Journal of Clinical Developmental Biology

Keywords

Developmental delay; Common developmental delay; Regression; Etiology; Seizure; Behavioral problem; Learning disability

Introduction

Clinical suspicion of delay in developmental milestones is assessed in domains of motor development, verbal-and nonverbal languages, learning in class-setting, and social interaction [1]. Global developmental delay is defined by a delay in 2 or more domains of developmental milestones [2, 3].

The spectrum of developmental impairments are subject to pathophysiological variations. Developmentally affected children, at the very least, have a learning disability. Neurologically, there are three main reasons to evaluate developmental delays: (1) To identify a treatable condition or etiology, (2) To institute an early intervention, (3) To expect and manage future comorbidities, and (4) To identify those parents who will need genetic counseling.

Based on what is known and longitudinal clinical observation, we propose and describe a common neurological profile in children with common developmental delay to aid in clinical diagnosis.

Notably, children with common developmental delay are born at full-term gestation. They have no adverse perinatal events such as maternal–fetal infection, fetal alcohol syndrome, or cerebral malformations. They are medically in good health and they are intellectual normal. Interestingly, their developental milestones do not regress, rather the children gain their developmental milestones overtime.

Method

Literature search

An exhaustive review of published literature was undertaken using the electronic databases PubMed, Embase, OVID Medline, Global Health, WHO-LIS and WHO regional databases. Different combinations of the terms “developmental delay”, “neurodevelopmental delay”, “comorbid” (comorbid, comorbidity, comorbidities), “ADHD”, “epilepsy” (epilepsy, epilepsies, epileptic),”seizure”, “neuropsychiatric”, “associate” (association, associated), “behavior” (behavior, behavioral), “disorder” with appropriate variations were used. Terms were slightly modified where necessary to fit the search terms offered in the respective databases. Final searches on all databases were undertaken on November 30, 2014. Reference lists of all selected articles were additionally screened.

Inclusion and exclusion criteria

Comorbidities were defined as any other medical conditions coexisting in addition to developmental delay. All articles linking developmental delay of unknown etiology without regression to co-existing medical conditions (“comorbidities”) were included. Any articles involving developmental delay with regression or of known etiology (including ischemic injury at birth) were excluded. All studies examining specific population subsets such as very low birth weight or extremely premature neonates were excluded.

Results

The phrase “developmental delay” or “neurodevelopmental delay” alone produced 7689 articles. In combination with other terms, the largest number of results with any search was 4972. A total of 24 studies met inclusion criteria (Table 1). The terms “Neurodevelopmental delay without regression”, “developmental delay without regression” and “developmental delay of unknown etiology” did not produce any results with any combination.

Table 1: Summarizes what is known from those studies that imply children as“common developmental disorder” [4-16]. DD:Developmental Delay

Past Reports of Developmental Delay

No studies were reported from a pediatric neurology setting and no studies were carried out exclusively in children with “common developmental delay”.

Table 1summarizes what is known from those studies that imply children as common developmental disorder [4-6].

General Consideration

Children with common developmental delay are generally unrecognized in general population. When seen in acute neurological setting, their developmental status is likely to be overlooked.

Terminology

Currently, no uniform term is in use to express children with developmental delay who are seen on a daily basis in child neurology clinics. Previous studies have used several different terms such as “non specific” or “routine” developmental delay, “developmental coordination disorder”, “developmental delay with no specific diagnosis”, and simply “developmental delay” [10]. The term has been intermixed with the classification, domain of developmental disability, severity, and comorbidities [12-17].

Recently, the term “Mental retardation” has been replaced by “Intellectual disability”.

Children with “common developmental delay” may have a learning disability, but they are not intellectual disable. In this clinical review, we coined the term “common developmental delay” to express a homogenous group of full-term children with “developmental delay of unknown etiology without regression”. The use of this new term collectively provides: (1) A clinically based common diagnosis, (2) Differentiates it from other groups of developmental delay which may require further investigation, (3) Most importantly, the proposed term separates the diagnosis from other aspects of developmental delay such as the domains of disability and comorbidity.

Arguably, the term “common developmental delay” can be seen as unfocused and a label of exclusion.

Classification

The literatures have placed emphasis on the classification of developmental disability domain rather than the spectrum of developmental disorder. Most classification systems have focused on specific etiologies or impairments such as motor impairment in cerebral palsy, intelligence quotient (IQ) less than 70 in intellectual desible, and interpersonal or societal interaction impairment in autism.

