---

Denys-Drash Syndrome

Definition

1. Gonadal dysgenesis (male pseudohermaphroditism — 46,XY individuals with ambiguous or female external genitalia)
2. Early-onset nephropathy progressing to renal failure
3. Wilms tumor (nephroblastoma) — risk is ~90%

---

Genetic Basis

• Caused by a dominant-negative missense mutation in the zinc-finger region of the WT1 gene (chromosome 11p13), which encodes a DNA-binding transcription factor
• This mutation disrupts WT1's DNA-binding properties and interferes with the function of the remaining wild-type allele
• Notably, the germline mutation alone causes genitourinary abnormalities, but Wilms tumors require biallelic inactivation of WT1 (a second somatic hit)
• WT1 is critical for normal development of the kidney and gonads during embryogenesis

---

Renal Pathology

• The hallmark glomerular lesion is diffuse mesangial sclerosis
• Leads to nephrotic syndrome and early progression to renal failure

---

Wilms Tumor Risk

• ~90% lifetime risk — one of the highest among any predisposing syndrome
• DDS accounts for a small subset of all Wilms tumors, but has been instrumental in understanding its biology
• Patients are also at increased risk for gonadoblastomas (germ cell tumors), a consequence of disrupted gonadal development

---

Comparison with Related Syndromes

---

Key Points to Remember

• WT1 mutation type distinguishes DDS from WAGR (deletion) and Frasier (splice mutation)
• The same WT1 protein acts as both a transcriptional activator and repressor depending on binding partners
• DDS provides a model for the two-hit tumor suppressor hypothesis — germline mutation + somatic second hit
• Wilms tumor in DDS demonstrates biallelic WT1 inactivation

---

---

Tuberculosis — Treatment & Drugs

---

Treatment Overview

Directly Observed Therapy (DOT) is paramount, especially for twice/thrice-weekly regimens, HIV patients, and drug-resistant TB.

---

Standard Regimens for Drug-Susceptible TB

4-Month Regimen (newer, non-inferior option)

• Intensive phase (8 weeks): Rifapentine (RPT) + Moxifloxacin (MOX) + INH + PZA daily
• Continuation phase (9 weeks): RPT + MOX daily
• Non-inferior to 6-month regimen in adults/adolescents ≥12 years, ≥40 kg

6–9-Month Regimen (standard)

• Intensive: INH + RIF + PZA + EMB daily × 8 weeks
• Continuation: INH + RIF (or INH + Rifapentine) × 18 weeks

• Intensive: INH + RIF + PZA + EMB daily × 2 weeks → twice weekly × 6 weeks
• Continuation: INH + RIF twice weekly × 18 weeks

• INH + RIF + PZA + EMB three times weekly × 8 weeks → INH + RIF three times weekly × 18 weeks

---

First-Line Drugs

1. Isoniazid (INH)

• Dose: 5 mg/kg/day (max 300 mg/day); 15 mg/kg for intermittent dosing
• MOA: Inhibits mycolic acid synthesis (cell wall)
• Side effects:
  • Hepatitis — major toxicity; risk increases with age (0.3% age 21–35 → 2.3% age >50); also increased in alcohol use, pregnancy
  • Peripheral neuropathy — due to relative pyridoxine (B6) deficiency; prevented/treated with pyridoxine 10 mg/day
  • CNS toxicity (rare): memory loss, psychosis, seizures
  • Drug-induced lupus
• Monitor: LFTs in high-risk patients

2. Rifampin (RIF)

• Dose: 10 mg/kg/day (max 600 mg/day)
• MOA: Binds β subunit of bacterial DNA-dependent RNA polymerase → inhibits RNA synthesis; bactericidal
• Penetration: Excellent — intracellular organisms, abscesses, lung cavities, meninges
• Side effects:
  • Hepatitis, GI disturbance
  • Orange discoloration of urine/secretions (harmless)
  • Thrombocytopenia
  • Major drug interactions — potent CYP inducer; reduces levels of many drugs (antiretrovirals, OCP, warfarin, etc.)
• Resistance: Mutations in rpoB gene; cross-resistance to other rifamycins

3. Pyrazinamide (PZA)

• Dose: 25 mg/kg/day (max 2 g/day); reduce to thrice-weekly if CrCl <30 mL/min
• MOA: Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase (pncA); disrupts cell membrane metabolism in acidic environments (lysosomes) → kills intracellular organisms
• Role: Key "sterilizing" agent in short-course (6-month) regimens
• Side effects:
  • Hepatitis
  • Hyperuricemia (inhibits renal urate excretion) → arthralgia/gout
  • GI disturbance

4. Ethambutol (EMB)

• Dose: 15–25 mg/kg/day
• MOA: Inhibits arabinosyl transferase → disrupts arabinogalactan cell wall synthesis
• Side effects:
  • Retrobulbar (optic) neuritis — loss of visual acuity and red-green color blindness; dose-related; ~2% at 15 mg/kg
  • Peripheral neuropathy
• Monitoring: Baseline and monthly visual acuity + color discrimination testing
• Relative CI: Children too young for visual assessment
• Always used in combination (resistance emerges rapidly alone)

---

Second-Line Drugs (for Drug-Resistant TB)

---

Latent TB Treatment

• INH alone × 9 months — standard; ~70% reduction in conversion risk
• INH + Rifapentine × 3 months — preferred for those unlikely to complete 9 months
• RIF + PZA × 2 months — for INH-resistant strains or INH intolerance (with hepatotoxicity monitoring)

---

Paradoxical Reaction / Immune Reconstitution Syndrome

• Some patients worsen after starting therapy — especially HIV+ with CD4 ≤50
• Features: fever, worsening infiltrates, lymphadenopathy, hepatosplenomegaly, meningitis, hypercalcemia (unique feature)
• Results from immune recovery → enhanced inflammatory response as mycobacteria clear
• Must distinguish from treatment failure, drug resistance, or non-compliance

---

Key Adverse Effects Summary

---