Genetic Syndromes Flashcards
Chromosomal abnormalities are detectable in a…
Karyotype
Most chromosomal abnormalities are due to…
- Most are due to abnormalities in meiosis during gamete formation
- Most are not inherited
Common clinical features of chromosomal abnormalities include…
- Malformations
- Developmental delay
- Poor physical growth
- Reproductive failure
Single gene defects…
- Not detectable in karyotype
* Some are new mutations, but most are inherited
Transmission of autosomal dominant disorders…
- Transmitted vertically
* At least one parent is usually affected, but some new mutations occur
Clinical features of autosomal dominant disorders are modified by…
- Reduced penetrance (some individuals inherit the mutant gene but appear normal)
- Variable expressivity (the gene is expressed differently among people who exhibit the trait)
- Age of onset often delayed.
Transmission of autosomal recessive diseases…
- Horizontal transmission: siblings may be affect, but parents and offspring usually are not
- Usually, both parents and some of the phenotypically normal children are carriers.
Clinical features of autosomal recessive diseases…
- Expression is more uniform.
- Complete penetrance is more common than in AD disorders
- New mutations are rarely clinically evident.
- Onset is frequently early in life.
In many cases, clinical effects of autosomal recessive diseases due to…
• Deficiency of specific enzymes:
- Consequent accumulation of substrate or intermediate products
- or lack of the end product necessary for normal function
Factors suggesting that oral lesions have genetic origin…
- Family history of similar lesions
- Early age of onset
- Multiple lesions
- Symmetrical distribution
- Stigmata in other organs
Benign conditions include…
- Leukoedema
- White sponge nevus
- Keratosis follicularis (Darier’s disease)
- Hereditary gingival fibromatosis
Demographics of leukoedema
- It is noted more frequently in black people than in whites.
- More often in men than in women.
- Occurs in most adults and some authorities regard it as a “variation of normal”
Clinical features of leukoedema
- This is a gray-white, bilaterally symmetrical, appearance of the buccal mucosa.
- DOES NOT rub off, but is reduced by stretching. ***
- Asymptomatic, and increases with age.
- Ranges from a filmy, milky opalescence to a gray-white, coarsely wrinkled or corrugated surface.
Sites where leukoedema may occur…
- Buccal mucosa
- May extend onto the labial mucosa
- Also reported in the larynx and vagina
Diagnosis of leukoedema
• Presumptive diagnosis is often made on the basis of clinical features
Histology of leukoedema
Biopsy revealed:
• Thickened stratified squamous epithelium with irregular, elongated rete ridges
• Cells of the spinosum are enlarged and exhibit marked intracellular edema and pyknotic nuclei ***
• Surface is usually parakeratinized.
White sponge nevus is also known as…
- Familial white folded dysplasia
* Cannon’s disease
White sponge nevus is caused by mutations in…
- Keratin 4 genes
- Keratin 13 genes
Note: one or both may have mutation
White sponge nevus is inherited as an…
- Autosomal dominant trait
* High degree of penetrance and variable expressivity
Clinical features of white sponge nevus…
- Bilateral and symmetrical
- Asymptomatic
- White (or gray-white), thickened, velvety or corrugated (sometimes deeply folded) plaques
- Lesions are spongy in consistency
- Usually appear early in life
Sites where white sponge nevus may occur…
- May cover a small, or large area of the buccal mucosa
- May affect other parts of the mouth
- May also affect the nasal cavity, larynx, esophagus, and ano-genital region
White sponge nevus histology
- Marked hyperparakeratosis, acanthosis, and spinous layer intracellular edema and pyknotic nuclei (which are also seen in leukoedema).
- Parakeratotic plugs may extend from the surface into the spinosum.
- Perinuclear, eosinophilic condensation (due to tangled masses of keratin tonofilaments) is a distinctive feature which is seen in some cases.
Bilateral buccal mucosa white plaques include…
• Leukoedema • Morsicatio buccarum • Lichen planus • Lichenoid mucositis - e.g. cinnamon • White sponge nevus • L E • Candidiasis
What is keratosis follicularis (Darier’s disease)?
• Rare, mainly cutaneous, disease
• Desmosome-tonofilament defects are linked to acantholysis
AD with high penetrance and variable expressivity
• New mutations also occur
Etiology of Keratosis Follicularis (Darier’s disease)
- Mutations in gene ATP2A2 on 12q23-24.1
- Encodes ER Ca2+-ATP isoform 2 protein (SERCA2), a calcium pump. ***
- Transports Ca2+ from cytosol back to ER lumen.
