Genetics E2- CT, Renal, & Blood

What gene is involved in Marfan syndrome (MFS)?

FBN1 on 15q21 which encodes fibrillin-1

What type of inheritance pattern does MFS have?

Autosomal dominant; 25% d/t de novo mutation

The following skeletal findings are seen in what condition?

• excess linear growth of long bones & joint laxity

• pectus excavatum or carinatum

• hind foot valgus w/ pes planus

• dolichostenomelia

• scoliosis, kyphosis

• dura ectasia

• skin striae

MFS

What other non-skeletal clinical features are seen in MFS?

Aortic dissection, MVP, ectopia lentis (subluxated lens), joint hyper mobility, high-arched palate, predisposed to spontaneous pneumothorax

What term refers to a decreased UE/LE ratio and increased arm span to height ratio?

Dolichostenomelia

What is the management for MFS?

Atenolol and/or Losartan

Annual echo & eye exams, scoliosis screening, orthodontic evaluation

What should be avoided in MFS?

CCBs bc can worsen aortic dilation

What BB should be used in pregnancy for MFS?

Labetalol

What are the 4 Ps associated with thoracic aortic dissections?

Pallor. pulselessness, paresthesias, paralysis

What are ssx of TAAD?

Severe CP referred to shoulder (MC left); abd pain; pallor, pulselessness, paresthesias, paralysis

What inheritance pattern does familial thoracic aortic aneurysm disease (TAAD) have?

Autosomal dominant

What genes are involved in TAAD?

ACTA2, MYH11, TGFBR2, MYLK, PRKG1

Which generally presents with an aortic dissection at an older age: familial TAAD or MFS?

Familial TAAD

What is the major diagnostic criteria for TAAD?

Presence of dilation and/or dissection of ascending aorta; dissection of descending aorta distal to subclavian artery

*confirm: measure dimensions w/ CT, MRI, or TEE & compare w/ age-appropriate nomograms

What is the management for familial TAAD?

Control HTN, repair TAAs ≥ 5.0cm, genetic counseling

What should be avoided in familial TAAD?

Isometric exercises (weightlifting), rapid deceleration (MVA), contact sports

What screening should be done for first-degree relatives of those with familial TAAD?

Annual echo, full aortic imaging (CT or MRI) every 6-24 mos if abnormal

Which types of ehlers-danlos (EDS) syndrome have known genetic causes?

Classical & vascular

What is the trait of features associated with EDS?

Skin hyper extensibility, atrophic scarring, generalized joint hypermobility

What are the major types of EDS?

Hypermobile, classical, vascular

When do ~50% of ADPKD patients progress to ESRD?

60 y/o

What genes are involved in ADPKD?

PKD1 on chrom 16 (MC; more severe)

PKD2 on chrom 4 (milder, slower progression)

What autosomal dominant condition, diagnosed by US, is characterized by BL renal cysts and an increased risk of intracranial aneurysms?

ADPKD

What screening should be done for the offspring of a parent with ADPKD?

Renal US

What extra renal manifestations are associated with ADPKD?

Hepatic & pancreatic cysts, HTN (early sign), intracranial aneurysms, MVP, abd or inguinal hernias

What is the diagnostic criteria for ADPKD?

*criteria applies to those with known family history

15-39 y/o: ≥ 3 cysts total

40-59 y/o: ≥ 2 cysts in each kidney

≥ 60 y/o: ≥ 4 cysts in each kidney

What autosomal recessive condition presents in children is characterized by hepatobiliary disease (hepatosplenomegaly, progressive portal HTN), and has a high mortality rate (30% in first month)?

ARPKD

When will ~50% of ARPKD patients progress to ESRD?

First decade

What is the treatment for PCKD?

ACEI or ARBs (target 120-130/70-80 in early dz)

Kidney transplant or dialysis if ESRD

Regular imaging for cyst growth, monitor renal function & CV RF

What lifestyle modifications should be implemented for PCKD?

