Skeletal dysplasias — MCQs
A 27-year-old G1P0 at 12 weeks gestation presents to her obstetrician for her first prenatal visit. She and her husband both have achondroplasia, and she is curious what are the chances that they will have a child of average height. What percent of pregnancies between two individuals with achondroplasia that result in a live birth will be expected to be offspring that are unaffected by this condition?
A 4-year-old boy is brought to the pediatrician by his mother for a routine medical examination. His medical history is relevant for delayed gross motor milestones. The mother is concerned about a growth delay because both of his brothers were twice his size at this age. Physical examination reveals a well-groomed and healthy boy with a prominent forehead and short stature, in addition to shortened upper and lower extremities with a normal vertebral column. The patient’s vitals reveal: temperature 36.5°C (97.6°F); pulse 60/min; and respiratory rate 17/min and a normal intelligence quotient (IQ). A mutation in which of the following genes is the most likely cause underlying the patient’s condition?
An 11-year-old girl presents to her primary care physician because she has been having difficulty hearing her teachers at school. She says that the difficulty hearing started about a year ago, and it has slowly been getting worse. Her past medical history is significant for multiple fractures in both her upper and lower extremities. She also recently had a growth spurt and says that her friends say she is tall and lanky. A mutation in which of the following genes is most likely associated with this patient's condition?
A 15-year-old boy comes to the physician for the evaluation of progressive difficulty climbing stairs for the last 2 years. During this period, he has also had problems running and standing up from a seated position. He is at the 50th percentile for height and weight. Examination shows enlarged calf muscles bilaterally and a waddling gait. Which of the following is the most likely cause of this patient's condition?
A 2860-g (6-lb 3-oz) male newborn is born at term to a primigravid woman via spontaneous vaginal delivery. The mother has had no routine prenatal care. She reports that there is no family history of serious illness. The initial examination of the newborn shows bowing of the legs and respiratory distress upon palpation of the chest. The skin and joints are hyperextensible. X-rays of the chest and skull show multiple rib fractures and small, irregular bones along the cranial sutures. The patient is at increased risk of which of the following complications?
A 3-year-old child presents with respiratory distress and a history of recurrent respiratory infections. Based on the provided imaging, what is the most likely diagnosis?
A 2 -month-old child presents with the following condition as shown in the image. What is the ideal management protocol?
A 13-year-old boy presents with jaundice, fatigue, muscle stiffness, tremors, and behavioral changes. Examination reveals an enlarged liver and spleen. A Kayser-Fleischer ring was noted. What is the definitive diagnostic test?
A patient presents with an X-ray showing cardiomegaly, along with symptoms of hypotonia, macroglossia, hepatomegaly, and floppy baby syndrome. The X ray of the infant is shown below. What is the most likely diagnosis?
What is the diagnosis based on the image shown 
Skeletal dysplasias US Medical PG Practice Questions and MCQs
Question 1: A 27-year-old G1P0 at 12 weeks gestation presents to her obstetrician for her first prenatal visit. She and her husband both have achondroplasia, and she is curious what are the chances that they will have a child of average height. What percent of pregnancies between two individuals with achondroplasia that result in a live birth will be expected to be offspring that are unaffected by this condition?
