🧬 FCPS Paediatrics TOACS · Ataxia‑Telangiectasia (Louis‑Bar syndrome)
📖 Nelson's Chapter 164 & 165 · DNA Repair Defects / Combined Immunodeficiencies
📚 paeds.online – Paeds Online
🩺 OBSERVED/INTERACTIVE STATION · CPSP FORMAT · 10 MINUTES · NEUROLOGICAL + IMMUNOLOGICAL APPROACH
📋 Observed Station – “5‑year‑old with progressive ataxia, slurred speech, telangiectasias, and recurrent infections”
👦🏼 Clinical scenario (displayed / read to candidate):
A 5‑year‑old boy presents with progressive truncal ataxia and slurred speech (dysarthria) noticed over the past 18 months. He has a history of frequent sinopulmonary infections (recurrent otitis media, pneumonia) and chronic cough. On examination, you note conjunctival telangiectasias (visible on bulbar conjunctiva) and a few cutaneous telangiectasias on the malar area. Neurological exam reveals unsteady gait, intention tremor, and difficulty with rapid alternating movements. There is no family history of similar illness, but parents are first cousins.
🎯 Task (examiner observed): Recognize the likely diagnosis of Ataxia‑Telangiectasia (Louis‑Bar syndrome). Explain the underlying genetic defect (ATM gene, DNA repair disorder), the immunologic abnormalities (T‑cell deficiency, IgA deficiency, IgG subclass deficiency), the significance of elevated alpha‑fetoprotein (AFP), and the increased risk of malignancy. Discuss your diagnostic approach, management of recurrent infections (immunoglobulin replacement, antibiotic prophylaxis), and important precautions (avoid radiation, live vaccines).
📸 Key image concept (telangiectasias + ataxia):
A 5‑year‑old boy presents with progressive truncal ataxia and slurred speech (dysarthria) noticed over the past 18 months. He has a history of frequent sinopulmonary infections (recurrent otitis media, pneumonia) and chronic cough. On examination, you note conjunctival telangiectasias (visible on bulbar conjunctiva) and a few cutaneous telangiectasias on the malar area. Neurological exam reveals unsteady gait, intention tremor, and difficulty with rapid alternating movements. There is no family history of similar illness, but parents are first cousins.
🎯 Task (examiner observed): Recognize the likely diagnosis of Ataxia‑Telangiectasia (Louis‑Bar syndrome). Explain the underlying genetic defect (ATM gene, DNA repair disorder), the immunologic abnormalities (T‑cell deficiency, IgA deficiency, IgG subclass deficiency), the significance of elevated alpha‑fetoprotein (AFP), and the increased risk of malignancy. Discuss your diagnostic approach, management of recurrent infections (immunoglobulin replacement, antibiotic prophylaxis), and important precautions (avoid radiation, live vaccines).
📸 Key image concept (telangiectasias + ataxia):
Figure: Bulbar conjunctival telangiectasias – a hallmark of ataxia‑telangiectasia. Oculocutaneous telangiectasias typically appear between ages 3‑6 years.
🔬 Nelson's Chapter 165 (DNA Repair Defects – Table 165.3):
Ataxia‑telangiectasia (ATM gene) – progressive decrease in T cells, poor T‑cell proliferation, elevated alpha‑fetoprotein, oculocutaneous telangiectasias, ataxia, increased radiosensitivity, chromosomal instability (translocations involving 7:14), and predisposition to lymphoreticular malignancy. IgA deficiency occurs in 50‑80% of patients.
Ataxia‑telangiectasia (ATM gene) – progressive decrease in T cells, poor T‑cell proliferation, elevated alpha‑fetoprotein, oculocutaneous telangiectasias, ataxia, increased radiosensitivity, chromosomal instability (translocations involving 7:14), and predisposition to lymphoreticular malignancy. IgA deficiency occurs in 50‑80% of patients.
💡 Examiner probes: “What is the triad that should alert you to ataxia‑telangiectasia?” → Progressive cerebellar ataxia + oculocutaneous telangiectasias + recurrent sinopulmonary infections (combined immunodeficiency). Also ask about family history of consanguinity or early malignancy.
