Ataxia Telangiectasia (Louis-Bar syndrome)

• Inheritance: AR

• Gene

  • ATM: 11q22-q23.1, mediates cell cycle arrest in response to ionizing radiation through the phophorylation of targets including p53, cAbl, BRCA1, H2AX, IkB-alpha and chk1.

• Clinical Manifestations

  • Onset during 2nd year of life: progressive cerebellar ataxia, oculomotor apraxia, dysarthria, and dystonia; muscular atrophia;

  • Telangiectasia: facial region exposed to sunlight, and eyes (conjunctiva).

  • Combined immunodeficiency (70 %): thymus hypoplasia, and IgG2/4, IgA, IgE deficiency.

  • Other features: growth retardation; hypogonadism; occasionally diabetes mellitus.

• Neoplastic Risks

  • 100× risk of cancers, mainly of T- cell tumor (a 70× and 250× risks of leukemia and lymphoma respectively) and B-cell malignancies, but not myeloid leukemia.

  • Carcinomas of the skin, ovary, breast, and stomach have also been described.

Bannayan-Riley-Ruvalcaba Syndrome (Bannayan-Zonana syndrome, Riley-Smith syndrome)

• Inheritance: AD

• Gene

  • PTEN, 10q23. protein tyrosine phosphatase, tumour suppressor gene.

• Clinical Manifestations

  • Overgrowth at birth, postnatal growth decelerates;

  • Macrocephaly, hypotonia and mental deficiency;

  • Subcutaneous and visceral lipomas and hemangiomas, and intestinal juvenile polyposis;

  • Myopathy of the proximal type in 2/3 of cases, pigmentation spots of the male genitalia;.

• Neoplastic Risks

  • multiple lipomas (75% of cases).

  • hemangiomas (40%).

  • hamartomatous polyps (ileum and colon; 45%).

  • lymphangiomas (10%).

Beckwith-Wiedemann Syndrome (EMG syndrome)

• Inheritance: AD;

• Gene

  • H19, IGF2, CDKN1C; 11p15.5.

• Clinical Manifestations

  • EMG triad: exomphalos-macroglossia-gigantism;

  • Abdominal wall defects and pre- and postnatal growth abnormalities, earlobe pits or creases, facial nevus flammeus, hypoglycemia;

  • Renal abnormalities and hemihypertrophy (unilateral overgrowth).

• Neoplastic Risks

  • Nephroblastoma (Wilms tumour);

  • Adrenocortical carcinoma;

  • Rhabdomyosarcoma;

  • Myxoma, fibroma, hamartoma

  • Hepatoblastoma.

Birt-Hogg-Dubé Syndrome (BHD)

• Inheritance: AD

• Gene

  • FLCN, 17p11.2.

• Clinical Manifestations

  • Triad: benign tumors of the hair follicle, spontaneous pneumothorax and kidney tumors;

  • Colonic polyps and colorectal cancer;

  • Multiple angiofibromas, lipomas and collagenomas have also been reported.

• Neoplastic Risks

  • Renal tumors (27%):chromophobe (34%), hybrid chromophobe/oncocytic (50%), oncocytoma (5%), and clear cell renal carcinoma (9%);

  • Benign tumors of the hair follicle: fibrofolliculomas, trichodiscomas and/or acrochordons.

Bruton's Agammaglobulinemia (X-linked agammaglobulinemia (XLA)

• Inheritance: XR

• Gene

  • BTK (Bruton's tyrosine kinase), Xq21.3-Xq22; Btk family of hematopoietic kinase.

• Clinical Manifestations

  • Immunological deficiency from late infancy, frequent bacterial infections start from 6 months of life;

  • Very small tonsils and lymph nodes;

  • Marked decrease of serum immunoglobulins of all isotypes.

• Neoplastic Risks

  • Low or no.

Carney Complex (CNC)

• Inheritance: AD. 70% CNC are familial

• Gene

  • CNC1: PRKARIA (100%), 17q23-24. Bind cAMP and regulate the function of the catalytic subunits of PKA, may act as a tumor-suppressor.

