Approach to aneuploidies and microdeletions: Clinical sciences

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Introduction0:00–0:34

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 enoploides or microdeletions. Now, if a pediatric patient presents with a chief concern, suggesting an uloid or a microdeletion, you should first perform an ABCD E assessment to determine if they are stable or unstable.

Unstable0:34–1:17

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 BP, heart rate and pulse oximetry.
Finally, if needed, provide supplemental oxygen. Now that we've discussed unstable patients, let's go back to the ABCD E assessment and look at stable ones.

Stable1:17–3:15

In this case, obtain a focused history and physical examination history might reveal abnormal findings on prenatal genetic and ultrasound testing, poor pre and postnatal 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 micro duplications.
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 trisomy 1318 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.
All right. Let's first look at conditions characterized by anya ploidy.

Aneuploidy/Neonate3:15–3:30

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.

Trisomy 183:30–4:18

18. These patients typically have a history of preterm delivery, poor pre and postnatal 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 in clinodactyly A chromosome analysis revealing 47 plus 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 in absence of a portion of the skin on the scalp should make you consider trisomy.

Trisomy 134:18–5:25

13. These patients typically have poor pre and postnatal 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 plus 13, diagnose trisomy 13 or PTA syndrome. Keep in mind that patients with trisomy 13 and 18 have a life expectancy of less than one year.

Trisomy 215:25–7:06

Now, if you don't identify a scalp abnormality, consider trisomy 21 these newborns usually have normal birth weight 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 up slanting palpebral fissures, epicanthal folds and macroglossia.
You will also find a short broad hand with a single palmar crease and a gap between the 1st and 2nd toes. If the chromosome analysis reveals 47 plus 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 fuses resulting in a normal number of chromosomes with additional genetic material at the fusion site.

Child/Adolescent7:06–7:17

Ok. Let's look at aneuploidies that typically present during childhood and adolescence.
Here, assess your patients stature and biological sex. If your patient has short stature and is biologically female.

Turner syndrome7:17–8:18

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 for DS 45 X diagnosed Turner syndrome, here is another clinical pearl.
While Turner Syndrome is usually associated with a 45 X karyotype, almost half of the patients have a mosaic pattern of either 45 X, 46 XX or 45 X 46 XY.
On the flip side, if your patient has tall stature and is biologically male, consider Klinefelter syndrome, if not diagnosed during infancy or childhood.

Klinefelter syndrome8:18–8:58

These patients often present with delayed puberty. Additionally, they usually have learning disabilities, language and processing defects and possibly ADHD or depression.
The physical exam often demonstrates long limbs and lack of secondary sexual characteristics if the chromosome analysis shows 47 X xy diagnosed Klinefelter syndrome.
Ok. Now, let's go back to chromosomal testing results and look at conditions characterized by euploidy and microdeletion.

Euploidy/Microdeletions8:58–9:22

Here consider contiguous gene syndromes which are caused by small structural changes in neighboring genes that result in a characteristic phenotype.
As a next step, assess the patients cry if it's high pitched and catlike, consider CRE Du Sha syndrome. These patients frequently have poor pre and postnatal growth, tracheal hypoplasia, intellectual disability and possibly cardiac anomalies.

Cri du chat9:22–10:08

The physical exam often reveals hypotonia and microcephaly along with facial features like hypertelorism, epicanthal folds downward, sloping, palpebral fissures, low set ears and possibly cleft lip and palate.
The CMA or fish will demonstrate a deletion of five P, the short arm of chromosome five, which confirms CRE Dua syndrome.
Alternatively, if your patient has a low pitched gravelly cry, consider Williams Syndrome history often reveals poor pre and postnatal growth as well as cardiac anomalies.

Williams syndrome10:08–11:05

Most commonly supravalvular aortic stenosis affected Children usually demonstrate intellectual disability with a gregarious personality and some have evidence of precocious puberty or autism spectrum disorder.
On exam. Look for short stature and characteristic craniofacial features such as bitemporal narrowing, prominent ears blue irises with a stellate pattern, a short nose and a long philtrum with a wide mouth.
If there's a chromosomal deletion on the long arm of chromosome 77 Q 11.2 diagnose Williams syndrome. All right.

