#1 detailed introduction early diagnosis and...

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PDF File #1: DETAILED INTRODUCTION

• EARLY DIAGNOSIS AND TREATMENT IMPROVE CANCER OUTCOME:

o Cancer is a relatively rare but costly disease:

§ Cancer is a relatively rare disease in children. Less than 1 in 600 children develops a malignancy before the age of 15 years. Cancer, however, causes considerable physical and mental pain and suffering and is economically, time and emotionally draining for children and their families, and very costly for the state. It, therefore, is justifiably a very frequent cause of concern for parents and physicians because it ranks second only to trauma as a cause of death in children.

o Cancer often occurs unexpectedly and without reason:

§ Most cancers occur unexpectedly without any family history, predilection and apparent warning. Children commonly have malignancies of the hematopoietic, reticuloendothelial, embryonal, central nervous system, germ cell and mesenchymal origins, different from adults who commonly have epithelial origin lung, breast, gastrointestinal, skin and prostate carcinoma. These variations between childhood and adult malignancies reflect differences in etiology and pathogenesis.

o Early diagnosis of cancer depends on a high index of suspicion:

§ Early diagnosis depends on the accuracy and persistence the parents and the child in presenting the complaints to a physician. It also depends on the vigilance of the physician in taking a focused history, conducting an accurate physical examination, instigating an appropriately informative line of investigation, and referring the child to the appropriate specialist, the pediatric oncologist.

o Congenital abnormalities may help diagnose cancer early:

§ Certain cancers are associated with congenital abnormalities that long preceded the presentation of malignancy. In some of the congenital abnormalities the genetics are known, in others they are not yet worked out. Some of the congenital abnormalities are gross but others could be subtle. Some abnormalities are present at birth but others may evolve over time. The early diagnosis of such cancers depends on astuteness of the physician in picking up relatively subtle clinical features, attaching the correct relevance to the abnormalities, and instituting the appropriate investigations that will lead to the making of a correct diagnosis of a particular type of malignancy for which the clinical clues suggest the predilection for a higher risk for malignancy.

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o Early diagnosis of cancer is important to patients and families:

§ Early recognition of congenital abnormalities that are associated with a predisposition to cancer allows early intervention that may be highly relevant for a better long term outcome of therapy. It also allows for the implementation of long term prevention strategies such as pre-symptomatic cancer screening for early diagnosis, risk identification for relatives, amniocentesis for siblings and offspring, and institution of preventive strategies, and counseling about recurrence and secondary cancer risk. Therefore, appropriate prevention, early identification and successful treatment of cancer represent considerable savings in terms of human suffering and the health dollar.

PDF File #2: DETAILED DESCRIPTION OF THE INCIDENCE OF CHILDHOOD CANCER.

• THE INCIDENCE OF CHILDHOOD CANCER:

o In 1978, Young et al reported the annual incidence of malignant tumors in U.S. children, in the American Cancer Society Professional Education Publication, “Cancer incidence, survival and mortality for children under 15 years of age”, the statistics of which Altman and Schwartz subsequently updated in 1983. Table #1 summarizes the data from these two and other reports. The overall incidence of cancer is 12.12/100,000/year in white children, and 9.33/100,000/year in black children.

Table #1: INCIDENCE OF SPECIFIC MALIGNANCIES OF CHILDHOOD

Malignancies White Children per 100,000/year

Black Children per 100,000/year

a. Leukemia ALL ANLL CML Others

3.74 2.47 0.55 0.09 0.63

2.27 1.05 0.46 0.08 0.68

b. Central nervous system 2.22 2.02 c. Lymphoma

Non-Hodgkin Hodgkin

1.68 0.93 0.75

1.05 0.58 0.46

d. Neuroblastoma 0.95 0.67 e. Soft-tissue sarcoma

Rhabdomyosarcoma Others

0.75 0.37 0.38

0.80 0.38 0.42

f. Wilms tumor 0.69 0.76 g. Bone cancer

Osteosarcoma 0.57

0.31 0.34

0.25

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Ewing’s & PNET Others

0.21 0.05

- 0.09

h. Retinoblastoma 0.3 0.38 i. Gonadal and germ cell tumor 0.28 0.39 j. Liver tumor 0.16 - k. Melanoma 0.12 0.04 l. Thyroid cancer

Nasopharyngeal carcinoma Others

0.19 0.02 0.45

0.08 - 0.55

• FACTORS THAT MAY AFFECT THE FREQUENCY OF CHILDHOOD CANCER:

o Epidemiologic factors, environmental factors, and congenital syndromes may play a role in the etiology and affect the incidence of some types of cancers. Table #2 summarizes those factors that may affect the incidence of childhood cancer.

Table #2: FACTORS THAT AFFECT THE FREQUENCY OF CHILDHOOD CANCER

Causes Of An Increase Incidence Factors That May Affect The Frequency

Epidemiologic factors: (A) Geographic.

(B) Race.

(C) Age.

(D) Sex.

(E) Country.

(F) Enviromental.

Environmental factors: (A) Physical agents.

(B) Chemical agents.

(C) Biological agents.

Congenital syndromes (A) Syndromes in which the genetics are known.

(B) Syndromes in which the genetics are unknown.

Other syndromes associated with childhood cancer

(A) Standard classification of syndromes according to their morphology.

(B) Newer classification of syndromes according to their main clinical identifiers. This classification allows physicians to search for a predisposition of childhood cancer associated with any clinical abnormalities that are observed in patients.

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PDF File #3:DETAILED DESCRIPTION OF THE EPIDEMIOLOGY FACTORS THAT AFFECT THE INCIDENCE OF CHILDHOOD CANCER:

Table #3: EPIDEMIOLOGY FACTORS THAT AFFECT THE INCIDENCE OF CHILDHOOD CANCER

Factors That Affect Incidence

Examples Of Factors That Affect The Cancer Frequency

Geographic § Highest in Israel and Nigeria § Lowest in India and Japan

Race § 12.12/100,000 for U.S. white children § 9.33/100,000 for U.S. black children

Age § Peaking before 4 years: neuroblastoma, Wilms tumor, testicular germ cell tumor, acute lymphoblastic leukemia, retinoblastoma, sacrococcygeal teratoma, medulloblastoma, glioma, rhabdomyosarcoma, hepatoblastoma - suggest prenatal factors affecting embryogenesis may be implicated in the pathogenesis

§ Peaking after 4 years: ovarian germ cell tumors, lymphoma, Hodgkin disease, bone sarcoma, soft-tissue sarcoma, thyroid cancer, acute myelogenous leukemia, brain tumor - suggest prenatal factors affecting embryogenesis may be implicated in the pathogenesis

Sex § More frequent in boys (especially prepubertal): acute lymphoblastic leukemia, lymphoma, Hodgkin disease, medulloblastoma

§ More frequent in girls: skin cancer

Country of origin § Wilms tumor is uniform worldwide

§ Leukemia varies worldwide (eg, acute myelomonocytic leukemia with orbital chloroma is very frequent in Turkey and Uganda)

§ Burkitt lymphoma is very common in Uganda

§ Intestinal lymphoma is very common in Israel

§ Hodgkin disease is common in Columbia

§ Hepatoblastoma is more common in the Far East

§ Retinoblastoma is more common in India

§ Neuroblastoma is more common in Western Europe

§ Pineal tumors is more common in Japan

§ Skin cancers in xeroderma pigmentosa is common in North Africa

§ Leukemia is almost twice as common in white than black U.S. children

§ Melanoma, Ewing’s sarcoma and testicular cancers are rare in black U.S. children

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Table #4: ENVIRONMENTAL AND ENDOGENOUS RISK FACTORS THAT INCREASE THE INCIDENCE OF CHILDHOOD CANCER

Factors That Affect Incidence

Examples Of Risk Factors That Increase The Cancer Frequency

Physical agents § Ultraviolet radiation: skin cancer (risk factors: fair-skin, xeroderma pigmentosa)

§ Therapeutic and other radiation: secondary cancers (risk factors: heritable retinoblastoma, p53 mutation) from low doses (leukemia, thyroid cancer), medium doses (thyroid cancer, salivary gland tumor, breast cancer, osteochondroma, meningioma, malignant astrocytoma, glioblastoma multiforme), and high doses (acute nonlymphoblastic leukemia, thyroid cancer, breast cancer, bone and soft-tissue sarcoma, malignant astrocytoma, glioblastoma multiforme), from the atomic bomb (acute leukemia, thyroid cancer, breast cancer), and from diagnostic fetal first trimester radiation (acute leukemia)

