Genetic Counseling in Inherited Blistering Diseases — MCQs

10 questions

In congenital dystrophic variety of epidermolysis bullosa, mutation is seen in the gene coding for:

All of the following are tests done for Turner mosaic screening except?

34 week primigravida punjabi khatri comes with history of consanguineous marriage, with history of repeated blood transfusion to her sibling since 8 months of age. The first diagnostic test is -

Which extra-intestinal symptom of inflammatory bowel disease worsens with exacerbation of disease activity?

Which one of the following is an autosomal dominant disorder?

A skin biopsy shows suprabasilar acantholysis with 'row of tombstones' appearance. Which immunofluorescence pattern would confirm pemphigus vulgaris?

Acantholysis is seen in all except which of the following conditions?

The following image shows a flaccid bulla. This finding is characteristically seen in:

A 54-year-old man presents after a syncopal episode with no recollection of the event, and bystanders report that he regained consciousness approximately 45 seconds after falling. He has a history of bipolar disorder managed with quetiapine, and recently experienced prostatitis treated with ciprofloxacin. His other medications include lisinopril and hydrochlorothiazide for hypertension, and cyclobenzaprine and a hydrocodone/acetaminophen combination pill for low back pain. On examination, the patient is alert and oriented, with a nonfocal neurological examination and an unremarkable cardiac examination. Electrocardiogram shows nonspecific ST and T wave changes and a prolonged QT interval (QTc of 540 milliseconds). What is the best initial management approach?

Q10

A patient with acute history of blistering and denudation involving >30% BSA along with erosions of the lips with hemorrhagic crusting and other mucosa for few days. What is the most common triggering factor?

Genetic Counseling in Inherited Blistering Diseases Indian Medical PG Practice Questions and MCQs

Question 1: In congenital dystrophic variety of epidermolysis bullosa, mutation is seen in the gene coding for:

A. Laminin 4
B. Keratin 14
C. Collagen type 7 (Correct Answer)
D. Alpha 6 integrin

Explanation: ***Correct: Collagen type 7*** - **Dystrophic epidermolysis bullosa** is characterized by defects in **collagen type 7**, which forms anchoring fibrils that connect the epidermis to the underlying dermal tissue. - Mutations in the gene *COL7A1* lead to fragile skin that **blisters easily** in the **dermo-epidermal junction** below the lamina densa (sublamina densa level). - This distinguishes it from other EB subtypes by its **sub-basement membrane zone** blistering. *Incorrect: Laminin 4* - Mutations in **laminin 332** (formerly laminin 5), not laminin 4, are associated with **junctional epidermolysis bullosa**, a different subtype. - Junctional EB primarily affects the **lamina lucida** within the dermo-epidermal junction. *Incorrect: Keratin 14* - Mutations in **keratin 5** and **keratin 14** are responsible for **epidermolysis bullosa simplex**, which involves blistering within the **basal layer of the epidermis**. - In this form, blisters occur *intraepidermally* above the basement membrane zone. *Incorrect: Alpha 6 integrin* - Mutations in **alpha 6 beta 4 integrin** subunits are also associated with **junctional epidermolysis bullosa**, specifically affecting the assembly of **hemidesmosomes**. - These defects lead to blistering within the **lamina lucida**, similar to laminin 332 mutations.

Question 2: All of the following are tests done for Turner mosaic screening except?

A. Karyotype
B. FISH
C. Serum FSH (Correct Answer)
D. Buccal smear

Explanation: ***Serum FSH*** - **Serum Follicle-Stimulating Hormone (FSH)** levels are used to assess ovarian function and can be elevated in conditions like Turner syndrome due to **gonadal dysgenesis**, but it is a **functional test**, not a screening tool for mosaicism. - While elevated FSH is a clinical feature of Turner syndrome, it does not directly screen for the chromosomal mosaicism itself. *Karyotype* - **Karyotyping** is the **gold standard** for diagnosing Turner syndrome and its mosaics by visualizing the entire set of chromosomes [1]. - It can identify various forms of mosaicism involving the X chromosome, where some cells have 45,XO and others have 46,XX or other variations [1]. *FISH* - **Fluorescence in situ hybridization (FISH)** is a molecular cytogenetic technique used to detect specific chromosomal abnormalities, including those associated with Turner mosaicism. - It uses DNA probes that bind to specific regions of the X chromosome, allowing for the rapid detection of **aneuploidy** or deletions that might indicate mosaicism [2]. *Buccal smear* - A **buccal smear**, historically used for **Barr body** analysis, can provide an initial screening for X chromosome abnormalities. - The presence of Barr bodies (inactive X chromosomes) can help differentiate between 45,XO (no Barr body) and mosaic variants like 45,XO/46,XX (variable number of Barr bodies). **References:** [1] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 54-55. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187.

