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?
Q2
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?
Q3
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?
Q4
A 16-year-old girl presents with primary amenorrhea. On exam, you note that she is short and has a shield chest. You order abdominal imaging, which suggests the presence of streak gonads.
Of the choices listed below, which of the following karyotypes is possible in this patient?
I: 45,XO
II: 45,XO/46,XX mosaicism
III: 46,X,del(Xp) or other structural X abnormalities
Q5
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?
Q6
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?
Q7
A 4-month-old boy with a history of multiple infections presents with muscle stiffness. On physical exam, he is found to have carpopedal spasm as well as a heart murmur. Based on your clinical suspicion you decide to obtain a chest X-ray which shows a diminished shadow in the mediastinum. A mutation in which of the following chromosomes is the most likely cause of this patient's presentation?
Q8
A 2-month-old boy is presented to the clinic for a well-child visit by his parents. They are concerned with his weak cry and difficulty with feeding. Birth history reveals that the boy was born at the 37th week of gestation by cesarean section due to poor fetal movement and fetal distress. His Apgar scores were 3 and 5 at 1st and 5th minute respectively and his birth weight was 2.5 kg (6 lb). His vital signs include heart rate 120/min, respiratory rate 40/min, blood pressure 90/50 mm Hg, and temperature 37.0°C (98.6°F). Physical examination reveals a malnourished boy with a small narrow forehead and a small jaw. His mouth is small and he has comparatively small genitals. He has a poor muscle tone. After repeated follow-up, he gains weight rapidly but his height fails to increase. Developmental milestones are delayed at the age of 3 years. Genetic testing reveals Prader-Willi syndrome. Which of the following is the most common mechanism for the development of this patient’s condition?
Q9
A 1-year-old girl born to a 40-year-old woman is undergoing an examination by a pediatric resident in the hospital. The pregnancy was uneventful and there were no complications during the delivery. The physical examination reveals midface hypoplasia with a flat nasal bridge and upslanting palpebral fissures. She has a small mouth and chest auscultation reveals a blowing holosystolic murmur that is heard best along the sternal border. The family history is unremarkable. A karyotype analysis is ordered because the resident suspects a numerical chromosomal disorder. Which of the following phenomena leads to the infant’s condition?
Q10
A 69-year-old man comes to the physician because of a 1-week history of blood in the urine and fatigue. He also has had a 5.0-kg (11-lb) weight loss during the past month. Physical examination shows pallor and cachexia. A nontender right flank mass is palpated. A CT scan of the chest, abdomen, and pelvis shows a 5-cm right upper pole renal mass and several pulmonary lesions. A biopsy specimen of an affected area of the lung is obtained. A photomicrograph of the biopsy specimen is shown. Molecular evaluation of the specimen is most likely to show which of the following genetic changes?
22q11.2 deletion syndrome US Medical PG Practice Questions and MCQs
Question 1: 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?
A. Catlike cry
B. Increased phenylalanine in the blood
C. Seizures (Correct Answer)
D. Webbing of the neck
E. Hyperthyroidism
Explanation: ***Seizures***
- This infant presents with features highly suggestive of **DiGeorge syndrome** (22q11.2 deletion syndrome), including **cleft palate**, **congenital heart defects** (Tetralogy of Fallot, indicated by VSD, pulmonary stenosis, overriding aorta, RV hypertrophy and boot-shaped heart), **low-set ears**, **micrognathia**, and **thymic aplasia/hypoplasia**.
- **Thymic aplasia** leads to **T-cell immunodeficiency**, and **parathyroid hypoplasia** (often associated with DiGeorge syndrome due to shared developmental origin from pharyngeal pouches) leads to **hypocalcemia**, which is the most common cause of **seizures** in these infants.
*Catlike cry*
- A **catlike cry** (or cri du chat) is characteristic of **Cri-du-chat syndrome** (5p deletion), which is not indicated by the constellation of symptoms presented.
- While Cri-du-chat syndrome can cause micrognathia and heart defects, it typically does not involve thymic aplasia or significant hypocalcemia leading to seizures.
*Increased phenylalanine in the blood*
- This is characteristic of **phenylketonuria (PKU)**, an inborn error of metabolism, which has no direct link to the symptoms described.
