Fragile X syndrome US Medical PG Practice Questions and MCQs
Practice US Medical PG questions for Fragile X syndrome. These multiple choice questions (MCQs) cover important concepts and help you prepare for your exams.
Fragile X syndrome US Medical PG Question 1: A 4-year-old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have macroorchidism, hypertelorism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG. What is the diagnosis of the boy?
- A. Huntington's disease
- B. Spinal and bulbar muscular atrophy
- C. Myotonic dystrophy type 1
- D. Fragile X syndrome (Correct Answer)
- E. Friedreich ataxia
Fragile X syndrome Explanation: ***Fragile X syndrome***
- The combination of **developmental delay**, characteristic physical features (**macroorchidism, large protruding ears, long thin face, large jaw**), and a **CGG repeat expansion** (250 repeats) is pathognomonic for Fragile X syndrome.
- This is an **X-linked disorder** caused by an expansion of CGG trinucleotide repeats in the *FMR1* gene, leading to reduced or absent fragile X mental retardation protein (FMRP).
*Huntington's disease*
- Characterized by **chorea**, psychiatric symptoms, and cognitive decline, typically manifesting in adulthood, not early childhood developmental delay.
- Caused by a **CAG trinucleotide repeat expansion** in the *HTT* gene, not CGG.
*Spinal and bulbar muscular atrophy*
- This is an **X-linked recessive** neurodegenerative disorder leading to muscle weakness and atrophy, which usually presents in adulthood.
- It is caused by a **CAG repeat expansion** in the androgen receptor gene.
*Myotonic dystrophy type 1*
- Presents with progressive **muscle wasting and weakness**, myotonia, cataracts, and cardiac conduction defects, typically later in childhood or adulthood.
- Caused by a **CTG trinucleotide repeat expansion** in the *DMPK* gene.
*Friedreich ataxia*
- Characterized by progressive **ataxia**, dysarthria, and loss of vibration/proprioception, usually beginning in childhood or adolescence.
- Caused by a **GAA trinucleotide repeat expansion** in the *FXN* gene.
Fragile X syndrome US Medical PG Question 2: A 3-year-old is brought in to the pediatrician's office for a routine checkup. Her parents report that they noticed some regression in their daughter's behavior. She seemed to be progressing well during the first 18 months of her life. She had started saying words such as 'I', 'you' and 'mama' and she was linking words together. She also learned to follow simple instructions. However, over the past few months, they have noticed that she has been forgetting some of the things that she had previously learned and has had difficulty walking. On examination, the physician observes an apparently healthy girl who refuses to make eye contact and only slowly responds to her name. She is observed to wring her hands repeatedly in her lap. Which of the following genetic patterns of inheritance is responsible for this behavioral regression?
- A. X-linked dominant (Correct Answer)
- B. Autosomal dominant
- C. Chromosomal trisomy
- D. X-linked recessive
- E. Autosomal recessive
Fragile X syndrome Explanation: ***X-linked dominant***
- The clinical presentation of a previously thriving girl with **developmental regression**, **loss of acquired skills**, **hand-wringing stereotypies**, and **loss of eye contact** is highly suggestive of **Rett syndrome**.
- Rett syndrome is a classic example of an **X-linked dominant** disorder, primarily affecting girls due to its severe, often lethal, impact in males.
*Autosomal dominant*
- While some neurodevelopmental disorders are autosomal dominant, the specific constellation of symptoms, particularly the **hand-wringing stereotypies** and almost exclusive occurrence in girls with typical male lethality, is not characteristic of typical autosomal dominant inheritance.
- Autosomal dominant disorders affect males and females equally, and severe forms would typically present with a clearer family history or variable expressivity in both sexes.
*Chromosomal trisomy*
- Chromosomal trisomies, such as Trisomy 21 (**Down syndrome**), typically present with congenital anomalies and global developmental delay evident from early infancy, rather than a period of normal development followed by significant regression.
- They also have distinct physical features not described in this case, and while some developmental plateaus can occur, the rapid regression of learned skills and specific motor stereotypies are less characteristic.
*X-linked recessive*
- **X-linked recessive** disorders predominantly affect males (e.g., Duchenne muscular dystrophy, fragile X syndrome), with females usually being carriers and often asymptomatic or having milder symptoms.
- The severe, progressive nature of the neurological regression and the almost exclusive manifestation in girls with Rett syndrome argue against an X-linked recessive inheritance pattern.