- Mutations affect synthesis, folding, or trafficking of desmosome components
- Causes defective desmosomes ***
Keratosis Follicularis (Darier’s disease) clinical features
- Skin papules are red and often pruritic
- Become brown, then purple, and crust over
- Lesions may be so extensive that disfiguring, foul smelling masses are removed
Keratosis follicularis (Darier’s disease) and oral lesions
- Oral lesions are reported in up to 50% of cases
- Asymptomatic
- Small, whitish, rough papules
- Most often affect keratinized areas
- Confluent papules create a cobblestone appearance
Keratosis follicularis (Darier’s disease) histology
• Central crater contains keratin plug
• Epithelium beneath crater exhibits
- intraepithelial clefting (a form of acantholysis due to desmosome defects)
- Elongated rete ridges
- Dyskeratosis ( represented by round bodies and grains)
• Acantholysis due to desmosome defects
Prognosis for keratosis follicularis (Darier’s disease)
• Chronic, slowly progressive problem
• Responds to treatment with vitamin A derivatives
- side effects may limit this therapy
Histology of keratosis follicularis (Darier’s disease)
• Intraepithelial clefts
• Acantholytic dyskeratosis
- Corps ronds
• Large, keratinized cells with intensely eosinophilic cytoplasm surrounding a round, basophilic nucleus
- Grains
• Small, elongated cells with pyknotic nuclei
Generalized gingival enlargement can occur due to…
- Nonspecific hyperplasia
- Primary HSV
- Granulomatous conditions
- Leukema
Nonspecific inflammatory hyperplasia that can cause generalized gingival enlargement include…
- Dental plaque
- Hormone inbalance
- Scurvy
Nonspecific fibrous hyperplasia that can cause generalized gingival enlargement include…
• Heredity:
1) metabolic diseases
2) Gingival fibromatosis
- Syndromal
- Non-syndromal (isolated finding)
• Drug-inducedGranulomatous conditions that cause generalized gingival enlargement include…
- MRS
- Wegener
- Sarcoidosis
- Crohn’s disease
- Foreign body reaction
Inherited gingival enlargement due to inborn errors of metabolism include…
- Mucopolysaccharidoses
- Mucolipidoses
- Juvenile hyaline fibromatosis
Inherited gingival fibromatosis occurrence
• Non-syndromal (isolated finding - without any other stigmata)
- more common than cases that are part of inherited syndromes
- 80% are familial (AD > AR)
- 20% are idiopathic (not inherited - condition occurs without a positive family history)
• Syndromal
- Zimmerman-Laband
- Cowden (multiple hamartoma and neoplasia)
- Cross and prune belly
• Associated with other abnormalities
- Hypertichosis
- Epilepsy
- Mental retardation
- Endocrine disturbances
Clinical features of hereditary gingival fibromatosis
- Enlargement often begins at time of eruption of primary or secondary teeth
- May involved attached gingivae as far as mucogingival line
- Teeth buried by dense, firm tissue
- Gingival overgrowth may be smooth or nodular, pink or pale
- Sometimes limited to regions or quadrants, rather than the gingivae of the entire dentition
- Tends to recur after gingivectomy
Histology of hereditary gingival fibromatosis
- Dense collagenous fibrous connective tissue
- Inflammation proportional to local irritating factors
- Surface epithelium is hyperplastic, often with long, narrow rete ridges.
Oral lesions are usually benign markers for…
Potentially fatal genetic syndromes affecting oral soft tissues
Most common chromosomal disorder
Down syndrome
Down syndrome
- Most common chromosomal disorder
- > 90% of cases have trisomy 21 (47 chromosomes)
- Parents have normal karyotype
- Aberattion occurs during gametogenesis
- ~4% of cases are familial
Familial down syndrome
• Affected child has 46 chromosomes (95% Downs have 47)
• Extra long arm of 21 fused to long arm of 22 or 14
- One chromosome very long
• Carrier gamete has normal chromosome 21 and another chromosome with an extra long arm of 21
• Fertilization results in cell with 3 long arms of 21
Clinical features of down syndrome
- Mental retardation
- Susceptibility to leukemia & infections
- Congenital heart disease is most common cause of early death.