Question 3: 34 week primigravida punjabi khatri comes with history of consanguineous marriage, with history of repeated blood transfusion to her sibling since 8 months of age. The first diagnostic test is -

A. HPLC
B. Bone marrow
C. Blood smear
D. Hb electrophoresis (Correct Answer)

Explanation: ***Hb electrophoresis*** - The patient's history of **consanguineous marriage**, a sibling requiring **repeated blood transfusions** since 8 months of age, and Punjabi Khatri ethnicity strongly suggest a **hemoglobinopathy**, likely **beta-thalassemia major or intermedia**. - **Hemoglobin electrophoresis** is the traditional gold standard for definitive diagnosis of various hemoglobin variants and thalassemia types, identifying and characterizing abnormal hemoglobin patterns (e.g., elevated HbF, HbA2). - It remains a primary diagnostic test for hemoglobinopathies, particularly useful for pattern recognition of various thalassemia syndromes. *HPLC* - **High-performance liquid chromatography (HPLC)** is an equally valid and increasingly preferred method for diagnosing hemoglobinopathies, offering automated, precise quantification of hemoglobin fractions (HbA, HbA2, HbF). - In modern practice, HPLC is often used as a first-line screening tool due to its accuracy, reproducibility, and ability to provide quantitative data crucial for thalassemia diagnosis. - Both HPLC and Hb electrophoresis are acceptable diagnostic approaches; the choice between them depends on laboratory availability and practice patterns. For this 2013 exam, Hb electrophoresis was considered the traditional first diagnostic test. *Blood smear* - A **peripheral blood smear** would show morphological changes like **microcytic hypochromic red blood cells**, **target cells**, **anisopoikilocytosis**, and **nucleated RBCs**, which are suggestive of thalassemia. - These findings are indicative but non-specific and require confirmatory tests like hemoglobin electrophoresis or HPLC to identify the specific hemoglobin disorder and establish a definitive diagnosis. *Bone marrow* - A **bone marrow** examination would show **erythroid hyperplasia** due to increased ineffective erythropoiesis in thalassemia but is an invasive procedure and not the initial diagnostic test for hemoglobinopathies. - It provides details about cellularity and maturation but does not directly identify hemoglobin abnormalities, making it unsuitable as the first diagnostic step in suspected hemoglobinopathies.

Question 4: Which extra-intestinal symptom of inflammatory bowel disease worsens with exacerbation of disease activity?

A. Primary sclerosing cholangitis
B. Uveitis
C. Arthritis (Correct Answer)
D. Erythema nodosum

Explanation: ***Arthritis*** - **Peripheral arthritis** associated with inflammatory bowel disease (IBD) often **worsens with intestinal disease exacerbations** and improves with resolution of flares [1]. - This type of arthritis typically affects larger joints and is **non-deforming and asymmetric**. *Erythema nodosum* - **Erythema nodosum**, a skin manifestation, is generally **correlated with IBD activity** and usually improves as the bowel disease is treated [1]. - It presents as **tender, red nodules** on the shins and is not consistently one of the symptoms that *worsens* with exacerbation, but rather is *present* during active disease. *Primary sclerosing cholangitis* - **Primary sclerosing cholangitis (PSC)** is a chronic liver condition that is **associated with IBD**, particularly ulcerative colitis. - However, the progression of PSC is largely **independent of the intestinal disease activity** and does not necessarily worsen during IBD exacerbations. *Uveitis* - **Uveitis**, an inflammation of the eye's middle layer, is an extra-intestinal manifestation of IBD that can occur **independently of intestinal disease activity**. - It does not consistently worsen during IBD exacerbations and may require separate focused treatment.

Question 5: Which one of the following is an autosomal dominant disorder?

A. Cystic fibrosis
B. Hereditary spherocytosis (Correct Answer)
C. Sickle cell anemia
D. G-6PD deficiency

Explanation: ***Hereditary spherocytosis*** - It is characterized by **autosomal dominant inheritance** [1], leading to the destruction of red blood cells. - Mutations in proteins that maintain the **red blood cell membrane** integrity result in spherocyte formation [1]. *Cystic fibrosis* - This condition follows a **autosomal recessive inheritance pattern**, requiring two copies of the mutated gene for disease manifestation. - It is caused by mutations in the **CFTR gene**, affecting chloride transport and leading to thick secretions. *G-6PD deficiency* - This disorder is inherited in an **X-linked recessive manner** [2], primarily affecting males and transmitted through carrier females. - Characterized by **hemolytic anemia** triggered by certain medications or infections, it does not follow dominant inheritance [2]. *Sickle cell anemia* - Sickle cell anemia is also an **autosomal recessive disorder** [3], meaning affected individuals must inherit two copies of the sickle cell gene. - It results in a mutation in the **HBB gene**, leading to the production of abnormal hemoglobin (HbS) [3].