🩸 Laboratory & genetic evaluation – Ataxia‑Telangiectasia
1 Serum alpha‑fetoprotein (AFP)
Elevated in >95% of patients with A‑T. Levels are typically >2‑3 SD above normal for age. It is a key screening test. (Note: mild elevation can occur in other ataxias but very high suggests A‑T).
Elevated in >95% of patients with A‑T. Levels are typically >2‑3 SD above normal for age. It is a key screening test. (Note: mild elevation can occur in other ataxias but very high suggests A‑T).
2 Quantitative immunoglobulins
Selective IgA deficiency (50‑80%), low IgG2/IgG4 subclass, low or normal IgG, sometimes elevated IgM. IgE may be low.
Selective IgA deficiency (50‑80%), low IgG2/IgG4 subclass, low or normal IgG, sometimes elevated IgM. IgE may be low.
3 Lymphocyte subsets (flow cytometry)
Low CD3+ T cells, low CD4+ T cells, increased γ/δ T cells, low switched memory B cells. Total lymphocyte count may be decreased with age.
Low CD3+ T cells, low CD4+ T cells, increased γ/δ T cells, low switched memory B cells. Total lymphocyte count may be decreased with age.
4 Karyotype / chromosomal breakage studies
Spontaneous chromosomal instability; increased breaks after irradiation (radiosensitivity). Translocations involving chromosomes 7 and 14 (T‑cell receptor loci) are characteristic.
Spontaneous chromosomal instability; increased breaks after irradiation (radiosensitivity). Translocations involving chromosomes 7 and 14 (T‑cell receptor loci) are characteristic.
5 Genetic testing – ATM gene sequencing
Confirmation: biallelic pathogenic variants in ATM (11q22.3). Carrier frequency 1% in general population. Prenatal diagnosis available.
Confirmation: biallelic pathogenic variants in ATM (11q22.3). Carrier frequency 1% in general population. Prenatal diagnosis available.
6 Functional assays (research)
ATM protein kinase activity (absent or reduced); phosphorylation of downstream targets (e.g., p53, CHK2).
ATM protein kinase activity (absent or reduced); phosphorylation of downstream targets (e.g., p53, CHK2).
⚠️ Critical safety note – RADIATION SENSITIVITY:
Patients with ataxia‑telangiectasia have extreme sensitivity to ionizing radiation (X‑rays, CT scans, radiotherapy). Minimize radiation exposure – use MRI/ultrasound instead of CT when possible. Radiotherapy is relatively contraindicated due to severe tissue damage and secondary malignancy risk.
Patients with ataxia‑telangiectasia have extreme sensitivity to ionizing radiation (X‑rays, CT scans, radiotherapy). Minimize radiation exposure – use MRI/ultrasound instead of CT when possible. Radiotherapy is relatively contraindicated due to severe tissue damage and secondary malignancy risk.
📊 Typical laboratory profile in A‑T (case example):
• AFP: 180 ng/mL (normal <8 ng/mL)
• IgA: <5 mg/dL (undetectable)
• IgG: 520 mg/dL (low for age), IgG2 subclass low
• Lymphocyte subsets: CD3+ 48% (↓), CD4+ 22% (↓), CD19+ normal
• Lymphocyte proliferation to PHA: reduced
• Karyotype: t(7;14) in lymphocytes
• ATM sequencing: compound heterozygous pathogenic variants
• Chromosomal breakage after irradiation: markedly increased.
• AFP: 180 ng/mL (normal <8 ng/mL)
• IgA: <5 mg/dL (undetectable)
• IgG: 520 mg/dL (low for age), IgG2 subclass low
• Lymphocyte subsets: CD3+ 48% (↓), CD4+ 22% (↓), CD19+ normal
• Lymphocyte proliferation to PHA: reduced
• Karyotype: t(7;14) in lymphocytes
• ATM sequencing: compound heterozygous pathogenic variants
• Chromosomal breakage after irradiation: markedly increased.
