Microdeletion Syndromes

Question 1

What is the genetic cause of Wolf-Hirschhorn Syndrome, how is it inherited and how common is it?

Answer 1

Deletion of the short arm of chromosome 4 (4p16.3). Larger deletions correlate with more severe phenotypes.
While most cases are de novo, some result from a parent with a balanced translocation.
1 in 20,000-50,000 live births, 2:1 female :male

Question 2

How is Wolf-Hirschhorn Syndrome diagnosed, and what testing is most accurate?

Answer 2

CMA is preferred BUT it will not detect a balanced translocation. FISH can be used as sensitive. Karyotyping but the deletion has to be a certain size

Question 3

What disorder has the following U/S findings?

1)UiGR
2)Microcephaly, Flattened nasal bridge, Prominent glabella
3)ASD, VSD or ToF
4)clubfoot or rocker-bottom feet. Hypoplastic or dysplastic nails or phalanges. Possible other vertebral abnormalities.
5) Renal agenesis, hydronephrosis, or other renal abnormalities. Polyhydramnios may occur due to swallowing difficulties caused by craniofacial abnormalities.

Answer 3

Wolf-Hirschhorn. The prominent glabella gives the Greek warrior helmet appearance

Question 4

What is the genetic basis of Cri du Chat Syndrome, and how is it inherited?

Answer 4

Genetic Cause: 5p deletion with larger deletions correlates with more severe phenotypes.
Inheritance: ~85% de novo; 10–15% are due to a parental balanced translocation.
Prevalence: 1 in 20,000–50,000 live births.

Question 5

How is Cri du Chat Syndrome diagnosed?

Answer 5

First-Line Test: Karyotype to detect large deletions.
Second-Line Test: FISH or CMA for smaller deletions or confirmation.

Question 6

What are the hallmark clinical features and ultrasound findings for Cri du Chat Syndrome?

Answer 6

Clinical Features:Neonatal high-pitched cry (cat-like cry).

Microcephaly, low-set ears, hypertelorism.
Intellectual disability, feeding difficulties, congenital heart defects, hypotonia, sever DD

Ultrasound Findings: severe IUGR, Micrognathia, prominent nasal bridge, and cardiac anomalies (VSD , ToF). There are no pathognomic U/S findings for this

Question 7

What is the genetic cause of Williams Syndrome, and how is it inherited?

Answer 7

Genetic Cause: Deletion of 7q11.23 involving the ELN gene (plus others)
Inheritance: Mostly de novo (~95–99%), with rare AD inheritance.
Prevalence: 1 in 7,500–10,000 live births.

Question 8

What are the hallmark features of Williams Syndrome?

Answer 8

Clinical Features: “Elfin” facies, ID, hypersociability (“cocktail personality”)

ID, mild to moderate with better verbal skills compared to non-verbal, impairments in fine motor coordination and executive functioning, impulsive and inattentive behaviors are common

Cardiac Features: supravalvular aortic stenosis (SVAS) is most common; other vascular anomalies may occur

Hypercalcemia occurs in infancy and can cause irritability, constipation, and feeding problems.
Hypercalciuria (high calcium in urine) can lead to nephrocalcinosis and kidney stones.

Increased risk in adulthood of glucose intolerance and diabetes:

Question 9

How is Williams Syndrome diagnosed and managed?

Answer 9

Diagnosis: CMA or FISH for 7q11.23 deletion.

Management:
Cardiac monitoring with regular echocardiograms.
Developmental support includes speech, occupational, and physical therapy.
Monitor for hypercalcemia and hypothyroidism.

Question 10

What disorder is the result of point mutations in the gene ELN

Answer 10

Williams Syndrome is caused by a larger deletion of ~26-28 genes in the 7q11.23 region, including ELN.
However, ELN Point Mutations result in isolated SVAS or autosomal dominant cutis laxa type 1, which lacks the craniofacial and neurodevelopmental features of Williams Syndrome.

Question 11

What is the genetic basis of WAGR Syndrome, and how is it inherited?

Answer 11

Deletion at 11p13 involving PAX6 and WT1.
Inheritance: Typically de novo, but may arise from a parental balanced translocation.

Question 12

What are the clinical features of WAGR Syndrome?

Answer 12

Wilms tumor (~45–60% risk).
Aniridia (partial or complete absence of the iris).
Genitourinary anomalies (e.g., cryptorchidism, streak gonads).
Developmental delay and obesity (if deletion extends into BDNF).

