Table 2.
Familial cancer syndromes involving the head and neck: disease phenotype
| Disease phenotype (gene) | Main H&N presentation | H&N lesion | H&N lesion | H&N lesion | Associated lesions |
|---|---|---|---|---|---|
| 1 | 2 | 3 | |||
| Nevoid basal cell carcinoma syndrome: | Multiple basal cell carcinomas; | Cleft lip/palate | Ocular anomalies | Macrocephaly | Calcification of the falx cerebri; |
| Nevoid basal cell carcinoma syndrome 1 (PTCH1) | Odontogenic keratocyst (OKC) of the jaw | Palmar and plantar pits; Bifid or fused ribs; Medulloblastoma | |||
| Nevoid basal cell carcinoma syndrome 2 (SUFU) | |||||
| Neurofibromatosis 1 (NF1) | Multiple café-au-lait macules; Cutaneous neurofibromas; Orbitofacial neurofibromatosis | Optic pathway glioma | Iris hamartomas (Lisch nodules) | Orbital dysplasia | Neurofibroma and MPNST; Skinfold freckling in the axillary, inguinal, and submammary regions; Duodenal neuroendocrine tumor |
| Pheochromocytoma and paragangliomas | |||||
| Malignant peripheral nerve sheath tumour (MPNST); Rhabdomyosarcoma, Glomus tumours of the digits | |||||
| Familial adenomatous polyposis with Gardner syndrome variant (APC) | Desmoid fibromatosis: maxillary sinus, nasopharynx, and oral cavity | Bone osteomas | Dental structures: supernumerary teeth | Compound odontomas located in the anterior maxilla, or complex odontomas in the posterior mandible or anterior maxilla | > 100 adenomatous colorectal polyps; Gastric and duodenal polyps; |
| Cribriform morular thyroid carcinoma; Hepatobiliary tree and pancreas carcinoma; | |||||
| Childhood hepatoblastoma (1%); Adrenocortical adenomas /adenocarcinomas; medulloblastoma (< 1%); Adamantinomatous craniopharyngioma | |||||
| Brooke-Spiegler syndrome (CYLD) | Salivary gland basal cell adenoma, membranous-type, multicentric and bilateral | Spiradenoma, cylindroma and spiradenocylindroma mainly involve the skin of the head and neck | Trichoepitheliomas predominantly affect the nasolabial folds | ||
| PTEN hamartoma tumor syndrome/Cowden syndrome: | Papillomas on the lips, tongue, buccal mucosa; | Mucocutaneous neuromas | Adult Lhermitte-Duclos disease (cerebellar tumors); | ||
| Cowden syndrome 1 (PTEN) | Facial trichilemmomas | Breast cancer; | |||
| Cowden syndrome 4 (KLLN) | Non-medullary thyroid cancer; | ||||
| Cowden syndrome 5 (PIK3CA) | Megalocephaly; Endometrial carcinoma; | ||||
| Cowden syndrome 6 (AKT1) | |||||
| Cowden syndrome 7 (SEC23B) | Multiple GI hamartomas or ganglioneuromas | ||||
| Hereditary paraganglioma syndromes: | |||||
| SDH-deficient syndromes: | |||||
| PGL1 (SDHD) | H&N Paraganglioma (most common head and neck PGL: ~ 50%) | Pheochromocytoma; Renal cell carcinoma; | |||
| Gastrointestinal stromal tumor; | |||||
| Pituitary tumor | |||||
| PGL2 (SDHAF2) | H&N Paraganglioma | ||||
| PGL3 (SDHC) | H&N Paraganglioma | Renal cell carcinoma; | |||
| Gastrointestinal stromal tumor | |||||
| PGL4 (SDHB) | H&N Paraganglioma | Renal cell carcinoma; | |||
| Gastrointestinal stromal tumor; | |||||
| Pituitary tumor | |||||
| Abdomen and thorax paraganglioma | |||||
| PGL5 (SDHA) | H&N Paraganglioma | Pheochromocytoma; Renal cell carcinoma; | |||
| Gastrointestinal stromal tumor; | |||||
| Pituitary tumor | |||||
| Multiple endocrine neoplasia type 2/MEN2 (RET) | H&N Paraganglioma rare | Medullary thyroid carcinoma; | |||