  • CNC2: CNC2, 2p16.

• Clinical Manifestations

  • Spotty skin pigmentation lesions: lentigines (small, brown to black, non or slightly elevated, round or irregular) and blue nevi (large, blue to black, domed lesion) observed primarily in the face, eyelids, ears, and borders of the lips are the most common clinical manifestation of CNC (77%). Lentigines tend to fade with the age, usually after the fourth decade of life.

  • Myxomas: multicentrical heart myxomas (53%); skin myxomas (33%) in the eyelid, the external ear canal, the nipple, the oropharynx, the female genital tract and the female pelvis. Breast myxomas are often bilateral and present in more than 70% of adult women with CNC.

  • Psammomatous melanotic shwannomas (10%): may occur anywhere in the peripheral nervous system, but most frequently in the gastrointestinal tract and paraspinal symphatetic chain.

  • Breast ductal adenomas (3%): unusual mammary tumors akin to intraductal papillomas, have been detected in  of CNC cases.

  • Endocrine lesions: testicular neoplasms (33%), primary pigmented nodule adrenocortical disease (PPNAD) (26%), growth hormone (GH) and prolactin-producing pituitary tumors (14%) and thyroid cancer (5%).

• Neoplastic Risks

  • Skin lesions: lentigines, blue nevi.

  • Myxoma: heart, skin and breast.

  • Psammomatous melanotic shwannoma.

  • Breast ductal adenomas.

  • Testicular tumors.

  • PPNAD.

  • Growth hormone and prolactin-producing pituitary tumors.

  • Thyroid neoplasms.

Congenital Myofibromatosis (Infantile myofibromatosis, Congenital generalized fibromatosis)

• Inheritance: AD

• Gene

  • Unknown.

• Clinical Manifestations

  • Common fibromatoses that present during childhood. Presentation may occur as an adult or even prenatally;

  • Grow and regress without known initiation factors;

  • Diagnostic classification depends solely upon the location of the tumors. Solitary infantile myofibromatosis involves the soft tissues.  Multiple infantile myofibromatoses also occur in the bone tissue, and Generalized infantile myofibromatosis  also involves visceral organs.

• Neoplastic Risks

  • Very low.

Congenital Neutropenia (Kostmann syndrome)

• Inheritance: AR

• Gene

  • Neutrophil elastase (ELA2), 19p13.3.

• Clinical Manifestations

  • Usually presents in early childhood and is slightly more common in males. Cyclic forms are slightly more common in females. 90% of patients are diagnosed by 6 months of age.

  • Frequent fevers, skin infections and stomatitis with organisms such as E. coli, S. aureus, and Pseudomonas species.

  • Pathology: neutrophil count usually < 0.2×10^9 /L. Bone marrow shows an arrest in maturation at the promyelocyte stage, often with a monocytosis and sometimes with eosinophilia. The peripheral blood shows a paucity of neutrophils and often monocytosis and eosinophilia.

• Neoplastic Risks

  • Myelodysplastic syndromes (MDS) (50%);

  • Therapy associated MDS (10%);

  • Acute myeloid leukemia (AML, de novo) (25%): most MDS patients transform into AML with a short preleukemic phase.

Multiple hamartoma syndrome (Cowden Disease)

• Inheritance: AD

• Gene

  • PTEN (MMAC1,TEP1), 10q23. Phosphatase, tumor suppressor, negative regulator of the PI3K/Akt signal cell pathway by dephosphorylating PIP3

• Clinical Manifestations

  • Usually occur during the 2nd and 3rd decade;

  • Mucocutaneous papillomatous lesions: facial papules, sometimes trichilemmoma; oral papillomatosis with cobblestone gingiva; acral keratoses;

  • Dystrophic and adenomatous multinodular goiter;

  • Intestinal tract polyps with variable histologies;

  • Adenosis and fibrocystic disease of the breast;

  • Macrocephaly;

  • Lipomas;

  • Genitourinary abnormalities.

