Common Aneuploidies

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Additional episodes that might be helpful for today:

What is aneuploidy?

  • The occurrence of one or more extra or missing chromosomes leading to an unbalanced complement.

  • Screening for aneuploidy occurs with either serum screening or cell free DNA.

    • Diagnostic testing for aneuploidy is done with chorionic villus sampling or amniocentesis.

      • As we discussed on the screening 2 episode; fluorescent in situ hybridization (FISH) can evaluate initially for common aneuploidies.

      • Karyotypes are the confirmatory testing for common aneuploidy, as well as other ways to get aneuploidy we’ll review (triploidy, balanced translocations).

      • Microarray can find other major aneuploidies, but can’t find triploidy or balanced translocations.

How does aneuploidy occur?

  • Meiosis is the process of cell division that produces gametes – eggs and sperm. 

    • Goal is to create daughter cells with a haploid chromosome number (in humans – 23).

    • The two gametes generally fuse to create a diploid zygote with 46 chromosomes.

      • If there’s an issue in the cell division process for a gamete, they may come into this fusion with an extra or missing chromosome.

    • Remember in cell division, we have multiple phases: prophase, metaphase, anaphase, telophase.

      • We’ll break it down simply into the stages you need to remember to get those bonus points!

  • Meiosis is broken into two phases: meiosis I and meiosis II.

    • In meiosis I, the starting cell is diploid – but after replication, ends up with 4n chromatids (held in 2n chromosome pairs, or sister chromatids). 

      • In prophase I, each pair of chromosomes lines up and matches with a homologous partner. This allows for the phenomenon of crossing over, where homologous portions of the chromosomes can rearrange and exchange portions of their DNA.

        • This is where things can get dicey for a particular type of uncommon aneuploidy, known as a translocation. 

          • That is, rather than recombining with a portion of the homologous chromosome, it attaches to a different chromosome.

          • These translocations can be:

            • Balanced, where the genetic information is not gained or lost, but just rearranged differently. 

              • So for example: A piece of chromosome 21 joins onto chromosome 14, and a piece of chromosome 14 joins onto the break at 21. 

                • The cell at this point still technically is diploid – but there can be problems with this later on!

            • Unbalanced, where the genetic information is split unequally.

              • In the same example: a piece of chromosome 21 joins onto 14, but the piece from 14 is lost.

          • A particular type of translocation is known as a Robertsonian translocation, which is where the full long arms of two acrocentric chromosomes are joined together.

            • The acrocentric chromosomes are where the short arms are extremely short - these are 13, 14, 15, 21, and 22 in humans.

            • One of the most discussed is a 14:21 translocation, which is responsible for some Down syndrome.

              • These translocations typically result in familial cases of aneuploidy, as a parent may be a balanced carrier of an abnormal chromosome – issues don’t arise for aneuploidy until they start trying to have children, and the chromosome complement ends up unbalanced in offspring.

      • In the female reproductive cycle, eggs arrest in the cell cycle at prophase I, and only complete the remainder of meiosis prior to that egg’s ovulation.

        • So an egg can be arrested for 30-40 years! 

        • Ultimately, with this extended pause, meiosis I in oocytes is where the majority of nondisjunction events occur.

      • To complete meiosis I:

        • Metaphase I: the homologous pair lines up across the metaphase plate (like a cell equator) to prepare for division

        • Anaphase I: the homologues are separated to the opposite ends of the cell

          • Or not, if they can’t be separated! – This is nondisjunction.

        • Telophase I: the new cells are haploid in chromosome pairs.

    • We then move to meiosis II, where the sister chromatids are split into haploid pairs:

      • Metaphase II: the sister chromatids line up across the metaphase plate.

      • Anaphase II: the sister chromatids are separated to the opposite ends of the cell.

        • This is another point where nondisjunction can occur (less common than in meiosis I, though)!