| Parathyroid proliferations; | |||||
| Oral ganglioneuromas; Mucosal neuromas oropharynx, lips, and eyelids | Pheochromocytoma | ||||
| VonHippel-Lindau (VHL) | H&N Paraganglioma rare | Central nervous system and retinal hemangioblastoma | Clear cell renal cell carcinoma; | ||
| Neuroendocrine tumors; | |||||
| Endolymphatic sac tumor of middle ear | Pancreatic serous cystadenomas | ||||
| Neurofibromatosis type 1 (NF1) | H&N Paraganglioma rare | Neurofibroma and MPNST; Ocular manifestations; Duodenal neuroendocrine tumor | |||
| Others syndromes/genes: MAX; TMEM127; FH; KIF1B; EGLN1,2,3; EPAS1; MEN1 | H&N Paraganglioma rare | ||||
| Multiple endocrine neoplasia type 2B/MEN2B (RET) | Oral ganglioneuromas; Mucosal neuromas in MEN 2B can involve the oropharynx, lips, and eyelids | Thickened corneal nerves | Medullary thyroid carcinoma; Pheochromocytoma; Parathyroid proliferations; | ||
| Oral and intestinal ganglioneuromas; Marfanoid body habitus | |||||
| Hyperparathyroidism-Jaw tumour syndrome (CDC73) | Cemento-ossifying fibroma | Parathyroid adenoma and carcinoma | Fibro-osseous jaw lesions | Renal and uterine tumours | |
| Li-Fraumeni syndrome: | H&N and laryngeal carcinomas | Squamous cell carcinomas larynx, pharynx and oral cavity | Breast, soft tissue, bone, brain, adrenal glands, and female genital tract carcinomas | ||
| Li–Fraumeni syndrome (TP53-associated) | |||||
| Li–Fraumeni syndrome (CHEK2-associated) | |||||
| Fanconi anemia (FANCA) | Head and neck squamous cell carcinoma (FA-HNSCC) frequently present as poorly differentiated | Oral potentially malignant disorders (OPMD) | Increased risk for hematologic and solid malignancies | ||
| Dyskeratosis congenita (DKCA) | Oral leukoplakia | Oral leukoplakia seen on the tongue | Triad of oral leukoplakia, nail dystrophy, and reticulate hyperpigmentation; | ||
| Bone marrow failure; Increased malignancy; Lung and liver diseases | |||||
| Ataxia telangiectasia syndrome (ATM) | Head and neck squamous cell carcinoma (HNSCC) | Lymphoid neoplasms of the B and T-cell lineage in the head and neck, including involvement of the Waldeyer ring | Telangiectases in sun exposed areas as bulbar conjunctiva and bridge of nose | Neurologic manifestations and conjunctival telangiectasias | |
| Bloom syndrome (BLM) | Head and neck squamous cell carcinoma (HNSCC) | Rash on cheeks and nose | Small size and lack of subcutaneous tissue | ||
| Men and infertile and women have early menopause | |||||
| Colorectal and breast cancer | |||||
| Von-Hippel Lindau syndrome (VHL) | Endolymphatic sac tumor, bilateral | Hemangioblastomas cerebellum, spinal cord, brain, and retina | Kidney cysts | ||
| and renal cell carcinomas; | |||||
| Adrenal pheochromocytomas and extraadrenal paragangliomas; | |||||
| Pancreatic neuroendocrine tumors; Cysts and serous cystadenomas | |||||
| Tuberous sclerosis syndrome: | Predominantly cutaneous and oral manifestations; | Fibrous cephalic plaques in forehead and scalp | Dental enamel loss on the incisal border and tooth | Cutaneous angiofibromas; Shagreen patches; Subungual fibromas; Cardiac rhabdomyomas; Pulmonary lymphangioleiomyomatosis; | |
| Tuberous sclerosis type 1 (TSC1) | Facial angiofibromas; | ||||
| Tuberous sclerosis type 2 (TSC2) | Shagreen patches and poliosis in scalp | Renal angiomyolipomas |