Question 13

How is WAGR Syndrome diagnosed and managed?

Answer 13

CMA to detect 11p13 deletion; FISH may confirm.
Management:
Regular abdominal ultrasounds for Wilms tumor surveillance.
Ophthalmologic care for aniridia.
Surgery for genitourinary anomalies.

Question 14

What is the genetic basis of Smith-Magenis Syndrome, and how is it inherited?

Answer 14

Deletion on 17p11.2 involving the RAI1 gene (90%); point mutations in RAI1 (10%) may also cause the syndrome.
Inheritance: Typically de novo; rare cases of familial inheritance.

Question 15

What are hallmark clinical and behavioral features of Smith-Magenis Syndrome?

Answer 15

Intellectual disability
Sleep disturbances (e.g., inverted melatonin secretion).
Self-injurious behaviors and impulsivity.
Hyperactivity and temper tantrums.
Brachycephaly (shortened skull) with a broad, square-shaped face and prominent forehead and deep-set eyes.
Short stature, obesity in older individuals.
Skeletal anomalies such as brachydactyly (short fingers), Congenital heart defects (in some cases).

Question 16

What two syndromes involve opposite genetic alterations in the same region of chromosome 17p11.2?

Answer 16

Smith-Magenis and Potocki-Lupski
Deletion → Loss of RAI1 → SMS.
Duplication → Extra copy of RAI1 → PTLS
Their shared genetic basis highlights the critical role of RAI1 in neurodevelopment and behavior but its the additional genes in each that shape disorders

Question 17

How is Smith-Magenis Syndrome diagnosed and managed?

Answer 17

Diagnosis: Start with CMA to large deletions (including 17p11.2) in ~90% of SMS cases. You’d reflex to RAI1 sequencing if no deletion is detected by CMA and clinical features (sleep disturbances, behavior, hypotonia, broad square face, injurious behavior) strongly suggest SMS.

Management:
Behavioral therapy for self-injury.
Melatonin for sleep disturbances.
Developmental interventions for delays.

Question 18

What are the hallmark clinical features of DiGeorge Syndrome?

Answer 18

Cardiac: Tetralogy of Fallot, interrupted aortic arch, ventricular septal defect (VSD), truncus arteriosus ( single blood vessel arises from the heart & serves as the outflow right and left ventricles), right-sided aortic arch

Craniofacial: Long face, bulbous nasal tip, cleft palate, micrognathia, low-set ears, hooded eyelids

Immune: Thymic hypoplasia with T-cell deficiency, recurrent infections, autoimmune disorders (e.g., autoimmune cytopenias), increased risk of lymphoma

Endocrine: Hypocalcemia due to parathyroid hypoplasia, thyroid abnormalities, growth hormone deficiency, adrenal insufficiency

Question 19

What gene accounts for most of DiGeorge’s hallmark features and why?

Answer 19

TBX1 Deletion.
TBX1 disruption affects the migration of neural crest cells, leading to abnormalities in the heart, thymus, parathyroid glands, and facial structures.

Specifically, TBX1 plays a pivotal role in the formation of the pharyngeal arches, which give rise to:
The great vessels of the heart.
The thymus.
The parathyroid glands.
Craniofacial structures.

Question 20

What two genes associated with DiGeorge Syndrome that when deleted are thought to contribute to psychiatric disorders and exacerbate heart defects

Answer 20

COMT (Catechol-O-Methyltransferase):
Involved in dopamine metabolism. Deletion may contribute to psychiatric disorders (e.g., anxiety, schizophrenia).

CRKL (CRK-Like): intracellular signaling pathways. Haploinsufficiency affects neural crest migration -> may exacerbate cardiac defects.

Question 21

How is DiGeorge Syndrome diagnosed and managed?

Answer 21

FISH or CMA for 22q11.2 deletion.

Management:
Corrective cardiac surgery.
Calcium supplementation for hypocalcemia.
Immune evaluation and avoidance of live vaccines if T-cell deficient.

Question 22

A 5-day-old infant is referred for evaluation of hypocalcemia and congenital heart disease. Echocardiography reveals truncus arteriosus, and serum calcium is significantly low. Physical examination shows a cleft palate, low-set ears, and a long face. The infant’s family history reveals that the mother was diagnosed with a learning disability as a child but is otherwise healthy. A CMA is run, what is the expected result?

Answer 22

22q11.2 deletion exhibiting variable expressivity given mom