- PKU primarily causes neurological damage if untreated, but not the specific craniofacial or cardiac anomalies seen here.
*Webbing of the neck*
- **Webbing of the neck** is a common feature of **Turner syndrome** (45,XO), particularly with lymphedema, and also seen in **Noonan syndrome**.
- These syndromes have different clinical presentations and genetic etiologies than what is described in this infant.
*Hyperthyroidism*
- **Hyperthyroidism** is not typically associated with DiGeorge syndrome or the specific symptoms presented here.
- While some genetic syndromes can affect thyroid function, the primary concern in DiGeorge syndrome related to endocrine function is **parathyroid hypoplasia** leading to hypocalcemia.
Question 2: 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?
A. Kidney stones
B. A positive Chvostek's sign (Correct Answer)
C. B-cell deficiency
D. Hypoactive deep tendon reflexes
E. A shortened QT Interval
Explanation: ***A positive Chvostek's sign***
- The constellation of **cleft palate**, **abnormal facial appearance**, **recurrent infections**, and a **ventricular septal defect (VSD)** strongly suggests **DiGeorge syndrome**.
- In DiGeorge syndrome, hypoparathyroidism leads to **hypocalcemia**, which can manifest as neuromuscular irritability, including a positive **Chvostek's sign** (facial muscle twitching upon tapping the facial nerve).
*Kidney stones*
- **Kidney stones** are typically associated with **hypercalcemia** or other metabolic disorders, not hypocalcemia seen in DiGeorge syndrome.
- While DiGeorge patients can have renal anomalies, **nephrolithiasis** is not a characteristic feature of the syndrome.
*B-cell deficiency*
- DiGeorge syndrome is characterized by **T-cell deficiency** due to thymic hypoplasia or aplasia, not primarily B-cell deficiency.
- While **B cells** may be secondarily affected due to lack of T-cell help, the primary immunodeficiency is related to T-lymphocytes.
*Hypoactive deep tendon reflexes*
- **Hypocalcemia** typically causes **hyperactive deep tendon reflexes** and increased neuromuscular excitability, not hypoactivity.
- **Hypoactive reflexes** might suggest conditions like hypothyroidism or certain neurological disorders.
*A shortened QT Interval*
- **Hypocalcemia** is associated with a **prolonged QT interval** on an electrocardiogram, not a shortened one.
- A **shortened QT interval** can occur in conditions like hypercalcemia or genetic channelopathies.
Question 3: 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?
A. Unilateral renal agenesis
B. An extra 18th chromosome
C. Autosomal recessive polycystic kidney disease (ARPKD)
D. A microdeletion in chromosome 22
E. Bilateral renal agenesis (Correct Answer)
Explanation: ***Bilateral renal agenesis***
- The combination of **amniotic fluid index (AFI) of 3 cm** (indicating **oligohydramnios**) and multiple facial and limb anomalies strongly suggests **Potter sequence**.
- **Bilateral renal agenesis** is the most common cause of **Potter sequence**, leading to absence of fetal urine production and subsequent oligohydramnios, which restricts fetal movement and lung development.
*Unilateral renal agenesis*
- **Unilateral renal agenesis** typically does not cause **oligohydramnios** because the single functioning kidney can produce sufficient urine.
- While it can be associated with other anomalies, the severe extent of Potter sequence features described here is unlikely with only unilateral involvement.
*An extra 18th chromosome*
- An extra 18th chromosome refers to **Edwards syndrome (Trisomy 18)**, which presents with severe intellectual disability, micrognathia, prominent occiput, and rocker-bottom feet.
- While Edwards syndrome is associated with a variety of anomalies, including renal issues, the constellation of features (especially the clear link to oligohydramnios and respiratory distress) points more directly to Potter sequence.
*Autosomal recessive polycystic kidney disease (ARPKD)*
- **ARPKD** causes **enlarged, cystic kidneys** and can lead to **oligohydramnios** and respiratory distress due to renal insufficiency.
- However, the description of **epicanthal folds, low-set ears, widely set eyes, and a broad, flat nose** is more characteristic of the **Potter facies** seen in severe oligohydramnios, rather than specific to ARPKD itself.
