Developmental Delay

Etiology

The etiology of developmental delay is multifactorial. The etiology for the vast majority of developmental delay is idiopathic.  When known, etiology may include genetic, environmental, and/or psychosocial factors.

Genetic: There is no known genetic substrate for developmental delay, per se.  However, developmental patterns are often familial, including late walking and talking.  Nonetheless, these developmental delays can also represent risks for syndromes or developmental disorders.  There is a considerable variation in the genetics of developmental disorders, ranging from copy number variants (CNV's), insertions, deletions, and duplications. While most are rare variants, some represent common variants. The most common, known genetic factor for ID is Fragile X syndrome, a trinucleotide repeat disorder (CGG) targeting the Fragile Mental Retardation 1(FMR1) gene located on X-chromosome. Fragile X appears to confer risk for ASD, as well. Imprinting can also be seen as is the case of Prader-Willi and Angelman syndrome, which vary with paternal (Prader-Willi) and maternal (Angelman) loss of function on chromosome 15q. Both developmental delay and physical phenotypes can be associated with other disorders in which there are extra chromosomes or pieces of chromosomes, for example, Down syndrome (trisomy 21), Edward syndrome(trisomy 18) & Patau syndrome (trisomy 13).[8][9][10][11] Other X-linked disorders include Coffin-Lowry syndrome predominantly in males and Rett syndrome in females.[6] 

Environmental: A wide number of environmental factors can lead to developmental delays and subsequent developmental disorders.  These factors can affect development at a single of multiple points in the developmental process. 

Antenatal:

• Heritable disorders — for example (e.g.) Fragile X syndrome, Down syndrome, or chromosomal microdeletion and duplications.
• Early maternal infections, (e.g., rubella, cytomegalovirus (CMV), toxoplasmosis
• Late maternal infections, (e.g., varicella, HIV, malaria, etc.)
• Primigravida
• Short inter-pregnancy interval
• Teen pregnancy
• Vascular — comprises of hemorrhage and occlusion
• Prescribed medications — include antiepileptic drugs (AEDs), cytotoxic
• Teratogens/toxins — include smoking, alcohol, opioids, etc.
• Poverty

Perinatal:

• Intrauterine growth restriction (IUGR), prematurity, periventricular leukomalacia
• Hypoxic-ischemic encephalopathy (HIE), perinatal asphyxia
• Metabolic — Hypoglycemia, bilirubin-related neurotoxicity, etc.
• Poverty

Postnatal:

• Metabolic disorders like hypoglycemia, hyponatremia, or hypovolemia
• Inborn errors of metabolism - PKU
• Teratogens/toxins — such as lead, arsenic, mercury, etc.
• Trauma — head trauma
• Infections (e.g., neonatal meningitis, encephalitis)
• Maternal stress — such as depression, anxiety, etc.
• Maltreatment, intimate partner, and/or domestic violence
• Poverty
• Malnutrition — especially multivitamins and minerals deficiency, such as iron, folate, Vitamin D, calcium, etc.[1][3][12]

Epidemiology

Globally, in 2016, approximately 52.9 million children reportedly had identifiable developmental problems delay. Since 95% of the population resides in low and middle-income countries (LMICs), there is an increased risk for developmental delays and disorders.[13] Although the exact prevalence of developmental delay is unknown, according to the World Health Organization (WHO), 10% of the population in each country population has a disability of one or another kind.[14] In the United States, roughly 15% of children have been reported to have at least one developmental problem.[15] In England, the prevalence of ID in children under age five and adults is 2.7% and 2.17%, respectively. The GDD incidence rate is 1% to 3% in school-age children or younger.[6] Autism prevalence is approximately 2.5%.[16] 

The prevalence of delay in development involving respective domains among children (which is based on data reported in children getting services in 2007 by USPSTF on their respective website) is given below:[15]

• Cognitive (1% to 1.5%)
• Learning disability (8%)
• Speech and language (2% to 19%)
• Any delay (15%)

According to Drakenstein Child Health Study (DCHS) conducted in Western Cape, South Africa, the risk of low developmental performance in the high-risk environment was high among boys. Likewise, several other studies have also reported a slightly increased incidence in males, possibly due to genetic variability on the X-chromosome.[6][12]

Pathophysiology

Except for specific syndromes that include developmental delay, the vast majority of developmental delay is idiopathic.  Although the exact underlying pathophysiology is unknown, several mechanisms have been proposed by epidemiologic studies that lead to some sort of developmental delay and/or disabilities. Since some forms of developmental delay may run in families, genes have been assumed to play a significant role in developmental delay. 

