Block 2 clinical correlations

Errors is Retinoic acid distribution in mesentary often can result in

Spontaneous abortions

Esophageal atresia/tracheoesophageal fistula

Failure in the tracheoesophageal septum to fully separate (week 4)

Pancreas divisum

Failure of complete pancreatic fusion

Complete pancreas divisum

Recurrent pancreatitis. Increased pain after meals. Can only be detected by expensive and risky modality of ERCPM(endoscopic retrograde cholosomething pancreotography). Dorsal pancreatic duct is too small to handle the processes produced independently.

Partial pancreas divisum

Often asymptomatic. Still fuse, dorsal duct dominant rather than ventral.

Duodenal stenosis/atresia

Improper apoptosis function in duodenum development, duodenum may remain solid or only partially recanalize.

Meckles diverticulum

A stand of embryologist vitilline duct persists. Only symptomatic if the pluripotent cells differentiate into stomach or pancreatic tissue. This will cause the secretion of HCl and ulcer development in the abdominal cavity. Rule of 2s: 2% of population, 2ft from ileocecal valve, 2 y/o, and 2 inches long.

Intestinal malrotation

Over or under rotation of midgut during development. Largely asymptomatic. 1/200-500 births. Often undiagnosed.

Symptomatic intestinal malrotation

1/6000 births. Occurs in final 90° of CCW rotation. Colon spirals around SI resulting in volvulus (rolls). Results in bile rich vomit after a meal. Detected by contrast CT or Xray modalities.

Ischemic colitis

Low bp resulting in decreased or cease of blood flow to watershed areas in the gut (Terminal branches of multiple blood supplies). Treatment can occur naturally. If severe (extended cease of blood flow) surgery is required.

Dynamic mutation disorder examples (autosomal dominant)

Huntingtons disease, Myotonic Dystrophy, Fragile X syndrome

Huntington’s disease

Repetition of CAG in 5’ region. Expresses chorea, cognitive impairment, dementia, and mood change. Codes for the Huntington protein.

Normal level of CAG coding for Huntington protein

Less than or equal to 26

Mutable level of CAG for Huntington Protein

27-35

Full penetrance of HD level of CAG

40+

Myotonic Dystrophy

Overexpression of CTG in 3’ region. Expresses progressive muscle weakness, myotonia, cataracts, and cardiac conduction defects.

Normal level of CTG for MD protein kinase

Less than 37

Full penetrance level of CTG for MD protein kinase

50-2000+

Fragile X syndrome

Overexpression of CGG. Occurs in 1/4000 male births. Most common form of inherited moderate intellectual disability. Exhibit long face, prominent forehead, high palate and dental crowding, hyper extensive joints, autism, and a number of symptoms. Expansion results in excessive methylation of FMR1 promoter.

Normal CGG expression

Up to 55 repeats

Permutation intermediate level of CGG repeats

56-200

Fragile X is expressed level of CGG repeats

Greater than 200 up into the thousands.

Cancer can result from

Abnormal epigenetic modification

α-1 antitrypsin deficiency (AATD)

Autosomal co-dominant, both alleles expressed. E.g., MZ ( half normal M and half severely deficient Z). Deficient AATD proteins increase risk of lung disease.

Co dominant alleles

Blood types. E.g. parents are AO and BO type. Offspring could be type A (AO) type AB (AB) Type B (BO) or type O (OO)

SHOX Genes

Pseudoautosomal dominant in PAR1 region, crucial for growth and development. Can result in Léri-Weill dyschonderosteosis (LWD) or larger mesomelic dysplasia

Beckwith Wiedmann Syndrome

Mutation in IGF2, CDKN1C, H19, and KCNQ1017. Pediatric growth disorder, example of genomic imprinting, expression depends on parental origin. Epigenetically regulated by DNA methylation and histone modification

Chromosome 15 conditions

Prader-willi (paternal deletion) and Angelman Syndrome (maternal deletion)

Prader-Willi

Deletion in paternal 15q (4mb deletion), results in short stature, obese, nonverbal, small hands and feet, mild intellectual disability, developmental delay, and 1/15000 births affected.

Angelman Syndrome

Maternal deletion in 15q. short and microcephalic stature, seizures, atoxic gate, speech impaired, severe intellectual disability, developmental delay, and 1/15000 births. Errors in IGF2 and H19 can also contribute.