• Neoplastic Risks

  • Arethyroid carcinoma (follicular type), 15%;

  • Breast carcinoma: 30%;

  • Other tumors: renal cell carcinoma, neuroendocrine cell carcinoma, germ cell tumor, melanoma, endometrial carcinoma.

Diamond-Blackfan anemia

• Inheritance: AD

• Gene

  • Ribosomal protein S19 (RPS19), 19q13.2;

  • Ribosomal protein S24 (RPS24), 10q22.3.

• Clinical Manifestations

  • Chronic constitutional aregenerative anemia with absent or decreased red cell precursors in bone marrow;

  • Macrocytosis, elevated fetal hemoglobin and increased erythrocyte adenosine deaminase activity;

  • Physical abnormalities (40%): craniofacial and thumb abnormalities, atrial or ventrucular septal defects, short stature, mild retardation.

• Neoplastic Risks

  • Age of malignancy onset from 2 to 43 years;

  • Hematological malignancy (2.5%): primarily ANLL with no FAB preference, ALL, and Hodgkin's disease;

  • Solid tumors: carcinoma of liver and stomach, osteogenic sarcoma.

Familial /sporadic gastrointestinal stromal tumors (GISTs)

• Inheritance: AD

• Gene

  • KIT, 4q12. A transmembrane SCF/MGF receptor with tyrosine kinase activity; binding of ligand (SCF) induces receptor dimerization, autophosphorylation and signal transduction via molecules containing SH2- domains.

• Clinical Manifestations

  • Hyperpigmentation and mast-cell disease may be associated

  • Etiology : GISTs originate from the CD34+/KIT+ interstitial cells of Cajal (ICCs);

  •  Germline/somatic KIT mutations in familial/solitary GISTs.

• Neoplastic Risks

  • GIST.

Familial adenomatous polyposis (FAP)

• Inheritance: AD

• Gene

  • APC, 5q21. Tumour suppressor gene; normally interacts with the adherens junction protein catenin.

• Clinical Manifestations

  • Multiple adenomatous polyps of the colon and the rectum;

  • Polyps also develop in the upper gastrointestinal tract;

  • Pigmented retinal lesions: congenital hypertrophy of the retinal pigment epithelium;

  • Other lesions: jaw cysts, sebaceous cysts, desmoid tumors, and osteomas.

• Neoplastic Risks

  • colorectal cancer: develop from the polyps through a dysplastic stage;

  • Other tumors: Liver (hepatoblastoma), brain (medulloblastoma), thyroid.

Fanconi anemia

• Inheritance: AR

• Gene

  • FANCA, 16q24; FANCC, 9q22; FANCG, 9p13.

• Clinical Manifestations

  • Growth retardation (70%);

  • Skin abnormalities (80%): hyperpigmentation and/or café au lait spots; 

  • Skeletal malformations (60%): particularly radius axis defects (absent or hypoplastic thumb or radius);

  • No immune deficiency (in contrast with most other chromosome instability syndromes);

  • Progressive bone marrow failure: mean age of onset of anemia, 8 yrs;

  • Other (10-30%): renal anomalies, hypogonadism, mental impairment, heart defects, and perhaps diabetes mellitus.

• Neoplastic Risks

  • Myelodysplasia (MDS) and acute non lyphocytic leukaemia (ANLL): 15% of cases, 15000×, mean age at diagnosis 13-15 yrs;

  • Hepatocarcinoma (androgen-therapy induced) in 10%; mean age at diagnosis, 16 yrs;

  • Other cancers in 2-5%: particular squamous cell carcinoma.

Hereditary Paraganglioma (PGL)

• Inheritance: AD

• Gene

  • SDHD, 11q23. A mtochondrial respiratory-chain protein, succinate dehydrogenase complex II, subunit D;

  • SDHC, 1q21. Succinate dehydrogenase complex II, subunit C;

  • SDHB, 1p36.1-p35. Succinate dehydrogenase complex II, subunit B.

• Clinical Manifestations

  • 35% of head and neck paragangliomas are inherited.