Question 6: A skin biopsy shows suprabasilar acantholysis with 'row of tombstones' appearance. Which immunofluorescence pattern would confirm pemphigus vulgaris?

A. Linear IgA deposits
B. Fishnet pattern of IgG (Correct Answer)
C. Granular IgG deposits
D. Linear C3 deposits

Explanation: ***Fishnet pattern of IgG*** - Pemphigus vulgaris is characterized by **autoantibodies** (predominantly **IgG**) directed against **desmogleins 1 and 3**, components of desmosomes in the epidermis. - This binding leads to the **loss of cell adhesion** (acantholysis) and results in the characteristic **net-like or "fishnet" pattern** of IgG positivity on direct immunofluorescence (DIF), outlining keratinocyte cell surfaces. *Linear IgA deposits* - **Linear IgA bullous dermatosis** is characterized by the presence of continuous linear deposits of IgA along the **dermoepidermal junction** on direct immunofluorescence. - This condition is clinically and immunologically distinct from pemphigus vulgaris, which involves **intraepidermal deposition of IgG**. *Granular IgG deposits* - **Granular IgG deposits** at the dermoepidermal junction are typically seen in conditions like **lupus erythematosus**, particularly in the form of a **lupus band test**, rather than in blistering diseases like pemphigus. - Pemphigus involves **intercellular IgG deposition** within the epidermis, not granular deposits at the junction. *Linear C3 deposits* - **Linear C3 deposits** (often accompanied by IgG) along the **dermoepidermal junction** are characteristic of **bullous pemphigoid**, another autoimmune blistering disease. - Unlike pemphigus vulgaris, bullous pemphigoid involves autoantibodies targeting hemidesmosomes, leading to subepidermal blistering rather than intraepidermal acantholysis.

Question 7: Acantholysis is seen in all except which of the following conditions?

A. Pemphigus vulgaris
B. Darier's disease
C. Bullous pemphigoid (Correct Answer)
D. SSSS

Explanation: ***Bullous pemphigoid*** - This condition involves **subepidermal blistering**, meaning the separation of the epidermis from the dermis, which occurs *below* the **basal cell layer**. - **Acantholysis**, the loss of cohesion between keratinocytes *within* the epidermis, does not occur in bullous pemphigoid, making it the correct answer. *Pemphigus vulgaris* - This is an **autoimmune blistering disease** characterized by the presence of autoantibodies against **desmoglein 3** (and often desmoglein 1). - This leads to intraepidermal blistering caused by **acantholysis**, the primary pathophysiological event. *Darier's disease* - This is an **autosomal dominant genodermatosis** characterized by abnormal keratinization and acantholysis. - Due to defects in **ATP2A2** (encoding SERCA2), there is impaired calcium handling in keratinocytes, leading to premature desmosomal degradation and **acantholysis**. *SSSS (Staphylococcal Scalded Skin Syndrome)* - Caused by **exfoliative toxins** (ETA and ETB) produced by *Staphylococcus aureus* that target **desmoglein 1**. - The cleavage of desmoglein 1 results in superficial **intraepidermal blistering** due to **acantholysis** in the granular layer of the epidermis.

Question 8: The following image shows a flaccid bulla. This finding is characteristically seen in:

A. Pemphigus vegetans
B. Pemphigus vulgaris (Correct Answer)
C. Pemphigus erythematosus
D. Bullous pemphigoid

Explanation: ***Pemphigus vulgaris*** - The image shows a **flaccid bulla** with purulent fluid, characteristic of **pemphigus vulgaris**. This condition is marked by autoantibodies against desmogleins 1 and 3, which are crucial for keratinocyte adhesion, leading to **intraepidermal blistering** and the **Nikolsky sign**. - The flaccid nature of the bulla, often leading to easy rupture and erosions, is a hallmark of superficial blistering in pemphigus vulgaris, caused by the **loss of cell-to-cell adhesion** within the epidermis. *Pemphigus vegetans* - This is a rare variant of pemphigus vulgaris characterized by **vegetating plaques** and **hyperkeratotic lesions**, particularly in intertriginous areas. - While it starts with bullae, the predominant feature is the development of fungating, vegetative lesions rather than the flaccid bulla seen here. *Pemphigus erythematosus* - Pemphigus erythematosus, also known as Senear-Usher syndrome, is considered a localized form of pemphigus foliaceus with features of **lupus erythematosus**. - It presents with **scaling, crusting, and erythematous lesions** resembling lupus, along with superficial bullae, typically on the face and scalp. *Bullous pemphigoid* - Bullous pemphigoid typically presents with **tense bullae** that are less prone to rupture, unlike the flaccid bulla shown in the image. - It is caused by autoantibodies against hemidesmosomal proteins (BP180 and BP230), resulting in **subepidermal blistering**, meaning the blister forms below the epidermis and is therefore more resilient.