A multitude of genes and mechanisms for genetic transmission have been proposed.  While some causes of developmental delay such as Fragile X or Down syndrome have known genetic etiologies, for most others, it is unclear. Even for well-characterized disorders like autism spectrum disorder, there are over 100 risk alleles. Perinatal complications, profound deprivation, and poverty, among other environmental stressors, can play a role in causing developmental delays, but special causal links remain elusive.

The hypothalamic-pituitary axis (HPA) is responsible for the normal regulation of stress response in progenies. Psychosocial stressors during pregnancy, maternal immune activation (MIA), and modification of HPA may significantly affect fetal brain development, but there are no specific cause and effect relationships for most disorders. Boyce and his colleagues offered the concept of differential susceptibility. This suggests that the risk for developmental anomalies is increased by a variety of factors that create a biological vulnerability to environmental stressors but are only expressed when the environmental stresses occur. Furthermore, even vulnerable children can do well if environmental circumstances are highly favorable and foster resilience.[17][18]

History and Physical

A comprehensive history and thorough physical examination are essential elements of the examination of children with developmental delays. Additional information can also be gathered by a play interaction with the child us age-appropriate toys (e.g., toy cars, blocks, crayons, and paper) as well as watching the child move around the clinic. Additionally, home videos may prove to be useful.[1]

History

• Collect comprehensive data on the entirety of the child's development from conception to the current age.
• Collect a detailed family history of at least first, second, and third-degree relatives. The construction of a pedigree chart is often helpful.
• Prepare a detailed narrative of the presentation and course of the relevant developmental delays.
• Obtain and review prenatal, perinatal/birth, and postnatal records when they are available.
• Check the neonatal history for adverse events, including HIE, jaundice, hypotonia, hypothyroidism, congenital abnormalitiesChart each of the developmental lines by listing each critical developmental milestone, including sitting, crawling, walking, talking, social interaction, language, learning, etc.
• Obtain an immunization history
• Obtain a nutritional history — (i.e., feeding and eating habits).
• Collect a detailed medical history, including hospitalization, surgeries, accidents, injuries, medications, etc.
• Collect data on social and academic performance in school[6][19]

Physical Examination

• Growth parameters — such as occipitofrontal circumference, weight, height, and BMI.
• General physical examination involving head-to-toe assessment.
• Detailed neurologic exam, including hearing and vision evaluation.
• Examination for dysmorphology.[3][6][19]

Evaluation

Assessment of developmental delays often requires the work of a team with experts in general and specific areas.  This should start with primary care providers followed by pediatric subspecialists such as neurologists, child and adolescent psychiatrists, developmental and behavioral pediatricians, and other pediatric subspecialists as indicated. Besides, the skills from other disciplines may be necessary, for example, psychology, genetics, speech and language pathology, occupational therapy, physical therapy, nutritionists, etc. The United States Preventive Services Taskforce (USPSTF) offers specific recommendations for speech and language delays and autism but does not explicitly cover other developmental delays. Clinicians, particularly primary care providers, must have a sound understanding of developmental milestones and patterns, as well as up-to-date knowledge about screening tests and their strengths & limitations, to ensure proper screening for a referral if the clinical suspicion of developmental screening is high.[1][15][20] 

During each well-child encounter, a PCP should encourage parents to express their concerns about their child's behavior or developmental milestones.[3] Furthermore, since developmental delay can be due to normal variations or can be an indicator of a developmental disorder such as sensory or cognitive impairment, cerebral palsy, or autism, thorough evaluation and follow-up is warranted. Therefore, in addition to direct physical examination and observation, the use of validated screening instruments at every well-child visit can aid in the early detection of problematic developmental delays. Developmental screening should take place in response to parental concerns or clinicians' observations as well as during every well-child visit at 9, 18, and 30 months of age. An autism-specific screening test is recommended at 18 and 24 months. Among many general developmental screening instruments, The Ages and Stages Questionnaire, Third Edition (ASQ-3), and the Parents' Evaluation of Developmental Status (PEDS) are commonly used parent-report tools for use during well-child encounters. Hamilton et al. 2016, cited by Vitrikas, reported the sensitivity and specificity of PEDS questionnaires for all ages 75% and 74%, respectively. Although the sensitivity and specificity for ASQ-3 vary among different age groups; however, overall sensitivity is 85%, and specificity is 86%.[15][21][22][23]

Laboratory Workup

Laboratory evaluations of children with developmental delays should be done judiciously.  There should be careful attention to resource utilization and the risk-benefit analysis for each test.  Since most causes of developmental delay are idiopathic, it is rare to obtain significant or pathognomonic findings in laboratory testing.  Therefore, aside from routine healthcare assessments, testing should only be completed if there is a specific indication.