📌 Pearl for TOACS: A child with progressive ataxia + telangiectasias + elevated AFP = ataxia‑telangiectasia until proven otherwise. Also consider differentials: Friedreich ataxia (normal AFP, no telangiectasias, cardiomyopathy), early‑onset ataxia with oculomotor apraxia, and other DNA repair disorders (Nijmegen breakage syndrome, Bloom syndrome).
🗨️ Examiner Q&A · Ataxia‑Telangiectasia · DNA repair · Combined immunodeficiency
❓ Q1 (Examiner): “What is the underlying genetic defect in ataxia‑telangiectasia? Which chromosome?”
✅ ATM gene (Ataxia Telangiectasia Mutated) located on chromosome 11q22.3. Encodes a serine/threonine protein kinase involved in DNA double‑strand break repair, cell cycle control, and telomere maintenance. Inheritance: autosomal recessive.
❓ Q2 (Examiner): “Why do patients with ataxia‑telangiectasia have progressive neurological deterioration?”
✅ ATM is critical for DNA repair and maintenance of neuronal survival, especially Purkinje cells in the cerebellum. Loss of ATM function leads to accumulation of unrepaired DNA damage, oxidative stress, and progressive neurodegeneration (cerebellar atrophy). This manifests as gait ataxia, dysarthria, choreoathetosis, oculomotor apraxia, and peripheral neuropathy.
❓ Q3 (Examiner): “What are the immunological abnormalities in ataxia‑telangiectasia? (Nelson’s Chapter 165)”
✅ Combined immunodeficiency (variable):
• T‑cell lymphopenia (low CD4+ T cells), poor T‑cell proliferation to mitogens.
• B‑cell defects: IgA deficiency (50‑80%), IgG2 subclass deficiency, specific antibody deficiency.
• Increased γ/δ T cells.
• Thymic hypoplasia with absent Hassall’s corpuscles.
• Recurrent sinopulmonary infections (bacterial, viral, and opportunistic).
• T‑cell lymphopenia (low CD4+ T cells), poor T‑cell proliferation to mitogens.
• B‑cell defects: IgA deficiency (50‑80%), IgG2 subclass deficiency, specific antibody deficiency.
• Increased γ/δ T cells.
• Thymic hypoplasia with absent Hassall’s corpuscles.
• Recurrent sinopulmonary infections (bacterial, viral, and opportunistic).
❓ Q4 (Examiner): “What is the significance of elevated alpha‑fetoprotein (AFP) in this condition?”
✅ AFP is markedly elevated in >95% of patients with A‑T due to a combination of liver dysregulation and impaired DNA repair. AFP levels remain elevated throughout life (unlike normal physiological decline after infancy). It is an excellent screening marker but is not diagnostic alone; moderately elevated AFP can also be seen in ataxia with oculomotor apraxia (AOA2) and other disorders.
❓ Q5 (Examiner): “Why is there an increased risk of malignancy in ataxia‑telangiectasia? Which cancers are most common?”
✅ ATM is a tumor suppressor gene involved in DNA damage response. Defective repair leads to genomic instability, increasing cancer risk up to 25‑40% by adulthood. Most common: lymphomas (B‑cell non‑Hodgkin lymphoma, Hodgkin lymphoma), leukemias (T‑cell ALL). Also solid tumors (breast, gastric, ovarian, brain) in older patients. Carriers have moderately increased breast cancer risk.
❓ Q6 (Examiner): “What are the contraindicated interventions in ataxia‑telangiectasia?”
✅ 1. Ionizing radiation (X‑rays, CT scans, radiotherapy) – extreme sensitivity → use MRI/ultrasound.
2. Live vaccines (MMR, varicella, rotavirus, BCG) – T‑cell deficiency may cause vaccine‑related disseminated disease. Only inactivated vaccines are safe.
3. Clastogenic chemotherapy agents (if malignancy develops) – require dose modification.
2. Live vaccines (MMR, varicella, rotavirus, BCG) – T‑cell deficiency may cause vaccine‑related disseminated disease. Only inactivated vaccines are safe.