Tumor suppressor genes (normal genes suppressing cell cycle checkpoints).

RB1, TP53, BRCA 1 & 2, WT1

Oncogenes

Mutated proto-oncogene. Increased activity leading to increased proliferation. (Gain of function or gene dosage).

Proto-oncogenes

Normal genes in cell cycle, e.g., TFs, Growth factors, etc.

Neural tube defects: spina bifida & anencephaly

Increased risk when no Folic Acid is taken during first pregnancy. Probability then increases with each subsequent pregnancy. (FA deficient).

Cleft lip/palate

Increased risk with increased # of relatives

Pyloric Stenosis

opening between stomach and SI is narrowed. Resulting in vomiting and dehydration. Gender biased towards males. Though maternal carriers increase risk for offspring compared to paternal carriers.

Hypertension

Polygenetic, epigenetic factors and rare single gene mutations. Heritability only causes 30-50%. Environmental factors make up the rest.

Type 2 diabetes

Family history and obesity both relevant. Identified variants of TCF7L2 genes in all populations studied.

Cancer

Polygenetic factors: numerous loci, can be autosomal dominant, pathological variants of BRCA 1 & 2, also environmental factors, e.g., carcinogens, poor diet, lifestyle, stress.

Retinoblastoma

Malignant tumor of retina, primarily in young children. 1/20,000 births, first to support 2 hit hypothesis, RB1 gene, stops dividing after embryogenesis, has 90% penetrance. Treated by chemo, radiation, laser, cryogenic.

Familial breast and ovarian cancer

BRCA 1 & 2 genes account for only 1-3% of cancers. Though result in increased risk in breast, ovarian, prostate, and pancreatic cancers.

Sporadic cancers

Result from oncogenes. Inherited cancers are only a small percentage, Ras mutations in 30% of all cancers.

Philly chromosome

BCR-ABL1 fusion gene coded. Resulting in increased activity of ABL1. Which results in increased leukemia.

Osteogenesis imperfects relevant enzyme

Prolyl hyroxylase

Ehlers Danos syndrome relevant enzymes (collagen 3 and 5)

pro collagen N proteinases and Lysyl oxidase

Thoracic aortic aneurysms relevant enzymes

Lysyl oxidase

Type 2 collagenopathies

Genetic diseases that mostly affect cartilage, skeletal development, and vitreous. Most severe kind involve the absence or reduction of type 2 collagen.

Acondrogenesis 2, hypochondrogenesis, spondyloepiphsyeal dysplasia congenita

Mutations in the gene for aggrecan (main proteoglycan in cartilage. Mild collagenopathies).

Junctional epidermolysis bullosa

a blistering disease of the skin and mucous membrane in between the dermis and epidermis. Due to laminin gene mutations.

Alport Syndrome

Type 4 collagen affected. Impacts kidneys, ears, and eyes. X-linked COL4A5 gene

Fibrorectin Glomerulopathy

Heterozygous FN1 gene mutation, resulting renal failure.

Hyaluronic acid (GAGs)

Lubricant in joint, shock absorber in cartilage, used to treat osteoarthritis

Proteoglycans (GAGs on protein backbone)

Decorin (collagen formation in CT). Perlecan (basement membrane charge selectivity molecule). Syndecan (binds growth factors)

Matrix metalloproteinases (MMPs)

Enzymes that target matrix components and are involved in tissue remodeling and wound healing. Regulated by (TIMPs) Tisssue inhibitors of metalloproteinases

Matrix remodeling enzymes

Hyaluran idases and Heparonase

Hyaluran idases

Breakdown increased of hyaluronic acid, triggering inflammation and cancer progression

Heparonase

Shortens heparin sulfate chains, promoting cancer cell growth, metastasis and angiogenesis.

Mucopolysaccharidosis

Group of disorders caused by deficiency in lysosomal enzymes needed to breakdown GAGs. Increased [GAG] means negative outcomes

Fibrosis

Abnormal tissue repair, impacts various organs and tissues in the body, replaces functional tissue with stiff ECM

Osteoarthritis

Cartilage breakdown, joint narrowing, bone remodeling and osteopathies formation. Accompanied by inflammation and linked to injuries.

