the benefit of interacting with a wide array of indisputably early material evidence, without placing undue emphasis on non-documentary sources. Radzinowicz, Ed. Noseda conveniently lists all extant some presently lost Qur'anic manuscripts written on papyrus. At least one other Qur'anic papyrus manuscript has come to light since Noseda wrote his article, see W.
Thesis unpublished , University of Utah, pp. See F. Volume I. Thesis unpublished , University of Birmingham, pp. Higham, C. Bronk Ramsey, D. Chivall, J. Graystone, D. Baker, E. Ansorge et al. Cultural Publications: Turkey, pp. Aspesi, V. Brugnatelli, A. Rosenzweig Eds. The table of contents provided here contains a few typos. Fedeli has kindly provided the authors with an updated folio by folio breakdown based on her second examination of the manuscript; C. Zink Eds. Ohlig Eds. Puin Eds. Nota bene : At this juncture, we should like to mention the authors do not necessarily agree with all the conclusions, inferences and conjectures mentioned in this article, as is the case with a number of the references supplied throughout our examination.
This is more than just an investigation into one folio of the codex. Rather it is a detailed scientific examination of the entirety of the manuscript, in particular the four auction folios, and the broad text critical conclusions and inferences one may deduce in respect of the transmission of the Qur'anic text as a whole. According to Sadeghi and Bergmann, the date which the scriptio superior text was written could be the first or second half of the 7th century or even the early 8th century more generally the 1st century hijra. Fedeli, " A.
Grohmann does not mention the contents of the manuscript; this has been established by reading the text from the published image, i. Noseda dates this manuscript to the 1st century hijra whilst Loebenstein dates it to the beginning of the 2nd century. Jenkins Ed.
Moritz Ed. Steiner: Wiesbaden, p. To quote Dr. The table of contents has been obtained from the Corpus Coranicum website. The catalogue entry suggests this manuscript could be linked to DAM However in recent times it has been separated into two sections due to the fact they are from different manuscripts. As far as we are aware, there are no published details of this manuscript. Flood, '' The Qur'an '', in H. Ratliff Eds. The contents of the manuscript were compiled by Dr. Alba Fedeli who has examined the manuscript first-hand.