- A. 0%
- B. 50%
- C. 75%
- D. 33% (Correct Answer)
- E. 25%
Explanation: ***33%*** - Achondroplasia is an **autosomal dominant** condition, meaning only one copy of the mutated gene is needed to express the trait. However, individuals with achondroplasia are typically **heterozygous (Aa)** because the homozygous dominant state (AA) is **lethal in utero** or shortly after birth. - When two heterozygous (Aa) parents mate, a Punnett square shows 25% AA, 50% Aa, and 25% aa. Since AA is a lethal genotype that is not viable for live birth, the surviving offspring will be 1/3 aa (unaffected) and 2/3 Aa (affected), meaning 33% will be of average height. *0%* - This would be true if all offspring were affected or if the condition was recessive and both parents were homozygous dominant, which is not the case for achondroplasia. - The possibility of having an unaffected child exists because affected individuals are generally heterozygous. *50%* - This would be the percentage of affected offspring if one parent was homozygous dominant and the other was homozygous recessive, or if one parent was homozygous dominant and the other heterozygous. - However, autosomal dominant traits typically result in a 2:1 ratio of affected to unaffected live births when both parents are heterozygous. *75%* - This would be the percentage of affected offspring if the homozygous dominant state were not lethal, resulting in 25% aa, 50% Aa, and 25% AA. - Achondroplasia, however, has a **lethal homozygous dominant genotype**, which alters the observed phenotypic ratios in live births. *25%* - This percentage represents the chance of having an unaffected offspring (aa) before considering the lethality of the homozygous dominant genotype (AA). - When accounting for the non-viability of AA genotypes, the proportion of unaffected offspring among live births increases.
Question 2: A 4-year-old boy is brought to the pediatrician by his mother for a routine medical examination. His medical history is relevant for delayed gross motor milestones. The mother is concerned about a growth delay because both of his brothers were twice his size at this age. Physical examination reveals a well-groomed and healthy boy with a prominent forehead and short stature, in addition to shortened upper and lower extremities with a normal vertebral column. The patient’s vitals reveal: temperature 36.5°C (97.6°F); pulse 60/min; and respiratory rate 17/min and a normal intelligence quotient (IQ). A mutation in which of the following genes is the most likely cause underlying the patient’s condition?
- A. Runt-related transcription factor 2
- B. Alpha-1 type I collagen
- C. Fibroblast growth factor receptor 3 (Correct Answer)
- D. Insulin-like growth factor 1 receptor
- E. Fibrillin-1
Explanation: ***Fibroblast growth factor receptor 3*** - The constellation of **short stature**, prominent forehead, and **shortened upper and lower extremities** with a normal vertebral column in a child with normal intelligence is characteristic of **achondroplasia**. - Achondroplasia is caused by a gain-of-function mutation in the **fibroblast growth factor receptor 3 (FGFR3)** gene, which inhibits chondrocyte proliferation and differentiation, leading to impaired endochondral ossification. *Runt-related transcription factor 2* - Mutations in **Runt-related transcription factor 2 (RUNX2)** are associated with **cleidocranial dysplasia**, a condition characterized by absent or hypoplastic clavicles, delayed closure of fontanelles, and dental abnormalities, which are not described in this patient. - While it affects bone development, the specific features of achondroplasia, such as rhizomelic dwarfism and a prominent forehead, are not typical of RUNX2 mutations. *Alpha-1 type I collagen* - Mutations in **collagen genes**, particularly type I collagen (COL1A1, COL1A2), are linked to **osteogenesis imperfecta**, characterized by **fragile bones**, blue sclera, and hearing loss. - The patient's presentation does not include these features, and the primary issue is disproportionate short stature due to impaired cartilage growth, not bone fragility. *Insulin-like growth factor 1 receptor* - Mutations in the **insulin-like growth factor 1 receptor (IGF1R)** can lead to **pre- and postnatal growth retardation** and microcephaly, often associated with developmental delay and feeding difficulties. - While IGF1R mutations cause short stature, the specific skeletal dysmorphology (e.g., prominent forehead, shortened limbs) and normal intelligence are much more suggestive of achondroplasia. *Fibrillin-1* - Mutations in **fibrillin-1** are responsible for **Marfan syndrome**, which typically presents with **tall stature**, long limbs (dolichostenomelia), joint hypermobility, and cardiovascular abnormalities such as aortic root dilation. - The patient's short stature and shortened limbs directly contradict the clinical picture of Marfan syndrome.
Question 3: An 11-year-old girl presents to her primary care physician because she has been having difficulty hearing her teachers at school. She says that the difficulty hearing started about a year ago, and it has slowly been getting worse. Her past medical history is significant for multiple fractures in both her upper and lower extremities. She also recently had a growth spurt and says that her friends say she is tall and lanky. A mutation in which of the following genes is most likely associated with this patient's condition?