      • Telophase II: the new cells are haploid with 23 single chromosomes (no longer in pairs).

The robertsonian translocation and gamete production

Trisomy 21: Down Syndrome

  • Syndrome resulting from the addition of an extra chromosome 21. 

  • Most common aneuploidy: affects about 1 in 700 births in the USA.

  • Occurs via:

    • Nondisjunction event: 95% of occurrences

    • Robertsonian translocation: 5% of occurrences

    • Mosaicism: infrequent (~1-2% max)

      • This is where some cell lines have aneuploidy, and others do not. This occurs usually in early mitosis of the zygote, where the embryo during cell division recognizes the extra chromosome and tries to “kick it out” with aneuploidy rescue. We won’t spend too much time on that today! 

  • Prenatal testing characteristics of trisomy 21:

    • Cell free DNA: excellent test performance with 99% sensitivity and specificity.

      • However, false positives still occur frequently, particularly in low-prevalence populations (i.e., around 50% false-positive risk in women aged 25).

    • Serum screening: 

      • Low msAFP

      • Low estriol

      • High HCG

      • High inhibin A

    • Ultrasound:

      • 1st trimester: elevated NT (64-70%), absent/hypoplastic nasal bone.

      • 2nd trimester:

        • Various soft markers all have significance for T21: pyelectasis, echogenic bowel, echogenic cardiac focus, short femur.

        • Most significant soft marker: thickened nuchal fold (LR 11-18 for T21)

        • Practically pathognomonic findings:

          • “Double bubble sign” – duodenal atresia - familiarize yourself with this ultrasound as it’s very commonly tested!

          • Cardiac anomalies in ~50% – particularly significant / common are atrioventricular septal defects.

DOUBLE BUBBLE - RADIOPAEDIA

Trisomy 18: Edward syndrome 

  • Syndrome resulting from additional chromosome 18.

  • Frequency: about 1 in 2k - 6k live births in USA.

  • Occurs via:

    • Nondisjunction event: over 95% of cases

    • Mosaicism: around 4-5% of cases

    • Translocations: rare, but has been reported.

  • Prenatal testing characteristics:

    • Cell free DNA: good, with over 96% sensitivity and over 99% specificity.

      • However, given its infrequency, the positive-predictive value can still be low – 40% PPV in a woman at age 35. 

    • Serum screening:

      • All analytes decrease (though inhibin A can be normal).

    • Ultrasound:

      • 1st trimester: elevated NT, absent / hypoplastic nasal bone.

      • 2nd trimester: multiple characteristic signs:

        • Choroid plexus cysts are the most common soft-marker (though non-specific)

        • “Strawberry skull” – flattened occiput, pointed frontal bones

        • Clenched hands with overlapping fingers

        • Rocker-bottom feet

        • Cardiac anomalies

        • Esophageal atresia, diaphragmatic hernias

        • Growth restriction

STRAWBERRY SKULL

Trisomy 13: Patau syndrome

  • Syndrome resulting from additional chromosome 13

  • Frequency: about 1 in 10k-16k live births in USA

  • Occurs via:

    • Nondisjunction event: most common

    • Chromosome 13 is one of the acrocentric chromosomes so Robertsonian translocation can occur and familial forms have been reported.

    • Mosaicism is also possible.

  • Prenatal testing characteristics:

    • Cell free DNA: similar story to trisomy 18. Sensitivity is around 91% and specificity over 99%.

      • Given the low prevalence, positive-predictive values can still be low – around 20% for a woman at age 35. 

    • Serum screening:

      • No well-defined pattern, but elevated msAFP may be present given common CNS and other anomalies present in this syndrome.