• Neoplastic Risks

  • Paraganglioma.

Hereditary non polyposis colorectal carcinoma (HNPCC Syndrome, Lynch Syndrome)

• Inheritance: AD

• Gene: These protein works on DNA mismatch repair pathways. hMSH2 and hMLH1 participate to the recognition of DNA mismatch during DNA replication. They formed complex with hMSH3, hMSH6 and PMS2 allowing the mismatch repair.

  • hMSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1), 2p22-p21;

  • hMLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2), 3p21.3;

  • hMSH6 (mutS homolog 6), 2p16;

  • PMS2 (postmeiotic segregation increased 2), 7p22;

  • PMS1 (postmeiotic segregation increased 1), 2q31.1;

  • TGFßR2 (transforming growth factor beta receptor II), 3p22.

• Clinical Manifestations

  • colorectal cancer, endometrial carcinoma and ovary carcinoma, urinary tract carcinomas, stomach, small bowel and biliary tract carcinoma, and brain tumors. Colorectal carcinoma is characterized by early age at onset, predominantly right sided with an excess of synchrounous and metachronous tumors..

• Neoplastic Risks

  • Colorectal cancer: up to 75% by age 75. The average age of diagnosis, 45 years;

  • Uterine cancer: up to 40%;

  • Ovarian cancer:  <10%.

Hereditary papillary renal cell carcinoma

• Inheritance: AR, AD

• Gene

  • MET, 7q31. Transmembrane tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF)

• Neoplastic Risks

  • Multiple and/or bilateral papillary renal cell carcinomas, median age 45 yrs at diagnosis.

Hereditary breast cancer

• Inheritance: AD

• Gene

  • BRCA1, 17q21. Role in DNA replication, repair transcriptional activation, cell cycle progression;

  • BRCA2, 13q12-13.

  • p53, 17p13. Ubiquitous nuclear protein involved in the control of genome integrity by preventing cells dividing before DNA damage is repaired;

  • PTEN, 10q23. Tumour suppressor;

  • LKB1, 19p13. Serine/threonine kinase; tumor suppressor gene;

  • ATM, 11q22-23. At the cell cycle checkpoint; induces G1 phase arrest.

• Clinical Manifestations

  • BRCA1 (17q12-21) mutation carrier : early age at onset, risk for breast cancer 50 -85 %, ovarian cancer 15-45 %; possible increased risk of prostate cancer and colon cancer

  • BRCA2 (13q12-13) mutation carrier: risk for breast cancer 30-85 %; male breast cancer (6 %) and ovarian breast cancer (10 -20%); increased risk of prostate, laryngeal cancer and pancreatic cancer.

  • other genetic conditions associated with increased breast cancer risk are:

    • Li-Fraumeni syndrome (p53 mutation, 17p13):  very early onset of neoplasms, including soft tissue sarcoma, osteosarcoma, brain tumors, leukemia, lung cancer, laryngeal cancer and adrenocorteal cancer; lifetime risk for cancer: about 90 % for women and 70 % for men

    • Cowden syndrome (PTEN, 10q23): inherited condition of multiple hamartomas with increased risk of bilateral breast cancers and thyroid tumors;

    • Muir-Torre Syndroma ( MSH2 , MLH1): cancers of breast,  gastro intestinal-tract, skin, genitourinary system;

    • Peutz-Jeghers Syndrome: abnormal melanin deposits, GI-polyposis, cancer of breast, GI-tract, uterus, ovary and testis.

    • Ataxia-teleangiectasia (chromosome 11q21).

• Neoplastic Risks

  • 5-10 % of all breast cancers have hereditary background;

  • In hereditary breast cancer: 30-40 % BRCA1, 10-30 % BRCA2, <1 % Tp53, <1 % o PTEN, 1/3 unknown mutations.

Li-Fraumeni Syndrome

• Inheritance: AD

• Gene

  • p53, 17p13.

