Genetic and Pediatric Diseases PDF

Genetic and Pediatric Diseases Catherine M. Flaitz, DDS, MS May 2024 Points of Discussion ▪ ▪ ▪ ▪ ▪ ▪ Overview of genome and genetic disorders Chromosomal basis of genetic disease Single gene disorders Modes of inheritance Syndromes with head & neck manifestations Common congenital anomalies Genome:...

Genetic and Pediatric Diseases Catherine M. Flaitz, DDS, MS May 2024 Points of Discussion ▪ ▪ ▪ ▪ ▪ ▪ Overview of genome and genetic disorders Chromosomal basis of genetic disease Single gene disorders Modes of inheritance Syndromes with head & neck manifestations Common congenital anomalies Genome: Fast Facts ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Total DNA content of a cell Makes up the entire genetic information available to organism Encodes all information for cell growth, division, and responsiveness to environment Organized into 23 linear double stranded DNA molecules (46 chromosome: 1-22, plus sex chromosomes) Somatic cells (body cells) have two copies of each chromosome; two copies of each gene The human genome has 20,000 to 25,000 genes and contains 3.3 billion DNA base pairs. The DNA of any 2 humans is 99.9% identical. Non-coding DNA in nucleus provides the “architectural planning” and makes up >95% of nuclear genome Common Terms ▪ ▪ Hereditary disorders are transmitted in the parents’ gametes and are familial. Congenital means “present at birth”. ▪ ▪ Congenital diseases do not need to be genetic (congenital syphilis) Not all genetic diseases are congenital, such as Huntington disease. Four Major Categories of Genetic Disorders Mendelian disorders: resulting from mutations in a single gene Complex disorders: involving multiple genes and environmental influences (multifactorial or polygenetic inheritance) Diseases due to chromosomal abnormalities Other genetic diseases: involve a single gene mutation but do not follow the Mendelian rules of inheritance. Includes triplet repeat mutations, mutations in the mitochondrial DNA and epigenetic phenomenon Mutation As a Cause of Disease Likely to be disease-causing if: ▪ Does not occur in the normal population (people that do not express the phenotype) ▪ Alters the protein function or expression ▪ Segregates with disease in a given family and is absent in unaffected family members Mutations Permanent change in the DNA Affecting germ cells – can be inherited Affecting somatic cells – not inherited but may result in tumor or developmental abnormality (congenital malformations) Types of mutations Point mutation – change in single nucleotide base within a gene (single base is substituted) Frameshift – insertion/deletion of 1-2 base pairs alters the reading frame of the DNA strand Trinucleotide repeat – amplification of 3-nucleotide sequence (e.g., Fragile X syndrome has 200-4000 repeats of the sequence CGG within the FMR1 (fragile X messenger ribonucleoprotein 1) gene. Normally only 29 repeats) Additional factors affecting gene function Polymorphisms: Single nucleotide polymorphisms Copy number variations Epigenetic Changes Chemical compounds that are added to single genes can regulate their activity; do not change the DNA sequence Methylation of cytosine residues Alterations in Non-Coding RNAs microRNAs (miRNAs) long non-coding RNAs (lncRNAs) >200 nucleotides Polymorphism involves one of two or more variants of a particular DNA sequence. The most common type of polymorphism involves variation at a single base pair (SNP) Types of Genetic Disorders Mendelian Disorders Autosomal Dominant Autosomal Recessive Sex-linked (X-linked) Disorders Disorders with multifactorial (polygenic) inheritance Cytogenetic Disorders (chromosomal aberrations) Autosomes Sex chromosomes Mendelian Disorders Single-gene defects Nucleus contains 23 pairs of chromosomes (22 autosomes; 1 pair of sex chromosomes) Chromosomes consist of a series of genes Genes contain information to produce proteins that perform specific functions Patterns of inheritance Autosomal Dominant Autosomal Recessive Sex-linked (X-linked) Disorders Reference: Online Mendelian Inheritance in Man (OMIM) database (https://www.omim.org/) Treacher-Collins