What is the best approach to diagnose and manage a 14-year-old girl with suspected autistic (Autism Spectrum Disorder (ASD)) or Down syndrome traits?

Distinguishing Autism Spectrum Disorder from Down Syndrome in a 14-Year-Old Girl

This 14-year-old girl requires immediate referral to a multidisciplinary diagnostic team including a psychologist, developmental pediatrician or child neurologist, and speech/language pathologist for comprehensive evaluation using standardized diagnostic tools (ADOS-2 and ADI-R), as these conditions have overlapping phenotypes that require expert differentiation. 1, 2

Critical First Step: Establish the Correct Diagnosis

Down syndrome should be immediately apparent or ruled out through physical examination and genetic testing, as it is a chromosomal disorder with characteristic dysmorphic features that are typically identified at birth or early childhood. 3 If Down syndrome has not been previously diagnosed by age 14, it is highly unlikely to be the diagnosis unless there is mosaic Down syndrome, which requires high-resolution chromosomal analysis or karyotype. 3

The key clinical distinction is:

• Down syndrome is diagnosed through genetic testing (karyotype showing trisomy 21), not behavioral assessment 3
• ASD is diagnosed through behavioral assessment using standardized tools, not genetic testing alone 2, 4

Pre-Evaluation Requirements Before Any Genetic Testing

Before proceeding with any evaluation, the following must be completed:

• Formal audiogram to rule out hearing loss that could mimic ASD symptoms, as children with significant hearing loss have difficulties with socialization and communication that may be misidentified as autism 3, 2
• Confirmation of diagnosis by a professional trained in autism diagnosis using objective criteria and standardized tools 3, 4
• Cognitive testing to establish baseline developmental level 3, 1
• Review of newborn screening results 3

If Down Syndrome is Already Confirmed: Evaluating for Co-occurring ASD

ASD occurs in 12-41% of individuals with Down syndrome, making dual diagnosis common but underdiagnosed. 5 The challenge is distinguishing which behavioral features are attributable to Down syndrome versus ASD. 5, 6

Key Differentiating Features

ASD-specific symptoms that best distinguish DS-only from DS+ASD include:

• Nonverbal communication deficits beyond what is expected for Down syndrome 6
• Social-emotional understanding impairments 6
• Quality of social interaction (not just quantity) 6
• Independent play patterns 6
• Restrictive and repetitive behaviors and interests 6
• Sensory processing abnormalities 6

Non-ASD symptoms (expressive/receptive language delays, adaptive skills, challenging behaviors) are less useful for differentiation as they overlap significantly between DS-only and DS+ASD groups. 6

Comprehensive Diagnostic Evaluation Protocol

Multidisciplinary Team Assessment

Refer immediately to a multidisciplinary autism diagnostic clinic rather than attempting single-provider evaluation, as this is insufficient for accurate diagnosis. 1, 2

The team must include:

• Psychologist to conduct cognitive assessment measuring sustained attention, working memory, and processing speed 1
• Speech/language pathologist to evaluate receptive, expressive, and pragmatic language skills 1
• Physician (developmental pediatrician, neurologist, or child psychiatrist) to conduct medical assessment and rule out other conditions 1, 2

Standardized Diagnostic Tools Required

• Autism Diagnostic Observation Schedule-Second Edition (ADOS-2): sensitivity 91%, specificity 76% 2
• Autism Diagnostic Interview-Revised (ADI-R): sensitivity 80%, specificity 72% 2
• Direct observation focusing on social interaction patterns and restricted/repetitive behaviors, modified based on developmental level 2

Critical pitfall to avoid: Screening tools like M-CHAT are not diagnostic and should not be relied upon for older children who require comprehensive clinical evaluation with ADOS and ADI-R. 1

Essential Medical Workup

Physical examination must include:

• Wood's lamp examination for tuberous sclerosis signs 3, 2
• Examination for dysmorphic features to identify syndromic causes 3
• Assessment for head circumference (if >2.5 SD above mean, triggers specific genetic testing) 3

Tiered Genetic Evaluation

A genetic consultation should be offered to all persons with ASD, as thorough evaluation identifies an underlying etiology in 30-40% of individuals. 3, 2

First-tier genetic testing (order these initially):

• Chromosomal microarray (CMA): 10% diagnostic yield, now standard of care 2
• Fragile X DNA testing: 1-5% yield 3, 2
• High-resolution karyotype: 3-5% yield (if not already performed) 3, 2

Second-tier genetic testing (order based on specific clinical features):

• MECP2 gene testing in females: 4-5% yield 3, 2, 4
• PTEN gene testing if head circumference >2.5 SD above mean: 3-5% yield 3, 2, 4

Do not order extensive genetic testing without clinical geneticist evaluation first, as the stepwise approach with higher-tier tests having greater diagnostic yield is more cost-effective and better tolerated by families. 2

Developmental and Psychological Assessment

• Cognitive testing with global ability assessment including verbal and nonverbal components, expecting considerable scatter in results with possible splinter skills 1, 2
• Adaptive functioning assessment across multiple real-world skill domains 1
• Motor skills evaluation (fine and gross motor), as motor dysfunction occurs in nearly all ASD cases 1
• Assessment for areas of intense, circumscribed interests in higher-functioning individuals 2

Detailed Developmental History

Obtain the following specific information:

• Timing of symptom onset and whether regression occurred 2
• Response to previous interventions 2
• Family psychiatric history 2
• Key early signs between 12-24 months: reduced eye contact and social smiling, limited nonverbal behaviors to initiate shared experiences, atypical object use, repetitive behaviors 2

Management Approach

Immediate Actions While Awaiting Evaluation

Do not delay intervention waiting for formal diagnosis. Refer immediately to early intervention services or school-based special education. 1

Treatment Once Diagnosis is Established

Intensive behavioral interventions based on applied behavior analysis are first-line therapy, particularly for children 5 years or younger, focusing on improving language, play, and social communication skills with small to medium effect sizes. 1, 2 Some programs require up to 40 hours per week. 1

Pharmacotherapy is reserved for co-occurring conditions and specific symptoms, not core ASD features. 2 Screen for comorbid psychiatric conditions including ADHD, anxiety disorders, and mood disorders, as approximately 75% of children with ASD have comorbid psychiatric conditions. 1

Genetic Counseling and Family Planning

Provide genetic counseling to all families regardless of whether an etiology is identified. 2

For families without identified etiology, use empiric recurrence risk data:

• Full sibling recurrence risk: 3-10% 2
• Modified by sex: 7% if affected child is female, 4% if affected child is male 2
• With two or more affected children: at least 30% recurrence risk 2

Schedule periodic reevaluations for patients without a definitive etiology, as diagnostic technology and understanding continue to evolve. 2

Critical Pitfalls to Avoid

• Do not attempt single-provider diagnosis—multidisciplinary input is mandatory 1, 2
• Do not skip the formal audiogram—hearing loss can mimic ASD symptoms 3, 2
• Do not delay diagnosis due to misconceptions about presentation in adolescents or atypical cases 2, 4
• Do not fail to provide recurrence risk information to families, as this is essential for family planning 2
• Do not order a large battery of tests initially—use the stepwise tiered approach as it is better tolerated by families and more cost-effective 3, 2