§ Asbestos: mesothelioma, lung cancer (risk factor: cigarette smoking)

Chemical agents § Chemotherapy: secondary acute nonlymphoblastic leukemia (risk factors: early alkylators, epipodophyllotoxins)

§ Immunosuppressant therapy: lymphatic cancer (risk factors: congenital and acquired immunodeficiency)

§ Diethylstilbestrol: vaginal and cervical cancer (risk factor: prenatal transplacental exposure)

§ C-17 alkylated androgens: hepatocellular carcinoma (risk factors: Fanconi and aplastic anemia)

§ Fungal aflatoxin B1: hepatocellular carcinoma

§ Chemical risk factors: vinyl chloride and arsenic insecticides (hepatic angiosarcoma); arsenic (lung and skin cancer); aromatic amines (bladder cancer); benzene (myelodysplasia, acute nonlymphoblastic leukemia); benzidene (bladder cancer); chloromethyl ether, chromium and mustard gas (lung cancer); isopropyl oil and nickel (nasal sinus carcinoma); phenacetin (renal cancer); polycyclic aromatic hydrocarbons (skin and lung cancer)

Biological agents § Schistosoma haematobium: bladder cancer

§ Viral risk factors: Epstein-Barr virus (Burkitt lymphoma, nasopharyngeal carcinoma); hepatitis B (hepatocellular carcinoma); Papilloma virus, (squamous cell carcinoma); a Type C retrovirus (cutaneous T-cell lymphoma); Herpes simplex Type II virus (cervical carcinoma); cytomegalic inclusion virus (Kaposi sarcoma); a Type C RNA virus (acute myelogenous leukemia); a Type B virus (breast cancer); in utero influenza (leukemia, lymphoma); in utero chicken pox (leukemia, medulloblastoma)

§ GLOBAL OVERGROWTH SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #5: PATIENTS THAT ARE “BIG-FOR-AGE” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes

Main Symptoms and Signs Genetics & Key Diagnostic Assays

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Beckwith-Wiedemann syndrome (BWS) • Wilms tumor risk (10%) • hepatoblastoma • adrenal cancer • leukemia • brain tumor • neuroblastoma • rhabdomyosarcoma

o high birth weight, macrocephaly, macrosomia, macroglossia, hemihypertrophy

o mental & postnatal growth retardation o prominent eyes, shallow infraorbital

region o earlobe creases, helical pits o omphalocele & umbilical hernia (70%) o neonatal hypoglycemia o renal cysts, nephromegaly,

hydronephrosis

§ family history (15%) § high resolution

chromosome study for 11p15 duplication

§ overexpression of IFG-2 at 11p15

§ WT1 mutation & IFG-2 expression studies (if available)

Simpson-Golabi-Behmel (SGB) • Wilms tumor risk

o high birth weight, macrocephaly, macrosomia, macroglossia

o polydactyly o hypertelorism o cardiac defects o genital defects o renal cysts, nephromegaly,

hydronephrosis

§ X-linked recessive § GPC3 gene

mutation at Xp26 § WT1 mutation

studies (if available)

Sotos • Wilms tumor risk • acute lymphoblastic

leukemia • non-Hodgkin lymphoma • small-cell lung cancer • hepatocellular cancer • neuroblastoma

o high birth weight, postnatal overgrowth, macrocephaly, advanced bone age

o abnormal facies o psychomotor abnormalities

§ genetics not known § WT1 mutation


Hemihypertrophy • Wilms tumor risk • neuroblastoma • hepatoblastoma • adrenal cancer

o regional overgrowth of tongue, face, torso, limb



• GLOBAL UNDERGROWTH SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #6: PATIENTS THAT ARE “SMALL-FOR-AGE” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes


Bloom • leukemia risk (25%) • lymphoma • stomach cancer • colon cancer • breast cancer • Wilms tumor

o small-for-age o microcephaly o malar hypoplasia o “café-au-lait” patches, hypopigmentation

(poikiloderma), skin photosensitivity, facial telangiectatic rash

§ autosomal recessive § DNA-repair disorder

with increased sister-chromatid exchange

§ BLM (DNA helicase) mutation at 15q26.1

§ radiation, mitomycin C chromosome breakage assays

§ WT1 mutation studies (if available)

Fanconi aplastic anemia (VACTERL association) • leukemia risk (10%) • myelodysplasia (5%) • hepatocellular

o small-for-age (33%) o café-au-lait patches increase with age o skeletal anomalies (66%), radial ray

defects (49%), clinodactyly, abnormal toes, vertebrae defects

§ autosomal recessive § heterogeneous

disorder with at least 4 gene mutations

§ radiation chromosome

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carcinoma (5%) • other tumors (5%)

o microcephaly o microphthalmia, short palpebral fissure,

ptosis o hydrocephalus o males have hypospadias, small penis,

undecended testes (20%) o tracheoesophageal fistula, gut atresia,

anorectal malformation (15%) o pancytopenia, progressive bone marrow

failure, high red cell MCV o congenital heart disease (13%) o ectopic, horseshoe, dysplastic,

malformed or absent kidney (34%)

chromosome breakage assay

Ataxia-telangiectasia • lymphoreticular cancer • acute lymphoblastic

leukemia • breast cancer (including

carriers that have increased risk)

o small-for-age o bulbar telangiectasia, facial & pinna

telangiectasia o progressive ataxia, neural degeneration,

motor delay o variable immunodeficiency

§ autosomal recessive § DNA repair disorder § ATM mutation at

11q22-23 § radiation


§ high serum a�� fetoprotein

§ immunodeficiency DeSantis-Cacchione xeroderma pigmentosa • early skin cancer with

cancer death by 10-20 years

o small-for-age o microcephaly o skin marked photosensitivity, atrophic

skin changes, progressive freckling, hyperpigmentation

o neural degeneration

§ autosomal recessive § DNA exicision-repair

disorder § heterogeneous

disorder at several gene loci

§ ultra violet chromosomal damage assay

Yunis-Ramsay 13q

deletion • bilateral retinoblastoma

risk (100%) • osteosarcoma • soft-tissue sarcoma • melanoma • glioblastoma multiforme • other cancers

spontaneous & secondary to radiation

o small-for-age o microcephaly o microphthalmia o hypertelorism o bat-like ears o fish-like mouth o mental & physical retardation o skeletal defects o cardiac defects

§ autosomal dominant § RB1 oncogene

mutation at 13q14 § karyotyping with

FISH & chromosome painting for confirmation

§ RB1 gene mutation molecular identification (if available)

• HYPERPIGMENTATION, TELANGIECTASIA AND LIPOMA SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #7A: PATIENTS WITH “CAFÉ-AU-LAIT” PATCHES AS MAIN INDENTIFIER Cancer-Associated Syndromes


Von Recklinghausen neurofibromatosis Type I • malignant peripheral

nerve sheath tumor • leukemia (AML, JCML)

o café-au-lait patches, axi lla & groin freckling

o dermal neurofibroma o optic glioma o acoustic neuroma o benign plexiform neurofibroma

§ autosomal dominant § 1/3000 individuals,

50% new mutations § NF1 putative tumor

suppressor gene mutation at 17q11.2

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o café-au-lait patches increase with age o small-for-age (33%) o skeletal anomalies (66%), radial ray



ptosis o hydrocephalus o males have hypospadias, small penis,



failure, high red cell MCV o congenital heart disease (13%) o ectopic, horseshoe, dysplastic,