    • Most commonly mutated gene in human cancers possessing multiple properties;

    • Two major roles: firstly in cell cycle arrest, predominantly in the G1 phase of the cell cycle, but also with a role in G2 and mitotic checkpoints; secondly the induction of apoptosis;

    • Both these are induced upon DNA damage, and the response depends on many things including the type of damage and the cell type

    • p53 is a transcription factor with a central sequence-specific DNA binding domain and a N-terminal transactivation domain; upon DNA damage, the level of p53 increases markedly, and the DNA-binding properties are activated; the levels of p53 are regulated primarily post-transcriptionally (including phosphorylation and acetylation)

• Clinical Manifestations

  • Li-Fraumeni syndrome (LFS) are defined by: a proband with a sarcoma aged under 45 years, with a first degree relative with cancer under 45 years and another first or second degree relative with any cancer under 45 years or a sarcoma at any age.

• Neoplastic Risks

  • Tumors of bone, cartilage and soft tissue, early-onset female breast cancer, brain and spinal cord tumours, childhood adrenocortical tumours, Wilms' tumour and malignant phyllodes tumors;

  • No increased incidence of cancers of colorectal, lung, bladder and gynecological;

  • Other tumors: pancreas, peripheral nervous system, leukemia and stomach.

Multiple Endocrine Neoplasia type 1 (MEN1, Wermer's syndrome)

• Inheritance: AD

• Gene

  • MEN1, 11q13. growth-suppressor gene.

• Clinical Manifestations

  • Early onset (15-40 yrs) in 90-100% patients;

  • Presentation: hyperparathyroidism related to multiglandular hyperplasia and/or adenomas; pancreatic neuroendocrine tumors (50-70%), pituitary adenoma (20-40%), adrenocortical hyperplasia, adenomas or cancers (20-70%) and thymic/bronchial neuroendocrine tumors (5-10%); cutaneous lesions, such as angiofibromas, collagenomas, lentiginosis, melanocytic lesions and lipoma (5-10%); less common lesions are infratentorial papillary ependymoma, rhabdomyosarcoma and leiomyosarcoma, and renal and thyroid cancers.

• Neoplastic Risks

  • Pancreatic neuroendocrine tumors: gastrinoma, insulinoma, glucagonoma and VIPoma;

  • Pituitary adenomas;

  • Parathyroid adenomas;

  • Cutaneous and CNS lesions: melanomas, ependymomas and rare astrocytomas.

Multiple Endocrine Neoplasia type 2 (MEN2, 2A-Sipple syndrome, 2B-Gorlin syndrome )

• Inheritance: AD

• Gene

  • RET, 10q11.2. Receptor tyrosine kinase.

• Clinical Manifestations

  • MEN2A (Sipple syndrome): the most frequent form, MTC (95%), pheochromocytoma (50%) and parathyroid hperplasia or adenoma (25%);

  • Familial MTC (FMTC): MTC is the only clinical manifestation;

  • MEN2B (Gorlin syndrome): the least frequent variant, MTC, pheochromocytoma and marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract.

Neurofibromatosis type 1 (NF1, Von Recklinghausen neurofibromatosis, Peripheral neurofibromatosis)

• Inheritance: AD

• Gene

  • NF1/neurofibromin, 17q11.2; GTPase activating protein (GAP), tumour suppressor.

• Clinical Manifestations

  • Diagnosis is made on the ground of at least 2 of the following:

    • café-au-lait spots (no 6 or more with 0. 5 cm of diameter (in pre-puberty))

    • 2 neurofibromas or 1 plexiform neurofibromas (mainly cutaneous)

    • 2 Lisch nodules (melanocytic hamartomas of the iris)

    • freckling in the axillary/inguinal region (Crowe's sign)

    • glioma of the optic nerve

    • distintive bone anomalies (scoliosis, pseudoarthroses, bony defects (orbital wall) ...)