*Autosomal recessive*
- **Autosomal recessive** disorders affect males and females equally and often involve metabolic or storage disorders that can cause developmental regression (e.g., Tay-Sachs disease, lysosomal storage disorders).
- However, the specific **hand-wringing movements** and the high prevalence in females with Rett syndrome are not typical features of most autosomal recessive neurodegenerative conditions, which often have different ages of onset and specific neurological findings.
Fragile X syndrome US Medical PG Question 3: A 5-year-old boy is brought to the clinic by his mother for an annual check-up. The family recently moved from Nebraska and is hoping to establish care. The patient is home schooled and mom is concerned about her son’s development. He is only able to say 2 to 3 word sentences and has been “behind on his alphabet." He always seems to be disinterested and "just seems to be behind.” The patient is observed to be focused on playing with his cars during the interview. Physical examination demonstrate a well-nourished child with poor eye contact, a prominent jaw, a single palmar crease, and bilaterally enlarged testicles. What is the most likely mechanism of this patient’s findings?
- A. CGG trinucleotide repeat expansion (Correct Answer)
- B. Microdeletion of the long arm of chromosome 7
- C. Meiotic nondisjunction of chromosome 21
- D. CTG trinucleotide repeat expansion
- E. Microdeletion of the short arm of chromosome 5
Fragile X syndrome Explanation: ***CGG trinucleotide repeat expansion***
- The patient presents with key features of **Fragile X Syndrome**: developmental delay ("behind on his alphabet," 2-3 word sentences), poor eye contact, prominent jaw, and **bilaterally enlarged testicles (macroorchidism)**.
- Fragile X Syndrome is caused by an expansion of a **CGG trinucleotide repeat** in the *FMR1* gene on the X chromosome.
*Microdeletion of the long arm of chromosome 7*
- This mechanism is associated with **Williams Syndrome**, characterized by elfin facies, an outgoing personality, and cardiovascular anomalies (especially supravalvular aortic stenosis).
- These features differ significantly from the patient's presentation; specifically, macroorchidism and poor eye contact are not typical of Williams Syndrome.
*Meiotic nondisjunction of chromosome 21*
- This leads to **Down Syndrome**, which presents with intellectual disability, distinctive facial features such as epicanthal folds and a flat nasal bridge, a single palmar crease, and hypotonia.
- While a single palmar crease is present in this patient, the prominent jaw, poor eye contact, and macroorchidism are not characteristic of Down Syndrome.
*CTG trinucleotide repeat expansion*
- A **CTG trinucleotide repeat expansion** is associated with **Myotonic Dystrophy**, a multisystem disorder characterized by myotonia, muscle wasting, cataracts, and frontal baldness.
- This condition typically presents with muscle weakness and myotonia, which are not described in the patient's symptoms, and does not cause macroorchidism or prominent jaw.
*Microdeletion of the short arm of chromosome 5*
- This microdeletion causes **Cri-du-chat syndrome**, characterized by a distinctive high-pitched cry resembling a cat's meow, microcephaly, intellectual disability, and widely spaced eyes.
- The patient's symptoms (e.g., prominent jaw, macroorchidism, no mention of a characteristic cry) do not align with the typical presentation of Cri-du-chat syndrome.
Fragile X syndrome US Medical PG Question 4: A 4-year-old girl is brought to the pediatrician by her parents for a 1-year history of gradual loss of speech and motor skills. Pregnancy and delivery were uncomplicated, and development was normal until the age of 3 years. Her parents say she used to run and speak in short sentences but now is only able to walk slowly and cannot form sentences. She avoids eye contact and constantly rubs her hands together. There are no dysmorphic facial features. Neurologic examination shows marked cognitive and communicative delay. She has a broad-based gait and is unable to hold or pick up toys on her own. Which of the following mutations is the most likely underlying cause of this patient's condition?
- A. Partial deletion of short arm of chromosome 5
- B. Mutation in MECP2 gene on X-chromosome (Correct Answer)
- C. CGG trinucleotide repeat in FMR1 gene on X-chromosome
- D. Partial deletion of long arm of chromosome 7
- E. CTG trinucleotide repeat in DMPK gene on chromosome 19
Fragile X syndrome Explanation: ***Mutation in MECP2 gene on X-chromosome***
- The patient's presentation with **normal early development** followed by **regression of speech and motor skills**, social withdrawal, and characteristic **hand-wringing stereotypies** in a 4-year-old girl is highly suggestive of **Rett syndrome**.
