400C Final

Sickle Cell Disease

Gene: HBB

Chromosome: 11p15.5

Inheritance: AR

Genotype: HbS/HbS or βS/βS

Mutation: Glu6Val

Qualitative hemoglobinopathy

Findings: Mild-severe hemolytic anemia, vaso-occlusion (pain crises, acute chest syndrome, dactylitis, priapism, avascular necrosis, stroke), crew cut skull, aplastic crisis, autosplenectomy w/Howell-Jolly bodies (risk of Salmonella osteomyelitis infection), splenic infarct, and hematuria/renal papillary necrosis

Treatment: hydroxyurea (increased HbF)

Sickle Cell Trait

Gene: HBB

Chromosome: 11

Genotype: HbA/HbS or βA/βS

Findings: Usually asymptomatic, hematuria, splenic infarction at high altitude, heterozygote advantage against malaria

HbSC Disease

Gene: HBB

Chromosome: 11

Genotype: HbS/HbC or βS/βC

Mutation: Glu6Lys

Qualitative hemoglobinopathy

Findings: Sickle disease (usually milder than HbSS), mild anemia, retinal artery occlusion (retinopathy)

HbC Disease

Gene: HBB

Chromosome: 11

Genotype: HbC/HbC or βC/βC

Mutation: Glu6Lys

Qualitative hemoglobinopathy

Findings: Mild hemolytic anemia, HbC crystals

Beta Thalassemia Trait (Minor)

Gene: HBB

Chromosome: 11

Genotype: β/β+ or β/β0

Quantitative hemoglobinopathy

Findings: Mild microcytic anemia, elevated HbA2, often confused with iron deficiency

Beta Thalassemia Intermedia

Gene: HBB

Genotype: β+/β+ or mild β+/β0 combinations

Quantitative hemoglobinopathy

Findings: Variable anemia (asymptomatic-severe), may require transfusions, elevated HbA2, low MCV

Beta Thalassemia Major (Cooley Anemia)

Gene: HBB

Genotype: β0/β0 or severe β+/β0

Quantitative hemoglobinopathy

Findings: Severe anemia after ~6 months (develops after HbF declines), transfusion dependent, splenomegaly, iron overload, crew-cut skull, chipmunk facies (bone marrow expansion), extramedullary hematopoiesis, low MCV, jaundice, iron chelation

Alpha Thalassemia Silent Carrier

Genes: HBA1 or HBA2

Chromosome: 16p13.3

Genotype: -α/αα

Quantitative hemoglobinopathy

Findings: Usually normal CBC (measures red blood cells, white blood cells, hemoglobin, hematocrit, and platelets), some mild anemia

Alpha Thalassemia Trait

Genotypes: -α/-α (trans) or --/αα (cis)

Chromosome: 16

Quantitative hemoglobinopathy

Findings: Mild microcytic hypochromic anemia, low MCV, low MCH, cis deletion is important in Southeast Asian populations

Common in African Americans, Mediterraneans, and some Asians

HbH Disease

Genotype: --/-α

Chromosome: 16

Quantitative hemoglobinopathy

Findings: Moderate-severe microcytic hypochromatic anemia, HSM, jaundice, β4 tetramers, hemolysis, hepatosplenomegaly, bone changes (chipmunk facies), extramedullary hematopoiesis, gallstones, infections, folic acid deficiency

Common in Southeast Asians over African Americans

Hb Bart Syndrome

Genotype --/--

Chromosome: 16

Quantitative hemoglobinopathy

Findings: severe anemia, heart failure, hepatosplenomegaly, maternal pregnancy risks, low MCV, low MCH, γ4 tetramer (prenatally), hydrops fetalis, usually lethal

Hereditary Persistence of Fetal Hemoglobin (HPFH)

Genotype: HBB cluster

Chromosome: 11

Findings: Elevated HbF throughout life

Improves: Sickle cell disease, Beta thalassemia

Hemophilia A

Gene: F8

Chromosome: Xq28

Inheritance: X-linked recessive

Mutation: Intron 22 inversion

The most common X-linked bleeding disorder after von Willebrand disease

Severity: Severe <1%, Moderate 1–5%, or Mild >5–40%

Findings: Hemarthroses, deep tissue bleeding, prolonged PTT, and normal PT/platelets

Mild: no spontaneous bleeding except trauma, surgery, or pregnancy

Hemophilia B

Gene: F9

Chromosome: Xq27.1

Inheritance: X-linked recessive

Severity: Severe <1%, Moderate 1–5%, or Mild >5–40%

Much less prevalent than Hemophilia A

Findings: Hemarthroses, deep tissue bleeding, prolonged PTT, and normal PT/platelets

Mild: no spontaneous bleeding except trauma, surgery, or pregnancy

Factor V Leiden (Thrombophilia)

Gene: F5

Chromosome: 1q24

Inheritance: AD with incomplete penetrance

Most common thrombophillia

Findings: venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), activated protein C resistance, and clotting

X-Linked Agammaglobulinemia

Gene: BTK

Chromosome: Xq21.3-Xq22

Inheritance: X-linked recessive

Findings: Absent B cells, low immunoglobulins, absent tonsils, and recurrent bacterial infections after 6 months