Dietary Na restriction < 2g/day, hydration 2-2.5L/day, avoid contact sports & heavy lifting

What vasopressin V2-receptor antagonist can be used for rapidly progressive ADPKD to slow the growth of cysts & preserve renal function?

Tolvaptan

Which monitors the intrinsic pathway: PT or PTT?

PTT

Which monitors the extrinsic pathway: PT or PTT?

PT

What X-linked recessive condition is d/t a mutation of the F8 gene which results in functionally impaired VIII proteins?

*”classic hemophilia”

Hemophilia A

How are factor VIII levels in carrier females on hemophilia A?

50% normal (show a bleeding predisposition)

Which x-linked recessive condition is d/t a mutation of the F9 gene, resulting in functionally impaired factor IX proteins?

Hemophilia B

How will the offspring be affected if the father has hemophilia A and the mother is not a carrier?

Sons are unaffected; daughters are carriers

How will the offspring be affected if the mother is a carrier for hemophilia A but the father does not have it?

50% of sons will be affected; 50% of daughters will be carriers

What condition typically presents with a 5 day old male with prolonged bleeding following circumcision?

Hemophilia

What is the treatment for hemophilia?

Replace factor VIII or IX

What is the MC inherited bleeding disorder?

VWD

What predominantly autosomal dominant condition is due to a mutation on VWF gene located on chromosome 12 & affects males and females equally?

*3 types; type 1 MC

VWD

What should VWD patients avoid?

ASA & NSAIDs d/t bleeding risk

What 2 critical functions does VWF have in primary hemostasis?

Acts as bridging molecule at sites of injury for normal plt adhesion & promotes plt aggregation

What sx are typically seen with VWD?

Epistaxis, easy bruising, bleeding w/ dental extractions or other surgeries

What is the treatment for VWD?

DDAVP for type 1; VWF concentrates for more severe types

Antifibrinolytics (tanexamic acid) for mucosal bleeding

What gene is involved in sickle cell disease?

Specific point mutation on HBB that substitutes valine for glutamic acid at position 6 of B-globin chain

What is normal adult hemoglobin?

HbA

What is adult sickle hemoglobin?

HbS

Who is sickle cell disease MC in?

African American, Cuba, South America, Central America, Saudi Arabia, India, mediterranean ancestry

What is heterozygous advantage?

Carriers for an autosomal recessive condition have higher survival & reproductive fitness than affected & unaffected homozygotes

What condition are sickle cell carriers (HbS heterozygous) protected from?

Severe malaria

What is the pathophysiology of sickle cell disease (SCD)?

Hypoxia & dehydration triggers sickling → membrane distortion → rigid RBC stickiness → hemolysis & vaso-occlusion

What are hallmark clinical presentations of SCD?

Pain, infections, bone infarctions, normocytic anemia

What inheritance pattern does sickle cell disease (SCD) have?

Autosomal recessive

What clinical features of SCD can be seen in infancy?

FTT, pain, anemia, splenomegaly, multiple chronic infections, swelling of extremities d/t vaso-occlusion

How can an acute sickle cell crisis present?

Severe abd pain, stroke, acute chest syndrome, renal necrosis, leg ulcers, priapism, loss of vision d/t massive vaso-occlusive infarction

What does hemolysis cause in sickle cell disease?

Inc bilirubin → cholelithiasis; chronic anemia & subsequent jaundice; predisposes to aplastic crisis

What is acute chest syndrome (AChS)?

New radio density on CXR & fever/respiratory sx in sickle cell patient

What might be seen on CBC in sickle cell patients?

Normocytic anemia, target cells, sickled cells (when hypoxemic)

What are the MC types of sickle cells disease?

HbSS followed by HbSC

What is the treatment for SCD?

Hydroxyurea, blood transfusion, prophylactic PCN, routine childhood vaccines

What targeted therapies are available for SCD?

L-glutamine: dec frequency of pain crises

Crizanlizumab: P-selectic inhibitor for VOC prevention

Voxelotor: Inc hgb, dec hemolysis

What are curative options for SCD?

Allogeneic HSCT, gene therapy (casgevy & lyfgenia)