Normal Cry/ Prader-Willi syndrome11:05–12:07

Let's look at conditions characterized by a normal cry to narrow the differential. Further assess your patient's motor function.
If there's a history of neonatal hypotonia, consider Prader Willi syndrome. These patients usually have poor feeding and poor weight gain during infancy, followed by hyperphagia in childhood.
Some also have mild to moderate intellectual disability and behavioral issues and they may experience delayed puberty and endocrine abnormalities.
Exam findings typically include central obesity, short stature, Alman shaped, dyes, small hands and feet and evidence of hypogonadism such as delayed genital development.
The CMA or fish will reveal a deletion on the long arm of chromosome 1515 Q 11 to Q 13, which confirms Prader Willi Syndrome.

Angelman syndrome12:07–13:18

On the other hand, if your patient demonstrates severe ataxia, consider Angelman Syndrome, these Children usually have seizures, absent speech, inappropriate laughter or smiling and intellectual disability.
The physical exam often reveals microcephaly, a short broad skull, widely spaced teeth, a large tongue and large jaw. If the CMA or fish reveals a deletion at the long arm of chromosome 1515 Q 11 to Q 13 diagnose Angelman syndrome.
Here's a high yield fact, even though Prader Willi and Angelman Syndrome are caused by the same microdeletion, they present with very different phenotypes.
This is an example of genomic imprinting where either maternal or paternal inheritance determines gene expression. A deletion in the maternally inherited chromosome results in Angelman syndrome.
While a deletion in the paternally inherited chromosome results in Prader Willi Syndrome. Finally, let's look at patients without motor dysfunction.

No motor dysfunctin/ Velocardiofacial/DiGeorge syndrome13:18–14:37

Here, you should assess for characteristic facial features. If your patient has hypertelorism, cleft, lip and palate and micrognathia, consider velocardiofacial and George syndrome.
These syndromes are caused by the same microdeletion which can result in a continuum of related findings. Affected individuals often have charge association which include coloboma, heart defects, typically a conotruncal anomaly, coal atresia restricted growth, genital abnormalities and ear abnormalities.
Some patients also have a small or absent thymus, immunodeficiency, speech and language difficulty and possibly hypocalcemia induced seizures.
The exam often demonstrates additional characteristic features like a long face and a prominent nose with a broad root. If the CMA shows a deletion on the long arm of chromosome 2222 Q 11.2 diagnose velocardiofacial or Digeorge syndrome.

Wilms/WAGR syndrome14:37–15:26

Lastly, if your patient has aniridia, think of Wilms Wager syndrome. Wager stands for Wilms tumor, aneura genitourinary anomalies and range of intellectual and developmental delays.
History typically reveals Wilms tumor which is a malignant embryonal renal tumor as well as a range of intellectual disabilities and developmental delays.
Physical exam often reveals genitourinary anomalies like cryptorchidism and hypospadias and some patients have short stature and microcephaly.
If there's a deletion on the short arm of chromosome 1111 p 13 diagnose willms Wager syndrome. All right.

Review15:26–16:32

As a quick recap when assessing for aneuploidy or microdeletion. Order, a chromosomal analysis, CMA and fish test conditions characterized by alo include trisomy 1318 and 21 which present during the neonatal period and Turner or Klinefelter syndromes which often present during childhood or adolescence.
On the other hand, if CMA or fish reveals a microdeletion, assess the patient's cry. A high pitched catlike cry is characteristic of Cri Du Shas syndrome.
While a low-pitched gravelly cry is a feature of Williams syndrome. Neonatal hypotonia is suggestive of Prader Willi Syndrome.
But with severe ataxia, consider Angelman syndrome. Finally, if there is no motor dysfunction, think velocardiofacial or de George syndrome, or alternatively Wilms Wager syndrome.