Untitled Deck Flashcards
What genes/changes cause Alagille Syndrome
JAG1 seq (83%), JAG1 del (11%), NOTCH2 (2.5%)
What is the disease mechanism for Alagille?
JAG1 truncated protein product rendering it unable to bind to the cell membrane resulting in functional haploinsufficiency
What are the proteins and gene locations in Alagille?
JAG1 = jagged 1 on 20p12.2, NOTCH2 = neurogenic locus notch homolog protein 2 on 1p12
Clinical features of Alagille syndrome?
Bile duct paucity, cardiac defects (peripheral PS stenosis), cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior embryotoxon), characteristic facial features, DD, growth failure
Inheritance pattern for Alagille
autosomal dominant, but 50-70% de novo
What are the facial features of Alagille
prominent/broad forehead, deep-set eyes w/ moderate hypertelorism, pointed chin, saddle or straight nose w/ bulbous tip
What is the primary gene, protein, and cytogenetic location for Brugada Syndrome
SCN5A, sodium channel protein type 5 subunit alpha, 3p22.2
What is the inheritance pattern for Brugada?
autosomal dominant. Except for KCNE5 which is XLR
What is the disease mechanism for Brugada?
LOF mutations in SCN5A cause lack of expression of or acceleration in the inactivation of cardiac sodium channels
What is a common clinical feature of Brugada Syndrome related to sleep?
Nocturnal agonal respiration
This refers to abnormal breathing patterns during sleep, often associated with serious medical conditions.
In which leads are ST-segment abnormalities observed in Brugada Syndrome?
Leads V1-V3 on EKG
These leads are part of a standard 12-lead electrocardiogram used to assess heart function.
What is a significant risk associated with Brugada Syndrome?
High risk of ventricular arrhythmias and sudden death
Ventricular arrhythmias can lead to life-threatening heart rhythms and sudden cardiac events.
At what stage of life does Brugada Syndrome primarily manifest?
Primarily in adulthood
Symptoms and complications typically arise in adult patients.
What is the mean age of sudden death in individuals with Brugada Syndrome?
40 years
This statistic highlights the serious nature of the condition and its impact on lifespan.
How may Brugada Syndrome present in infants?
As SIDS or sudden unexpected nocturnal death
SIDS stands for Sudden Infant Death Syndrome, which is a critical concern in pediatric populations.
What family history may be relevant in cases of Brugada Syndrome?
Family history of sudden cardiac death
This can indicate a genetic predisposition to arrhythmias and related conditions.
What is the management for Brugada syndrome?
implantable defibrillators (controversial in ASx patients)
What medication is used to treat electrical storm in Brugada patients?
isoproterenol
What circumstances should be avoided in Brugada syndrome?
fever, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic antagonists, TCAs, 1st gen antihistamines, cocaine, class 1C antiarrhythmic drugs, Class 1A agents (procainamide, disopyramide)
What are the genes/proteins and their locations that cause Cardio-Facio-Cutaneous (CFC) syndrome
BRAF1 (B-Raf proto-oncogene serine/threonine protein kinase) on 7q34, MAP2K1 on 15q22.31, MAP2K2 on 19q13.3 (mitogen-activated protein kinase 1 and 2), KRAS (GTPase Kras) on 12p12.2
What is the inheritance pattern for CFC Syndrome
Autosomal dominant, but majority are de novo
What is the disease mechanism for CFC syndrome
sustained activation of the Ras MAPK pathway downstream effectors: MEK and/or ERK
What cardiac abnormalities are seen in CFC syndrome?
pulmonic stenosis, septal defects, hypertrophic cardiomyopathy, arrhythmias
What neurologic manifestations are in CFC syndrome?
hypotonia, seizures, mild-severe ID
What are the ectodermal findings seen in CFC syndrome?
xerosis, sparse/curly/wooly/brittle hair, dystrophic nails, nevi
What clinical features are seen in CFC syndrome?
cardiac abnormalities, distinctive facial features, severe feeding issues, poor growth, relative macrocephaly, ectodermal findings, ID, hypotonia, seizures, eye abnormalities, a few w/ malignancy (ALL)
What malignancy can be seen in CFC syndrome?
ALL
What are the facial features of CFC syndrome?
relative macrocephaly, triangular facies, high forehead w/ bitemporal narrowing, low-set posteriorly rotated ears w/ thick helices, hypertelorism w/ down slanting palpebral fissures, epicanthal folds and ptosis, short nose w/ depressed nasal bridge w/ anteverted nares, high arched palate, cupid’s bow lips, deep philtrum, more coarse facial features and more dolichocephaly than noonan syndrome
What is the percentage of CFC syndrome cases caused by each gene?
BRAF seq 75%, KRAS <2%, MAP2K1/2 together is 25%
What genes/proteins and their locations that cause Hereditary Hemorrhagic Telangiectasis (HHT)?
ACVRL1 (activin A receptor type II-like kinase 1) on 12q13.3, ENG (endoglin) on 9q34.11, SMAD4 (Mothers against decapentaplegic homolog 4) on 10q11.22
What percentage of HHT cases are caused by each gene?
ACVRL1 (52%) ENG (44%) SMAD4 (1%)
What are the clinical characteristics of HHT?
epistaxis, mucocutaneous telangiectasias (lips, oral cavity, fingers, nose), visceral AVM (cerebral, pulmonary, GI, hepatic, spinal), 1st degree relative w/ HHT. At risk for colon cancer w/ SMAD4
What additional screening is needed for HHT caused by SMAD4?
at risk for colon cancer. colonoscopy starting at 15yo, every 3 years w/o polyps or annually with an EGD if polyps are found
What clinical tests are needed for HHT?
stool for occult blood, CBC (eval anemia or polycythemia), contrast echo for pulm AVM, Head MRI for cerebral AVM, doppler US vs CT/MRI for hepatic AVM, colon cancer screen for SMAD4 variants
What is the inheritance pattern for HHT?
Autosomal dominant,
What is the disease mechanism for HHT?
haploinsufficiency
What genes/proteins and their locations cause Holt-Oram syndrome?
TBX5 (T-box transcription factor TBX5) on 12q24.1
SALL4 (Sal-like protein 4) on 20q13.2
How is Holt-Oram syndrome inherited?
autosomal dominant, 85% de novo
What is the disease mechanism for Holt-Oram syndrome?
TBX5 protein product is a transcription factor w/ important role in both cardiogenesis and limb development. TBX5 mutations lead to mutant TBX5 mRNAs that are rapidly degraded or to transcripts w/ diminished DNA binding resulting in HAPLOINSUFFICIENCY
What are the clinical features of Holt-Oram syndrome?
upper limb defects (variable, carpal bone abnormalities are almost always present, radial ray defects, unilateral or bilateral),
CHD (most often ASD or VSD),
arrhythmia even w/o CHD
What percentage of Holt-Oram syndrome is caused by each gene?
TBX5 seq (>70%)
TBX5 del/dup (<1%)
SALL4 (which can also cause Duane-radial ray syndrome and acro-renal-ocular syndrome which can look similar)