- A. Type 4 collagen
- B. Type 3 collagen
- C. Fibrillin
- D. Type 1 collagen (Correct Answer)
- E. Fibroblast growth factor receptor
Explanation: ***Type 1 collagen*** - This patient's symptoms—hearing difficulty, multiple fractures, and tall/lanky stature—are classic signs of **osteogenesis imperfecta (OI)**, a genetic disorder caused by mutations in genes encoding **Type I collagen**. - **Type I collagen** is a major component of bone, so defects lead to fragile bones and susceptibility to fractures, and it also plays a role in the structure of the ear, affecting hearing. *Type 4 collagen* - Mutations in **Type 4 collagen** are primarily associated with **Alport syndrome**, which classically presents with **hematuria**, progressive renal failure, and hearing loss. - While hearing loss is present, the patient's other key symptoms of **multiple fractures** and **tall, lanky stature** are not characteristic of Alport syndrome. *Type 3 collagen* - Defects in **Type 3 collagen** are linked to **Ehlers-Danlos syndrome, vascular type**, which is characterized by fragile blood vessels, organs, and skin, leading to easy bruising, arterial rupture, and bowel perforation. - While Type 3 collagen is found in connective tissues, its primary clinical manifestations do not align with the patient's presentation of recurrent fractures and hearing loss. *Fibrillin* - Mutations in **fibrillin-1** are responsible for **Marfan syndrome**, which presents with tall stature, long limbs (**arachnodactyly**), and cardiovascular issues like aortic dilation. - While tall stature is observed, the patient's primary complaints of **recurrent fractures** and hearing loss are not typical features of Marfan syndrome. *Fibroblast growth factor receptor* - Mutations in **fibroblast growth factor receptor 3 (FGFR3)** are most commonly associated with **achondroplasia**, a form of dwarfism characterized by short stature, short limbs, and a large head. - This is inconsistent with the patient's **tall and lanky stature** and does not account for the recurrent fractures or hearing difficulties.
Question 4: A 15-year-old boy comes to the physician for the evaluation of progressive difficulty climbing stairs for the last 2 years. During this period, he has also had problems running and standing up from a seated position. He is at the 50th percentile for height and weight. Examination shows enlarged calf muscles bilaterally and a waddling gait. Which of the following is the most likely cause of this patient's condition?
- A. Large deletions (Correct Answer)
- B. Frameshift mutation
- C. Splice site mutation
- D. Missense mutation
- E. Nonsense mutation
Explanation: ***Large deletions*** - The presented symptoms (progressive difficulty climbing stairs, running, standing, enlarged calf muscles, waddling gait) are classic for **Duchenne muscular dystrophy (DMD)**. - **Large deletions** (involving one or more exons) are the **most common cause of DMD**, accounting for approximately **60-70%** of cases. - These deletions typically cause a **frameshift** that leads to a premature stop codon, resulting in absent or severely truncated **dystrophin protein**. - The **dystrophin gene** is one of the largest human genes, making it particularly susceptible to deletion mutations. *Frameshift mutation* - A **frameshift mutation** (insertion or deletion of nucleotides not in multiples of three) leads to an altered reading frame, resulting in a **premature stop codon** downstream. - While frameshifts do cause **DMD**, they are typically the **consequence** of deletions or small insertions/duplications, not a primary mutation category. - The question asks for the underlying genetic cause, which is most commonly a large deletion. *Splice site mutation* - **Splice site mutations** affect the splicing of introns and exons, potentially leading to exon skipping or inclusion of intronic sequences. - These account for a small percentage of **DMD** cases but are much less common than large deletions. - While they can disrupt the reading frame, they represent a minority of causative mutations. *Missense mutation* - A **missense mutation** results in a single amino acid change, producing an altered but full-length protein. - This type of mutation is more characteristic of **Becker muscular dystrophy (BMD)**, a milder form with later onset and slower progression. - The severe, early-onset phenotype described here is typical of **DMD**, which requires near-complete absence of functional dystrophin. *Nonsense mutation* - A **nonsense mutation** introduces a premature stop codon, leading to a truncated protein. - While nonsense mutations do cause **DMD**, they account for only about **10-15%** of cases as part of the broader category of point mutations. - Large deletions remain significantly more common as the causative mutation type.