Cholelithiasis

Gall stones

Cholecystitis

Gallbladder inflammation, usually due to the prescience of a lodged stone

Choleducholithiasis

Common bile duct stone

Cholangitis

Bile duct inflammation, you guessed it, likelihood of a stone being present is high.

Nephrolithiais

Kidney stones

Common kidney stone locations

Superior to inferior order: ureteropelvic junction, pelvic inlet, uretovesical junction.

Applications of PCR

Detect pathogenic gene sequences in blood

Single mutation in FGFR3 gene resulting in an additional restriction site

Muenke syndrome/craniosynostosis syndrome

Disruption of Intermediate filament function can lead to

Skin disorders

Bullos Pemphigoid

autoimmune antibodies function against hemidesmosome. (antigen or BPAG2). Tense subepidermal blisters. Nikolsky sign (-)

Pemphigus vulgaris

Autoimmune antibody against desmosome (desmoglein), 40-60 y/o onset, Supra basal seperation of mucous membrane and skin, flaccid blisters and erosions, Nikosky sign (+).

Epidermolysis bullosa simplex

Mutations in K5 and K14 genes. Causes IF weakness and hereditary skin blistering soon after birth. Skin blisters early at sites subject to pressure (especially palms and feet). Thicker unformed nails, no cure, care based on blister care and prevention, may improve with age

Desminopathies

Multi system disorder, skeletal, cardiac, and smooth muscles. Myopathic organ dysfunctions, cardiomyopathy, and a progressive disorder.

Progeria:

nuclear lamins (Rapid aging)

Amyotrophic lateral sclerosis

Neurofilaments may be involved

wiplash

Injury to cervical soft tissues, facets and other osseous structures, ligaments, spinal nerve, and cervical vertebral discs.

Wiplash increased risk when

Female, stationary vehicle, rear accidents, younger individuals, neck pain complaints, not at fault, monotonous work.

Relief of whiplash pain after one year normally only occurs when

Treatment has been given and financial compensation has been delivered

Obstetric conjugate

Narrowest rigid distance from the sacral promentary to pubic symph.

Diagonal conjugate

Actual measurable distance. Subtract 1.5cm from length of index finger for thickness of pubic symph.

Measurements relative to childbirth

Obstetric and diagonal conjugates.

Hemophilias

Present with hemarthrosis (bleeding into joints) and muscular or soft tissue hematomas

Hemophilia A

Reduced factor VIII activity, x-linked recessive, 80% of cases

Hemophilia B

Factor IX reduced, x-linked recessive, 20% of cases

Hemophilia C

Very rare, mostly Eastern European Jews, factor XI reduced, autosomal recessive.

Hyposystematic rickets inheritance

X- linked dominant.

Rett syndrome inheritance pattern

X-Linked dominant

Cystic fibrosis

Mutation in CFTR gene (affects chloride transport), autosomal recessive inheritance pattern, leads to mucus buildup in deficient chloride transport channels and increased levels of chloride in sweat,

Pancreatic insufficiency and malabsorption.

Marian system inheritance pattern

Autosomal dominant

Hypohidrotic ectodermal dysplasia

EDA gene mutation, x-linked recessive, X chromosome inactivation, displays as mosaisism in females, can express, impaired development of hair sweat glands and teeth

Somatic mosaicism

Mitotic errors and penetrate to body systems

Duchenne and Becker MD mode of inheritance

X-linked recessive

Leukocyte adhesion deficiency mode of inheritance

Autosomal recessive

Idiopathic pulmonary fibrosis can result from

Change sin collagen and elastin concentrations in the lung ECM

Pyruvate kinase deficiency inheritance model

Autosomal recessive

Episiotomy

Cut in perineum sometimes required for childbirth. Typically done at perineal body so it may be built back up properly.

Pudendal nerve block

Used during childbirth. Numbs perineum by palpating isicial spine and local anesthetic administered

Indirect inhuman hernias pass through

The deep ring, composed of peritoneum and running down into tunica vaginalis’ layers.

Vericoseal

Enlarged collection of veins in the spermatic cord. May appear as a “bag of worms” during physical exam if large enough.

Vasectomy

Ductus deferens is transected and removed for sterilization