§ radiation chromosome breakage assay

Peutz-Jeghers • pancreatic cancer • breast cancer • lung cancer • genitourinary cancer

o mucocutaneous café-au-lait patches o macrocephaly o gut hamartomatous polyposis causing

colic, gastrointestinal bleeding & intussusception, extruded rectal polyp

o nasal polyposis o lipoma o hemangioma

§ autosomal dominant § STK11 (LKB1)

tumor suppressor gene mutation at 19p13.3

TABLE #7B: PATIENTS WITH “CAFÉ-AU-LAIT” PATCHES, HYPOPIGMENTATION, AND PHOTOSENSITIVITY AS THE MAIN INDENTIFIERS


o “café-au-lait” patches, hypopigmentation (poikiloderma), skin photosensitivity, facial telangiectatic rash

o small-for-age o microcephaly o malar hypoplasia






Rothmund-Thomson (RTS) • multicentric

osteosarcoma • skin cancer

o Poikiloderma Triad of skin atrophy, telangietasia, pigmentation

o sparse hair o radial ray defects o juvenile cataracts o hypogonadism

§ autosomal recessive § DNA repair disorder § fibroblast

chromosomal instability

TABLE #7C: PATIENTS WITH “GENERALIZED TELANGIECTASIA” BUT WITHOUT RASH OR HYPERPIGMENTATION AS THE MAIN INDENTIFIERS



o bulbar telangiectasia, facial & pinna telangiectasia

o small-for-age o progressive ataxia, neural degeneration,

motor delay



chromosome

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o variable immunodeficiency



§ immunodeficiency Gardner syndrome (FAP familial adenomatous polyposis polyposis coli with extracolonic disease) • colorectal cancer • hepatoblastoma • brain tumor • adrenal adenoma

o telangiectasia o epidermal sebaceous cysts o hypertrophic retinal pigmented epithelium o maxilla & mandible osteoma o jaw cyst

§ autosomal dominant § APC tumor

suppressor gene mutation at 5q21-22

§ colonoscopy as recommended by screening programs

§ protein truncation assay (if available)

§ linkage studies (if available)

Familial Turcot • colorectal cancer • brain tumor

(medulloblastoma, glioblastoma multiforme)

• lymphoma

o telangiectasia o hypertrophic retinal pigmented epithelium o familial adenomatous polyposis coli

§ autosomal recessive § APC, p53, PMS2

gene mutations § DNA replication

errors & instability

TABLE #7D: PATIENTS WITH “LIPOMA-ANGIOLIPOMA-HEMANGIOMA” AS THE MAIN INDENTIFIERS

Bannayan-Riley-Ruvalcaba-Myhre-Smith • breast cancer • renal cancer

o large skin lipoma, hemangioma, angiolipoma

o penile pigmentation o hamartomatous polyps causing

intussusception & gastrointestinal bleeding

o Cowden phenotype o macrocephaly

§ autosomal dominant § PTEN tumor


§ mostly in males


o lipoma o hemangioma o gut hamartomatous polyposis causing


o nasal polyposis o mucocutaneous café-au-lait patches o macrocephaly



• MACROCEPHALY SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #8: PATIENTS WITH “BIG-HEADS” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes


Bannayan-Riley-Ruvalcaba-Myhre-Smith • breast cancer • renal cancer

o macrocephaly o large skin lipoma, hemangioma,

angiolipoma o penile pigmentation o hamartomatous polyps causing

intussusception & gastrointestinal bleeding

§ autosomal dominant § PTEN tumor


§ mostly in males

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o Cowden phenotype Gorlin nevoid basal cell carcinoma (NBCCS) • basal cell carcinoma

(90%) • medulloblastoma (5%) • melanoma • breast cancer • lung cancer • leukemia (CLL) • non-Hodgkin lymphoma

o macrocephaly (80%) o falx calcification o broad facies o hypertelorism o palm & sole pits o jaw odontogenic keratocyst (75%) o bifid ribs o ovarian fibroma o cardiac fibroma

§ autosomal dominant § family history § PATCH gene

mutation at 9q


o macrocephaly o mucocutaneous café-au-lait patches o gut hamartomatous polyposis causing


o nasal polyposis o lipoma o hemangioma



• MICROCEPHALY SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #9: PATIENTS WITH “SMALL-HEADS” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes





ptosis o hydrocephalus o café-au-lait patches increase with age o small-for-age (33%) o skeletal anomalies (66%), radial ray


o males have hypospadias, small penis, undecended testes (20%)

o tracheoesophageal fistula, gut atresia, anorectal malformation (15%)

o pancytopenia, progressive bone marrow failure, high red cell MCV

o congenital heart disease (13%) o ectopic, horseshoe, dysplastic,






o microcephaly o malar hypoplasia o small-for-age o “café-au-lait” patches, hypopigmentation







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DeSantis-Cacchione xeroderma pigmentosa • early skin cancer with


o microcephaly o small-for-age o skin marked photosensitivity, atrophic

skin changes, progressive freckling, hyperpigmentation






Yunis-Ramsay 13q




o microcephaly o small-for-age o microphthalmia o hypertelorism o bat-like ears o fish-like mouth o mental & physical retardation o skeletal defects o cardiac defects





• OCULAR ABNORMALITY SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #10A: PATIENTS WITH “WIDE-SET EYES (HYPERTELORISM)” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes



o hypertelorism o high birth weight, macrocephaly,

macrosomia, macroglossia o polydactyly o cardiac defects o genital defects o renal cysts, nephromegaly,

hydronephrosis




Gorlin nevoid basal cell carcinoma (NBCCS) • basal cell carcinoma


o hypertelorism o macrocephaly (80%) o falx calcification o broad facies o palm & sole pits o jaw odontogenic keratocyst (75%) o bifid ribs o ovarian fibroma o cardiac fibroma


mutation at 9q

Yunis-Ramsay 13q



o hypertelorism o microphthalmia o microcephaly o small-for-age o bat-like ears o fish-like mouth o mental & physical retardation o skeletal defects o cardiac defects




§ RB1 gene mutation molecular identification (if

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identification (if available)

TABLE #10B: PATIENTS WITH “PROMINENT EYES” (PROPTOSIS- SHALLOW INFRAORBITAL REGION) AS THE MAIN INDENTIFIERS


o prominent eyes, shallow infraorbital region

o high birth weight, macrosomia, macroglossia, hemihypertrophy

o mental & postnatal growth retardation o earlobe creases, helical pits o omphalocele & umbilical hernia (70%) o neonatal hypoglycemia o renal cysts, nephromegaly,

hydronephrosis





TABLE #10C: PATIENTS WITH “NO-IRIS” (ANIRIDIA) AS THE MAIN INDENTIFIER

Wilms-aniridia-genital anomalies (WAGR) • Wilms tumor risk (50%)

o sporadic aniridia o male genital anomalies o mental retardation

§ sporadic § contiguous WT1 &

PAX6 gene deletion at 11p13

§ WT1 is a tumor suppressor gene & a GU morphogenesis transcription factor


TABLE #10D: PATIENTS WITH “SMALL EYES” (MICROPHTHALMIA-SHORT PALPEBRAL FISSURE-PTOSIS) AS THE MAIN INDENTIFIERS



o microphthalmia, short palpebral fissure, ptosis

o microcephaly o hydrocephalus o café-au-lait patches increase with age o small-for-age (33%) o skeletal anomalies (66%), radial ray










TABLE #10E: PATIENTS WITH “TELANGIECTASIA OF THE EYES” (BULBAR TELANGIECTASIA) AS THE MAIN INDENTIFIER


leukemia




11q22-23

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§ immunodeficiency

• LIP, TEETH AND JAW ABNORMALITY SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #11A: PATIENTS WITH “PROMINENT BUMPY LIPS” (PROMINENT LIPS-MUCOSAL NEUROMA) AS THE MAIN INDENTIFIERS Cancer-Associated Syndromes


Multiple endocrine neoplasia Type 2B (MEN 2B) • multifocal medullary

thyroid carcinoma risk (100%)

• pheochromocytoma

o prominent lips with lip & tongue mucosal neuroma

o mudullated corneal nerves o marfanoid habitus o gastrointestinal ganglioneuromatosis

causing constipation and diarrhea

§ autosomal dominant § RET oncogene

mutation at 10q11.2

TABLE #11B: PATIENTS WITH “DENTAL CYSTS” (ODONTOGENIC KERATOCYST) AS THE MAIN INDENTIFIER



o jaw odontogenic keratocyst (75%) o hypertelorism o macrocephaly (80%) o falx calcification o broad facies o palm & sole pits o bifid ribs o ovarian fibroma o cardiac fibroma


mutation at 9q

TABLE #11C: PATIENTS WITH “JAW OSTEOMA-CYSTS” (MAXILLA/MANDIBLE-OSTEOMA/CYST) AS THE MAIN INDENTIFIERS

Gardner syndrome (FAP familial adenomatous polyposis polyposis coli with extracolonic disease) • colorectal cancer • hepatoblastoma • brain tumor • adrenal adenoma

o maxilla & mandible osteoma o jaw cyst o telangiectasia o epidermal sebaceous cysts o hypertrophic retinal pigmented epithelium






