Developmental Delay/Intellectual Disability Diagnostic Evaluation Clinical Pathway — Primary Care

Standard Evaluation by General Pediatrician for DD/ID

Consider a tiered approach to laboratory testing, and subspecialty consultation to identify an underlying cause.
Goal of tiered testing is to optimize outcomes by timely treatment and referral to early intervention.
Specific testing and referral are recommended if a diagnosis is suspected via history and physical exam.

Testing Recommendations for Common Recognizable Syndromes

Financial Clearance and Authorization for Genetic Testing

Laboratory Instructions and Recommendations

1^st Tier Testing

Consider these tests if the initial evaluation via history and physical does not suggest a specific diagnosis.

Chromosomal microarray
Fragile X testing

Consider Additional 1st Tier Tests for These Specific Indications

Indications	Labs to Consider
If symptoms of thyroid dysfunction, or if Newborn Screen is not available	TSH
If dietary restriction or pica is present	Ferritin, Vitamin B₁₂
If risk factors for exposure are present	Lead level

2^nd Tier Testing

Consider testing for different categories of inborn errors of metabolism if 1^st tier testing does not reveal an underlying diagnosis AND if the child has any of the concerning features below.

Intermediary Metabolism Defects or Mitochondrial Disorders

Concerning Features	Labs/Referrals to Consider
Recurrent vomiting with or without poor feeding Failure to thrive Liver dysfunction, including elevated liver enzymes Dietary preferences such as aversion to protein Loss of skills (regression), especially if provoked by fevers or illness Positive family history of similar condition, neurological disorder, unexplained early death, recurrent miscarriages	Labs Plasma amino acids Plasma acylcarnitine profile Urine organic acids Plasma total homocysteine Additional Labs to Consider if Using CHOP Main Lab Lactate/pyruvate ratio Ammonia Specimen requires special handling Referral Considerations Metabolism and Neurology for neurological concerns

Concerning Features

Labs/Referrals to Consider

Recurrent vomiting with or without poor feeding
Failure to thrive
Liver dysfunction, including elevated liver enzymes
Dietary preferences such as aversion to protein
Loss of skills (regression), especially if provoked by fevers or illness
Positive family history of similar condition, neurological disorder, unexplained early death, recurrent miscarriages

Labs
- Plasma amino acids
- Plasma acylcarnitine profile
- Urine organic acids
- Plasma total homocysteine

Additional Labs to Consider if Using CHOP Main Lab
- Lactate/pyruvate ratio
- Ammonia
  - Specimen requires special handling

Referral Considerations
- Metabolism
- and
- Neurology for neurological concerns

Mucopolysaccharidosis and Oligosaccharidosis

Concerning Features	Labs/Referrals to Consider
Coarse facial features with/without hepatosplenomegaly If this group of disorders is not diagnosed early, clinical manifestations would progress to involve neuroregression, joint stiffness or limited range of motion, behavioral problems or sleeping disturbance History and Physical	Labs Urine glycosaminoglycan (GAGs) Additional Lab Urine oligosaccharides Required to be sent to specialized laboratory Consider if urine GAGs is negative Referral Considerations Metabolism

3^rd Tier Testing

Consider other categories of inborn errors of metabolism if 2^nd tier testing does not reveal an underlying diagnosis. Testing for these groups of disorders requires sample analysis at specialized laboratories and results interpretation by a specialist. The primary care physician may pursue these tests in consultation with an appropriate specialist.

Creatine Disorders or Purine and Pyrimidine Disorders

Concerning Features	Labs/Referrals to Consider
Seizure Muscle weakness Autism Failure to thrive/poor feeding Neuroregression Self-mutilation or aggression Expressive aphasia	Labs Urine creatine disorders panel Urine purine and pyrimidine panel Referral Considerations Metabolism and/or Neurology

Congenital Disorders of Glycosylation

Concerning Features	Labs/Referrals to Consider
Failure to thrive Hypotonia Seizure Liver dysfunction, elevated liver enzymes Cutis laxa Inverted nipples Peculiar fat pads Genital abnormalities	Labs Carbohydrate deficient transferrin (CDT) N-glycan analysis Referral Considerations Metabolism and/or Neurology

Testing Recommendations for Special Circumstances

Testing recommendations if a Newborn Screen was not completed or if born outside U.S.
Plasma amino acids Urine organic acids Plasma acylcarnitine profile Plasma total homocysteine Urinary glycosaminoglycan (GAGS) Biotinidase activity, especially if a history of: Seizure Hypotonia Sensorineural hearing loss Vision impairment Optic atrophy Skin rash Alopecia Recurrent cutaneous candidiasis

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The clinical pathways are based upon publicly available medical evidence and/or a consensus of medical practitioners at The Children’s Hospital of Philadelphia (“CHOP”) and are current at the time of publication. These clinical pathways are intended to be a guide for practitioners and may need to be adapted for each specific patient based on the practitioner’s professional judgment, consideration of any unique circumstances, the needs of each patient and their family, and/or the availability of various resources at the health care institution where the patient is located.

Accordingly, these clinical pathways are not intended to constitute medical advice or treatment, or to create a doctor-patient relationship between/among The Children’s Hospital of Philadelphia (“CHOP”), its physicians and the individual patients in question. CHOP does not represent or warrant that the clinical pathways are in every respect accurate or complete, or that one or more of them apply to a particular patient or medical condition. CHOP is not responsible for any errors or omissions in the clinical pathways, or for any outcomes a patient might experience where a clinician consulted one or more such pathways in connection with providing care for that patient.