    • positive family history

  • Other features:

    • macrocephaly

    • epilepsy

    • mental retardation in 10 %; learning diabilities in half patients

    • sexual precocity and other endocrine anomalies

    • hypertension (renal artery stenosis)

• Neoplastic Risks

  • Neurofibromas: especially the plexiform variety;

  • Neurofibrosarcomatous transformation (malignant) in 5-10%:

  • Optic nerve gliomas

  • Childhood MDS (myelodysplasia) and ANLL, often with monosomy 7 (monosomy 7 syndrome, 'juvenile myelomonocytic leukaemia'): risk, increased by X 200 -500;

  • Pheochromocytomas

  • Rhabdomyosarcomas.

Neurofibromatosis type 2 (NF2, Central neurofibromatosis, Bilateral acoustic neurofibromatosis)

• Inheritance: AD

• Gene

  • NF2, 22q12. Membrane-cytoskeleton anchor; tumour suppressor.

• Clinical Manifestations

  • Bilateral schwannomas; other central or peripheral nerve schwannomas; meningiomas; ependymomas.

  • hearing loss (average age 20 yrs), tinnitus, imbalance, headache, cataract in 50%, facial paralysis.

  • café-au-lait spots and cutaneous and peripheral neurofibromas may be present, but far less extensively than in NF1.

• Neoplastic Risks

  • Represent about 5 % of schwannomas and meningiomas (2000 ×risk), appearing at the age of 20.

Noonan syndrome (Male Turner syndrome, Pseudo-Turner syndrome)

• Inheritance: AD

• Gene

  • PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11), 12q24.1. SH2 domain-containing protein tyrosine phosphatase, an intracellular signal transducer.
    .

• Clinical Manifestations

  • Facial dysmorphism: broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate and low-set, posteriorly rotated ears;

  • Congenital heart defects (85%): primarily pulmonic stenosis and hypertrophic cardiomyopathy, are present in up to  of affected individuals.

  • Other features: short stature, multiple skeletal defects (spine and chest), webbed neck, mental retardation, cryptorchidism and bleeding diathesis.

• Neoplastic Risks

  • Juvenile myelomonocytic leukemia (JMML):  most common;

  • Acute lymphoblastic leukemia and solid tumors (neuroblastoma and rhabdomyosarcoma).

Peutz-Jeghers syndrome

• Inheritance: AD

• Gene

  • STK11, 19p13.3. Serine/threonine protein kinase.

• Clinical Manifestations

  • Skin: numerous brown or bleuish mucocutaneous macules (melanin spots), especially around the orifices (mouth, including the buccal mucosa, eyes, nostrils, anus, genitalia), on the hands; they tend to disappear with age; (at puberty or in adulthood);

  • Gastrointestinal tract: polyps of amartomatous origin (with a characteristic arborization of nonstriated muscles), any portion of the GI tract; onset for symptoms occurs from the first year of life (median age10-25 years).

• Neoplastic Risks

  • small intestine: 500×

  • stomach: 200×

  • pancreas: 100×

  • colon: 85×

  • esophagus: 60×,

  • ovary: 30×

  • uterus, breast, lung: 15 to 20×

Retinoblastoma

• Inheritance: AD

• Gene

  • RB1 (retinoblastoma susceptibility gene), 13q14. Roles in cell cycle regulation.

• Neoplastic Risks

  • Early childhood: retinoblastoma;

  • Adolescence and adulthood: tumours outside the eye (second primary neoplasms):

    • osteosarcoma

    • melanoma

    • brain tumours (pinealoma), multiple lipomas

Sturge Weber syndrome (Encephalotrigeminal angiomatosis, Angio-encephalo-cutaneous syndrome)

• Inheritance: Sporadic

• Gene

  • N/D.

• Clinical Manifestations

  • Congenital intracranial vascular anomaly, leptomeningeal angiomatosis, mostly involving the occipital and parietal lobes;

  • An ipsilateral facial cutaneous capillary vascular malformation usually affects the upper face in the V1 distribution of the trigeminal nerve.

  • Hemiparesis, hemiatrophy, hemianopia and stroke-like events may occur contralateral to the cortical abnormality.

  • Venous stasis results in ischemia underlying the leptomeningeal angiomatosis leading to calcification and laminar cortical necrosis.