- **Rett syndrome** is overwhelmingly caused by a mutation in the **MECP2 gene** (methyl-CpG binding protein 2) located on the X-chromosome.
- Rett syndrome is an X-linked dominant disorder that almost exclusively affects females, as the mutation is typically lethal in males.
*Partial deletion of short arm of chromosome 5*
- This chromosomal abnormality is associated with **Cri-du-chat syndrome**, characterized by a **high-pitched cry** resembling a cat, intellectual disability, and microcephaly, which are not the primary features described here.
- Patients with Cri-du-chat typically present with severe developmental delay from birth and **dysmorphic facial features**, unlike the regression pattern seen in this patient.
*CGG trinucleotide repeat in FMR1 gene on X-chromosome*
- This mutation causes **Fragile X syndrome**, which is characterized by intellectual disability, **large ears**, prominent jaw, and **macroorchidism** in males.
- While it causes developmental delay and often presents with features of autism, it typically does not involve a distinct period of **normal development followed by regression** as seen in this patient.
*Partial deletion of long arm of chromosome 7*
- Deletions on the long arm of chromosome 7 are associated with various conditions, but a well-known example is **Williams syndrome** caused by a microdeletion at 7q11.23.
- Williams syndrome involves intellectual disability, distinctive **"elfin" facial features**, and cardiovascular problems (e.g., supravalvular aortic stenosis), which do not align with the patient's symptoms of developmental regression and hand stereotypies.
*CTG trinucleotide repeat in DMPK gene on chromosome 19*
- This mutation is responsible for **Myotonic dystrophy type 1**, an autosomal dominant disorder characterized by progressive muscle weakness and myotonia, often presenting in adolescence or adulthood.
- It does not present with a period of normal development followed by global developmental regression and specific hand stereotypies in early childhood.
Fragile X syndrome US Medical PG Question 5: A 28-year-old G2P1 female is concerned that she may give birth to another child with Down syndrome. She states that she may not be able to take care of another child with this disorder. Which of the following tests can confirm the diagnosis of Down syndrome in utero?
- A. Ultrasound
- B. Triple marker test
- C. Integrated test
- D. Quadruple marker test
- E. Amniocentesis (Correct Answer)
Fragile X syndrome Explanation: ***Amniocentesis***
- **Amniocentesis** is a **diagnostic procedure** that involves collecting amniotic fluid to obtain fetal cells for **karyotyping**, which can definitively confirm the presence of an extra chromosome 21, the cause of Down syndrome.
- This test is typically performed between **15 and 20 weeks of gestation** and carries a small risk of complication but offers conclusive results.
*Ultrasound*
- **Ultrasound** is a **screening tool** that can detect anatomical features suggestive of Down syndrome, such as **nuchal translucency** or heart defects, but it cannot definitively diagnose the condition.
- It identifies **markers** that increase the suspicion of Down syndrome, prompting further diagnostic testing, but does not provide genetic confirmation.
*Triple marker test*
- The **triple marker test** is a **screening test** that measures levels of **alpha-fetoprotein (AFP)**, **unconjugated estriol (uE3)**, and **human chorionic gonadotropin (hCG)** in maternal blood.
- While it can estimate the risk of Down syndrome, it is not a diagnostic test and only provides a **risk assessment**, not a definitive diagnosis.
*Integrated test*
- The **integrated test** combines results from first-trimester screening (nuchal translucency and PAPP-A) and second-trimester screening (quadruple marker test) to provide a **single risk assessment**.
- Like other screening tests, it calculates a **risk probability** for Down syndrome but does not offer a definitive diagnosis.
*Quadruple marker test*
- The **quadruple marker test** measures AFP, uE3, hCG, and **inhibin A** in maternal blood during the second trimester.
- It is a **screening test** used to assess the risk of Down syndrome and open neural tube defects, but it is not a diagnostic tool.
Fragile X syndrome US Medical PG Question 6: A 3-year-old boy is brought to the physician for evaluation of developmental delay. He could sit alone at 12 months and started walking with support at the age of 2 years. He can name only very few familiar objects and uses simple two-word sentences. He cannot stack more than 2 blocks. His parents report that he does not like playing with other children. He is at the 80th percentile for head circumference, 85th percentile for height, and 50th percentile for weight. He has a long and narrow face as well as large protruding ears. His thumbs can be passively flexed to the ipsilateral forearm. This patient is at increased risk of developing which of the following conditions?