• CONGENITAL HEART DEFECT SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #12: PATIENTS WITH “CONGENITAL HEART DEFECTS” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes


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o congenital heart disease (13%) o microcephaly o microphthalmia, short palpebral fissure,

ptosis o hydrocephalus o café-au-lait patches increase with age o small-for-age (33%) o skeletal anomalies (66%), radial ray





o ectopic, horseshoe, dysplastic, malformed or absent kidney (34%)




Down • leukemia (acute

megakaryocytic myelogeneous & lymphoblastic leukemia & pseudoleukemia) risk (1% or 20-30 fold higher for age)

• lymphoma • Wilms tumor (rarer) • neuroblastoma (rarer)

o congenital heart defects especially endocardial cushion defects

o tracheoesophageal fistula, gut atresia and anorectal malformation (12%)

o microcephaly o small-for-age o clinodactyly

§ trisomy 21 or translocation 21

§ karyotypic study

Rubinstein-Taybi • medulloblastoma risk

(5%) • neuroblastoma • leiomyosarcoma • seminoma • embryonal carcinoma

o congenital heart defects (25%) o maxilla hypoplasia o broad thumbs & toes o growth & psychomotor retardation

§ autosomal dominant § CREB-binding

protein gene mutation with microdeletion & re-arrangement at 16p13.3

• BOWEL POLYPOSIS AND GANGLIONEUROMA AND ABDOMINAL WALL ABNORMALITY SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #13A: PATIENTS WITH “BOWEL POLYPOSIS” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes



o gut hamartomatous polyposis causing colic, gastrointestinal bleeding & intussusception, extruded rectal polyp

o nasal polyposis o lipoma o hemangioma o macrocephaly o mucocutaneous café-au-lait patches



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TABLE #13B: PATIENTS WITH “BOWEL GANGLIONEUROMA” AS THE MAIN INDENTIFIER




o gastrointestinal ganglioneuromatosis causing constipation and diarrhea

o prominent lips with lip & tongue mucosal neuroma

o mudullated corneal nerves o marfanoid habitus

§ autosomal dominant § RET oncogene

mutation at 10q11.2

TABLE #13C: PATIENTS WITH “OMPHALOCELE-UMBILICAL HERNIA” AS THE MAIN INDENTIFIERS


o omphalocele & umbilical hernia (70%) o high birth weight, macrocephaly,

macrosomia, macroglossia, hemihypertrophy


region o earlobe creases, helical pits o neonatal hypoglycemia o renal cysts, nephromegaly,

hydronephrosis





TABLE #13D: PATIENTS WITH “GUT ANOMALIES” (TRACHEOESOPHAGEAL FISTULA-GUT ATRESIA-ANORECTAL MALFORMATION) AS THE MAIN INDENTIFIERS




















§ karyotypic study

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• HORSE-SHOE, ENLARGED AND CYSTIC KIDNEY SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #14A: PATIENTS WITH “ABNORMAL KIDNEYS” (ECTOPIC, HORSESHOE, DYSPLASTIC, MALFORMED, ABSENT) AS THE MAIN INDENTIFIERS Cancer-Associated Syndromes











o congenital heart disease (13%)




TABLE #14B: PATIENTS WITH “ENLARGED KIDNEYS” (NEPHROMEGALY-RENAL CYSTS-HYDRONEPHROSIS) AS THE MAIN INDENTIFIERS


o renal cysts, nephromegaly, hydronephrosis

o omphalocele & umbilical hernia (70%) o high birth weight, macrocephaly,

macrosomia, macroglossia, hemihypertrophy


region o earlobe creases, helical pits o neonatal hypoglycemia






o renal cysts, nephromegaly, hydronephrosis

o high birth weight, macrocephaly, macrosomia, macroglossia

o polydactyly o hypertelorism o cardiac defects o genital defects




Denys-Drash (DDS) • Wilms tumor risk (90%)

o glomerulosclerosis with proteinuria, progressive renal failure

o genetic males with incomplete masculinization & ambiguous genitalia

o genetic females have no genital

§ sporadic § autosomal dominant § WT1 mutation at Zn

finger region § WT1 mutation

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anomalies studies (if available) Frasier • Wilms tumor risk • gonadoblastoma

o focal segmental glomerulosclerosis, progressive renal failure

o genetic males with complete sex reversal appearing as XY females with streaked gonads

o genetic females have no genital anomalies

§ autosomal dominant § WT1 mutation at a

donor splice-site junction


• MALE AND FEMALE HYPOGONADISM SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #15A: MALE PATIENTS WITH “HYPOGONADISM” AS THE MAIN INDENTIFIER Cancer-Associated Syndromes


Denys-Drash (DDS) • Wilms tumor risk (90%)

o genetic males with incomplete masculinization & ambiguous genitalia


o glomerulosclerosis with proteinuria, progressive renal failure

§ sporadic § autosomal dominant § WT1 mutation at Zn

finger region § WT1 mutation

studies (if available) Frasier • Wilms tumor risk • gonadoblastoma

o genetic males with complete sex reversal appearing as XY females with streaked gonads


o focal segmental glomerulosclerosis, progressive renal failure

§ autosomal dominant § WT1 mutation at a



Severe male genital anomaly • Wilms tumor risk

o penoscrotal-perineal hypospadias, undescended testes

§ sporadic or multifactorial disorders

§ some have protein-truncating type of WT1 mutation


45X/46XY mixed gonadal dysgenesis • gonadoblastoma

o mixed gonadal dysgenesis, ambiguous genitalia

§ 45X/46XY § karyotypic study









o pancytopenia, progressive bone marrow




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failure, high red cell MCV o congenital heart disease (13%)

Klinefelter • germ cell tumor

(mediastinal & cerebral) • male breast cancer

o hypogonadism, small firm testes o gynecomastia

§ sporadic § XXY § karyotypic study

TABLE #15B: FEMALE PATIENTS WITH “HYPOGONADISM” AS THE MAIN INDENTIFIER

Ullrich-Turner • gonadoblastoma

o hypogonadism, absence of spontaneous puberal development

o short stature o cystic hygroma, lymphedema o webbed neck, cervical ribs o sensorineural hearing loss o neurodevelopmental changes deficits o aortic aneurysm

§ sporadic § 45X/46XX with low-

level XY mosaicism

• DEFECTIVE RADIAL RAY-CLINODACTYLY-ABNORMAL TOES-DEFECTIVE VERTEBRAE SYNDROMES ASSOCIATED WITH INCREASED CANCER RISK

TABLE #16: PATIENTS WITH “ABNORMAL DIGITS AND VERTEBRAE” (DEFECTIVE RADIAL RAY-CLINODACTYLY-ABNORMAL TOES) AS THE MAIN INDENTIFIERS Cancer-Associated Syndromes




o skeletal anomalies (66%), radial ray defects (49%), clinodactyly, abnormal toes, vertebrae defects


ptosis o hydrocephalus o café-au-lait patches increase with age o small-for-age (33%) o males have hypospadias, small penis,



failure, high red cell MCV o ectopic, horseshoe, dysplastic,





TABLE #17: THE ENDOGENOUS MORPHOLOGIC SYSTEM TRADITIONAL USED FOR CLASSIFYING THE CANCER-PREDISPOSING SYNDROMES Morphological Classification

Cancer-Associated Syndromes

Cancers Associated with Each Syndromes

• Hereditary cutaneous syndromes

o Gorlin nevoid basal cell carcinoma (NBCCS)

§ basal cell carcinoma (90%), medulloblastoma (5%), melanoma, breast & lung cancers, leukemia (CLL), non-Hodgkin lymphoma

19

o Multiple benign cystic epithelioma (Familial trichoepithelioma)

§ basal cell carcinoma

o Tylosis § esophageal squamous carcinoma o DeSantis-Cacchione

xeroderma pigmentosa § early skin cancer with cancer death by

10-20 years o Albinism § squamous cell carcinoma of skin o Werner’s (Adult progeria) § carcinoma, sarcoma o Familial atypical molecule-

malignant melanoma (FAMMM)