Blood: Routine complete blood count (CBC), electrolytes, and lead screening are appropriate for most children, along with a lipid panel. If indicated, additional testing may include a metabolic chemistry panel(CMP), iron,  calcium, phosphate, creatinine kinase (CK) enzyme. Additionally, uric acid level, thyroid function tests, lactic acid, very-long-chain fatty acids (VLFA), transferrin, lead, copper, ceruloplasmin level, ammonia, and acylcarnitine levels.

Urine: A routine urinalysis is appropriate but additional studies may be added to include organic acids, amino acids, oligosaccharides, sialic acids, glycosaminoglycans, urea, urine purine, and pyrimidines, etc.

Cerebrospinal fluid (CSF): CSF analysis is rarely appropriate for developmental assessment delay.  If there is a specific indication for a lumbar puncture, it can be considered.  The particular indication will largely determine appropriate assessments of the spinal fluid, which may include glucose, lactic acid, glycine, pyruvate, etc.

Other tests need to be done to rule out TORCH (Toxoplasma, Others (HBV, HIV), Rubella, CMV, and Herpesvirus) infections.

Genetic: In general, genetic testing is not indicated for developmental delay unless there is a specific indication or evidence of a discrete syndrome.  If further genetic testing is indicated, this should begin with a chromosomal microarray (CMA). Since the most commonly known genetic cause of intellectual delay is Fragile X, FraX screening may be appropriate. As per Moeschler et al., CMA is required for Fragile X syndrome. The detection of significant copy number variants and approximated diagnostic yield of microarray tests are 15-20% and 12%, respectively. If further genetic testing is indicated, referral to a geneticist is indicated. Consideration of a whole exome scan (WES) or whole-genome scan will determine the clinical syndromes being considered.[6][11][15]

Additional Assessments

Magnetic resonance imaging (MRI) brain — In the absence of discrete family history, specific injury, or focal neurological finding, MRI is rarely indicated in the routine assessment of children with developmental delay.  This is because children under the age of 7 or 8 will have difficulty being still, and so movement artifacts will make interpretation of the scans difficult to impossible. Examinations can be completed using anesthesia, but, in most cases, the risk of anesthesia outweighs the potential benefit of the MRI scan. MRI is used to evaluate for microcephaly, macrocephaly, seizures, abnormal neurologic signs and symptoms, and hydrocephalus. One prospective and observational study compared the MRI findings of eighty-one (n=81) pediatric patients. Among them, 68% of cases showed abnormal MRI findings compared to 32%  normal MRI results. The abnormal 68% MRI results demonstrated by traumatic/ neurovascular diseases (31%), congenital & developmental (17%), neoplastic (2.5%), metabolic & degenerative (10%), and non-specific (7.5%).

Electroencephalography (EEG) — In the absence of discrete family history, specific injury, or focal neurological findings, EEG studies are rarely indicated in the routine assessment of children with developmental delay.  EEG may be useful if there is a clear history of regression and/or directly observed seizure activity.[3][6][24]

To summarize, children with developmental delays are usually identified as a result of parental concern, school/daycare observation, or during the course of routine care in primary care settings. When there is information from parents and/or teachers, the primary care provider should take it seriously and carefully assess the developmental delay and its possible causes.

Treatment / Management

The management of developmental delay is a team effort that includes primary care providers as well as pediatric subspecialists such as neurologists, child and adolescent psychiatrists, developmental and behavioral pediatricians, and other pediatric subspecialists as indicated. Also, the skills from other disciplines may be necessary, for example, psychology, genetics, speech and language pathology, occupational therapy, physical therapy, nutritionists, etc. In short, treatment strategies are usually multi-modal.