Syndrome Jono Lancaster is a advocate for syndrome Mendelian Disorders Genetic alteration (mutation) often results in production of abnormal protein, which can alter phenotype Mutations of a gene locus may affect one or both chromosomes in a pair When one chromosomal locus has a mutated gene, the patient is heterozygous If the loci on both chromosomes have the mutated gene, the patient is homozygous A single gene mutation may have many phenotypic effects known as pleiotrophy Mutations at several genetic loci may produce the same trait, known as genetic heterogeneity Treacher-Collins Syndrome Mendelian Disorders Single gene defects Biochemical defects, including inherited metabolic disorders Usually expressed in childhood Incidence ≈ 0.36% in live born 1-3% of children have some congenital malformation 50% involve oral/facial development Heritable genetic disorders Autosomal Dominant Disorders Mutated gene on an autosome Expressed in heterozygous state, one parent usually affected Both males and females affected and both can transmit the condition Not all patients have affected parents May present with outward physical changes in early childhood, but may have delayed onset in adulthood, (e.g., Huntington’s disease) Clinical findings are modified by reduced penetrance (phenotypically normal) of mutated gene and variable expressivity in which the mutant gene is expressed differently among persons carrying the same gene. Autosomal Dominant Disorders If a person has a mutant gene, but doesn’t or partially expresses it phenotypically: reduced or incomplete penetrance If expression can be identified in all affected persons, but to differing degrees: variable expressivity If neither parent affected/no family history: new or “de novo” mutation Modes of Inheritance of Single Gene Disorders Autosomal Dominant (AD) Diagram represents a pedigree chart Phenotype expressed in every generation Child of affected parent has 50% risk of inheriting trait Mutation in one allele causes phenotype New mutations may occur (de novo) Autosomal Dominant Oral Conditions Familial hypodontia: Reduction in number of teeth May be alone or associated with syndrome Some examples associated with risk for colorectal cancer (AXIN2 gene mutation) Familial gingival fibromatosis: Collagenous overgrowth of gingival fibrous connective tissue May be alone or associated with syndrome Some syndromes associated with cancer risk Gene mutation: Son-of-Sevenless-1 (SOS-1) Huntington Disease Adult onset neurodegenerative disorder Incidence, 1/10,000 persons of European origin Autosomal dominant inheritance Mutation in the Huntington gene Amplification of a trinucleotide repeat (CAG) Confirmation of clinical diagnosis through DNA testing for the CAG repeat size Can test for mutation in family members prior to clinical symptoms Ethical issues Huntington Disease: Molecular Testing Autosomal Recessive Disorders (AR) Largest group of Mendelian disorders Affected patients are homozygous; parents usually appear unaffected 25% of offspring are affected; 50% of offspring are carriers If the recessive gene is rare, disorder may be result of consanguinity Many AR conditions are enzyme defects, leading to metabolic dysfunction Expression of the defect tends to be more uniform than AD disorders Heterozygous patients (carriers) are unaffected clinically due to reduced, but still adequate, levels of the normal enzyme Age of onset is often early in life; complete penetrance is common New mutations occur, but are rarely detected clinically Autosomal Recessive (AR) Rare diseases: expression of phenotype requires inheritance of mutant allele from each parent Phenotype observed among sibling of proband, not parents, offspring, or other relatives Carriers have one normal allele and one mutated allele → no phenotype Recurrence risk for each sibling of proband is 1 in 4 One parent is carrier, the other is affected Parents are unaffected carriers B b B b BB Bb homozygote normal Bb heterozygote carrier heterozygote carrier bb homozygote affected 1:4 (25%) recurrence risk b b B b Bb bb heterozygote carrier homozygote affected Bb bb heterozygote carrier