§ melanoma, breast & colon cancers, leukemia, lymphoma, sarcoma

o Epidermodysplasia verruciformis

§ basal & squamous cell carcinomas

o Polydysplastic epidermolysis bullosa

§ squamous cell carcinomas occurring in scars

o Dyskeratosis congenita § skin & mucosa squamous carcinoma o Von Recklinghausen

neurofibromatosis Type I § malignant peripheral nerve sheath tumor,

leukemia (AML, JCML) o Tuberous sclerosis § brain tumor (1-3%)

• Hereditary neurocutaneous syndromes (Phakomatoses)

o Von Hippel-Lindau § renal cell carcinoma, ependymoma, pheochromocytoma

o Gardner syndrome (FAP familial adenomatous polyposis polyposis coli with extracolonic disease)

§ colorectal cancer, hepatoblastoma, brain tumor, adrenal adenoma

o Familial Turcot § colorectal cancer, brain tumor

(medulloblastoma, glioblastoma multiforme), lymphoma

o Peutz-Jeghers § pancreatic, breast, lung & genitourinary cancers

o Ulcerative colitis § colorectal carcinoma risk (20%)

• Hereditary & acquired gastrointestinal syndromes

o Crohn’s colitis § small bowel & colorectal carcinoma o Down § leukemia (acute megakaryocytic

myelogeneous & lymphoblastic leukemia & pseudoleukemia) risk (1% or 20-30 fold higher for age), lymphoma, Wilms tumor & neuroblastoma (rarer)

o Klinefelter § germ cell tumor (mediastinal & cerebral), male breast cancer

o Ullrich-Turner § gonadoblastoma o Yunis-Ramsay 13q

deletion § bilateral retinoblastoma risk (100%),

osteosarcoma, soft-tissue sarcoma, melanoma, glioblastoma multiforme, other cancers spontaneous & secondary to radiation

o Wilms-aniridia-genital anomalies (WAGR)

§ Wilms tumor risk (50%)

o Familial t(3;8) § renal cell carcinoma

• Chromosomal aneuploidy, deletion, translocation & fragility syndromes

o Bloom § leukemia risk (25%), lymphoma, stomach, colon & breast cancers, Wilms tumor

20

o Fanconi aplastic anemia (VACTERL association)

§ leukemia risk (10%), myelodysplasia (5%), hepatocellular carcinoma (5%), other tumors (5%)

o Ataxia-telangiectasia § lymphoreticular cancer, acute lymphoblastic leukemia, breast cancer (including carriers that have increased risk)

o Wiscott-Aldrich § lymphoreticular cancer o Bruton’s

agammaglobulinemia § acute lymphoblastic leukemia

o Common variable immunodeficiency

§ lymphoreticular cancer

o IgA deficiency § colon, lung, stomach, breast & skin cancers

o X-linked lymphoproliferative

§ lymphoreticular cancer

o Ataxia-telangiectasia § lymphoreticular cancer, acute lymphoblastic leukemia, breast cancer (including carriers that have increased risk)

o Transplantation immunosuppression

§ lymphoreticular & epithelial cancers

o Dermatomyositis § miscellaneous cancers

• Immuno-deficiency syndromes

o Systemic lupus § cervix carcinoma o Wilms-aniridia-genital

anomalies (WAGR) § Wilms tumor risk (50%)

o Hemihypertrophy § Wilms tumor risk, neuroblastoma, hepatoblastoma, adrenal cancer

o Beckwith-Wiedemann syndrome (BWS)

§ Wilms tumor risk (10%), hepatoblastoma, adrenal cancer, leukemia, brain tumor, neuroblastoma, rhabdomyosarcoma

o Cryptorchidism § testicular malignancy o Gonadal dysgenesis § gonadoblastoma o Ollier enchondromatosis § chrondrosarcoma

• Sporadic congenital malformation syndromes

o Maffucci § chrondrosarcoma o Chediak-Higashi § lymphoma o Familial Sipple multiple

endocrine neoplasia § multifocal medullary thyroid carcinoma

• Miscellaneous syndromes

o Tyrosinemia § hepatocellular carcinoma o Retinoblastoma

sibling/first cousin § if one parent is a carrier or has

bilateral/heritable retinoblastoma, there is a 50% risk of retinoblastoma (associated with spontaneous & radiation-induced osteosarcoma, soft-tissue sarcoma, melanoma, glioblastoma multiforme risk)

o Wilms sibling § small increase in Wilms & cancer risk o Neuroblastoma sibling § small increase in neuroblastoma &

cancer risk o Leukemia sibling § small increase in leukemia & cancer risk

• Siblings with malignancy & familial cancers

o Thyroid, bladder & urologic tumor family

§ familial thyroid, bladder & urologic tumors

21

o Sarcoma, breast, brain, lung, leukemia, larynx & adrenal tumor (SBLA) family

§ familial sarcoma, breast, brain, lung, leukemia, larynx & adrenal tumors

o Colon & endometrial adenocarcinoma

§ familial colon & endometrial adenocarcinoma

o Lymphoma & colon cancer

§ familial lymphoma & colon cancer

o Bilateral retinoblastoma survivor

§ each offspring has a 50% risk of bilateral retinoblastoma (patient & offspring associated with spontaneous & radiation-induced osteosarcoma, soft-tissue sarcoma, melanoma, glioblastoma multiforme risk)

o Wilms survivor § radiation-induced benign osteochrondroma, osteosarcoma, breast cancer

• Survivors of prior malignancy

o Hodgkin lymphoma survivor

§ Radiation-induced osteochrondroma, osteosarcoma, breast cancer; alkylator or etoposide-induced acute nonlymphoblastic leukemia

PDF File #4: DETAILED DESCRIPTION OF THE ENDOGENOUS MORPHOLOGIC SYSTEM TRADITIONAL USED FOR CLASSIFYING THE CANCER-PREDISPOSING SYNDROMES.

• This morphologic classification system detailed in Table #18 illustrates the difficulty of using the traditional system to search for any association between an observed clinical finding or an aggregate of clinical findings and a clinical syndrome that may be associated with an increased cancer risk:

TABLE #18: HEREDITARY CUTANEOUS SYNDROMES: Cancer-Associated Syndromes




o jaw odontogenic keratocyst (75%) o hypertelorism o macrocephaly (80%) o falx calcification o broad facies o palm & sole pits o bifid ribs o ovarian fibroma o cardiac fibroma


mutation at 9q

Multiple benign cystic epithelioma (Familial trichoepithelioma) • Basal cell carcinoma

o Multiple symmetrical tumors on face & upper body

§ sporadic § aggregate of clinical

features

Tylosis • esophageal squamous

cell carcinoma (late)

o keratosis of palms & soles


features DeSantis-Cacchione xeroderma pigmentosa

o microcephaly o small-for-age


22

• early skin cancer with cancer death by 10-20 years

o skin marked photosensitivity, atrophic skin changes, progressive freckling, hyperpigmentation





Albinism • squamous cell

carcinoma of skin

o ultra-violet photosensitivity o tumors induced by sun exposure


features Werner’s (Adult progeria) • carcinoma & sarcoma

o scleroderma-like skin o soft tissue calcification o growth retardation o cataracts o arteriosclerosis o short lifespan


features

Familial atypical molecule-malignant melanoma (FAMMM) • Melanoma • breast cancer • colon cancer • leukemia • lymphoma • sarcoma

o multiple moles, melanomas § family history § aggregate of clinical

features

Epidermodysplasia verruciformis • Basal cell carcinoma • squamous cell

carcinoma

o multiple virus-induced warty lesions o tumors induced by sun exposure


features

Polydysplastic epidermolysis bullosa • squamous cell

carcinoma

o bullous skin eruptions, erosion, healing with thin-scarring especially in extremities & joints

o tumors occurring in scars


features

Dyskeratosis congenital • Squamous cell

carcinoma (skin & mucosa)

o skin pigmentation & atrophy o nail dysplasia o mucosa leukoplakia o may have Fanconi anemia stigmata


features

HEREDITARY NEUROCUTANEOUS SYNDROMES (PHAKOMATOSES): Von Recklinghausen neurofibromatosis Type I • malignant peripheral

nerve sheath tumor • leukemia (AML, JCML)

o café-au-lait patches, axilla & groin freckling

o dermal neurofibroma o optic glioma o acoustic neuroma o benign plexiform neurofibroma