3. Clastogenic chemotherapy agents (if malignancy develops) – require dose modification.
❓ Q7 (Examiner): “How do you manage recurrent infections in a child with ataxia‑telangiectasia?”
✅ • Immunoglobulin replacement (IVIG/SCIG) if IgG ± IgA deficiency with recurrent sinopulmonary infections or poor specific antibody responses.
• Prophylactic antibiotics (azithromycin or amoxicillin) during winter months to reduce exacerbations.
• Prompt treatment of infections with appropriate antibiotics.
• Pneumococcal, Hib, influenza, and COVID‑19 vaccines (inactivated) recommended.
• Monitor for bronchiectasis with low‑dose chest CT (one baseline, then only if clinically indicated, balancing radiation risk).
• Prophylactic antibiotics (azithromycin or amoxicillin) during winter months to reduce exacerbations.
• Prompt treatment of infections with appropriate antibiotics.
• Pneumococcal, Hib, influenza, and COVID‑19 vaccines (inactivated) recommended.
• Monitor for bronchiectasis with low‑dose chest CT (one baseline, then only if clinically indicated, balancing radiation risk).
❓ Q8 (Examiner): “What is the role of hematopoietic stem cell transplantation (HSCT) in ataxia‑telangiectasia?”
✅ HSCT can correct the immunodeficiency but does NOT halt or reverse neurological degeneration. Given the high toxicity (radiation sensitivity, chemotherapy toxicity, increased graft failure, severe organ damage), HSCT is generally not recommended for classical A‑T. It may be considered in selected cases with severe combined immunodeficiency but with poor outcomes. Supportive care is mainstay.
❓ Q9 (Examiner): “How does Nijmegen breakage syndrome differ from ataxia‑telangiectasia?”
✅ Nijmegen breakage syndrome (NBS1 gene) – also has microcephaly, dysmorphic facies (bird‑like face), growth retardation, combined immunodeficiency, and increased cancer risk. No telangiectasias, no ataxia (but mild coordination issues may occur). Immunodeficiency more severe. Both have chromosomal instability and radiation sensitivity.
❓ Q10 (Examiner): “What is the prognosis and life expectancy in ataxia‑telangiectasia?”
✅ Progressive neurodegeneration → wheelchair by adolescence (10‑12 years). Most common causes of death: chronic respiratory failure (bronchiectasis, recurrent pneumonia), malignancy (lymphoma/leukemia), and infections. Median life expectancy is 20‑25 years, but some patients survive into 30s‑40s with aggressive supportive care. Prenatal diagnosis is available for subsequent pregnancies.
📘 Nelson’s Chapter 165 – Management & Multidisciplinary care for Ataxia‑Telangiectasia
🧠 Neurology
Physical therapy, occupational therapy, speech therapy. Manage spasticity, dystonia, and dysphagia (aspiration precautions). Annual brain MRI to monitor cerebellar atrophy.
Physical therapy, occupational therapy, speech therapy. Manage spasticity, dystonia, and dysphagia (aspiration precautions). Annual brain MRI to monitor cerebellar atrophy.
🩸 Immunology
Monitor lymphocyte subsets, Igs, specific antibody responses annually. IVIG/SCIG for significant humoral deficiency. Pneumococcal, influenza (inactivated), and COVID‑19 vaccines. Avoid live vaccines.
Monitor lymphocyte subsets, Igs, specific antibody responses annually. IVIG/SCIG for significant humoral deficiency. Pneumococcal, influenza (inactivated), and COVID‑19 vaccines. Avoid live vaccines.
🫁 Pulmonary
Chest physiotherapy, treat infections aggressively. Baseline low‑dose chest CT to assess bronchiectasis. Prophylactic azithromycin if recurrent exacerbations. Manage GERD to reduce aspiration.
Chest physiotherapy, treat infections aggressively. Baseline low‑dose chest CT to assess bronchiectasis. Prophylactic azithromycin if recurrent exacerbations. Manage GERD to reduce aspiration.