    • Ultrasound:

      • 1st trimester: elevated NT, absent / hypoplastic nasal bone

      • 2nd trimester: multiple characteristic signs, but remember: midline and CNS are classic:

        • Holoprosencephaly: failure to divide brain into cerebral hemispheres (so no midline falx cerebri)

        • Facial anomalies: cleft lip/palate, proboscis, micropthalmia/anopthalmia or cyclops eye

        • Cardiac abnormalities - up to 80%

        • Omphalocele

        • Enlarged echogenic kidneys or horseshoe kidney

ALOBAR HOLOPROSENCEPALY - RADIOPAEDIA

Monosomy X: Turner Syndrome

  • Syndrome results from a missing sex chromosome - so 45, XO.

    • 80% of the time this is paternally derived – one of the few circumstances this is the case!

  • Frequency: 1 in 2k-5k live births

  • Occurs via:

    • Nondisjunction event: most common

      • On the paternal side, given the mismatch of X and Y, the Y chromosome can be subject to “getting lost” in meiosis.

    • Mosaicism can also occur with Turner syndrome in about 50% of individuals

      • Cell lines are able to be mixed as 45, XO/46, XX, or 45, XO / 46, XY most commonly

        • If Y chromosome is detected, gonadectomy is advised to reduce risk of gonadoblastoma in later life. 

  • Prenatal testing characteristics:

    • Cell free DNA: overall has about 90% sensitivity and over 99% specificity.

      • Similarly: PPV is limited by prevalence

      • cfDNA also has difficulty with mosaicism and delineating this specifically. 

    • Ultrasound:

      • The most commonly tested finding: cystic hygroma

        • Present in 1st and/or 2nd trimester

        • Can also present with more generalized edema

      • Horseshoe kidney, cardiac abnormalities may also be present.

CYSTIC HYGROMA - RADIOPAEDIA

Genetic Carrier Screening

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Additional Reading
CO 690: Carrier Screening in the Age of Genomic Medicine
CO 691: Carrier Screening for Genetic Conditions
CO 816: Consumer Testing for Disease Risk

Previously on the podcast, we have talked through aneuploidy screening. But we’ve not talked in depth about carrier screening, so today’s podcast is dedicated to the other form of prenatal genetics we often consider! 

What is carrier screening?

  • Aneuploidy screening: looking at some biochemical marker in an already pregnant individual to understand risk of trisomy (typically).

  • Carrier screening: looking at genetics of parental contributions to assess potential risk in a current or hypothetical pregnancy. 

    • So this tells you - do you carry a condition that you are not affected by?

    • Only needs to be performed once in a lifetime - as opposed to aneuploidy screening, which needs to be re-performed with every pregnancy. 

  • ACOG recommends that “information about carrier screening should be provided to every pregnant individual.” 

  • Carrier screening most commonly looks for autosomal recessive conditions - that is, both parents need to be carriers in order for there to be a 25% risk of fetus being affected.

    • Certain X-linked conditions (i.e., hemophilia, Fragile X) can also be screened.

      • Information can be used in pregnancy planning, understanding risk of fetal condition that may impact life/lifespan of fetus, and choice for IVF with PGT or invasive testing in pregnancy.

    • Some other conditions may be discouraged from carrier screening (i.e., Huntington’s disease, BRCA genes) because of ethical concerns with doing carrier screening on fetuses, given these are adult-onset conditions. 

    • No “official threshold” for carrier screening generally, but most panels select conditions with a carrier frequency of ~1/100 or greater → generally a disease incidence of 1 in 40,000.

  • There always remains some residual risk for carriage state/disease, even after carrier screening.

What strategies have been suggested for carrier screening?

  • Historically, carrier screening was considered on an ethnicity basis (i.e., ethnic-based screening)

    • However, multiple limitations to this approach:

      • Challenging for individuals to define ancestry

      • Ancestral “mixing” between partners of different ethnicities causing different risks

      • The “pretest” probability of a positive is difficult to predict given these limitations

      • Couples with consanguinity may be at higher risk of recessive conditions being expressed in offspring, regardless of ethnic background.

  • Current approaches favor panethnic or expanded carrier screening 

    • Panel of disorder screening is offered to all individuals regardless of ancestry.