homozygote affected 1:2 (50%) recurrence risk Autosomal Recessive Disorders Cystic fibrosis Abnormal ion transport protein Sickle cell anemia Abnormal hemoglobin Phenylketonuria (PKU) Enzyme deficiency (Phenylalanine hydroxylase deficiency) Wilson’s disease Copper metabolism Wilson disease: ✓ Inherited, metabolic liver disease ✓ Toxic copper accumulation ✓ Affects liver, kidney, brain, eye, nerves ✓ Liver, neuropsychiatric disease, hemolysis ✓ Early detection, treatment is important Ellis van Crevald Syndrome AR bone disorder Mutations in EVC gene, chromosome 4p16 responsible for phenotype Dwarfism Polydactyly Malformed toe and finger nails Narrow chest Dental anomalies: missing teeth, hyperplastic frenulae, absence of anterior vestibule, notching of alveolar ridge, malformed teeth, neonatal teeth, +/- partial cleft lip, enamel hypoplasia Congenital heart disease = 50% X-linked Diseases Mutation of genes on X chromosome – sex-linked disorders Males with mutations on Y chromosome are infertile – no Mendelian disorders Phenotypic expression generally in males or very mild in females All daughters of affected males carry the his X chromosome - the mutated gene responsible for the condition Sons of carrier females are at 50% risk for inheritance of mutated gene Ectodermal Dysplasia Genetic Features X-linked recessive, AD, AR 192 subtypes of ED; some associated with CL/CP Most common is hypohidrotic variant Skin, hair, nails, teeth, sweat glands Gene: EDA1 (X-linked) – most common ED: Physical Features Fine, sparse hair Reduced eyebrow, eyelash hair Dry skin, eyes Periorbital wrinkling, pigmentation ↓ sweat glands +/- dystrophic nails Photophobia Normal mental status Dental/Craniofacial Features Midface hypoplasia Protuberant lips Oligodontia→ anodontia Microdontic, conical teeth Under-developed alveolar ridges; decreased vertical dimension Hypoplastic salivary glands ED: Complications Hyperpyrexia - 30% mortality rate Febrile seizures, neurological complications Pharyngitis, otitis, rhinitis Conjunctivitis Chronic eczema Xerostomia Dental caries Oral candidiasis Trauma from appliances X-Linked Mental Retardation Syndrome https://rarediseases.oscar.ncsu.edu/disease/atkin-flaitz-syndrome/about/ J F Atkin, K Flaitz, S Patil, W Smith. A new X-linked mental retardation syndrome. Am J Med Genet 1985 Aug;21(4):697-705. Fragile-X Syndrome: X-linked Dominant Condition Biochemical Basis and Inheritance Pattern for Selected Mendelian Disorders Diseases with Mutations in Structural Proteins These disorders are inherited in a variety of patterns Mutation of genes that encode proteins necessary for formation of normal bone and connective tissues Neurofibromatosis, type I AD disease with nearly 100% penetrance – nearly everyone who has this mutation will show evidence of this relatively common (1/3,000 live births) condition Highly variable expressivity Biochemical basis: abnormal protein Neurofibromin-1 (function - growth regulation) Key features: Café au lait macules (6+) Plexiform neurofibromas Freckling in axillary or inguinal regions Lisch nodules (eyes) Optic glioma Café au lait macule and axillary freckles Neurofibromatosis: Facial Findings Mild expression Severe expression Marfan Syndrome Autosomal dominant disorder Affects the connective tissue Prevalence of approximately 1:5,000 Mutation of the FBN1 gene Fibrillin, glycoprotein necessary for normal elastic fiber production Olympic Swimmer, Michael Phelps has the phenotype but not the syndrome Marfan Syndrome Elongated head Tall, thin body habitus Abnormally long legs Arachnodactyly: long fingers Dislocation of lens of the eye Aortic aneurysm and dissection; heart failure & aortic rupture Floppy mitral valve Very flexible Marfan Syndrome: Oral Manifestations Malocclusion Small mandible (retrognathia) High-arched palate Dental crowding Enamel hypoplasia Root deformity TMJ subluxation Ehlers-Danlos Syndromes (EDSs) There are 13 types or clinical variants; dominant and recessive forms Problem with collagen synthesis, ~ 30 distinct types of collagen Variable tissue distribution of collagens may explain clinical heterogeneity of EDSs Oral findings: Periodontal disease, poor wound healing, easy bruising, temporomandibular joint dislocation/hypermobility Periodontal disease Poor wound healing Easy bruising TMJ dislocation Ehlers-Danlos Syndromes Hyper-elasticity of the skin Scarring of the skin Hypermobile joints Scoliosis Rupture of cornea, detached retina Ruptured arteries, colon Ehlers-Danlos Syndrome Hypermoible joints Joint dislocations Contortionists Diseases with Mutations of Receptor Proteins or Channels Examples: Familial hypercholesterolemia LDL (low-density lipoprotein) receptor Cystic fibrosis Chloride channel protein Familial Hypercholesterolemia One of the more common inherited disorders – autosomal dominant Frequency of 1:500 Mutation of LDL receptor gene caused by loss of function mutation Impaired metabolism & increased LDL cholesterol in plasma Premature Atherosclerosis Familial Hypercholesterolemia Multiple xanthomas of the skin Premature, rapidly progressive atherosclerosis Heterozygotes – 2-3x increased LDL Homozygotes – over 5x normal levels Homozygotes often die of MI by age 20 Rx: lomitapide, mipomersin and PCSK9 inhibitors to treat homozygous patients Xanthomas of the skin Cystic Fibrosis (AR) Disorder of epithelial ion transport CFTR gene Affects fluid secretion in: Exocrine glands, including salivary glands Linings of respiratory, sinuses, gastrointestinal and, reproduction tracts Diseases with Mutations in Enzyme Proteins Examples: Phenylketonuria (PKU) Lysosomal storage diseases Lysosomal Storage Diseases Inherited metabolic diseases characterized by abnormal build-up of various toxic materials in cells due to enzyme deficiencies AR transmission Commonly affect infants and young children Accumulation of large, insoluble molecules (sphingolipids, mucopolysaccharides) by macrophages leads to hepatosplenomegaly Frequent CNS involvement leads to neuronal damage, mental disability and/or early death Lysosomal Storage Diseases Tay-Sachs disease Niemann-Pick disease Gaucher disease Mucopolysaccharidoses Mucopolysaccharidosis Syndromes Group of metabolic disorders that lack enzymes to process glycosaminoglycans Mucopolysaccharides accumulate in liver, spleen, heart, blood vessels, brain, cornea and joints Most are autosomal recessive 1 in 15,000-29,000 births Multiple types: Hurler (AR) Scheie (AR) Hunter (X-linked recessive) Sanfilippo-A, B (AR) Morquio-A, B (AR) Maroteaux-Lamy (AR) Hurler Syndrome Coarse facies, large head Corneal clouding Growth retardation Stiff joints Decreased intelligence Coronary artery disease Seizure disorder +/Macroglossia, gingival hyperplasia, tooth spacing Enlarged dental follicle, unerupted teeth Tx: Bone marrow transplant; enzyme replacement therapy, laronidase (Cochrane Rev 2016) Hurler Syndrome ✓ Swollen, claw-like hands ✓ Joint stiffness ✓ Macroglossia ✓ Gingival hyperplasia Summary: Transmission Patterns of Single-Gene Disorders AD disorders: Characterized by expression of in the heterozygous state; affects ♂ and ♀ equally; both can transmit disorder AD disorders often involve dysfunctional receptors and structural proteins AR disorders: Both copies of gene are mutated and often involve enzymes; affects ♂ and ♀ equally X-linked disorders: transmitted by heterozygous ♀ to sons, who manifest the disease. ♀ carriers often unaffected or mildly affected because of random inactivation of one X chromosome Multifactorial (polygenic) disorders Two or more genes responsible, plus environmental (nongenetic) influences Polymorphism: a genetic variant that occurs in 1% of the population Complex multigenic disorder: caused by many polymorphisms that are coinherited Governs many physiologic traits (height, weight, blood pressure, hair color) Thought to underlie common diseases: diabetes, hypertension, gout, schizophrenia, bipolar disorder, others. Thought to be important for oral diseases: Dental caries Periodontal disease Temporomandibular dysfunctions Clefting disorders Head and neck cancers Study of the genome by examining chromosome number and structure Constitutional karyotype: in all cells of body Acquired chromosome abnormalities: cancer cells Chromosome Abnormalities: Number Monosomy = one of the chromosome pair Trisomy = an extra chromosome in the pair Structure: balanced and unbalanced chromosome abnormalities Translocations and their derivatives Deletions, duplications, rings Inversions and their recombinants Composite of stained human chromosome strand pairs Normal karyotype contains 23 pairs of chromosomes: 22 pairs of autosomes & 1 pair of sex chrom - XX (♀), XY (♂) Normal chromosome count = 46 Cytogenetic Studies Are Performed to Diagnose & Understand Genetic Diseases Indications for constitutional cytogenetic studies Suspicion of a cytogenetic syndrome Multiple congenital abnormalities without a known etiology Developmental delay and minor anomalies Family history of the above History of a familial chromosomal abnormality Intrauterine growth reduction or failure to thrive without a known etiology History of spontaneous abortion Genetic Studies: Common Specimen Types Peripheral blood Skin biopsy Cord blood Amniotic Fluid Chorionic villi Products of conception Saliva and buccal samples Bone marrow biopsy/aspirate Lymph nodes; fresh tumor tissue Paraffin embedded samples Touch preps of tissue Cytogenetic Disorders Estimated that 1:200 newborns have a chromosomal abnormality Contributes to 50% of spontaneous abortions in the 1st trimester Disorders due to alterations in number or structure of chromosomes May affect autosomes or sex chromosomes Trisomy 13: Patau Syndrome ✓ Death due to cardiac defect ✓ Cleft lip/palate ✓ Microcephaly / mental deficits ✓ Polydactyly ✓ Renal defects Autosomal Aberrations - Numeric Normal chromosomal count (2 X 23 = 46) is termed euploidy Increased chromosome count that is a multiple of that normally seen (i.e. 3 X 23 or 4 X 23) is termed polyploidy: generally results in spontaneous abortion Aneuploidy refers to any chromosome number that is not an exact multiple of the haploid number of chromosomes (which is 23 in humans). Extra chromosome (trisomy; 2x23+1= 47) Absence of a chromosome (monosomy; 2x23–1= 45) Monosomy of autosomes are incompatible with life, but compatible with life if sex chromosomes Trisomy of certain autosomes are compatible with life (Trisomy 21, 18, 13) Mosaicism: 2 or more populations of cells with different complements of cells in same individual Autosomal Aberrations - Structural Structural abnormalities result from chromosome breakage followed by loss or rearrangement of material Multiple types of rearrangements Translocation is transfer of a part of one chromosome to another nonhomologous chromosome Deletion is the loss of a portion of chromosome Inversions occur when there are 2 breaks in chromosome and the segment reunites after a complete turnaround Ring chromosome is a deletion variant that forms a ring Chromosomal Anomalies Down Syndrome http://2011gtms8f.wikispaces.com/trisomy+13,18,21+Diego+r Trisomy 21 – chromosomal sporadic mutation Down Syndrome – Trisomy 21 CLINICAL : 75% of conceptions lost 1/650 - 1/800 live births Hypotonia Distinct facial features Small ears Single palmar crease Intellectual disability Abnormal immune response From Jorde, et al, Medical Genetics, 1999 Down Syndrome – Trisomy 21 ▪ ▪ ▪ ▪ Down syndrome, first described by John Langdon Down in 1862 Trisomy 21 and DS first reported by Lejeune and Gautier, 1959 Most common chromosomal abnormality in live born individuals Most common cause of cognitive disability Maternal Age and Risk for Trisomy Positive correlation with incidence of trisomies 21, 18, and 13 with advanced maternal age Genetic counseling for advanced maternal age Risk for autosomal trisomies and AMA Frequency in liveborn population ―Trisomy 21:1/650 ―Trisomy 18:1/8000 ―Trisomy 13:1/20,000 Risk for Down Syndrome (Trisomy 21) child Risk increases with maternal age Age 30: 1% Age 35: 2.8% Age 40:10.4% Down Syndrome Characteristic Physical Features Hypotonia Dry skin ↑ in cardiac defects ↑ in gastrointestinal problems ↑ in hypothyroidism ↑ in ALL and AML ↑ dementia Celiac disease ↑increase infections, ear, sinus respiratory Sleep apnea Facial Characteristics Small ears Inner epicanthal folds Up-slanting palpebral fissures Midface hypoplasia Down turned lips Often