Question 5: A 2860-g (6-lb 3-oz) male newborn is born at term to a primigravid woman via spontaneous vaginal delivery. The mother has had no routine prenatal care. She reports that there is no family history of serious illness. The initial examination of the newborn shows bowing of the legs and respiratory distress upon palpation of the chest. The skin and joints are hyperextensible. X-rays of the chest and skull show multiple rib fractures and small, irregular bones along the cranial sutures. The patient is at increased risk of which of the following complications?
- A. Hearing loss (Correct Answer)
- B. Spinal canal stenosis
- C. Costochondral junction enlargement
- D. Intestinal rupture
- E. Intellectual disability
Explanation: ***Hearing loss*** - The described clinical picture of **bone fragility (multiple rib fractures, bowing of legs)**, **hyperextensible skin and joints**, and **wormian bones** (small, irregular bones along cranial sutures) is classic for **osteogenesis imperfecta (OI)**. - Individuals with OI are at increased risk for **conductive or sensorineural hearing loss**, which can manifest in childhood or adolescence. *Spinal canal stenosis* - While patients with OI can develop **scoliosis** and **vertebral compression fractures**, resulting in spinal cord compression, **spinal canal stenosis** itself is not a primary or direct complication of the underlying collagen defect in the same way hearing loss is. - The primary spinal complications are related to **vertebral fractures** and **deformities**. *Costochondral junction enlargement* - **Costochondral junction enlargement** (rachitic rosary) is a hallmark of **rickets**, a disorder of **vitamin D or phosphate metabolism**, not osteogenesis imperfecta. - The described features point to a **collagen synthesis defect**, not mineralization issues. *Intestinal rupture* - While there can be some smooth muscle abnormalities, **intestinal rupture** is not a commonly described or significant complication of osteogenesis imperfecta. - The primary systemic manifestations relate to **collagen defects** in bone, skin, tendons, and blood vessels, but not typically leading to spontaneous gastrointestinal rupture. *Intellectual disability* - **Intellectual function** is typically **unaffected** in osteogenesis imperfecta. - The disease primarily affects **connective tissue**, particularly bone development, and does not directly cause cognitive impairment.
Question 6: A 3-year-old child presents with respiratory distress and a history of recurrent respiratory infections. Based on the provided imaging, what is the most likely diagnosis?
- A. CPAM (Congenital Pulmonary Airway Malformation) (Correct Answer)
- B. Lung abscess
- C. Pyopneumothorax
- D. CDH (Congenital Diaphragmatic Hernia)
- E. Pulmonary sequestration
Explanation: ***CPAM (Congenital Pulmonary Airway Malformation)*** - The imaging shows **cystic lesions** within the lung parenchyma, which are characteristic of CPAM. These lesions can cause **respiratory distress** and predispose to **recurrent infections**. - The age of the child (3 years old) and the history of recurrent respiratory infections are consistent with CPAM, as these malformations often manifest with symptoms in early childhood. *Lung abscess* - A lung abscess typically presents as a **cavity with an air-fluid level** and surrounding consolidation, usually in a single, well-defined area. - While recurrent infections can occur, the widespread cystic appearance on imaging makes an abscess less likely than CPAM. *Pyopneumothorax* - Pyopneumothorax is characterized by the presence of both **pus and air in the pleural space**, leading to a visible air-fluid level that occupies the pleural cavity. - The imaging does not show evidence of gas and fluid within the pleural space, nor the typical chest wall separation seen in pneumothorax. *CDH (Congenital Diaphragmatic Hernia)* - CDH involves the **herniation of abdominal contents** into the chest cavity, displacing lung tissue and often causing severe respiratory distress from birth due to pulmonary hypoplasia. - The images show cystic changes within the lung parenchyma, not abdominal organs in the chest, and the age of presentation makes a new diagnosis of uncorrected CDH less likely, as it usually presents as a neonatal emergency. *Pulmonary sequestration* - Pulmonary sequestration is a congenital malformation characterized by **non-functioning lung tissue with aberrant systemic arterial supply**, typically from the aorta. - While it can present with recurrent infections, the imaging typically shows a **solid or mixed solid-cystic mass**, often in the lower lobes with visible feeding vessels on contrast imaging, rather than the predominantly multicystic appearance seen in CPAM.