- Short stature
- Midface skeletal deficiency
- Small sinuses
- Ocular hypertelorism
- Flattened nasal bridge
- Relative mandibular prognathism
Oral features of down syndrome
- Macroglossia
- Fissured tongue
- Protruding tongue and open mouth
- Periodontal disease
- Developmental tooth abnormalities (e.g. retarded eruption, hypodontia, taurodontia)
Cowden syndrome (multiple hamartoma and neoplasia syndrome) is transmitted as…
- Autosomal dominant trait with high penetrance and varied expressivity
- Mutation of the PTEN (phosphatase and tensin homolog) gene on chromosome 10q
- It’s a single gene defect
Clinical presentation of skin lesions in Cowden syndrome (Multiple hamartoma and neoplasia)
• Multiple, small, warty papules (trichilemmomas and non-specific papules)
- Creates toad-skin facial appearance
• Periorificial lesions
• Warty growths of hands (acral keratosis)
• Other benign tumors (lipomas, hemangiomas, neuromas)
Internal tumors that may occur in Cowden syndrome (multiple hamartoma and neoplasia)
- Thyroid goiter, adenomas, adenocarcinoma
- Breast fibrocystic disease and cancer
- GI tract multiple benign and malignant tumors
Note: there is an increased risk for malignancies of breast, female genito-urinary tract, and thyroid gland
Oral manifestations in Cowden syndrome
- Mucosa coarsely granular, warty, or cobblestone in appearance due to multiple papules which are benign, non-specific, fibro-epithelial proliferations.
- The gingivae may be markedly hyperplastic and the dorsum of the tongue may be pebbly.
Diagnosis of Cowden syndrome (Multiple hamartoma and neoplasia)
Diagnosis can be made on the basis of two of three signs:
• Multiple facial trichilemmomas
• Multiple oral papules
• Acral keratoses
Transmission of tuberous sclerosis is…
• Autosomal dominant, but two thirds of cases are new mutations.
• Mutations occur on one of two genes:
- TSCI on chromosome 9 or
- TSC2 on chromosome 16
Which genes have mutations in tuberous sclerosis? Consequences?
• Mutations on one of two genes:
- TSCI on chromosome 9
- TSC2 on chromosome 16
• Disruption of these suppressor genes leads to multiple hamartomatous growths.
Clinical features of tuberous sclerosis
• Main features: - Mental retardation - Seizure disorders • Accompanied by clinical lesions: - Angiofibromas - Shagreen patches - Ash-leaf (hypopigmented) spots - Ungual fibroma
Describe appearance of angiofibromas as observed in tuberous sclerosis
Multiple, smooth-surfaced papules on the face (especially nasolabial fold area) and under nails
Describe appearance of Shagreen patches as observed in tuberous sclerosis
Resemble sharkskin-derived shagreen cloth.
Oral manifestations of tuberous sclerosis…
• Multiple fibrous papules
• Jaw radiolucencies
- represent dense fibrous connective tissue proliferations
• Enamel pitting
Multiple endocrine neoplasia type 2B or III (Multiple mucosal neuroma syndrome) transmission is…
• Autosomal dominant, although approximately 50% of cases are spontaneous mutations
Mutation in multiple mucosal neuroma syndrome occurs on…
- Mutations of the RET (Rearranged during Transfection) protooncogene
- Present on chromosome 10 at position 11.2
- Genetic analysis: heterozygous for a missense mutation (M918T) in exon 16 of RET protooncogene
Clinical features of multiple mucosal neuroma syndrome
• Marfanoid appearance:
- Most affected individuals have long, thin limbs, and narrow face
• +/- Cafe au lait cutan macules
• Multiple, painless papules or nodules
- covered by mucosa of normal color
• On tongue, lips, other oral sites and other mucosae
Histology of mucosal neuromas
- Hyperplastic peripheral nerve fiber bundles
- Thick perineurium
- Normal or loose C.T. stroma
Medullary thyroid carcinoma…
• Occur in > 90% of cases of multiple mucosal neuroma syndrome
- Most are diagnosed between the ages of 18 and 25
- Unless thyroidectomy is performed,, average age of death is 21
• RET mutation on genetic testing warrants thyroidectomy
- Elevated serum and urinary calcitonin
Pheochromocytoma
- In at least 50 cases of multiple mucosal neuroma syndrome
- 10% occur in familial syndromes
- Increased urinary excretion of catecholamines and their metabolites (vanillymandelic acid and metanephrines)
- Catecholamines cause sweating, diarrhea, flushing, tremors, abrupt, and precipitous hypertension and heart palpitation.
