Comprehensive Etiology Workup Approach
A comprehensive etiology workup should include targeted genetic testing, laboratory studies, imaging, and specialist consultations based on presenting symptoms and suspected conditions, prioritizing tests with the highest diagnostic yield for the specific clinical presentation.
Genetic Testing Workup
When evaluating for genetic causes, particularly for neurodevelopmental disorders:
First-Tier Genetic Testing
- Chromosomal microarray (CMA) as first-line test for unexplained developmental delay, intellectual disability, autism spectrum disorder, or congenital anomalies 1
- Fragile X testing for males with developmental delay/intellectual disability 1
- Whole exome sequencing (WES) or whole genome sequencing (WGS) as first- or second-tier test for unexplained developmental delay/intellectual disability 1
Second-Tier Genetic Testing
- MECP2 sequencing for females with autism or intellectual disability 1
- MECP2 duplication testing in males with suggestive phenotype 1
- PTEN testing if head circumference is >2.5 SD above mean 1
- X-linked ID panel for family history suggestive of X-linked disorder 1
Laboratory Workup
Basic Laboratory Panel
- Complete blood count (CBC) with differential 2
- Comprehensive metabolic panel
- Urinalysis (targeted based on symptoms rather than routine) 3
- Inflammatory markers (ESR, CRP) when infection or inflammation suspected
Disease-Specific Testing
- Metabolic testing if clinically indicated (amino acids, organic acids, lactate/pyruvate) 1
- Autoimmune panels when appropriate:
Endocrine Workup
- Thyroid function tests (TSH, free T4)
- Morning cortisol and ACTH when adrenal insufficiency suspected 1
- Diabetes screening (glucose, HbA1c)
Imaging Studies
Neurological Evaluation
- MRI of brain with and without contrast for neurological symptoms 1
- MRI of spine with and without contrast for spinal symptoms 1
- Consider pituitary protocol MRI when pituitary dysfunction suspected 1
Other Imaging
- Chest X-ray for respiratory symptoms or suspected mediastinal mass 1
- PET/CT when malignancy or lymphoma suspected 1
- Scrotal ultrasound when testicular involvement suspected in males 1
Specialized Testing
Neurological Workup
- Lumbar puncture with CSF analysis when CNS involvement suspected:
- Cell count, protein, glucose
- Oligoclonal bands
- Viral PCR studies
- Cytology 1
- Electrodiagnostic studies (EMG/NCS) for peripheral nerve or muscle symptoms 1
- EEG for suspected seizure activity 1
Immunological Workup
- Flow cytometry for immunophenotyping in suspected hematologic malignancies 1
- T-cell and B-cell subset analysis for immunodeficiencies
Common Pitfalls to Avoid
Ordering non-targeted tests: Avoid routine screening tests without clinical indication, as they rarely impact patient care (only 1.3% of routine urinalyses affect therapy) 3
Missing syndromic diagnoses: Perform comprehensive physical examination looking for dysmorphic features that may guide targeted testing 1
Inadequate sample collection: Prioritize proper specimen collection to avoid inconclusive results, particularly for small-volume samples 4
Failure to consider rare diagnoses: Include appropriate metabolic and mitochondrial testing when clinical indicators suggest these conditions 1
Not consulting specialists: Early referral to genetics, neurology, or other specialists can guide more efficient diagnostic workup 1
Special Considerations
- For suspected immune-related adverse events, follow specific diagnostic algorithms based on symptom severity 1
- In pediatric patients, consider age-appropriate normal values and developmental context 1
- For patients with suspected malignancy, incorporate disease-specific markers and staging procedures 1
By following this structured approach to etiology workup, clinicians can efficiently identify underlying causes while minimizing unnecessary testing, leading to improved patient outcomes through earlier diagnosis and appropriate management.