Question 7: A 2 -month-old child presents with the following condition as shown in the image. What is the ideal management protocol?
- A. Operate immediately
- B. Surgery after 6 months of age
- C. Surgery after 2 years of age
- D. Medical management (Correct Answer)
- E. Refer to pediatric ophthalmology for evaluation
Explanation: ***Medical management*** - The image shows **epicanthal folds**, which are normal in many Asian infants and children. They are **congenital, benign skin folds** that cover the inner corner of the eye. - In a 2-month-old child, these folds are a normal variant and typically **recede with age**. No medical intervention, surgical or otherwise, is usually required. *Operate immediately* - **No medical indication** for immediate surgery as epicanthal folds are not a pathological condition requiring urgent correction. - Surgical intervention for cosmetic purposes is typically considered much later in life, if at all, when facial features are more developed. *Surgery after 6 months of age* - Epicanthal folds are **still a normal finding** in infants up to 6 months of age and often persist for several years. - Premature surgical correction could be unnecessary as the folds may resolve naturally with the development of the **nasal bridge**. *Surgery after 2 years of age* - While epicanthal folds can still be present at 2 years of age, surgery is **rarely indicated** unless they cause significant vision problems (e.g., pseudostrabismus) or severe cosmetic concerns that persist into later childhood. - By this age, many children will have developed a more prominent nasal bridge, which can lessen the appearance of the folds naturally. *Refer to pediatric ophthalmology for evaluation* - While specialist referral might be considered if there are concerns about **vision impairment or true strabismus**, isolated epicanthal folds in a 2-month-old infant are a **normal anatomical variant** that does not require specialist evaluation. - Referral would be appropriate only if there were functional concerns beyond the cosmetic appearance of the folds.
Question 8: A 13-year-old boy presents with jaundice, fatigue, muscle stiffness, tremors, and behavioral changes. Examination reveals an enlarged liver and spleen. A Kayser-Fleischer ring was noted. What is the definitive diagnostic test?
- A. Urinary copper
- B. Serum ceruloplasmin
- C. Hepatic parenchymal copper concentration (Correct Answer)
- D. Slit lamp examination
- E. Genetic testing for ATP7B mutation
Explanation: ***Hepatic parenchymal copper concentration*** - This is considered the **gold standard** for diagnosing **Wilson's disease**, as it directly measures the accumulation of copper in the liver, which is the hallmark of the condition. - A concentration of **>250 mcg/g of dry liver weight** is diagnostic of Wilson's disease, irrespective of other laboratory findings. *Urinary copper* - While **elevated 24-hour urinary copper excretion** is a common finding in Wilson's disease, it can also be influenced by other conditions and may not always be definitively diagnostic on its own. - It is a **screening tool** and part of the diagnostic workup, but not the definitive diagnostic test as it's an indirect measure of copper overload. *Serum ceruloplasmin* - **Low serum ceruloplasmin levels** are characteristic of Wilson's disease because ceruloplasmin is the primary copper-carrying protein in the blood. - However, ceruloplasmin levels can be **normal in some Wilson's patients**, especially those presenting with hepatic manifestations, and can be low in other conditions like severe liver failure or malabsorption. *Slit lamp examination* - A **slit lamp examination** is used to identify **Kayser-Fleischer rings**, which are corneal copper deposits. - While their presence is highly suggestive of Wilson's disease, especially with neurological symptoms, they **may be absent in up to 30-50% of patients** with hepatic-only presentations, and their absence does not rule out the disease. *Genetic testing for ATP7B mutation* - **Molecular genetic testing** can identify mutations in the ATP7B gene, which encodes the copper-transporting ATPase. - While highly specific for confirming Wilson's disease and useful for family screening, it is a **confirmatory test** rather than the definitive diagnostic test, as over 500 different mutations exist and not all are identified in routine testing. - Hepatic copper measurement remains the diagnostic standard as it directly demonstrates the pathophysiologic defect.