    • The cost of screening has come down significantly, allowing for screening for hundreds of conditions at reasonable cost to patient.

  • If family history of mutations/conditions are known, targeted screening can be considered to look for specific mutations.

What limitations are there in carrier screening? What does “residual risk” after carrier screening mean?

  • These carrier screening panels look for known mutations in a population, based on a reference genome.

    • These reference genomes are overwhelmingly represented by White populations, so:

      • Carrier screening may not detect all mutant variants of an allele → residual risk

      • Carrier screening does not recognize new, potentially disease-causing variants.

        • Carrier testing is not sequencing! 

What conditions are recommended by ACOG to be screened for with carrier screening?

  • Spinal muscular atrophy

    • Autosomal recessive disease with spinal cord motor neuron degeneration due to biparental inheritance of an SMN1 mutation/deletion.

    • Leading genetic cause of infant death.

    • Incidence of disease around 1 in 6-10k; carrier frequency in most populations around 1:40 to 1:60.

      • 2% of cases are the result of a new gene mutation. 

    • SMA has an interesting genetic profile:

      • There is generally one copy of SMN1 per chromosome, and a deletion/abnormality in each parental contribution leads to disease (again, autosomal recessive).

      • However, some of the population have two copies of SMN1 on a chromosome, and 0 copies on the other – so they are technically carriers (because of the chromosome with 0 copies).

      • Carrier screening tests for SMA generally look for the number of copies of SMN1 - so a patient with this particular variation (2+0) would be missed.

        • This 2+0 variation is much more common in African Americans - lowering the carrier detection rate of SMA from 95% in White patients to 71% in African Americans.

        • This leads to a higher residual risk from these tests as they may miss the 2+0 mutation.

  • Cystic fibrosis

    • Most common life-threatening AR condition in White population.

      • Incidence 1/2500 in White; considerably less common in other ethnic groups.

    • Two copies of CFTR mutations (chromosome 7) cause the disease.

    • Most carrier screening looks for one of the 23 most common mutations that exist – again, predominantly in White populations.

      • But there are over 1700 CFTR mutations identified that can lead to CF!

      • Performance ranges from 94% sensitivity in Ashkenazi Jewish populations to less than 50% in Asian populations. 

      • Because of the number of mutations, some have advocated for CFTR sequencing to supplant panel testing as a way to determine carrier status and reduce residual risk amongst all populations. 

  • Hemoglobinopathies

    • We have talked about these on the show before - thalassemias and sickle cell disease.

    • CBC and RBC indices should be performed in all pregnant persons to assess for anemia and risk of hemoglobinopathy.

      • Hb electrophoresis can be considered in all patients with anemia, particularly if there is family history or ethnicity-based risk factor, to screen for hemoglobinopathy.

      • Alpha thalassemias, though, can only be detected with molecular genetic studies - so if the electrophoresis is not conclusive, DNA-based testing should be pursued to assess for alpha thal. 

  • Fragile X Syndrome

    • Most common inherited form of intellectual disability; distinctive facial features in males, enlarged testicles, delay in fine and gross motor skills are some manifestations.

    • 1 in 3600 males; 1 in 4k-6k females. 

    • Carrier frequency in the US around 1 in 250 for no known risk factors, or 1 in 86 for those with a family history of intellectual disability.

    • X-linked disorder of mutation in FMR1 gene.

      • The mutation is characterized by expansion of a trinucleotide repeat sequence (CGG); the more repeats, the more significant the mutation:

        • Intermediate (45-54 repeats)

        • Premutation (55-200 repeats)

        • Full mutation (>200 repeats)

      • Females carrying a premutation or full-mutation X chromosome are also at risk for premature ovarian insufficiency. Females with full mutation may also have fragile X characteristics of disease like in males, though with variable expression. 

We hear a lot about “Ashkenazi Judaism” and carrier screening. What does that mean and what conditions should be screened?