Treatment strategies require that the lead member of the team, often the primary care provider, establishes a therapeutic partnership with the pediatric care team, educating and providing parents/families with necessary information about the developmental delay and any evidence of an evolving syndrome, including the course of the disorder, diagnosis, prognosis, and complications. Additionally, psychosocial support and parental counseling/guidance are essential elements of care. Information should be provided at a level consistent with the ability of the parents to understand as this will enhance acceptance and adherence to care plans.[6] 

For some families, social work support services may be necessary for coordination and transportation services, regular home visits, and other services essential to complete evaluations.[15] If there is significant clinical concern that the developmental delay represents an evolving clinical syndrome and the parents appear to not understand or be in denial, then follow-up appointments with the primary care provider during the developmental evaluation will be helpful.[3] Other recommendations for early interventions and referrals are given below:

1. Early childhood education
2. Early intervention programs
3. Early and periodic screening, diagnostic, and treatment (EPSDT)
4. Parenting problems – consider referral for parent training. This might include parent-child interaction therapy (PCIT) consisting of two phases, such as parent-directed interaction (PDI) and child-directed interaction (CDI). Additionally, parents may need help in providing their children with appropriately stimulating environments at home, school, and daycare. Many children with developmental delays are eligible for community-based services. Primary care providers should be familiar with these services, eligibility, and how to make referrals.  Among many, these include:
5. Behavior Problems – consider referral to child and adolescent psychiatrist and/or behavior therapist (BCBA board-certified behavior analyst)
6. Social skills problems – consider referral for social skills training (individual and group_
7. Auditory impairment – consider referral to audiology (15)
8. Visual impairment – consider referral to ophthalmology.
9. Gross or fine motor delay— consider referral to physical therapy and/or occupational therapy (PT/OT)
10. Speech & language delay — consider referral to a speech and language pathologist.
11. HeadStart
12. Special Education (via Individualized Education Program (IEP) or 504 Plan)
13. Other community service agencies and programs[7][15][25]
(B3)

Differential Diagnosis

Most developmental delay is idiopathic and time-limited. There is no differential diagnosis, per se. However, for some children, developmental delay is the first step toward a "development disorder," one of a large group of syndromes for which there are specific diagnostic procedures undertaken by specialists to arrive at a diagnosis. Examples of these progressions include;[1][3][19][26]

Developmental Delay Milestones Risks

• Intellectual disability (ID)
• General developmental delay (GDD)
• Fragile X syndrome
• Failure to thrive (FTT)
• Anemia
• Thyroid deficiency
• Social deprivation

 Delayed Speech and Language

• General speech delay
• Developmental language disorder
• Intellectual disability (ID)
• Autism spectrum disorder
• Social communication disorder
• Developmental language disorder
• Social deprivation

 Sensory Impairment

• Developmental hearing disorder
• Deaf
• Developmental vision disorder
• Blind
• Poor visual acuity

 Behavior Problems

• Attention deficit hyperactivity disorder (ADHD)
• Oppositional defiant disorder (ODD)
• Disruptive mood dysregulation disorder (DMDD)
• Autism spectrum disorder (ASD)
• Childhood-onset schizophrenia

 Mood/Affect Regulation

•  Autism spectrum disorder
•  Intellectual disability
•  Mood disorder
•  Childhood-onset schizophrenia

 Learning Problems

•  Intellectual disability (ID)
•  Sensory deficits (hearing or vision)
•  Dyslexia
•  Autism spectrum disorder (ASD)

 Movement Disorders

• Epilepsy
• Tourette syndrome
• Chronic tic disorder

 Motor Delays

• Cerebral palsy
• Muscular dystrophy
• Spinal muscular atrophy
• Epilepsy
• HIE
• Intellectual disability
• Autism spectrum disorder

Prognosis

Since most developmental delays resolve spontaneously, the prognosis is generally good. However, developmental delay is a significant and powerful risk for progression to a neurodevelopmental disorder or syndrome.  As a result, it is critical that each developmental delay is carefully followed until it resolves or evolves into a developmental disorder.  There are many factors associated with both poor and better developmental outcome. Some of the prognostic factors associated with poor behavioral outcomes or serious delay in the development of children ranging from 18 to 30 months are lack of parental education, anemia during pregnancy, malnutrition, premature babies, male gender, low birth weight (LBW), prenatal and postnatal depression, intimate partner violence (IPV), use of drugs, tobacco or alcohol in pregnancy, and poverty.[12][27] 

Moreover, some other alarming features (if not effectively addressed, may result in significant developmental deficit) are hearing and/or vision loss at any age, loss of previously learned developmental skills, persistent hypotonia or hypertonia, asymmetrical movements, no communicative speech at 16 months, and disproportionate head circumference (either > 99.6 percentile or <0.4 percentile).[1] In contrast, maternal education, access to basic life and health resources, and older child age have been associated with a better outcome.[12]

Complications

Most developmental delays resolve without complications. Those that evolve into developmental syndromes require careful assessment by skilled experts in the areas affected by the developmental disruption.[3][7]