Question 9: A patient presents with an X-ray showing cardiomegaly, along with symptoms of hypotonia, macroglossia, hepatomegaly, and floppy baby syndrome. The X ray of the infant is shown below. What is the most likely diagnosis?
- A. Pompe's disease (Correct Answer)
- B. Ebstein anomaly
- C. Transposition of great arteries
- D. Von Gierke's disease
- E. Congenital hypothyroidism
Explanation: ***Pompe's disease*** - Pompe's disease (Type II glycogen storage disease) is characterized by a deficiency of **alpha-glucosidase**, leading to **glycogen accumulation** in lysosomes. - This accumulation results in **cardiomegaly**, **hypotonia** ("floppy baby"), **hepatomegaly**, and **macroglossia**, which perfectly match the clinical presentation. *Ebstein anomaly* - This is a congenital heart defect involving the **tricuspid valve**, leading to its displacement into the right ventricle. - While it causes cardiomegaly, it does not typically present with the systemic features like **hypotonia, macroglossia, or hepatomegaly** described. *Transposition of great arteries* - This is a complex congenital heart defect where the **aorta and pulmonary artery are switched**, resulting in two separate circulatory systems. - It causes severe cyanosis and cardiomegaly but does not explain the widespread glycogen storage symptoms such as **hypotonia** or **hepatomegaly**. *Von Gierke's disease* - **Von Gierke's disease** (Type I glycogen storage disease) is caused by a deficiency of **glucose-6-phosphatase**. - It primarily affects the **liver and kidneys**, causing severe hypoglycemia, hepatomegaly, and **nephromegaly**, but typically not significant cardiomegaly or profound hypotonia. *Congenital hypothyroidism* - Can present with **macroglossia, hypotonia, and hepatomegaly** similar to Pompe's disease. - However, the **massive cardiomegaly** seen on X-ray is not typical of hypothyroidism, and other features like prolonged jaundice, constipation, and umbilical hernia would be more prominent.
Question 10: What is the diagnosis based on the image shown 
- A. Bladder exstrophy (Correct Answer)
- B. Omphalocele
- C. Umbilical hernia
- D. Gastroschisis
- E. Epispadias
Explanation: ***Bladder exstrophy*** - The image distinctly shows an **exposed urinary bladder** on the abdominal wall, a hallmark of bladder exstrophy. - This congenital anomaly results from a **failure of midline closure** of the infraumbilical abdominal wall and bladder. *Omphalocele* - An omphalocele involves protrusion of **abdominal viscera** (intestines, liver) into the base of the umbilical cord. - The herniated organs are typically **covered by a sac** composed of peritoneum and amnion, which is absent in the image. *Umbilical hernia* - An umbilical hernia is a protrusion of abdominal contents through the **umbilical ring**, but the skin remains intact and covers the defect. - The image clearly shows an **exposed organ** without skin coverage, ruling out an umbilical hernia. *Gastroschisis* - Gastroschisis involves the **evisceration of intestines** through a full-thickness abdominal wall defect, usually to the right of the umbilical cord. - Unlike the image, the defect in gastroschisis is typically **much smaller** and primarily involves the bowel, not the bladder, and there is no covering sac. *Epispadias* - Epispadias is a **urethral defect** where the urethral opening is on the dorsal (upper) surface of the penis or anterior bladder neck. - While epispadias is part of the **exstrophy-epispadias complex** and often associated with bladder exstrophy, it does not present with an **exposed bladder** on the abdominal wall as seen in the image.
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