- Sudden cardiac death may occur.
- Isolated benign tumors are excised
- Multifocal lesions require long-term treatment for HTN
What is hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease)?
• Multiple mucocutaneous telangiectasias (dilated small vessels) involving the respiratory, GI, and urinary tracts
Transmission of hereditary telangiectasia (Osler-Rendu-Weber disease) is…
• Autosomal dominant trait
• Mutation of one of two genes:
- In HHT1, it is ENG (endoglin) on chromosome 9q34
- Mutation of ALK1 (activin receptor-like kinase-1) on chromosome 12q13 produces HHT2
Where do telangiectasias for Osler-Rendo-Weber occur? Appearance?
- Face, lips, tongue, and gingivae
- Circumoral lesions are characteristic
- May be pinpoint, macular, papular, nodular, or spider-like
- Blanch on pressure
- Internal organs, including the brain, liver and spleen, may be affected by telangiectasias and other vascular anomalies with consequences which are occasionally fatal.
Hemorrhage (including epistaxis)) in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) may cause…
Anemia
Lesions in Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) are become evident when?
Lesions are evident early in life and worsen with age.
Diagnosis of Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) involves…
Diagnosis is made in patients with three of four criteria:
• Recurrent spontaneous epistaxis
• Telangiectasias of mucosa and skin
• A-V malformation in lungs, liver or CNS
• Positive family history of HHT
Transmission of neurofibromatosis type 1 (Von Rechlinghausen’s disease) is…
• This relatively common disease is transmitted in an autosomal dominant manner, but 50% of cases are new mutations
Gene and chromosome implicated in neurofibromatosis type 1 (Von Rechlinghausen’s disease)
- Defects in the NF1 gene on chromosome region 17q11.2
* Disables a tumor suppressor, neurofibromin
Stigmata of neurofibromatosis type 1 (Von Recklinghausen’s disease) includes…
• Cutaneous cafe au lait macules
• Multiple neurofibromas
• Lisch nodules
- Hamartomas presenting as pigmented iris spots
• Freckling in the axillary or inguinal regions
• Optic glioma
• Distinctive osseous lesion (e.g. sphenoid dysplasia)
• First degree relative with NF1
Diagnosis; two or more criteria are required for diagnosis
Describe the appearance of cafe au lait macules in Neurofibromatosis type 1 (Von Recklinghausen’s disease)
- Smooth outline
* Six or more macules, each 1.5 cm or more in diameter, is an important diagnostic criterion
Describe the appearance of neurofibromas in neurofibromatosis type 1 (Von Recklinghausen’s disease)
- Cutaneous and subcutaneous neurofibromatosis affect the skin and mucosae and may involve any internal sites.
- Mucocutaneous neurofibromas may be discrete nodules or huge, pendulous cutaneous masses (“elephantiasis neuromatosa”)
- Plexiform neurofibromas are pathognomonic
________ ________ are pathognomonic for neurofibromatosis type 1 (Von Recklinghausen’s disease)
Plexiform neurofibromas
Describe plexiform neurofibromas in neurofibromatosis type 1 (Von Recklinghausen’s disease)
- Pathognomonic
- Expansile, intraneural lesions
- Tortuous and thickened nerves contain proliferating Schwann cells, neurites, and fibroblasts in a myxoid stroma
- Sarcomatous change occurs in about 5% of patients with plexiform neurofibromas
- 5 year survival rate is only 15%
Consequences of tumors in neurofibromatosis type 1 (Von Recklinghausen’s disease)
- CNS tumors may cause epilepsy and mental retardation
* Central and peripheral bone tumors may cause skeletal, including mandibular, abnormalities
Oral clinical features of neurofibromatosis type 1 (Von Recklinghausen’s disease)
- Lingual fungiform papillae are often enlarged
- Oral neurofibromas may be discrete or cause an enlarged, misshapen tongue
- Generalized gingival enlargement may occur
Transmission of Peutz-Jeghers syndrome is via…
• Autosomal dominant basis, but 35% of cases are new mutations
Gene and chromosome implicated in neurofibromatosis type 1 (Von Recklinghausen’s disease)
- Most cases are due to mutation of the STK11 gene (also known as LKB1) on chromosome 19q13.3
- It encodes for a serine/threonine kinase
Clinical presentation of Peutz-Jeghers syndrome
- Pigmented macules on the digits, around the body orifices and on the oral mucosa due to prolonged melanin retention in melanocytes which have elongated dendrites.
