A healthy, full-term 1-day-old female infant is evaluated after birth. She is noted to have a cleft palate and a systolic ejection murmur at the left intercostal space. Low-set ears and micrognathia are also noted on examination. A chest radiograph is obtained which reveals a boot-shaped heart and absence of thymus. Vital signs are unremarkable. Echocardiography is performed which demonstrates a ventricular septal defect, pulmonary valve stenosis, a misplaced aorta, and a thickened right ventricular wall. Family history is non-contributory; not much is known about the father. Based on this clinical presentation, which complication is this infant most likely to develop?

Increased phenylalanine in the blood

A 1-year-old boy presents to pediatrics clinic for a well-child visit. He has no complaints. He has a cleft palate and an abnormal facial appearance. He has been riddled with recurrent infections and is followed by cardiology for a ventricular septal defect (VSD). Vital signs are stable, and the patient's physical exam is benign. If this patient's medical history is part of a larger syndrome, what might one also discover that is consistent with the manifestations of this syndrome?

Hypoactive deep tendon reflexes

A child is born by routine delivery and quickly develops respiratory distress. He is noted to have epicanthal folds, low-set ears that are pressed against his head, widely set eyes, a broad, flat nose, clubbed feet, and a receding chin. The mother had one prenatal visit, at which time the routine ultrasound revealed an amniotic fluid index of 3 cm. What is the most likely underlying cause of this patient's condition?

Autosomal recessive polycystic kidney disease (ARPKD)

A microdeletion in chromosome 22

A 36-year-old G3P2002 presents to her obstetrician’s office for her first prenatal visit at ten weeks and two days gestation. She notes that she has felt nauseous the last several mornings and has been especially tired for a few weeks. Otherwise, she feels well. The patient has had two uncomplicated spontaneous vaginal deliveries at full term with her last child born six years ago. She is concerned about the risk of Down syndrome in this fetus, as her sister gave birth to an affected child at age 43. The patient has a history of generalized anxiety disorder, atopic dermatitis, and she is currently on escitalopram. At this visit, this patient’s temperature is 98.6°F (37.0°C), pulse is 70/min, blood pressure is 121/67 mmHg, and respirations are 13/min. The patient appears anxious, but overall comfortable, and cardiopulmonary and abdominal exams are unremarkable. Pelvic exam reveals normal female external genitalia, a closed and slightly soft cervix, a ten-week-sized uterus, and no adnexal masses. Which of the following is the best next step for definitively determining whether this patient’s fetus has Down syndrome?

Genetic testing of patient’s sister

An 8-year-old boy is brought to the physician for evaluation of developmental delay and recurrent tonic-clonic seizures. There is no family history of seizures or other serious illness. Current medications include risperidone for hyperactivity. He is at the 17th percentile for head circumference. Examination shows protrusion of the mandible, strabismus, and a laughing facial expression. His gait is unsteady. He has a vocabulary of about 200 words and cannot speak in full sentences. Karyotype analysis shows a 46, XY karyotype without chromosomal deletions. Which of the following genetic mechanisms best explains this patient's findings?

Uniparental disomy of chromosome 15

Trinucleotide repeat in FMR1 gene

De novo mutation of MECP2 on the X chromosome

Nondisjunction of chromosome 21 during meiosis I

22q11.2 deletion syndrome for USMLE Step 2 CK: High-Yield Pediatrics Lessons

Basics - The Chromosome 22 Glitch

Microdeletion on the long arm (q) of chromosome 22 at position 11.2.
Pathogenesis: Defective development of the 3rd and 4th pharyngeal pouches, leading to a spectrum of disorders.
Inheritance:
- ~90% of cases are de novo mutations.
- ~10% are inherited in an autosomal dominant pattern.
Key Gene: TBX1 is the major gene implicated, crucial for the development of the heart, parathyroid, thymus, and face.

⭐ 22q11.2 deletion syndrome is the most common microdeletion syndrome in humans.

Chromosome 22 with 22q11.2 deletion region highlighted

📌 Mnemonic: CATCH-22

Cardiac anomalies (esp. conotruncal)
Abnormal facies
Thymic aplasia/hypoplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism

Clinical Features - CATCH-22 Unpacked

📌 CATCH-22 mnemonic outlines the classic pentad, though presentation is highly variable.

Cardiac Anomalies (~75%)
- Most common: Conotruncal defects (e.g., Tetralogy of Fallot, truncus arteriosus, interrupted aortic arch).
Abnormal Facies
- Long face, small mouth, hooded eyelids, bulbous nose, low-set ears.
Thymic Hypoplasia/Aplasia
- Leads to T-cell immunodeficiency.
- Results in recurrent viral and fungal infections.
Cleft Palate
- Includes submucous cleft palate or velopharyngeal incompetence, causing hypernasal speech.
Hypocalcemia/Hypoparathyroidism
- Due to parathyroid hypoplasia.
- Can present with seizures in the neonatal period.

⭐ In neonates, 22q11.2 deletion syndrome is a primary differential for seizures secondary to hypocalcemia.

Diagnosis & Management - Confirm & Care

Diagnosis:
- Prenatal: ↑ Nuchal translucency, polyhydramnios, or cardiac anomalies on ultrasound.
- Postnatal: Suspected based on CATCH-22 features.
- Confirmation: Fluorescence In Situ Hybridization (FISH) is the gold standard, detecting the microdeletion on chromosome 22. Chromosomal microarray (CMA) is also highly sensitive.
Management (Multidisciplinary Team):
- Cardiac: Echocardiogram & surgical correction for conotruncal anomalies.
- Immunology: T-cell count assessment. Prophylaxis against Pneumocystis jirovecii. Irradiated blood products.
- Endocrinology: Monitor for hypocalcemia; treat with calcium & vitamin D.
- Development: Early intervention for speech/palatal defects & learning disabilities.

⭐ Patients have a ~25% risk of developing schizophrenia in adulthood, a rate significantly higher than the general population.

High‑Yield Points - ⚡ Biggest Takeaways

Also known as DiGeorge syndrome and Velocardiofacial syndrome (VCFS).

Results from a microdeletion on chromosome 22q11.2; it is the most common microdeletion syndrome.

Classic mnemonic is CATCH-22: Cardiac anomalies, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism.

Thymic aplasia leads to deficient T-cell immunity and recurrent infections.

Hypoparathyroidism causes neonatal hypocalcemia and tetany.

Most common cardiac defects are conotruncal anomalies (e.g., Tetralogy of Fallot, truncus arteriosus).

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