  • Ashkenazi Jewish is defined in the committee opinions as individuals of Eastern and Central European Jewish descent.

    • Not a super accurate or helpful designation, as most individuals with Jewish ancestry in the USA are descended from these areas.

  • Recommendations for specific screening:

    • Tay Sachs Disease - severe, progressive neurodegenerative disease with functional deficiency in the gene encoding the hexosaminidase A enzyme. 

      • Carrier rate in Ashkenazi Jewish populations around 1 in 30.

    • Cystic fibrosis

    • Canavan disease - severe degenerative neurologic disease

    • Familial dysautonomia - severe disorder of sensory and autonomic nervous systems

    • Multiple others are also considered, including Gaucher disease, Joubert syndrome, maple syrup urine disease, Niemann-Pick disease, and a few others. 

      • The panels developed for this population are very ethnicity-specific - so while great for this population, residual risk discussion can be complicated in non-Jewish individuals (as the incidence of carriage is often very low).

What about the genetic screening tests advertised to patients online?

  • There are a whole host of “carrier screens” that are direct-to-consumer, and even some of the more reputable companies in this space have direct-to-consumer options given the decreasing expense of this technology. 

  • However, these companies have varying degrees of privacy protections for genetic data.

  • They also may have implications on patient’s eligibility for disability and other types of insurance; long-term care considerations; and ownership of one’s own genetic data.

  • Some direct-to-consumer testing uses different kinds of technology to develop a picture of risk for a patient, that may or may not be helpful in their context. Abnormal results of concern should always be reviewed with a genetic counselor.

    • If you have any concerns or need more time for your patients to discuss whether they want to have carrier screening, it’s worthwhile to send them to a GC! They can help patients navigate targeted vs expanded carrier screening and help make decisions that are right for each individual patient. 

Thalassemias, feat. Dr. David Abel

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Here’s the RoshReview Question of the Week!

A 31-year-old G1P1 woman of Southeast Asian descent with a history of intrauterine fetal demise presents to your office for preconception counseling. She also reports a history of mild anemia due to alpha-thalassemia. You order DNA testing. Which of the following is most likely her genotype?

Check if you got the right answer and get a special deal on the CREOG Q-Bank at link above!

The Basics of Hemoglobin

  • The major oxygen carrying pigments of the body. Carries oxygen from the lungs to the tissues to meet the needs of cells for oxidative metabolism.

    • We carry almost two pounds of hemoglobin at any given time!

  • The hemoglobin molecule is a tetramer.

    • Typically, this tetramer is composed of two alpha chains and two non-alpha globin chains.

    • The molecular mass of a hemoglobin tetramer is large, approximately 64,000 daltons. 

    • The primary structure of a particular hemoglobin is determined by its covalent bonds between the amino acids that form these polypeptide globins, and it is this primary structure that determines the behavior of a particular hemoglobin.

  • Hemoglobin synthesis is controlled by two multigene clusters, the alpha and beta globin genes.

    • The alpha genes are on chromosome 16.

      • Both genes for alpha globin are duplicated, thus there are four genes at the alpha globin locus, with two genes inherited from each parent.

    • The beta genes are on chromosome 11.

      • The beta globin gene consists of two genes, one inherited from each parent. 

    • Each of these two gene clusters also contain other genes!

Common Hemoglobin Molecules and Embryology of Hemoglobin

  • Hemoglobin changes during fetal development.

    • The switch from embryonic to fetal to adult hemoglobin synthesis is a major mechanism by which the developing fetus adapts from the hypoxic intrauterine environment, as each hemoglobin has its own oxygen dissociation curve.

  • In the embryonic stage of development, there exists both zeta and epsilon globin chains that are synthesized by yolk sac erythroblasts.

    • The zeta gene is part of the alpha globin gene cluster, and the epsilon gene is part of the beta globin gene cluster.