§ autosomal dominant § 1/3000 individuals,

50% new mutations § NF1 putative tumor


Tuberous sclerosis • brain tumor (1-3%)

o adenoma sebaceum o epilepsy o mental retardation triad o brain, retina, lung, kidney hamartomas


features

Von Hippel-Lindau • renal cell carcinoma • ependymoma • pheochromocytoma

o Retinal angiomatosis o cerebellar angiomatosis


features

23

HEREDITARY & ACQUIRED GASTROINTESTINAL SYNDROMES: Gardner syndrome (FAP familial adenomatous polyposis polyposis coli with extracolonic disease) • colorectal cancer • hepatoblastoma • brain tumor • adrenal adenoma

o maxilla & mandible osteoma o jaw cyst o telangiectasia o epidermal sebaceous cysts o hypertrophic retinal pigmented epithelium








• lymphoma

o telangiectasia o hypertrophic retinal pigmented epithelium o familial adenomatous polyposis coli

§ autosomal recessive § APC, p53, PMS2

gene mutations § DNA replication

errors & instability


o gut hamartomatous polyposis causing colic, gastrointestinal bleeding & intussusception, extruded rectal polyp

o nasal polyposis o lipoma o hemangioma o macrocephaly o mucocutaneous café-au-lait patches



Ulcerative colitis • colorectal cancer (20%)

o severe prolonged ulcerative colitis § sporadic § aggregate of clinical

features Crohn’s colitis • small bowel carcinoma • colorectal carcinoma

o severe prolonged especially obstructive Crohn’s colitis


features

CHROMOSOMAL ANEUPLOIDY, DELETION, TRANSLOCATION & FRAGILITY SYNDROMES: Down • leukemia (acute







§ karyotypic study


(mediastinal & cerebral) • male breast cancer

o hypogonadism, small firm testes o gynecomastia

§ sporadic § XXY § karyotypic study

24


o hypogonadism, absence of spontaneous puberal development

o short stature o cystic hygroma, lymphedema o webbed neck, cervical ribs o sensorineural hearing loss o neurodevelopmental changes deficits o aortic aneurysm

§ sporadic § 45X/46XX with low-

level XY mosaicism

Yunis-Ramsay 13q




o hypertelorism o microphthalmia o microcephaly o small-for-age o bat-like ears o fish-like mouth o mental & physical retardation o skeletal defects o cardiac defects





Wilms-aniridia-genital anomalies (WAGR) • Wilms tumor risk (50%)






Familial t(3;8) • renal cell carcinoma

o early onset multifocal tumors § family history § balanced reciprocal

t(3;8) on karyotyping Bloom • leukemia risk (25%) • lymphoma • stomach cancer • colon cancer • breast cancer • Wilms tumor

o microcephaly o malar hypoplasia o small-for-age o “café-au-lait” patches, hypopigmentation









o skeletal anomalies (66%), radial ray defects (49%), clinodactyly, abnormal toes, vertebrae defects


ptosis o hydrocephalus o café-au-lait patches increase with age o small-for-age (33%) o males have hypospadias, small penis,




25



failure, high red cell MCV o ectopic, horseshoe, dysplastic,

malformed or absent kidney (34%) Ataxia-telangiectasia • lymphoreticular cancer • acute lymphoblastic










§ immunodeficiency

CONGENITAL & ACQUIRED IMMUNODEFICIENCY SYNDROMES: Wiscott-Aldrich • lymphoreticular tumors

o no specific clinical features § sporadic § no aggregate of

clinical features Bruton’s agammaglobulinemia • acute lymphoblastic

leukemia


clinical features

Common variable immunodeficiency • lymphoreticular tumors


clinical features IgA deficiency • colon cancer • lung cancer • stomach cancer • breast cancer • skin cancer


clinical features

X-linked lymphoproliferative • lymphoreticular tumors


clinical features Ataxia-telangiectasia • lymphoreticular cancer • acute lymphoblastic










§ immunodeficiency Transplantation immunosuppression • lymphoreticular tumors • epithelial tumors

o clinical features related to chronic immunosuppressant therapy

§ aggregate of clinical features

Dermatomyositis • miscellaneous cancers

o clinical features related to dermatomyositis

§ aggregate of clinical features

26

Systemic lupus • cervix carcinoma

o clinical features related to lupus § aggregate of clinical features

SPORADIC CONGENITAL MALFORMATION SYNDROMES: Wilms-aniridia-genital anomalies (WAGR) • Wilms tumor risk (50%)






Hemihypertrophy • Wilms tumor risk • neuroblastoma • hepatoblastoma • adrenal cancer

o regional overgrowth of tongue, face, torso, limb




o prominent eyes, shallow infraorbital region

o high birth weight, macrosomia, macroglossia, hemihypertrophy

o mental & postnatal growth retardation o earlobe creases, helical pits o omphalocele & umbilical hernia (70%) o neonatal hypoglycemia o renal cysts, nephromegaly,

hydronephrosis





Cryptorchidism • testicular malignancy

o cryptorchidism § clinical diagnosis

Gonadal dysgenesis • gonadoblastoma

o gonadal dysgenesis § clinical diagnosis

Ollier enchondromatosis • chrondrosarcoma

o enchondromatosis § clinical diagnosis

Maffucci • chrondrosarcoma

o enchondromatosis o hemangiomatosis

§ clinical diagnosis

MISCELLANEOUS SYNDROMES:

Chediak-Higashi • lymphoma

o partial albinism o recurrent bacterial infections o neutropenia, granulocytic swollen cytosol

lysosomes

§ autosomal recessive § aggregate of clinical

feature

Familial Sipple multiple endocrine neoplasia • multifocal medullary

thyroid carcinoma • pheochromocytoma

o marfanoid habitus, acromegalic facies o scoliosis, pectus excavatum, pes cavus o hypotonia o mucosal neuroma o parathyroid hyperplasia

§ aggregate of clinical feature

Tyrosinemia • hepatocellular

carcinoma

o nodular liver cirrhosis, hepatosplenomegaly

o renal tubular defect

§ autosomal recessive § aggregate of clinical

feature § tyrosine metabolism

disorder, high plasma tyrosine

27

levels

SIBLING WITH MALIGNANCY AND FAMILIAL CANCER: Retinoblastoma sibling/first cousin • retinoblastoma risk (5%

unless one parent is a carrier or affected when the risk is 50%)

o if one parent is a carrier or has bilateral/heritable retinoblastoma, there is a 50% risk of retinoblastoma (associated with spontaneous & radiation-induced osteosarcoma, soft-tissue sarcoma, melanoma, glioblastoma multiforme risk)





Wilms sibling • Wilms tumor risk (small

increase) • other cancer risk (small

increase)

o rare familial cases § possible autosomal dominant in some familial cases

§ WT1 mutation study (if available)

Neuroblastoma sibling • neuroblastoma risk

(small increase) • other cancer risk (small

increase)


Leukemia sibling • leukemia risk (small

increase) • other cancer risk (small

increase)

o rare familial cases § genetics not known

Thyroid, bladder & urologic tumor family • thyroid tumor risk • bladder tumor risk • urologic tumor risk

o rare familial cases § aggregate of clinical feature

Sarcoma, breast, brain, lung, leukemia, larynx & adrenal tumor (SBLA) family • sarcoma risk • breast cancer risk • brain tumor risk • lung cancer risk • laryngeal cancer risk • adrenal tumor risk


Colon & endometrial adenocarcinoma • colon cancer risk • endometrial

adenocarcinoma risk


Lymphoma & colon cancer • lymphoma risk • colon cancer risk


28

SURVIVORS OF PRIOR MALIGNANCY Bilateral retinoblastoma survivor • retinoblastoma risk in

offspring (50%)

o each offspring has a 50% risk of bilateral retinoblastoma (patient & offspring associated with spontaneous & radiation-induced osteosarcoma, soft-tissue sarcoma, melanoma, glioblastoma multiforme risk)