*A microdeletion in chromosome 22*
- A microdeletion in chromosome 22 typically refers to **22q11.2 deletion syndrome (DiGeorge syndrome)**, which is associated with **cardiac defects**, **abnormal facies**, **thymic hypoplasia**, **cleft palate**, and **hypocalcemia**.
- While renal anomalies can occur in DiGeorge syndrome, the primary presentation is not characterized by the severe oligohydramnios and classic Potter sequence features described.
Question 4: A 16-year-old girl presents with primary amenorrhea. On exam, you note that she is short and has a shield chest. You order abdominal imaging, which suggests the presence of streak gonads.
Of the choices listed below, which of the following karyotypes is possible in this patient?
I: 45,XO
II: 45,XO/46,XX mosaicism
III: 46,X,del(Xp) or other structural X abnormalities
A. I and III
B. I, II, and III (Correct Answer)
C. II and III
D. I and II
E. I only
Explanation: ***I, II, and III***
- The patient's presentation with **primary amenorrhea**, **short stature**, a **shield chest**, and **streak gonads** is classic for **Turner syndrome**.
- All three listed karyotypes (I: **45,XO**, II: **45,XO/46,XX mosaicism**, and III: **46,X,del(Xp)** or other structural X abnormalities) are recognized variants that cause Turner syndrome.
*I and III*
- This option incorrectly excludes 45,XO/46,XX mosaicism, which is a common and clinically significant **karyotype in Turner syndrome**.
- Mosaicism can lead to a milder phenotype but still presents with the characteristic features described.
*II and III*
- This option incorrectly excludes **45,XO**, which is the most classic and common karyotype found in individuals with Turner syndrome.
- The absence of a second X chromosome is the hallmark genetic defect.
*I and II*
- This option incorrectly excludes **structural X abnormalities** (e.g., deletion of the short arm of the X chromosome, **46,X,del(Xp)**), which are known causes of Turner syndrome.
- These structural changes lead to a similar clinical picture due to the loss of critical genes on the X chromosome.
*I only*
- While **45,XO** is the most common karyotype in Turner syndrome, confining the possibility to only this option is too restrictive.
- Both mosaicism and structural X abnormalities also result in the clinical features of Turner syndrome.
Question 5: 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?
A. Anatomy ultrasound
B. Genetic testing of patient’s sister
C. Chorionic villus sampling (Correct Answer)
D. Nuchal translucency test
E. Amniocentesis
Explanation: ***Chorionic villus sampling***
- **Chorionic villus sampling (CVS)** is a diagnostic procedure performed between 10 and 13 weeks of gestation that involves taking a sample of placental tissue for genetic analysis. It provides a definitive diagnosis for chromosomal abnormalities like **Down syndrome** earlier in pregnancy than amniocentesis.
- Given the patient's anxiety and desire for definitive diagnosis due to family history, CVS is the most appropriate next step for an early and conclusive result.
*Anatomy ultrasound*
- An **anatomy ultrasound** (typically performed at 18-20 weeks) is a screening, not diagnostic, tool for fetal anomalies. While it can detect **structural abnormalities** associated with Down syndrome, it cannot definitively diagnose the condition.
- It would be too late to provide the early definitive diagnosis the patient is seeking regarding **Down syndrome**.
*Genetic testing of patient’s sister*
- The sister's genetic testing would confirm her child's diagnosis or carrier status for **chromosomal translocations**, but it does not provide information about the current patient's fetus.
- A definitive diagnosis for the current pregnancy must come from **fetal genetic material**.
*Nuchal translucency test*
- The **nuchal translucency test** is a **screening test** performed between 11 and 14 weeks that measures the fluid at the back of the fetal neck and is used in conjunction with biochemical markers (first-trimester screening) to assess the risk of Down syndrome. It is not diagnostic.
- An abnormal result would indicate an increased risk but would still require a **diagnostic test** like CVS or amniocentesis for confirmation.
*Amniocentesis*
- **Amniocentesis** is a diagnostic procedure that samples amniotic fluid for genetic analysis, typically performed between 15 and 20 weeks of gestation.
- While it provides a definitive diagnosis for **chromosomal abnormalities**, it is usually performed later in pregnancy than CVS. The patient is at 10 weeks and two days, making CVS a timelier option for early diagnosis.
Question 6: 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?