      • Hb Gower-1: two zeta and two epilson chains

      • Hb Gower-2: two alpha and two episilon chains

      • Hb Portland: two zeta and two gamma chains. 

  • After the first trimester, the zeta and epsilon globin chains are replaced by hemoglobin F, the dominant hemoglobin in-utero.

    • Hb F is composed of two fetal gamma globin chains and two alpha globin chains.

      • The gamma gene is a fetal gene that is part of the beta globin gene cluster.  

  • Hemoglobin F declines in the third trimester of pregnancy and is slowly replaced by hemoglobin A, which consists of two alpha and two beta chains.

    • Also keep in mind that expression of delta globin begins near birth. The delta gene is also part of the beta globin cluster, and contributes to hemoglobin A2 (two alpha, two delta globins).

  • At birth, hemoglobin F accounts for approximately 75-80 percent of hemoglobin and hemoglobin A accounts for 20-25 percent.

    • Postnatally, hemoglobin F is slowly replaced by hemoglobin A so that infants do not rely heavily on normal amounts and function of hemoglobin A until they are between 4 and 6 months old. 

  • In adults, hemoglobin A makes up approximately 97%, hemoglobin A2 approximately 2.5% and less than 1% consists of hemoglobin F. 

The Basics of Hemoglobinopathy and Thalassemias

  • Hemoglobinopathies arise when a change occurs in the structure of a peptide chain or a defect compromises the ability to synthesize a specific polypeptide chain.

    • Can be qualitative or quantitative defects.

      • Thalassemias are quantitative disorders. 

  • Thalassemia is derived from a Greek term that roughly means “the sea” (Mediterranean) in the blood.  

    • It was first applied to the anemias frequently encountered in people from the Italian and Greek coasts and nearby islands. 

    • Individual syndromes are named according to the globin chain whose synthesis is adversely affected.

      • Alpha thalassemia represents either a reduction or complete absence of production of alpha globin chains

      • Beta thalassemia is a reduction or complete absence of beta globin production. 

    • Among the most common autosomal recessive disorders worldwide. More than 100 genetic forms of alpha thalassemia have been identified. 

  • By contrast, conditions such as sickle cell anemia represent a structural hemoglobinopathy, a qualitative defect.

Beta Thalassemias

  • Hemoglobin electrophoresis can be used to diagnose beta thalassemia. This can reveal:

    • Reduction in the expression of beta globin (b+) or

    • Complete absence of beta globin expression (b0).

  • Complete absence of beta globin expression is referred to as beta thalassemia major, aka Cooley’s anemia or transfusion-dependent thalassemia.

    • Little to no beta globin chain production and thus minimal to absence of hemoglobin A.

    • Symptoms usually manifest 6-12 months of life.

    • Since there is no hemoglobin A due to the lack of beta globin, hemoglobin F persists.

      • On a hemoglobin electrophoresis, you will see at least 95% of hemoglobin F, and  hemoglobin A2 will usually range between 3.5 and 7%.

      • The circulating red blood cells are very hypochromic, abnormal in shape, and the hemoglobin is markedly reduced, somewhere around 3-4 g/dl. 

    • Anemia of beta thalassemia major is so severe that long-term blood transfusions are usually required for survival.

      • The severe anemia results in extramedullary erythropoiesis, delayed sexual development and poor growth.

      • Death may occur by age 10 unless treatment with periodic blood transfusions is initiated.

  • Beta thalassemia intermedia, now referred to as non-transfusion dependent beta thalassemia, presents as a less severe clinical phenotype.

    • A moderate microcytic anemia is present.

      • On hemoglobin electrophoresis, up to 50% of hemoglobin F will be noted and just as in beta thalassemia major, hemoglobin A2 will usually range between 3.5 and 7%.

    • May result from different mechanisms:

      • I.e., inheriting both a mild and severe beta thalassemia mutation, or

      • The inheritance of two mild mutations, or,

      • The inheritance of complex combinations of mutations.

