What is the most likely diagnosis for a 29-year-old man with intermittent painless hematuria, muscle cramps with strenuous exercise since childhood, microcytic anemia, and a family history of anemia?

Most Likely Diagnosis: Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) Syndrome

The most likely diagnosis is HANAC syndrome, a rare monogenic disorder presenting with the classic triad of intermittent painless hematuria, muscle cramps with exercise, and microcytic anemia due to chronic iron loss from recurrent hematuria. 1

Key Diagnostic Features Supporting HANAC Syndrome

Clinical Presentation Matches HANAC Syndrome Precisely

• Intermittent painless hematuria for 6.5 years is the hallmark presentation of hereditary glomerular disorders, particularly HANAC syndrome, which frequently presents with isolated microscopic hematuria in young adults 1

• Muscle cramps with strenuous exercise since childhood is a pathognomonic feature of HANAC syndrome that distinguishes it from other hereditary nephropathies like Alport syndrome or thin basement membrane nephropathy 1

• Microcytic anemia (MCV 72, Hgb 12.5) results from chronic iron deficiency secondary to years of recurrent hematuria—this is NOT a primary hematologic disorder but rather a consequence of chronic blood loss 2

• Family history of anemia in brother suggests an inherited condition affecting both siblings, consistent with the autosomal dominant inheritance pattern of HANAC syndrome 1

Urinalysis Findings Consistent with Glomerular Source

• Absence of dysmorphic erythrocytes on microscopy does NOT exclude glomerular disease—standard light microscopy without phase contrast has limited sensitivity for detecting dysmorphic RBCs, and HANAC syndrome may not always produce the classic >80% dysmorphic RBCs seen in other glomerulonephritides 3

• Trace proteinuria (plus one) is consistent with HANAC syndrome, which typically presents with mild proteinuria rather than nephrotic-range proteinuria 1

• Absence of leukocytes effectively excludes urinary tract infection as the cause 2

Alternative Diagnoses to Consider (But Less Likely)

Why NOT Exercise-Induced Hematuria?

• Exercise-induced hematuria is transient and self-limited, typically resolving within 24-72 hours of rest 4, 5, 6

• This patient has persistent intermittent hematuria for 6.5 years—far exceeding the temporal pattern of benign exercise hematuria 6

• Exercise hematuria does NOT cause chronic microcytic anemia or have a familial pattern 4

Why NOT Alport Syndrome?

• Alport syndrome classically presents with progressive hearing loss and ocular abnormalities (lenticonus), which are not mentioned in this case 2, 3, 1

• The muscle cramps with exercise are characteristic of HANAC syndrome specifically, not Alport syndrome 1

• However, audiogram and slit lamp examination should still be performed to definitively exclude Alport syndrome 2, 3

Why NOT IgA Nephropathy?

• IgA nephropathy typically presents with episodic gross hematuria coinciding with upper respiratory infections (synpharyngitic hematuria), not exercise-related symptoms 1, 7

• The muscle cramps with exercise are not a feature of IgA nephropathy 1

Why NOT Thin Basement Membrane Nephropathy?

• Thin basement membrane nephropathy is the most common cause of benign familial hematuria but does NOT cause muscle cramps or significant anemia 3, 1

• This diagnosis remains possible but less likely given the distinctive muscle cramp phenotype 1

Recommended Diagnostic Workup

Immediate Laboratory Evaluation

• Serum creatinine and BUN to assess renal function 2, 3

• Complete metabolic panel including albumin and total protein 3

• Spot urine protein-to-creatinine ratio to quantify proteinuria (normal <0.2 g/g) 3

• Serum ferritin and iron studies to confirm iron deficiency anemia secondary to chronic blood loss 2

• Urinalysis with microscopy using phase contrast to properly assess for dysmorphic RBCs (>80% suggests glomerular origin) 3

Specialized Testing for Hereditary Nephropathy

• Genetic testing for COL4A1 mutations is diagnostic for HANAC syndrome 1

• Audiogram and slit lamp examination to exclude Alport syndrome (COL4A3/A4/A5 mutations) 2, 3, 1

• Family screening with urinalysis of first-degree relatives (brother with anemia) may reveal similar findings and support hereditary diagnosis 3, 1, 7

Imaging and Invasive Procedures

• Renal ultrasound to assess kidney size, echogenicity, and structural abnormalities before potential renal biopsy 2, 3

• Renal biopsy with electron microscopy may be necessary for definitive diagnosis if genetic testing is unavailable or inconclusive—electron microscopy can reveal characteristic basement membrane abnormalities in HANAC syndrome 1, 7

• Cystoscopy is NOT indicated in this young patient with clear glomerular features (proteinuria, chronic course, family history) and no risk factors for malignancy 3, 8

Critical Clinical Pearls

Common Pitfalls to Avoid

• Do NOT attribute the hematuria to exercise alone without excluding hereditary glomerular disease—the 6.5-year duration and family history demand thorough evaluation 6

• Do NOT dismiss the microcytic anemia as unrelated—chronic hematuria from glomerular disease commonly causes iron deficiency anemia 2

• Do NOT rely on absence of dysmorphic RBCs on standard microscopy—phase contrast microscopy is required for accurate assessment, and some hereditary nephropathies may not produce classic dysmorphic RBCs 3

Prognosis and Management Implications

• HANAC syndrome has variable prognosis—some patients develop progressive chronic kidney disease requiring monitoring 1

• Nephrology referral is mandatory for genetic counseling, family screening, and long-term renal function monitoring 3, 1

• Iron supplementation will be needed to correct the microcytic anemia secondary to chronic blood loss 2

• Genetic testing provides critical prognostic information relevant to the patient and family, particularly if kidney transplantation becomes necessary 1