- A. Mitral regurgitation (Correct Answer)
- B. Type 2 diabetes mellitus
- C. Acute myeloid leukemia
- D. Aortic dissection
- E. Hyperuricemia
Fragile X syndrome Explanation: ***Mitral regurgitation***
- The patient's presentation with **developmental delay**, **relatively large head circumference** (80th percentile), **long narrow face**, **large protruding ears**, and **hyperextensible joints** (thumbs to forearm) is highly suggestive of **fragile X syndrome**.
- **Mitral valve prolapse** leading to **mitral regurgitation** is a common cardiac manifestation of fragile X syndrome, occurring in **50-80% of adult males** with the condition, due to **connective tissue dysplasia**.
*Type 2 diabetes mellitus*
- This condition is primarily associated with **obesity**, **insulin resistance**, and genetic predispositions unrelated to the features presented in this patient.
- While fragile X patients may have general health concerns, there is **no specific increased risk** of developing type 2 diabetes mellitus directly linked to the syndrome's pathology.
*Acute myeloid leukemia*
- There is **no established association** between fragile X syndrome and an increased risk of developing **acute myeloid leukemia**.
- AML is a **hematologic malignancy** with different risk factors, such as exposure to certain chemicals or prior chemotherapy.
*Aortic dissection*
- Aortic dissection is typically associated with conditions affecting **connective tissue** like **Marfan syndrome** or **Ehlers-Danlos syndrome**, or with **hypertension**.
- While fragile X syndrome involves connective tissue abnormalities, **aortic dissection is not a typical or significantly increased risk** compared to other connective tissue disorders.
*Hyperuricemia*
- **Hyperuricemia** is most commonly associated with conditions like **gout**, **kidney disease**, or certain **genetic metabolic disorders** (e.g., Lesch-Nyhan syndrome).
- There is **no direct link** between fragile X syndrome and an increased risk of hyperuricemia.
Fragile X syndrome US Medical PG Question 7: 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
Fragile X syndrome 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**.
Fragile X syndrome US Medical PG Question 8: A mother brings her son to the pediatrician because she is concerned about his health. She states that throughout her child's life he has demonstrated aggressive behavior. However, he has recently begun biting himself causing injury and bleeding. The patient has a past medical history of mental retardation and episodes of severe joint pain. His temperature is 99.5°F (37.5°C), blood pressure is 87/48 mmHg, pulse is 90/min, respirations are 17/min, and oxygen saturation is 98% on room air. Physical exam reveals a child attempting to bite his arms. Which of the following is the inheritance pattern of the disease with which this patient presents?
- A. X-linked dominant
- B. Autosomal dominant
- C. Autosomal recessive
- D. X-linked recessive (Correct Answer)
- E. Maternal
Fragile X syndrome Explanation: ***X-linked recessive***
- This patient's presentation of **self-mutilation**, **mental retardation**, and **aggressive behavior** is highly suggestive of **Lesch-Nyhan syndrome**.
- Lesch-Nyhan syndrome is an **X-linked recessive disorder** caused by a defect in the gene for **hypoxanthine-guanine phosphoribosyltransferase (HGPRT)**, leading to a build-up of uric acid.
*X-linked dominant*
- X-linked dominant disorders affect both males and females, though males are often more severely affected or may have more prominent symptoms.
- Affected fathers transmit the trait to all their daughters but no sons, which is not characteristic of Lesch-Nyhan syndrome.
*Autosomal dominant*
- Autosomal dominant disorders are inherited equally by males and females, and an affected individual has a 50% chance of passing the condition to each child.
- This inheritance pattern does not fit the typical presentation of Lesch-Nyhan syndrome, which primarily affects males.
*Autosomal recessive*
- Autosomal recessive disorders typically require two copies of the mutated gene (one from each parent) for the disease to manifest, affecting males and females equally.
- While some metabolic disorders are autosomal recessive, Lesch-Nyhan syndrome's sex-linked pattern of inheritance rules out this option.
*Maternal*
- Maternal inheritance refers to conditions passed down through **mitochondrial DNA**, affecting all children of an affected mother regardless of sex.
- Affected fathers do not pass mitochondrial conditions to any of their children, since sperm contribute minimal mitochondria.
