Diseases & Syndromes Flashcards
Abacavir-induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Autosomal co-dominant
Skin sloughing > 30% = toxic epidermal necrolysis,
< 10% = Stevens-Johnson syndrome
Adverse drug rxn due to CD8 t-cell mediated damage to skin and mucous membranes (eye, mouth, genitalia)
Fever, malaise, red/purple patches on skin - similar to a thermal burn
Mortality is 10-30%
Pharmacogenetics is standard of care as 50% of HLA-B*5701 individuals will get SJS/TEN when prescribed Abacavir (anti-retroviral) and 0% of patients w/out this allele with react this way.
Achondroplasia
Most common type of dwarfism
AD inheritance, full penetrance
FGFR3 (G380R) GoF mutation
> 80% of patients have a de novo mutation - these occur exclusively in the father’s germline and increase in frequency w/advanced paternal age
Features include frontal bossing, megalencephaly, midface hypoplasia, lumbar kyphosis, limited elbow extension, rhizomelia, trident hands, brachydactyly, and hypotonia.
Diagnosed via radiographic findings and DNA testing in ambiguous cases
Age-related macular degeneration (AMD)
Gradual loss of central vision
Complex inheritance
Predisposing and resistance alleles at several loci
Age of onset > 50 yrs
Drusen in the macula
Changes in retinal pigment epithelium
Y402H variant in CFH gene is responsible for ~50% of cases
In contrast, variants in CFB and C2 reduce the risk for AMD
Further divided into “wet” and “dry” types
Gene-environment interactions, i.e. smoking.
Smoking cessation and the use of antioxidants and zinc can slow progression, especially in “dry” types.
Alzheimer’s
Multifactorial or AD inheritance, variable expressivity
Linked to mutations in PSEN1 and APP (both are fully penetrant) and PSEN2 (not fully penetrant)
~5% of people over 70 have AD
Occurs as early onset familial (< 5%), late-onset familial (15-25%), and sporadic (~25%)
Key features include dementia, B-amyloid plaques, neurofibrillary tangles, amyloid angiopathy
Defects of B-amyloid precursor protein metabolism cause neuronal dysfunction and death
Both sporadic and late onset are strongly assoc w/allele e4 in the APOE gene, which is a dose-dpnt modifier (the more copies of e4, the earlier the onset)
10-20% of patients have a modest decrease in rate of cognitive decline if treated early w/drugs that increase cholinergic activity.
Old age, family hx, female sex, and Down syndrome are biggest risk factors
Autism
AD or de novo, incomplete penetrance
del(16)(p11.2)
This region contains 25 genes that are subsequently deleted
The reciprocal duplication of this region increases chances of mental disorder (schizophrenia)
Gonadal mosaicism can exist and therefore parental testing is crucial for appropriate genetic counseling
Beckwith-Widemann Syndrome (BWS)
Overgrowth syndrome, clinical spectrum
Typically de novo, AD if inherited
11p15 (CDKN1C) del or dup mut or paternal UPD, or loss of methylation
2 imprinting domains - IC1 (mat gain of methylation) and IC2 (mat loss of methylation - 50% of cases)
Pre- and postnatal overgrowth, macroglossia, omphalocele, visceromegaly, embryonal tumor in childhood (Wilms), hemihyperplasia, renal abnormalities, adrenocortical cytomegaly, neonatal hypoglycemia
20% fatality rate
Recurrence risk for siblings and offspring varies greatly w/the molecular basis of the patient’s condition.
3x higher risk of BWS in pregnancies occurring from assisted reproductive technologies - reason is unclear.
Hereditary Breast and Ovarian Cancer
BRCA1/BRCA2
AD inheritance, incomplete penetrance
LoF mutations in tumor suppressor gene
Two hit hypothesis
BRCA2 mutation prevalence 2x that of BRCA1
Both account for a small fraction of breast/ovarian cancers overall but 70-80% of familial breast cancers
Typically accompanied w/chromosomal instability and frequent mutations in other tumor-suppressor genes.
Population prevalence of these germline mutations varies widely, suggesting a founder effect.
BRCA1 mutations come w/an increased risk of prostate, melanoma, and colon cancers. BRCA2 comes w/higher rates of prostate, pancreatic, bile duct, gallbladder, melanoma, and male breast cancers.
Management w/these mutations includes increased screening.
Prophylactic mastectomy/ oophorectomy reduces risk by > 90%.
Charcot-Marie-Tooth Disease Type 1A
CMT1A
Caused by increased dosage of PMP22 secondary to duplication of PMP22 (17p11.2), resulting in an inability to form and maintain compact myelin
De novo dups account for 20-33% of CMT1A cases; of these, more than 90% arise during male meiosis
AD inheritance
Nearly full penetrance, but severity, onset, and progression vary markedly
Onset usually by 20 yo
Muscle weakness/atrophy primarily in distal leg muscles, mild sensory impairment, eventually leads to abnormal walking, dropped foot, foot deformities, and loss of balance
Marfan Syndrome
Systemic disorder of the connective tissue w/a broad phenotype.
AD inheritance, high penetrance
Must have path variant in FBN1 (15q.21.1) AND either an aortic root enlargement and/or ectopia lentis
Estimated prevalence: 1:5,000-10,000
No apparent enrichment in sexes or racial/ethnic groups.
Clinical findings can include ocular - myopia (most common); ectopia lentis (~ 60% of affected individuals), increased risk for retinal detachment, glaucoma, and early cataracts; skeletal system manifestations include: bone overgrowth and joint laxity, disproportionately long extremities for the size of the trunk (dolichostenomelia), overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum), and scoliosis
The major morbidity and early mortality relate to the cardiovascular system and include dilatation of the aorta
Beta blocks and losartan can be administered to help prevent aortic aneurysm.