  • Beta thalassemia minor, also referred to as beta thalassemia trait, is caused by the presence of a single beta-thalassemia mutation and a normal beta globin gene on the other chromosome.  

    • Significant microcytosis with hypochromia on the blood smear but a mild anemia.

    • In general, thalassemia minor has no associated symptoms.

      • On hemoglobin electrophoresis, hemoglobin F is present up to 5%, and hemoglobin A2 at 4% or more. 

Alpha Thalassemias

  • The alpha thalassemias are more difficult to diagnose because the typical elevations in hemoglobin F and A2 that are seen in the beta-thalassemias we have just discussed do not occur. This makes hemoglobin electrophoresis difficult to use for diagnosis.

    • Instead, molecular testing (DNA sequencing) is required for diagnosis.

    • More than 100 genetic forms of alpha thalassemia have been identified, with phenotypes ranging from asymptomatic to lethal.

    • The severity of this disorder is usually well correlated with the number of non-functional copies of the alpha globin genes (a one, two, three, or four-gene deletion).

  • Silent Carrier: one alpha globin gene deletion.

    • Essentially has no clinical consequences.

    • On the CBC, the MCV is usually normal or perhaps mildly decreased.

  • Alpha Thalassemia Minor: two gene deletion.

    • If two genes on the same chromosome are deleted, this is known as a cis deletion.

      • More commonly seen in those of southeast Asian ancestry.

      • If both parents carry a cis deletion, their offspring will have a 25% chance of having no functional alpha globin genes.

    • If the two deleted genes are on different chromosomes, this is trans deletion.

      • More common in those of African descent

      • If both parents have a two gene deletion in trans, their offspring will always have the same two gene deletion in trans.

  • Hemoglobin H: three gene deletion, which results in a moderate microcytic anemia.

    • When the alpha chains are reduced, the beta chains pair together and form beta globin tetramers, which is what this hemoglobin H represents.

    • In some cases, instead of the three gene deletion, a two gene deletion occurs with a mutant (i.e., non-functional) alpha globin mutation, such as hemoglobin Constant Spring.

      • This is referred to as nondeletional hemoglobin H.

      • Individuals with this nondeletional hemoglobiin H have a higher percentage of hemoglobin H, more splenomegaly and more advanced disease.

    • Most individuals with hemoglobin H don’t require regular transfusions. The anemia is typically mild; however, the phenotype is variable

      • With the dilutional anemia that occurs during pregnancy, the need of a transfusion may be increased. 

  • Alpha thalassemia major, or hemoglobin Barts: Four gene deletion that results in a gamma tetramer.

    • Normal Hb A and Hb F are totally absent.

    • Hemoglobin Barts is incompatible with life and results in hydrops in-utero and stillbirth.

      • Its oxygen dissociation curve is markedly shifted to the left, so it holds onto oxygen and very little is released to the tissues.

      • Usually, the fetus or newborn will have marked anasarca and hepatosplenomegaly, with a hemoglobin level of 3-10 g/dL.

    • If a fetus is known to have alpha thalassemia major, multiple intrauterine transfusions can help these fetuses survive.  

      • Prenatal diagnosis of the thalassemias can be performed using either chorionic villi from CVS or using cultured amniocytes obtained from an amniocentesis.

    • A study at the University of California at San Francisco is looking at the use of in utero stem cell transplantation during pregnancy to essentially cure the fetus before birth. 

Take Home: When to Work Up for Thalassemia

  • If the MCV is decreased (<80), a hemoglobin electrophoresis is very reasonable.

    • Ferritin to assess for iron deficiency is also something that can be performed at the same time.

      • Hemoglobinopathy and iron deficiency can coexist!

  • If the MCV is decreased, and both a ferritin and hemoglobin electrophoresis are normal, molecular studies to assess for alpha thalassemia would be appropriate.