A. Trinucleotide repeat in FMR1 gene
B. De novo mutation of MECP2 on the X chromosome
C. Chromosome 22q11 microdeletion
D. Uniparental disomy of chromosome 15 (Correct Answer)
E. Nondisjunction of chromosome 21 during meiosis I
Explanation: ***Uniparental disomy of chromosome 15***
- The presented symptoms—developmental delay, recurrent tonic-clonic seizures, mandibular protrusion, strabismus, paroxysmal laughter, unsteady gait, and speech impairment—are all characteristic features of **Angelman syndrome**.
- **Angelman syndrome** is typically caused by the loss of function of the maternal copy of the *UBE3A* gene on chromosome 15q11-q13. This can occur due to a maternal deletion, a paternal **uniparental disomy** (inheriting both copies of chromosome 15 from the father), or a mutation in the *UBE3A* gene.
- In this case, the normal karyotype without chromosomal deletions points to **paternal uniparental disomy** as the mechanism.
*Trinucleotide repeat in FMR1 gene*
- This describes the genetic basis of **Fragile X syndrome**, which is characterized by intellectual disability, behavioral problems (e.g., hyperactivity, autism-like features), and characteristic physical features such as a **long face**, large ears, and **macro-orchidism in males**.
- While there is developmental delay and hyperactivity, the specific facial features (mandibular protrusion, laughing expression) and unsteady gait are not typical for Fragile X syndrome.
*De novo mutation of MECP2 on the X chromosome*
- This describes the genetic basis of **Rett syndrome**, which almost exclusively affects females and is characterized by a period of normal development followed by regression in communication and motor skills, **stereotypic hand movements**, microcephaly, and seizures.
- The patient is a male and presents with features inconsistent with Rett syndrome.
*Chromosome 22q11 microdeletion*
- This is associated with **DiGeorge syndrome** or velocardiofacial syndrome, characterized by cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia.
- The symptoms described in the patient (seizures, laughing expression, gait ataxia) are not typical for 22q11 deletion syndrome.
*Nondisjunction of chromosome 21 during meiosis I*
- This is the most common cause of **Down syndrome** (Trisomy 21), characterized by intellectual disability, characteristic facial features (upslanting palpebral fissures, epicanthic folds, flat nasal bridge), and associated medical problems like congenital heart defects and hypotonia.
- The patient's symptoms, particularly the prominent mandible, strabismus, and laughing expression, do not align with the typical presentation of Down syndrome.
Question 7: A 4-month-old boy with a history of multiple infections presents with muscle stiffness. On physical exam, he is found to have carpopedal spasm as well as a heart murmur. Based on your clinical suspicion you decide to obtain a chest X-ray which shows a diminished shadow in the mediastinum. A mutation in which of the following chromosomes is the most likely cause of this patient's presentation?
A. Chromosome 22 (Correct Answer)
B. Chromosome 17
C. Chromosome 5
D. Chromosome 7
E. Chromosome X
Explanation: ***Chromosome 22***
- This patient's presentation with **multiple infections**, **muscle stiffness** (indicating hypocalcemia), **carpopedal spasm**, a **heart murmur**, and a **diminished thymic shadow** on chest X-ray are classic signs of **DiGeorge syndrome**.
- **DiGeorge syndrome** is caused by a microdeletion on **chromosome 22q11**, leading to abnormal development of the third and fourth pharyngeal pouches.
*Chromosome 17*
- Deletions or duplications on chromosome 17 are associated with conditions such as **Charcot-Marie-Tooth disease type 1A** or **Smith-Magenis syndrome**, which do not typically present with this constellation of symptoms.
- While these disorders involve developmental issues, they do not specifically cause thymic aplasia or congenital heart defects characteristic of DiGeorge syndrome.
*Chromosome 5*
- Deletions on chromosome 5 can lead to **Cri-du-chat syndrome**, characterized by a cat-like cry, intellectual disability, and microcephaly.
- This syndrome does not involve the characteristic immune deficiency or hypocalcemia seen in DiGeorge syndrome.
*Chromosome 7*
- Disorders associated with chromosome 7 include **Williams syndrome** (deletion on 7q11.23) and some forms of cystic fibrosis (due to mutations in the CFTR gene on 7q31.2).