  • Other findings: glaucoma, buphthalmos, enlargement of the choriod plexus and seizures.

• Neoplastic Risks

  • Angiomatosis of the leptomeninges or vessels of the eye (10%). The risk increases to 25% when the entire side of the face is involved and 33% when both sides of the face are affected by port-wine stain.

  • Bony and soft tissue hypertrophy can develop with structures underlying the port-wine stain.

Tuberous Sclerosis (TSC, Bourneville disease)

• Inheritance: AD

• Gene

  • TSC1, 9q34. Protein: Hamartin. Tumor suppressor.

  • TSC2, 16p13. Protein: Tuberin. Tumor suppressor.

• Clinical Manifestations

  • Definition of TS requires either two major features or one major feature plus two minor features.

    • Major features :

      - Facial angiofibromasor forehead plaque
      - Non traumatic ungual or periungual fibroma
      - Hypomelanotic macules (three or more)
      - Shagreen patch ( connective tissue nevus)
      - Multiple retinal nodular hamartomas
      - Cortical tuber
      - Subependymal nodule
      - Subependymal giant cell astrocytoma
      - Cardiac rhabdomyoma, single or multiple
      - Lymphangiomyomatosis
      - Renal angiomyolipoma

    • Minor features :
      - Multiple, randomly distributed pits in dental enamel
      - Hamartomatous rectal polyps
      - Bone cysts
      - Cerebral white matter radial migration lines
      - Gingival fibromas
      - Nonrenal hamartoma
      - Retinal achromic patch
      - " confetti " skin lesions
      - Multiple renal cysts

• Neoplastic Risks

  • Renal angiomyolipomas, multiple and bilateral (75% of children with TSC);

  • Cardiac rhabdomyomas, often congenital, tend to regress in infancy, remain identical in same size through out childhood and can then either again regress or progress (girls) in adolescence;

  • Brain tumors (5-14%), mostly (>90%) subependymal giant cell astrocytomas, or ependymomas;

  • Hamartomas in liver, spleen, and various tissues;

  • Pulmonary lymphangiomyomatosis.

Von Hippel-Lindau

• Inheritance: AD

• Gene

  • VHL, 3p25-26. Tumour-suppressor gene.

• Neoplastic Risks

  • Central nervous system hemangioblastomas (60-80%), frequent multiple tumors;

  • Retinal hemangioblastomas (50%), often multiple and bilateral, mostly occur peripherally but 15% optic disc  locations;

  • Renal cell carcinomas (75%), mostly multifocal and bilateral, always clear cell subtype;

  • Pheochromocytomas, often bilateral, are mostly found in a subset of families, where it can be the only sign of VHL. Extraadrenal paragangliomas are sometimes encountered.

  • Pancreas manifestations occur in up to 77% of patients: isolated or multiple cysts and serous cystadenomas are the most frequent lesions, neuroendocrine tumours occur in about 10-15 % of cases.

  • Endolymphatic sac tumours, only recently recognised as a manifestation of VHL disease, occur in up to 11% of cases.

  • Epididymal cysts, often bilateral, occur in about 54% of men.

  • Cystadenomas of the broad ligament ("adnexal papillary tumour of probable mesonephric origin") are extremely rare but highly specific.
    There are two main clinical types of VHL according to the absence (type 1) or presence of pheochromocytoma (type 2). The type 2 is subdivised in three subtypes, 2A (with low risk of renal cancer and pancreatic tumors); 2B (the full multi-tissues subtype), and 2C (pheochromocytomas only, recently individualised by molecular genetics).

WAGR (Wilms' tumor/aniridia/genitourinary anomalies/mental retardation syndrome)

• Inheritance: Sporadic

• Gene

  • WT1 (Wilms' tumor suppressor gene), 11p13.

• Clinical Presentations and Neoplastic Risks

  • Wilms' tumor: maybe bilaterally

  • aniridia

  • genitourinary anomalies: hypospadias and kryptorchism in males

  • mental retardation

  • growth retardation