Question 9: A 54-year-old man presents after a syncopal episode with no recollection of the event, and bystanders report that he regained consciousness approximately 45 seconds after falling. He has a history of bipolar disorder managed with quetiapine, and recently experienced prostatitis treated with ciprofloxacin. His other medications include lisinopril and hydrochlorothiazide for hypertension, and cyclobenzaprine and a hydrocodone/acetaminophen combination pill for low back pain. On examination, the patient is alert and oriented, with a nonfocal neurological examination and an unremarkable cardiac examination. Electrocardiogram shows nonspecific ST and T wave changes and a prolonged QT interval (QTc of 540 milliseconds). What is the best initial management approach?

A. Admit for permanent implantable cardioverter-defibrillator (ICD)
B. Admit and begin amiodarone infusion
C. Refer for genetic counseling
D. Admit the patient for telemetry and evaluate for reversible causes of QT prolongation (Correct Answer)

Explanation: ***Admit the patient for telemetry and evaluate for reversible causes of QT prolongation*** * The patient experienced a **syncopal episode** with a **prolonged QT interval (QTc of 540 ms)**, which significantly increases the risk of **Torsade de Pointes (TdP)** and sudden cardiac death [1]. * **Telemetry monitoring** is crucial to detect arrhythmias, and identifying and removing **QT-prolonging medications** (quetiapine, ciprofloxacin, hydrocodone) and correcting **electrolyte imbalances** are essential initial steps [1]. *Admit for permanent implantable cardioverter-defibrillator (ICD)* * While an ICD is used for prevention of sudden cardiac death in high-risk patients, it's generally considered after **reversible causes of QT prolongation** have been addressed and the patient remains at high risk or has recurrent **life-threatening arrhythmias**. * Implanting an ICD without first attempting to manage the modifiable risk factors like certain medications or electrolyte imbalances would be premature. *Admit and begin amiodarone infusion* * **Amiodarone** is an **antiarrhythmic drug** that itself can **prolong the QT interval**, which would exacerbate the patient's existing risk for TdP. * This medication would be contraindicated in the presence of an already prolonged QT interval due to the increased risk of potentially fatal arrhythmias. *Refer for genetic counseling* * While **congenital long QT syndrome** can cause profound QT prolongation, **acquired causes** (medications, electrolyte abnormalities) are far more common, especially given the patient's extensive medication list. * Genetic counseling may be considered if reversible causes are ruled out or if there's a strong family history, but it is not the immediate best management for an acute syncopal episode with acquired QT prolongation.

Question 10: A patient with acute history of blistering and denudation involving >30% BSA along with erosions of the lips with hemorrhagic crusting and other mucosa for few days. What is the most common triggering factor?

A. Drug induced (Correct Answer)
B. Viral infection
C. Idiopathic
D. Bacterial infection

Explanation: ***Drug induced*** - **Toxic epidermal necrolysis (TEN)**, characterized by blistering and denudation of >30% body surface area and mucosal involvement, is most commonly triggered by **drugs**, such as sulfonamides, antiepileptics, allopurinol, and NSAIDs. - The rapid onset and severe presentation are highly suggestive of an adverse drug reaction. *Viral infection* - While viruses can trigger some mucocutaneous reactions, severe widespread necrosis and denudation like in TEN are not typically **direct viral effects**. - **Herpes simplex virus (HSV)** can cause erythema multiforme, which is less severe and extensive than TEN. *Idiopathic* - While some cases of severe cutaneous adverse reactions can be idiopathic, the vast majority of **TEN cases have an identifiable trigger**, with drugs being the leading cause. - Attributing it to an unknown cause would be less precise given the common association with medications. *Bacterial infection* - Bacterial infections, such as **Staphylococcal scalded skin syndrome (SSSS)**, can cause blistering and desquamation, but it primarily affects children and involves a superficial epidermal split, rather than the full-thickness necrosis seen in TEN. - SSSS typically spares the **mucous membranes**, unlike the prominent mucosal involvement described in the patient.

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