- Pigmented macules are associated with multiple gastrointestinal hamartomatous polyps (which may cause obstruction).
In Peutz-Jeghers syndrome there is an increased risk for cancers such as…
- Colon
- Pancreas
- Male and female genital tracts
- Breast
- Ovary
Autoimmune polyendocrine candidiasis syndrome (candidiasis endocrinopathy syndrome) is transmitted by…
• Autosomal recessive basis
Gene and chromosome implicated in Autoimmune Polyendocrine Candidiasis syndrome (Candidiasis endocrinopathy syndrome)
- Mutations in the autoimmune regulator (AIRE) gene on chromosome region 21q22.3
- Results in autoantibodies
Autoimmune endocrinopathies observed in autoimmune polyendocrine candidiasis syndrome (Candidiasis endocrinopathy syndrome) include…
- Thyroiditis
- Hypoparathyroidism
- Addison’s disease
- Diabetes mellitis
- Ovarian pathology
Clinical features/stigmata of Autoimmune polyendocrine candidiasis syndrome (Candidiasis endocrinopathy syndrome) include…
• Chronic mucocutaneous candidiasis of the mucosae, skin, and nails • Other stigmata include: - Enamel hypoplasia - Iron deficiency anemia - Achlorhydria - Malabsorption - Eye lesions
In Autoimmune polyendocrine candidiasis syndrome (Candidiasis endocrinopathy syndrome), there is some evidence of increased prevalence of these two types of cancer…
Oral and pharyngeal carcinoma
What is epidermolysis bullosa?
- A group of INHERITED diseases characterized by mucocutaneous vesicles and bullae.
- Defective cellular cohesion causes clefting at various levels, within, or below the surface epithelium.
Broad categories of epidermolysis bullosa are…
- Simplex
- Junctional
- Dystrophic
- Hemidesmosomal
Note: there is an acquired, purely autoimmune form of epidermolysis bullosa
The most serious forms of epidermolysis bullosa are inherited on a what basis?
Autosomal recessive basis
Where does clefting occur in the junctional and dystrophic types of epidermolysis bullosa?
- Junctional type –> clefting is at the level of the lamina lucida
- Dystrophic types –> clefting is below the lamina densa
In the junctional type of epidermolysis bullosa, there are mutations in…
The genetic codes for the alpha-3, beta-3, and y-2 subunits of laminin
What is significantly increased in the junctional type of epidermolysis bullosa?
• Dental abnormalities
- Anodontia
- Enamel hypoplasia
- Pitting
Which form of dystrophic type Epidermolysis bullosa may be fatal?
- The generalized recessive dystrophic is one of the forms which may be fatal.
- Vesicles and bullae result from even minor trauma
Genes implicated in the dystrophic type of Epidermolysis bullosa…
Most of the dystrophic types are caused by mutations in genes responsible for the production of type VII collagen
Complications of dystrophic types of epidermolysis bullosa include…
- Secondary infections
- Loss of manual function due to scarring
- Squamous cell carcinoma arising in scarred skin
Oral problems in the dystrophic types of Epidermolysis bullosa include…
• In addition to extensive bullae, oral problems include:
- Microstomia
- Ankyloglossia due to scarring
- Soft, cariogenic diet results in carious destruction of teeth
Most lysosomal storage diseases are transmitted as…
• Autosomal recessive disorders
Lysosomal storage diseases include disturbances in…
- Lipids
- Glycosaminoglycans (mucopolysaccharides)
- Glycogen, etc.
Deficiency of lysosomal enzyme causes what?
- Accumulation of substrate in secondary lysosomes and extracellularly
- Somatic cells are affected and neurons in some conditions
- Extracellular accumulation occurs around tooth germs
Hurler syndrome results from what?
• A deficiency of alpha-L-iduronidase
What accumulates in Hurler Syndrome (MPS H), where does it accumulate, and what are the consequences?
- Accumulation of dermatan sulfate and heparan sulfate in fibroblasts, endothelial cells, and vascular smooth muscles.
- Causes death from cardiac disease by the age of ten
- Accumulation in neurons severely affects mental development
Clinical features of Hurler Syndrome (MPS H) in children…
- Children also exhibit corneal clouding, coarse facial features, short neck, large head, macroglossia, thick lips, and an open mouth.
- There are lucencies around developing teeth, slow eruption, and gingival hyperplasia.