Wilms tumor survivor • radiation-induced

benign osteochrondroma, osteosarcoma, breast cancer

o no clinical abnormalities § no aggregate of clinical features

Hodgkin lymphoma survivor • radiation-induced

osteochrondroma, osteosarcoma, breast cancer

• alkylator or etoposide-induced acute nonlymphoblastic leukemia

o no clinical abnormalities § no aggregate of clinical features

TABLE #19: SYNDROMES WITH KNOWN GENETICS FOR WHICH CANCER SCREENING AND SURVEILLANCE ARE RECOMMENDED Cancer-Associated Syndromes

Genetics Known General Cancer Screening and Surveillance Guidelines: Specific Recommendations should come from Institutional Genetists and Pediatric Oncologists

Beckwith-Wiedemann syndrome (BWS) • Wilms tumor risk

(10%) • hepatoblastoma • adrenal cancer • leukemia • brain tumor • neuroblastoma • rhabdomyosarcoma

o 11p15 duplication o overexpression of IFG-2

at 11p15

§ physical examination, abdominal ultrasound, urinalysis, CBC, serum alpha fetoprotein, and urine catecholamines, frequency as recommended

§ counsel patient & parental lifelong vigilance for cancer


o X-linked recessive o GPC3 gene mutation at

Xp26

§ physical examination, abdominal ultrasound, urinalysis, and CBC, frequency as recommended

§ counsel patient & parental lifelong

29

vigilance for cancer Bloom • leukemia risk (25%) • lymphoma • stomach cancer • colon cancer • breast cancer • Wilms tumor

o autosomal recessive o DNA-repair disorder


o BLM (DNA helicase) mutation at 15q26.1

§ physical examination, abdominal ultrasound, urinalysis, and CBC, frequency as recommended


§ colon and breast cancer screening programs in adulthood



o autosomal recessive o heterogeneous disorder

with at least 4 gene mutations

§ physical examination, abdominal ultrasound, CBC, and serum alpha fetoprotein, frequency as recommended


Ataxia-telangiectasia • lymphoreticular

cancer • acute lymphoblastic

leukemia • breast cancer

(including carriers that have increased risk)

o autosomal recessive o DNA repair disorder o ATM mutation at 11q22-

23

§ physical examination, abdominal ultrasound, and CBC, frequency as recommended


§ breast cancer screening program in adulthood

DeSantis-Cacchione xeroderma pigmentosa • early skin cancer with


o autosomal recessive o DNA exicision-repair

disorder o heterogeneous disorder

at several gene loci

§ physical examination, and dermatology and ophthalmology assessment, frequency as recommended


Yunis-Ramsay 13q

deletion • bilateral

retinoblastoma risk (100%)

• osteosarcoma • soft-tissue sarcoma • melanoma • glioblastoma

multiforme • other cancers


o autosomal dominant o RB1 oncogene mutation

at 13q14

§ Screening fundal EUA and clinical fundal examination, and oncology assessment, frequency as recommended


§ RB1 gene mutation molecular identification for at-risk individuals and family members (if available)

Von Recklinghausen neurofibromatosis Type I • malignant peripheral

nerve sheath tumor • leukemia (AML,

JCML)

o autosomal dominant o NF1 putative tumor


§ physical examination, and dermatology, ophthalmology, and auditory assessment, frequency as recommended


Peutz-Jeghers • pancreatic cancer • breast cancer • lung cancer

o autosomal dominant o STK11 (LKB1) tumor

suppressor gene mutation at 19p13.3

§ physical examination, testicular and GI examination, abdominal, pelvic & scrotal ultrasound, and chest X-ray, frequency as recommended

30

• genitourinary cancer § counsel patient & parental lifelong vigilance for cancer


Rothmund-Thomson (RTS) • multicentric

osteosarcoma • skin cancer

o autosomal recessive o DNA repair disorder o fibroblast chromosomal

instability

§ physical examination, and dermatology and bone scan assessment, frequency as recommended


Gardner syndrome (FAP familial adenomatous polyposis polyposis coli with extracolonic disease) • colorectal cancer • hepatoblastoma • brain tumor • adrenal adenoma

o autosomal dominant o APC tumor suppressor

gene mutation at 5q21-22

§ physical examination, abdominal ultrasound, serum alpha fetoprotein, and ophthalmologic and colonoscopy assessment, frequency as recommended


§ colon cancer screening program in adulthood



• lymphoma

o autosomal recessive o APC, p53, PMS2 gene

mutations o DNA replication errors &

instability

§ physical examination, CBC, and ophthalmologic and colonoscopy assessment, frequency as recommended


§ colon cancer screening program in adulthood

Bannayan-Riley- Ruvalcaba-Myhre-Smith • breast cancer • renal cancer

o autosomal dominant o PTEN tumor suppressor

gene mutation at 10q23.3

§ physical examination, abdominal ultrasound, and urinalysis, frequency as recommended


§ breast & renal cancer screening program in adulthood


(90%) • medulloblastoma

(5%) • melanoma • breast cancer • lung cancer • leukemia (CLL) • non-Hodgkin

lymphoma

o autosomal dominant o PATCH gene mutation

at 9q

§ physical examination, CBC, chest X-ray, echocardiogram, abdominal ultrasound, and dental and dermatology assessment, frequency as recommended


§ breast & lung cancer screening program in adulthood

Wilms-aniridia-genital anomalies (WAGR) • Wilms tumor risk

(50%)

o sporadic o contiguous WT1 &


§ physical examination, urinalysis, abdominal ultrasound, and ophthalmology assessment, frequency as recommended



thyroid carcinoma

o autosomal dominant o RET oncogene mutation

at 10q11.2

§ physical examination with BP assessment, urine catecholamines, and thyroid ultrasound, frequency as recommended

§ counsel patient & parental lifelong

31



vigilance for cancer § RET oncogene DNA testing for at-risk

individuals (if available) § some specialists suggest prophylactic

thyroidectomy at age 4-5 years in at-risk individuals




o trisomy 21 or translocation 21

§ physical examination, abdominal ultrasound, CBC, and urine catecholamines, frequency as recommended


Rubinstein-Taybi • medulloblastoma risk

(5%) • neuroblastoma • leiomyosarcoma • seminoma • embryonal carcinoma

o autosomal dominant o CREB-binding protein

gene mutation with microdeletion & re-arrangement at 16p13.3

§ physical examination, abdominal ultrasound, and urine catecholamines, frequency as recommended


Denys-Drash (DDS) • Wilms tumor risk

(90%)

o sporadic o autosomal dominant o WT1 mutation at Zn

finger region

§ physical examination, abdominal ultrasound, renal function tests, and urinalysis, frequency as recommended


Frasier • Wilms tumor risk • gonadoblastoma

o autosomal dominant o WT1 mutation at a


§ physical examination, abdominal ultrasound, renal function tests, and urinalysis, frequency as recommended


Severe male genital anomaly • Wilms tumor risk

o sporadic o some have protein-

truncating type of WT1 mutation

§ physical examination, abdominal ultrasound, and urinalysis, frequency as recommended


45X/46XY mixed gonadal dysgenesis • gonadoblastoma

o 45X/46XY § physical examination, and abdominal, pelvic & scrotal ultrasound, frequency as recommended


§ some specialists suggest prophylactic gonadectomy at diagnosis in at-risk individuals

32


o sporadic o 45X/46XX with low-level

XY mosaicism

§ physical examination, and abdominal & pelvic ultrasound, frequency as recommended


§ some specialists suggest prophylactic gonadectomy at diagnosis in at-risk individuals


(mediastinal & cerebral)

• male breast cancer

o sporadic o XXY

§ physical examination, serum alpha fetoprotein & beta HCG, and abdominal & pelvic ultrasound, frequency as recommended



§ some specialists suggest prophylactic mastectomies if gynecomastia present

PDF File #5: DETAILED DESCRIPTION OF THE SYNDROMES WITH UNKNOWN GENETICS FOR WHICH CANCER SCREENING AND SURVEILLANCE ARE ALSO RECOMMENDED.

• These recommendations in Table #20 are only meant to provide a general guideline. It is also recommended that the patients and their families be referred to a pediatric oncologist for counseling and education of their cancer risk, and for implementing standard practice cancer screening and surveillance. Although the genetics may be unknown, a genetic consultation is also recommended.

