Approach to aneuploidies and microdeletions: Clinical sciences

Aneuploidy refers to a missing or an extra chromosome, while microdeletions are small deletions of genetic material spanning multiple genes within a single chromosome. Aneuploidies and microdeletions are caused by errors in cell division, which often results in a characteristic phenotype and genetic syndrome. You can apply various genetic testing methods to categorize chromosomal abnormalities as aneuploidies or microdeletions.

Now, if a pediatric patient presents with a chief concern suggesting aneuploidy or a microdeletion, you should first perform an ABCDE assessment to determine if they are stable or unstable.

While most of these patients will be stable, some might have an associated anomaly that requires urgent intervention, such as a congenital heart defect. If the patient is unstable, stabilize the airway, breathing and circulation. Next, obtain IV access and put your patient on continuous vital sign monitoring, including blood pressure, heart rate, and pulse oximetry. Finally, if needed, provide supplemental oxygen.

Now that we’ve discussed unstable patients, let’s go back to the ABCDE assessment and look at stable ones. In this case, obtain a focused history and physical examination.

History might reveal abnormal findings on prenatal genetic and ultrasound testing, poor pre- and post-natal growth, or cardiac and renal anomalies. Affected patients may have intellectual or developmental delays, characteristic or unusual behaviors, and delayed puberty. The physical examination might demonstrate characteristic craniofacial features or limb abnormalities. With these findings, consider a chromosome abnormality and obtain further testing.

This might include cytogenetic chromosomal analysis to identify aneuploidy using cell culture, chromosome staining, and microscopy to assess chromosome number and structure. Additionally, order a chromosomal microarray, also called CMA for short, or a fluorescence in situ hybridization, or FISH, test. Both CMA and FISH testing use molecular techniques to identify changes in small segments of DNA, such as microdeletions or microduplications.

Here’s a clinical pearl! You can use noninvasive antenatal testing, like blood work and ultrasound, to assess the risk of specific genetic conditions, including trisomies 13, 18 and 21. However, to confirm the diagnosis, you’ll need to perform more invasive tests such as amniocentesis or chorionic villus sampling, to obtain tissue for cytogenetic analysis, CMA, or FISH.

Alright, let’s first look at conditions characterized by aneuploidy. Here, your next step is to assess your patient’s age. Let's start with conditions that present during the neonatal period.

First, assess for rocker bottom feet, and if present, consider Trisomy 18. These patients typically have a history of preterm delivery, poor pre- and post-natal growth, cardiac anomalies, and severe developmental delay.

The physical exam usually reveals microcephaly, tight palpebral fissures, a narrow nose, cleft lip or palate, and micrognathia. Additionally, affected patients often have clenched hands and clinodactyly. A chromosome analysis revealing 47, +18 confirms Trisomy 18, also called Edwards syndrome.

On the other hand, if there’s no evidence of rocker bottom feet, assess for a scalp abnormality. The presence of cutis aplasia, an absence of a portion of the skin on the scalp, should make you consider Trisomy 13. These patients typically have poor pre- and post-natal growth, cardiac and renal abnormalities, deafness, severe developmental delay, and occasionally, a history of preterm delivery.

The physical exam often reveals characteristic features, including microcephaly, a sloping forehead, and microphthalmia. Additionally, affected patients might have cleft lip and palate, clinodactyly and polydactyly, or missing ribs. If the chromosome analysis is 47, +13, diagnose Trisomy 13 or Patau syndrome. Keep in mind that patients with Trisomy 13 and 18 have a life expectancy of less than one year.

Now, if you don’t identify a scalp abnormality, consider Trisomy 21. These newborns usually have normal birthweight and length. Some may have congenital cardiac or gastrointestinal tract anomalies, and as they develop, patients typically demonstrate variable degrees of intellectual disability.

Key physical exam findings include newborn hypotonia and characteristic craniofacial features, such as brachycephaly, flattened occiput, hypoplastic midface with a flattened nasal bridge, as well as upslanting palpebral fissures, epicanthal folds, and macroglossia. You will also find a short broad hand with a single palmar crease and a gap between the first and second toes. If the chromosome analysis reveals 47, +21, your patient has Trisomy 21, or Down Syndrome.

Here’s another clinical pearl! Although Down syndrome is usually caused by full trisomy 21, in some cases it results from partial trisomy 21, where only a portion of the chromosome has an extra copy; or mosaic trisomy 21, where only some cells have the extra chromosome.

Finally, some cases of Down syndrome are caused by a Robertsonian translocation, which occurs when the long arms of two chromosomes fuse, resulting in a normal number of chromosomes with additional genetic material at the fusion site.

Okay, let's look at aneuploidies that typically present during childhood and adolescence. Here, assess your patient’s stature and biological sex. If your patient has short stature and is biologically female, consider Turner syndrome. These patients often present during adolescence with delayed puberty. Additionally, some have a history of cardiac or renal anomalies, like a horseshoe kidney.

The exam typically reveals a webbed neck, low-set ears, low hairline, and shield-like chest. If your patient is an adolescent, you will notice a lack of secondary sexual characteristics. If the chromosomal analysis reveals 45, X, diagnose Turner syndrome.