- Lesch-Nyhan syndrome is associated with a nuclear gene on the X chromosome, not mitochondrial DNA, making maternal inheritance incorrect.
Fragile X syndrome US Medical PG Question 9: A 16-year-old presents to the primary care physician because he has noticed an increase in the size of his breast tissue over the past 3 years. He states that he is significantly taller than his entire class at school although he feels increasingly weak and uncoordinated. He performs at the bottom of his grade level academically. On physical exam the patient has marked gynecomastia with small firm testes. The physician decides to perform a karyotype on the patient. What is the most likely outcome of this test?
- A. 47, XYY
- B. 45, XO
- C. 47, XXY (Correct Answer)
- D. 47, XXX
- E. 46, XY
Fragile X syndrome Explanation: ***47, XXY***
The constellation of **gynecomastia, tall stature, learning difficulties, and small testes** is classic for **Klinefelter syndrome**, which is characterized by a **47, XXY** karyotype.
The presence of an extra X chromosome leads to **hypogonadism** and **endocrine imbalances**, explaining the physical and developmental findings.
*47, XYY*
- Individuals with **47, XYY syndrome** are typically tall but do not usually present with breast enlargement or other features of hypogonadism.
- They may have an increased risk of learning difficulties and behavioral problems.
*45, XO*
- This karyotype, also known as **Turner syndrome**, is characterized by the absence of an X chromosome and typically affects **females**.
- Common features include **short stature, webbed neck, and ovarian dysfunction**, which are inconsistent with the patient's presentation.
*47, XXX*
- This karyotype, known as **Triple X syndrome**, affects **females** and is characterized by the presence of an extra X chromosome.
- While some individuals may experience learning difficulties or developmental delays, it does not cause gynecomastia or small testes in males.
*46, XY*
- This is the **normal male karyotype** and would not explain the patient's symptoms of gynecomastia, small testes, tall stature, or learning difficulties.
- These symptoms suggest an underlying chromosomal abnormality.
Fragile X syndrome US Medical PG Question 10: A 4-year-old boy is brought to the clinic by his mother with a history of multiple falls for the last 8 months. He was born at term without any perinatal complications. At birth, his weight and height were 57th and 62nd percentile for his age, respectively. For the first year, he had normal developmental milestones. He started walking at the age of 17 months and started climbing stairs at 2 years of age. For the last 8–10 months, he has been walking clumsily, has fallen multiple times, and is having difficulty standing from the sitting position. He is not able to climb the stairs now. Past medical history is unremarkable. His vaccinations are up-to-date. His maternal uncle had a similar history, and he became bed-bound at 12 years of age. During the physical examination, the patient stood up from sitting position slowly by placing hands on his knees. What additional findings will be present in this patient?
- A. Early contractures at multiple joints
- B. Inability to release grasp after handshake
- C. Rash over shoulders and anterior chest
- D. Inverted champagne bottle legs
- E. Pseudohypertrophy of the calf muscles (Correct Answer)
Fragile X syndrome Explanation: ***Pseudohypertrophy of the calf muscles***
- The patient's presentation with **Gowers' sign**, progressive muscle weakness, and a family history suggestive of X-linked inheritance (maternal uncle affected) strongly indicates **Duchenne muscular dystrophy (DMD)**.
- **Pseudohypertrophy** of the calves is a classic sign of DMD, caused by the replacement of degenerated muscle fibers with fat and connective tissue.
*Early contractures at multiple joints*
- While **contractures** do occur in DMD, they typically develop later in the disease progression, often after significant muscle wasting has occurred.
- The initial presentation is usually dominated by proximal muscle weakness and difficulty with motor tasks.
*Inability to release grasp after handshake*
- This symptom, known as **myotonia**, is characteristic of **myotonic dystrophy**, not Duchenne muscular dystrophy.
- Myotonia involves delayed relaxation of muscles after contraction.
*Rash over shoulders and anterior chest*
- A rash over the shoulders and anterior chest, particularly in a "V-neck" distribution, is a feature of **dermatomyositis**.
- This autoimmune condition is characterized by both muscle weakness and classic dermatological findings, which are not described in this patient.
*Inverted champagne bottle legs*
- **Inverted champagne bottle legs** (peroneal muscular atrophy) are a characteristic finding in **Charcot-Marie-Tooth disease**, a group of inherited peripheral neuropathies.
- This involves atrophy of the distal leg muscles, leading to a distinctive leg shape, and is not typical of DMD.
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