- **Williams syndrome** presents with distinct facial features, cardiovascular problems (supravalvular aortic stenosis), and intellectual disability, but not thymic aplasia or hypocalcemia.
*Chromosome X*
- Chromosome X abnormalities are linked to conditions like **Turner syndrome** (XO) or **Klinefelter syndrome** (XXY), which primarily affect sex development and reproduction.
- While X-linked disorders can cause various health issues, they do not typically manifest with the specific combination of thymic hypoplasia, hypocalcemia, and congenital heart defects indicative of DiGeorge syndrome.
Question 8: A 2-month-old boy is presented to the clinic for a well-child visit by his parents. They are concerned with his weak cry and difficulty with feeding. Birth history reveals that the boy was born at the 37th week of gestation by cesarean section due to poor fetal movement and fetal distress. His Apgar scores were 3 and 5 at 1st and 5th minute respectively and his birth weight was 2.5 kg (6 lb). His vital signs include heart rate 120/min, respiratory rate 40/min, blood pressure 90/50 mm Hg, and temperature 37.0°C (98.6°F). Physical examination reveals a malnourished boy with a small narrow forehead and a small jaw. His mouth is small and he has comparatively small genitals. He has a poor muscle tone. After repeated follow-up, he gains weight rapidly but his height fails to increase. Developmental milestones are delayed at the age of 3 years. Genetic testing reveals Prader-Willi syndrome. Which of the following is the most common mechanism for the development of this patient’s condition?
A. Anticipation
B. Heteroplasmy
C. Incomplete penetrance
D. Maternal uniparental disomy
E. Paternal deletion of 15q11-q13 (Correct Answer)
Explanation: ***Paternal deletion of 15q11-q13***
- This is the **most common genetic mechanism** (occurring in about 70-75% of cases) for Prader-Willi syndrome, involving the loss of genetic material from the paternally inherited chromosome 15 in the specified region
- The deletion affects genes that are **normally expressed only from the paternal chromosome** due to genomic imprinting, leading to the characteristic features of hypotonia, feeding difficulties in infancy, subsequent hyperphagia with obesity, hypogonadism, and developmental delays
*Incorrect: Anticipation*
- Anticipation describes a genetic phenomenon where a disorder appears earlier or symptoms become more severe with each successive generation
- This is typically seen in disorders caused by expanding **trinucleotide repeats** (e.g., Huntington's disease, myotonic dystrophy), not applicable to Prader-Willi syndrome
*Incorrect: Heteroplasmy*
- Heteroplasmy refers to the presence of more than one type of mitochondrial DNA within a cell or individual
- This concept is relevant to **mitochondrial genetic disorders** which are maternally inherited, not to Prader-Willi syndrome which is a nuclear chromosomal imprinting disorder
*Incorrect: Incomplete penetrance*
- Incomplete penetrance occurs when individuals carrying a pathogenic mutation do not express the associated clinical phenotype
- Prader-Willi syndrome typically presents with a **consistent set of features** when the genetic defect is present; incomplete penetrance is not the mechanism of disease development
*Incorrect: Maternal uniparental disomy*
- Maternal uniparental disomy (UPD) of chromosome 15 is the **second most common mechanism** for Prader-Willi syndrome (occurring in about 20-25% of cases)
- This involves inheriting **both copies of chromosome 15 from the mother** and none from the father, leading to absence of paternal gene expression in the critical 15q11-q13 region
- While less common than paternal deletion, this is still a significant cause of the syndrome
Question 9: A 1-year-old girl born to a 40-year-old woman is undergoing an examination by a pediatric resident in the hospital. The pregnancy was uneventful and there were no complications during the delivery. The physical examination reveals midface hypoplasia with a flat nasal bridge and upslanting palpebral fissures. She has a small mouth and chest auscultation reveals a blowing holosystolic murmur that is heard best along the sternal border. The family history is unremarkable. A karyotype analysis is ordered because the resident suspects a numerical chromosomal disorder. Which of the following phenomena leads to the infant’s condition?