overweight Macroglossia and scrotal (fissured) tongue Simian Crease Down Syndrome and Oral Findings Palate with v-shaped high vault Angle of mouth pulled down (result of hypotonic musculature) Small oral cavity Protruding tongue creates speech, articulation problems and open bite Malocclusion Crowding Crossbite Class III tendency Down Syndrome and Dental Anomalies 30-50% have microdontia: affects both dentition Additional features Supernumerary teeth Missing teeth Transposition Abnormal spacing Crown variants, tapered teeth Hypoplasia and hypocalcification Delayed eruption Taurodontism Root abnormalities Risk of periodontal disease Down: Dental Conditions Periodontal disease Delayed eruption and overretained teeth Taurodontism Transposition Atypical root morphology Abnormal palate Enamel hypoplasia Obstructive sleep apnea Caries risk is conflicting Down Syndrome Down Syndrome Increased Risk for Leukemia ✓ ✓ ✓ ✓ ✓ 18 YO with unrepaired atrioventricular septal defect Ruddy complexion Pruritic hands and feet Erythematous and hemorrhagic gingiva and mucosa Significantly elevated RBC count - polycythemia vera Periodontal Disease in Down Syndrome Prevalence: 50-90%, all under age 30 Prevalence increases with age Primary dentition involved in 36% patients Greater in Down than in general population Lower prevalence for Down at home Higher risk of necrotizing gingivitis in institutionalized Down May contribute to Alzheimer disease Mechanism of Periodontal Disease in Down Syndrome Periodontopathic bacteria colonize earlier than in non-Down (Carrada CF, et al. Plos One 2016;11(10):e0162988 Increase bleeding on probing PI – equivalent to control group C rectus, P gingivalis, T denticola, F nucleatum, P intermedia, P nigrescens Vasculature: abnormal capillary fragility Neutrophils: chemotactic and phagocytic defects T-cells dysfunctional: diminished ability to recognize and respond to specific antigens Down Syndrome Dental Treatment Evaluate for dental anomalies Evaluate for periodontal disease Congenital heart disease may require prevention of infective endocarditis Sedation or general anesthesia, consider following issues: Atlanto-axial instability Bradycardia Airway challenges Tendency for obesity https://www.ndsccenter.org/political-advocacy/policyadvocacy-events/ Cytogenetic Disorders: Sex Chromosomes In females, one X chromosomes, maternal or paternal, is randomly inactivated during development (Lyon hypothesis) Klinefelter syndrome: male hypogonadism with at least two X chromosomes and one or more Y chromosomes (most are 47, XXY) - 15% are mosaic Turner syndrome: female hypogonadism, partial or complete absence of one of X chromosomes (45,X) – 43% are mosaics Klinefelter Syndrome Phenotypically, patients are males Taller than normal, increased length of lower limbs; reduced body hair; gynecomastia; hypogonadism (most common cause of male sterility) Dental – increased frequency of taurodontism Turner Syndrome Markedly short stature Webbing of neck; low posterior hairline “Shield-like” chest High-arched palate Congenital cardiovascular malformations Failure to develop secondary sex characteristics; primary amenorrhea Indications for Genetic Analysis Prenatal: Mother’s age >34 years Parent is a carrier of chromosomal translocation or Xlinked disorder Hx of a previous child with chromosomal abnormality Indications for Genetic Analysis Postnatal: Multiple congenital anomalies Unexplained mental disability and/or developmental delay Suspected aneuploidy (e.g. Down) Suspected sex chromosomal abnormality Infertility Multiple spontaneous abortions Genetic factors affecting clinical picture Genetic heterogeneity Mutations of more than one gene cause the same disorder Clinical heterogeneity Mutations in same gene cause different disorders e.g. DiGeorge syndrome De novo (new) mutation e.g. cleft lip with or w/o cleft palate No family history Variable expressivity / incomplete penetrance Trait is expressed differently among individuals carrying the same mutant gene, even within a family Causes of Congenital Malformations ✓Genetic ✓Environmental ✓Multifactorial ✓Unknown Microcephaly from ZIKA virus infection