Charge Syndrome
AD inheritance
CHD7 mutation (8q12), rarely due to SEMA3E mutation
Mostly de novo but can be due to parental mosaicism (paternal is more common)
Coloboma, heart defects, atresia of the choanae, retardation of growth, genital abnormalities, and ear abnormalities
1:3,000-12,000
Behaviors can include hyperactivity, sleep disturbances, and OCD
> 500 CHD7 mutations have been ID’d in Charge patients, indicating that haploinsuffiency for the gene causes the disease
Diagnosable if 3-4 major criteria or 2 major and 3 minor are met
50% die perinatal or prior to 6 months of age mostly due to bilateral choanal atresia and congenital heart defects.
CML
Incidence is 1-2 per 100,000
Onset is middle to late adulthood
Expansion of transformed hematopoietic progenitor cells, increases circulating myeloid cells
9q34 is Abl, 22q11 is BCR, fusion protein varies in size according to length of BCR peptide attached to amino-terminus
BCR/abl has constitutive tyrosine kinase activity and is confined to the cytoplasm where it binds actin microfilaments. It also phosphorylates several cytoplasmic substrates activating signaling cascades that control growth and differentiation. Unregulated activation of these signaling pathways results in unregulated proliferation of HSCs and release of these cells from the BM
CML is bi or triphasic: chronic phase, accelerated phase, blast crisis
85% of patients are diagnosed in the chronic phase
85% of patients respond to imatinib mesylate but often cells develop resistance
BMT is the only curative therapy
Crohn Disease
Multifactoral/complex inheritance
Three SNPs in NOD2 are strongly associated w/CD but not necessary
These SNPs reduce the ability of NOD2 protein to activate NF-kB, suggesting that variants in this gene alter the ability of monocytes in the intestinal wall to respond to normal flora, thereby predisposing an abnormal, inflammatory response
Autoimmune disease
2-4x increase in people of Ashkenazi Jewish descent
Episodic abdominal pain, cramping, and diarrhea
External manifestations including inflammation of joints, eyes, and skin
Chromatinopathies
Group of Mendelian disorders resulting from germline mutations in genes encoding epigenetic machinery & chromatin-modifiers
Phenotypes generally include intellectual disability (83%) and growth abnormalities (71% - either growth retardation or overgrowth)
Most are AD inheritance due to haploinsufficiency
Genes are highly dose-sensitive
Can occur de novo
ASXL3 is commonly mutated in these disorders.
Sotos Syndrome
Overgrowth syndrome, gigantism
NDSD1 (5q35.3)
AD inheritance but mostly de novo
Key features: distinctive facial features (macrocephaly, protrusive forehead, pointy chin, down-slanting eyes), learning disability, and overgrowth
Bloom Syndrome
CIS
BLM (15q26), AR inheritance
1:100 carrier frequency for Ashkenazis
Severe growth deficiency, immune
abnormalities, sensitivity to sunlight, insulin resistance
Red, butterfly rash on face
Fanconi Anemia
CIS
AR inheritance w/one AD exception
Mutations in ~20 genes, mostly in FANCA, C, or G
More common in Ashkenazis
Radial ray abnormalities (bilateral absent thumbs)
BM transplant can cure
Ataxia Telangectasia
CIS
ATM (11q22-23), AR inheritance
Cerebellar degeneration, Oculocutaneous telangiectasias, increased AFP levels, immunodeficiency, radiosensitivity
Carriers estimated to account for 5% of cancers in US
Pierre-Robine sequence
Micrognathia -> tongue displacement -> cleft palate
Polycystic Kidney Disease
Renal disorder
PKD1 (85%, more severe disease) and PKD2 (15%, milder disease) mutations
AD inheritance, variable expressivity
90% inherited, 10% de novo mutations
Pan-ethnic, prevalence is 1:300~1,000
Cyst formation follows 2-hit mechanism (both alleles of affected gene must lose function for cysts to form.
Symptom onset at any age but most frequently begin in 3rd-4th decade.
UTIs, hematuria, urinary tract obstruction, nocturia, hemorrhage into a renal cyst, or flank pain
Other symptoms: hepatic, pancreatic, ovarian, and splenic cysts, intracranial aneurysms, mitral valve prolapse, and colonic diverticula
Hypertension, recurrent UTIs, male sex, and early clinical onset are most predictive of early renal failure.
~43% of patients w/ADPKD symptoms before or shortly after birth die of renal failure within the first year
Goal is to slow progression by aggressively treating hypertension and UTIs
Thin Basement Neuropathy and Alport Syndrome
Overlapping renal disorders affecting kidney glomeruli via abnormal collagen production
COL4A3, COL4A4, COL4A5
Symptoms: hematuria, proteinuria, hypertension, renal insufficiency
TBM is AD inheritance and less severe, can also be referred to as ADAS due to changing definitions
Alport can be X-linked (65%), AR (15%), or AD (20%) and also involves hearing loss and vision impairment (due to abnormal collagen)
End stage renal disease can occur, and kidney transplant is typically successful.
Hutchinson-Gilford Progeria Syndrome
Premature aging disorder
Heterozygous path variant in LMNA gene (c.1824 C>T), resulting in abnormal production of lamin A protein
Almost all cases are de novo but sibs within a family have a slight increased risk due to the possibility of germline parental mosaicism.
Normal at birth and then profound failure to thrive in first year.
Should be suspected in children with severe growth failure, areas of sclerodermatous skin, partial alopecia that progresses to total alopecia by age two years, generalized lipodystrophy, retrognathia, all in the setting of normal intellectual development.
Average lifespan is ~15 years; COD is usually heart attack, stroke, or severe arteriosclerosis