A. Meiotic non-disjunction (Correct Answer)
B. Uniparental disomy
C. Genomic imprinting
D. Partial deletion
E. Trinucleotide repeat
Explanation: ***Meiotic non-disjunction***
- The combination of **midface hypoplasia**, **upslanting palpebral fissures**, **flat nasal bridge**, and a **holosystolic murmur** (suggesting a **ventricular septal defect**) in an infant born to an older mother is highly characteristic of **Down syndrome (Trisomy 21)**.
- **Trisomy 21** is most commonly caused by **meiotic non-disjunction**, where homologous chromosomes fail to separate during meiosis I or sister chromatids fail to separate during meiosis II, resulting in a gamete with an extra chromosome 21.
*Uniparental disomy*
- **Uniparental disomy** occurs when an individual receives both copies of a chromosome from a single parent, rather than one from each parent.
- While it can lead to various genetic disorders, it does not typically cause **Trisomy 21** or the specific constellation of features described.
*Genomic imprinting*
- **Genomic imprinting** is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin specific manner.
- While relevant to conditions like Prader-Willi or Angelman syndromes, it is not the mechanism responsible for **Trisomy 21**.
*Partial deletion*
- A **partial deletion** refers to the loss of a segment of a chromosome.
- While chromosomal deletions cause various syndromes (e.g., Cri-du-chat syndrome), they would result in a **monosomy or partial monosomy**, not the extra chromosome seen in Trisomy 21.
*Trinucleotide repeat*
- **Trinucleotide repeat disorders** involve an abnormal expansion of a three-nucleotide sequence within a gene, leading to conditions like Huntington's disease or fragile X syndrome.
- This mechanism is not associated with the etiology of **Down syndrome**.
Question 10: A 69-year-old man comes to the physician because of a 1-week history of blood in the urine and fatigue. He also has had a 5.0-kg (11-lb) weight loss during the past month. Physical examination shows pallor and cachexia. A nontender right flank mass is palpated. A CT scan of the chest, abdomen, and pelvis shows a 5-cm right upper pole renal mass and several pulmonary lesions. A biopsy specimen of an affected area of the lung is obtained. A photomicrograph of the biopsy specimen is shown. Molecular evaluation of the specimen is most likely to show which of the following genetic changes?
A. NF1 gene inactivation
B. TSC1 gene insertion
C. WT1 gene deletion
D. PKD1 gene mutation
E. VHL gene deletion (Correct Answer)
Explanation: ***VHL gene deletion***
- The clinical presentation of a **right flank mass** with **hematuria**, **weight loss**, and **pulmonary lesions** points to **renal cell carcinoma (RCC)**, which is further supported by the photomicrograph showing clear cells. The **VHL gene** is a tumor suppressor gene, and its inactivation (e.g., through deletion) is the most common genetic alteration in **clear cell RCC**.
- The image displays classic features of **clear cell RCC**, characterized by cells with **clear cytoplasm** due to abundant lipids and glycogen, arranged in **nests or cords with fine vascular networks**.
*NF1 gene inactivation*
- **NF1 gene inactivation** is associated with **neurofibromatosis type 1**, a genetic disorder that predisposes individuals to various tumors, including neurofibromas, optic gliomas, and pheochromocytomas, but not typically clear cell RCC.
- While patients with neurofibromatosis type 1 can develop kidney tumors, they are usually not clear cell RCC and the absence of other NF1 stigmata makes this less likely.
*TSC1 gene insertion*
- **TSC1 gene mutations** are linked to **tuberous sclerosis complex**, a genetic disorder characterized by tumor formation in multiple organs, including the brain, skin, heart, and kidneys (e.g., angiomyolipomas).
- While kidney tumors can occur, typical clear cell RCC is not the primary renal manifestation, and the image does not suggest angiomyolipoma.
*WT1 gene deletion*
- **WT1 gene deletion** is primarily associated with **Wilms' tumor (nephroblastoma)**, a childhood kidney cancer.
- This patient is 69 years old, making Wilms' tumor highly unlikely.
*PKD1 gene mutation*
- **PKD1 gene mutations** are responsible for **autosomal dominant polycystic kidney disease (ADPKD)**, a condition causing multiple cysts in the kidneys and other organs.
- While ADPKD can lead to kidney failure and may rarely be associated with RCC, the clinical presentation and microscopic image are not characteristic of ADPKD or its associated RCC type, which is often papillary RCC.
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