TABLE #20: SYNDROMES WITH KNOWN GENETICS FOR WHICH CANCER SCREENING AND SURVEILLANCE ARE RECOMMENDED Cancer-Associated Syndromes

Genetics General Cancer Screening and Surveillance Guidelines: Specific Recommendations should come from Institutional Genetists and Pediatric Oncologists

Sotos • Wilms tumor risk • acute lymphoblastic

leukemia • non-Hodgkin

lymphoma • small-cell lung

cancer • hepatocellular

cancer • neuroblastoma

o genetics not known

§ physical examination, abdominal ultrasound, urinalysis, CBC, serum alpha fetoprotein, and urine catecholamines, frequency as recommended


Hemihypertrophy • Wilms tumor risk

o genetics not known § physical examination, abdominal ultrasound, urinalysis, CBC, serum alpha

33

• neuroblastoma • hepatoblastoma • adrenal cancer

fetoprotein, and urine catecholamines, frequency as recommended


PDF File #6: DETAILED DESCRIPTION OF RETINOBLASTOMA AS THE PARADIGM FOR CANCER SCREENING AND SURVEILLANCE BASED ON INFORMATIVE IDENTIFICATION OF THE UNIQUE RB1 GENE MUTATION IN EACH FAMILY.

• Retinoblastoma is a genetically induced cancer with a sporadic and a germline form. Sixty percent of cases are unilateral, and 40% are bilateral. Two-fifth to 1/2 of cases are heritable (all of the bilateral cases and 1/6 of the unilateral cases), with a germline RB1 gene mutation that 50% of their offspring will inherited causing them to develop retinoblastoma tumors.

o Since only one-tenth of cases are familial, and early warning symptoms are subtle and often missed by parents and physicians, early diagnosis of non-familial cases is rare. One possible solution to early diagnosis is state-mandated periodic dilated-pupil-retina-screening from infancy.

o Another one-tenth of cases exhibit the congenital abnormalities associated with the Yunis and Ramsay 13q deletion syndrome. The solution to early diagnosis in such patients is alertness on the part of physicians.

• Knudson (1971) has formulated a seminal “Two-Hit Hypothesis” on embryonal tumorigenesis based on the epidemiologic statistics for retinoblastoma, Wilms tumor, and neuroblastoma. Knudson proposed that tumor initiation requires two mutations: o For those patients with familial heritable retinoblastoma that carry on one

allele of chromosome 13q, a germline RB1 gene mutation (present since conception in every cell of the body), there is a predisposition for multiple early-onset retinal tumors in both eyes (approximately 1/4 of cases) or in only one eye (approximately 1/6 of cases), when random somatic inactivation (relatively common) occurs as a second event in the remaining allele.

o For those patients with sporadic non-heritable retinoblastoma that carry on two normal germline RB1 genes in every cell of the body, they could only develop a retinal tumor when two random somatic inactivation events (relatively uncommon) occurs in the RB1 gene on both alleles within a single retinal cell.

• Detection of unique familial mutations on the huge 180-kb 27-exon RB1 gene is difficult since there are no hot spots where the mutations cluster. o One of the most efficient ways is an automated multiplex RB1 mutation

identification strategy, which has an 80%-sensitivity and a 100%-specificity, performed on acid-citrate dextrose or heparinized blood leukocyte DNA from bilateral retinoblastoma patients, and from fresh or

34

leukocyte DNA from bilateral retinoblastoma patients, and from fresh or frozen tumor DNA from unilateral retinoblastoma patients (in which it is necessary to avoid misleading polymorphisms).

o First, all RB1 exons and the promoter region are analyzed by PCR for size-change and copy number-change.

o Then, the entire RB1 gene is directly sequenced if PCR has been non-informative.

• Because the one-time-cost of molecular mutation identification of the RB1 gene has been shown to be much less than the cumulative costs for repeated fundi screening for retinoblastoma tumors at EUAs and Clinic Visits for siblings and first cousins at-risk in the first 3-5 years of life, RB1 testing is fast becoming a part of universal health care. o Then, the entire RB1 gene is directly sequenced if PCR has been non-

informative.

• Early identificaton of RB1 gene mutations allows:

o Efficient pre-symptomatic cancer screening for at-risk siblings and first cousins by frequent EUAs to detect and treat small tumors by laser therapy and/or chemotherapy, so as to avoid enucleation and radiation for big tumors detected late.

o Elimination of repeated fundi screening for retinoblastoma tumors at EUAs and Clinic Visits in the first 3-5 years of life for siblings and first cousins proven not to be at-risk.

o Great savings in terms of potential morbidity, mental agony, medical costs, parental time and finances, and interrupted schooling.

o Risk identification for relatives provides a rational basis for genetic counseling and disease-risk counseling.

o Risk identification for relatives also allows the conveyance of reassuring definitive information critical for determination of life-style and family-planning for the present and the next generation.

o Informative amniocenthesis (16 weeks and 32-34 weeks) and chorionic villi biopsy (10 weeks) for prenatal identification of the RB1 gene mutation in siblings and offspring.

o Early detection and lasering of small tumors in affected babies identified by amniocenthesis or chorionic villi biopsy and induced early at 36 weeks.

o Close monitoring to detect tumors early in the first 3-5 years of life of affected babies identified by amniocenthesis or chorionic villi biopsy.

o Preventive strategies to attempt to avoid secondary cancer-inducing radiation and alkylating agent-type chemotherapy in heritable retinoblastoma patients identified.

o Education and counseling of heritable retinoblastoma patients identified

35

on their lifelong risk of approximately 6% for spontaneous secondary cancers (osteosarcoma, melanoma), their potential risk of up to 50% by 50 years for radiation-induced secondary cancers (osteosarcoma, undifferentiated sarcoma, melanoma, glioblastoma multiforme), and their potential risk of up to 5% for alkylating agent-induced or epipodophyllotoxin-induced secondary acute myeloid leukemia.

• Amniocenthesis is useless when the RB1 mutation has not been identified:

o In utero ultrasonographic screening may be performed in such cases, and babies at-risk considered for early induction at 36 weeks if a suspicious ocular lesion is identified.

• One possibility for diagnosing non-familial retinoblastoma early is to mandate retina screening as part of well-baby checkups. An example of this is the California legislature secured by the Retinoblastoma International in Los Angeles through the good offices of Assemblyman Robert Hertzberg, which designated October 1999 as the “Retinoblastoma Awareness Month”, and legislated in August 2000 the requirement for physicians to conduct dilated pupil eye examination in all infants by 2 months of age. This resolution is supported by the American Academy of Pediatrics, which has been charged with the task of establishing Implementation Guidelines nationwide by 2002.

PDF File #7: DETAILED CONCLUSIONS.

• Early diagnosis and treatment of cancer is of paramount importance:

o Although cancer is rare in children, it causes considerable suffering for patients and families, and ranks second only to trauma as the cause of death in children. It is a costly disease to prevent and to treat. It is a highly emotive disease, which is a significant cause of concern for parents and physicians. In most cases, cancer occur unexpectedly without any family history, predilection or apparent warning.

• Certain congenital abnormalities may forewarn a predisposition for cancer:

o Such congenital abnormalities may long precede the presentation of certain cancers. Some syndromes have known genetics but the genetics are unknown in other conditions. Some syndromes present with gross congenital abnormalities but others only show subtle findings. Some syndromes are obvious at birth but the abnormalities only evolve over time in others.

• Early diagnosis of certain cancers may be facilitated by the recognition of their associated syndromes:

o The traditional way is to classify syndromes morphologically. Using such a morphological classification schema, it is difficult and time-consuming

36

to identify and cross-reference the cancer-associated syndromes. o An alternative way is to classify and cross-reference the cancer-

associated syndromes by their major presenting clinical identifiers. Such an alternative classification schema facilitates early recognition of congenital abnormalities that are associated with a predisposition to cancer. Early diagnosis of such cancers allows early intervention, possibly resulting in a better outcome of therapy.

• Early diagnosis of cancers allows timely institution of preventive measures:

o Such preventive strategies include pre-symptomatic cancer screening, risk identification for relatives, informative amniocentesis for unborn siblings and offspring, genetic counseling and counseling for the risk of secondary cancers. Appropriate preventive strategies allow cancers to be diagnosed earlier and treated more successfully, thereby resulting in considerable savings in terms of human suffering and health economics.

PDF File #7: DETAILED BIBLIOGRAPHY.

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