🩸 Malignancy surveillance
Clinical vigilance for lymphadenopathy, fever, weight loss. Avoid unnecessary imaging; use ultrasound/MRI for cancer screening. If malignancy develops, consult experienced oncology team – reduce chemotherapy and avoid radiation.
Clinical vigilance for lymphadenopathy, fever, weight loss. Avoid unnecessary imaging; use ultrasound/MRI for cancer screening. If malignancy develops, consult experienced oncology team – reduce chemotherapy and avoid radiation.
🧬 Genetic counseling
Parents are carriers (autosomal recessive). Prenatal diagnosis via chorionic villus sampling (ATM sequencing or linkage). Carrier testing for at‑risk family members. Carrier risk for breast cancer (females) – offer increased surveillance.
Parents are carriers (autosomal recessive). Prenatal diagnosis via chorionic villus sampling (ATM sequencing or linkage). Carrier testing for at‑risk family members. Carrier risk for breast cancer (females) – offer increased surveillance.
⚠️ Radiation precautions
Medical alert bracelet: “Ataxia‑Telangiectasia – no radiation, no CT unless emergent.” Use MRI and ultrasound whenever possible. Inform radiology department before any X‑ray.
Medical alert bracelet: “Ataxia‑Telangiectasia – no radiation, no CT unless emergent.” Use MRI and ultrasound whenever possible. Inform radiology department before any X‑ray.
📖 Nelson’s Textbook direct quotation (Chapter 165, Table 165.3): “Ataxia‑telangiectasia – ATM gene – progressive decrease in T cells, poor T‑cell proliferation, elevated IgM? (correction: elevated AFP), ataxia, telangiectasia, elevated IgM? (classically low IgA), lymphoreticular malignancy, increased radiosensitivity, chromosomal instability and translocations. Treatment: immunoglobulin replacement, supportive care, avoid ionizing radiation.”
⭐ TOACS TAKE‑HOME POINTS (for candidates):
1. Classic triad: progressive cerebellar ataxia + conjunctival telangiectasias + recurrent sinopulmonary infections → Ataxia‑telangiectasia.
2. Elevated AFP is the key screening test (>95% sensitivity).
3. Immunodeficiency: IgA deficiency + T‑cell lymphopenia + poor specific antibody responses.
4. Absolute contraindications: ionizing radiation (CT, radiotherapy) and live vaccines (MMR, varicella, BCG).
5. High malignancy risk: lymphomas/leukemia – monitor clinically.
6. No curative therapy; supportive care: IVIG, antibiotics, PT/OT, respiratory support.
7. Autosomal recessive; ATM gene on 11q22.3.
8. Differential: Friedreich ataxia (no telangiectasias, normal AFP), Nijmegen breakage (microcephaly, no ataxia), ataxia with oculomotor apraxia (AOA2, elevated AFP but no telangiectasias).
1. Classic triad: progressive cerebellar ataxia + conjunctival telangiectasias + recurrent sinopulmonary infections → Ataxia‑telangiectasia.
2. Elevated AFP is the key screening test (>95% sensitivity).
3. Immunodeficiency: IgA deficiency + T‑cell lymphopenia + poor specific antibody responses.
4. Absolute contraindications: ionizing radiation (CT, radiotherapy) and live vaccines (MMR, varicella, BCG).
5. High malignancy risk: lymphomas/leukemia – monitor clinically.
6. No curative therapy; supportive care: IVIG, antibiotics, PT/OT, respiratory support.
7. Autosomal recessive; ATM gene on 11q22.3.
8. Differential: Friedreich ataxia (no telangiectasias, normal AFP), Nijmegen breakage (microcephaly, no ataxia), ataxia with oculomotor apraxia (AOA2, elevated AFP but no telangiectasias).
🔗 Online resources for candidates & families:
• Paeds Online – FCPS TOACS bank & revision
• GeneReviews – Ataxia‑Telangiectasia
• National Ataxia Foundation – resources for A‑T
• Paeds Online – FCPS TOACS bank & revision
• GeneReviews – Ataxia‑Telangiectasia
• National Ataxia Foundation – resources for A‑T