X-linked SCID

Gene: IL-2RG

Chromosome: Xq13.1

Inheritance: X-linked

Phenotype T-B+NK-

T cells: Absent or very low

B cells: Present in number but functionally defective due to lack of T cell help

Natural killer (NK) cells: Absent or very low

Findings: Failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, fungal, and protozoal infections, decreased TRECs, absence of thymic shadow, germinal centers, and T cells

Part of the newborn screen for SCID

Most common SCID

RAG Deficiency

Genes: RAG1 or RAG2

Chromosome: 11p13

Inheritance: AR

Phenotype: T-B-NK+

Mechanism: VDJ recombination defect

T cells: Absent or very low, leading to impaired cellular immunity

B cells: Present in number but functionally defective due to lack of T cell help

NK cells: Normal in number and relatively normal function, as NK cells do not require V(D)J recombination for development

Findings: Failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, fungal, and protozoal infections, decreased TRECs, absence of thymic shadow, germinal centers, and T cells

Part of the newborn screen for SCID

ADA Deficiency

Gene: ADA

Chromosome: 20q13.12

Inheritance: AR

Phenotype T-B-NK-

T cells: Absent or very low

B cells: Absent or very low

Natural killer (NK) cells: Absent or very low

Findings: Failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, fungal, and protozoal infections, decreased TRECs, absence of thymic shadow, germinal centers, and T cells

Part of the newborn screen for SCID

22q11.2 Deletion Syndrome

Gene: TBX1

Chromosome: 22q11.2

Inheritance: AD

Findings: Conotruncal heart defects, hypocalcemia, cleft palate, thymic hypoplasia, T-cell deficiency, Tetralogy of Fallot

Chronic Granulomatous Disease

Gene: CYBB (most common)

Chromosome: Xp21

Inheritance: Usually X-linked

Findings: Defective oxidative burst, abnormal DHR, recurrent catalase-positive infections

Hemophilia C

Gene: F11

Inheritance: AR

Findings: no hemarthroses or muscle bleeds, mild-moderate symptoms, bleeding after surgery, dental procedures, trauma (periods and nosebleeds)

Hyper-IgE Syndrome (Job Syndrome)

Gene: STAT3

Chromosome: 17q21

Inheritance: AD

Finding: Very high IgE, recurrent skin, abscesses, retained primary teeth, fractures, scoliosis, pneumatoceles

Hermansky-Pudlak Syndrome

Gene: HPS1

Puerto Rican Founder Type

Chromosome: 10q23

Inheritance: AR

Finding: Oculocutaneous albinism, easy bruising, platelet dysfunction, neutropenia, and pulmonary fibrosis

Familial Mediterranean Fever

Gene: MEFV

Chromosome: 16p13.3

Inheritance: AR

Findings: Recurrent fever, recurrent serositis, peritonitis, pleuritis, arthritis, renal amyloidosis

CHARGE Syndrome

Gene: CHD7

Chromosome: 8q12

Inheritance: AD

Findings: Coloboma, heart defects, atresia (choanal), restricted growth and development, genital anomalies, ear anomalies

Waardenburg Syndrome

Genes: PAX3 (classic)

Chromosome: 2q36

Inheritance: AD (common)

Findings: dystopia canthorum, white forelock, heterochromia, hearing loss

Marfan Syndrome

Gene: FBN1

Chromosome: 15q21

Inheritance: AD

Findings: Upward lens dislocation, aortic root dilation, tall stature

Homocystinuria

Gene: CBS

Chromosome: 21q22

Inheritance AR

Findings: Downward lens dislocation, thrombosis, developmental delay, and marfanoid habitus

Stickler Syndrome

Gene: COL2A1 (most common)

Chromosome: 12q13

Inheritance: AD

Findings: Retinal detachment, high myopia, midface hypoplasia, hearing loss

Bardet-Biedl Syndrome

Genes: Many (BBS genes)

Inheritance: AR

Findings: Cone-rod dystrophy, obesity, polydactyly, renal disease, hypogonadism

Tay-Sachs Disease

Gene: HEXA

Chromosome: 15q23

Inheritance: AR
Findings: cherry-red macula

Osteogenesis Imperfecta

Genes: COL1A1 and COL1A2

Chromosomes: 17

Findings: Blue sclera

Galactosemia

Gene: GALT

Chromosome: 9p13

Inheritance: AR

Findings: Bilateral cataracts, other findings, liver disease, E. coli sepsis, vomiting after milk feeds

Galactokinase Deficiency

Gene: GALK

Chromosome: 9p13

Inheritance: AR

Findings: Bilateral cataracts

Hemoglobin E

Gene: HBB

Chromosome: 11

Inheritance: AR

Ethnicity: Common in Southeast Asia

Findings: Microcytosis

βE/β0 or βE/β+ can cause moderate-severe anemia and can resemble β-thal intermedia/major

HbH Constant Spring

Gene: HBA

Chromosome: 16

Ethnicity: Southeast Asian ancestry

Findings: More severe anemia than deletional HbH and can worsen alpha-thalassemia phenotypes, especially when combined with alpha-globin deletions

G6PD Deficiency

Gene: G6PD

Chromosome: Xq28

Inheritance: X-linked

Findings: Episodic hemolysis after oxidative stress, fava beans, sulfa drugs, infections, Heinz bodies, and bite cells