A study of developmental delay was classified into the following subgroups: (1) Genetic syndromes with recognized etiology, (2) Global developmental delay / intellectual disability in association with dysmorphic features, but unknown etiology, (3) Global developmental delay / intellectual disability without dysmorphic features, (4) Recognized etiology, brain malformations, inborn errors of metabolism, leukoencephalopathies, epileptic syndromes and (5) Developmental language impairment, and neuromuscular disorders. Furthermore, 74 / 241 (31%) children with adverse events after preterm or at term delivery were classified into subgroups such as cerebral palsy and disabilities without cerebral palsy [18]. Fenichel’s text book of clinical pediatric neurology used the term “Psychomotor retardation” as equivalent to developmental delay and classified it by distinguishing it from “Psychomotor regression” [19].

Contrarary to the statement that “Given the complexity of neurodevelopmental disabilities, it is unlikely that a single classification system will fit all needs” [20], Table 2 lists a simple classification system for the entire clinical spectrum of developmental disorders based on their develomental course and etiology.

Table 2: Lists a simple classification system of the entire clinical spectrum of developmental disorders based on their developmental course and etiology.

The subject of this review, “Common Developmental Delay” is the most common amongst Group I. These children are born full-term, are in good health, and have no intellectual disability. They do not regress, rather improve in their already acquired developmental milesotones and cause is unknown.

Prevalence

In general , developmental disorders occur in 2% to 3% of all children [21].

The actual prevalence of common developmental delay in children is unknown. However, its daily encounter in child neurology practice can attest to its common occurrence.

In search for etiology and degree of intellectual disability in 241 children, a recent study identified etiology in 66.4%. A genetic diagnosis was made in 19.5%. More importantly, 167 / 241 (69%) of children with disability had no prenatal, perinatal, and neonatal adverse events [18].

Etiology

The etiology of common developmental delay in full-term children is unknown. It presumably has genetic or idiopathic etiology. The acceptance level of common developmental delay as a diagnois is low. However, common migraine in the same etiological profile is a well accepted neurological diagnosis.

Common Neurological Profile

A common neurological profile to aid in a clinical diagnosis of Arguably, the proposed “common neurologic profile” can be seen as a common core problem shared by other develomental disorders and the symptomatology in isolation may seem to have no relationships.

Conditions Mimicking Common Developmental Delay

Static encephalopathy

In the past, the term “static encephalopathy” has been used to imply a single adverse insult with no regression of an acquired developmental delay, which occurs during prenatal period such as fetal alcohol asyndrome [22] or postnatal period such as acute bacterial meningitis [23], herpes encephalitis [24], or shaken baby syndrome [25].

The static encephalopathy of childhood is not always a static condition. An X-linked dominant neurodegenerative disorder of iron accumulation of the brain, mimics static encephalopathy, which can regress in adulthood [26]. This is rare condition, which does not negate the general principle.

Primary autism spectrum disorder

Kanner was first to recognize the lack of affective component along with other signs and symptoms of developmental delay in children with autistic spectrum disorder [27].

DSM V that was published in 2013 defines autistic disorder as a qualitative impairment in social interaction and communication with restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. Symptoms must be present during dwvwlopmwntal years. The criteria no longer include delays in language. In autistic spectrum disorder , a specific cause can be found in a limited (10% to 30%) number of patients [28].

An additional domain of impair social interaction to common developmental delay profile characterizes primary autistic spectrum disorders [29]. Unlike autism, children with common developmental delay have an even sensorimotor profile.

Non-dysmorphic genetic disorders

The genetic syndrome is generally recognized by the presence of dysmorphic features [30].

However, genetic syndromes with no dysmorphism casued by microdeletion mimics common developmental delay, which can be differentiated by an abnormal chromosomal microarray.

About 20% to 30% of children with developmental delay with no obvious dysmorphic features have abnormal mocroarray DNA analyses. The importance of such genetic abnormalility largely remains unknown.

Cerebral palsy

The question is where cerebral palsy fits in the spectrum of developmental delay. Cerebral palsy is characterized by motor deficits, abnormal movement, and abnormal posture [31]. The motor deficits include hemiparesis, paraparesis, quadriplegia, or movement disorders. In practice, cerebral palsy is almost always associated with common neurological profile of common developmental delay.

Cerebral palsy-like syndromes should be considered in the presence of specific neurological signs, specific movements, or in the absence of intellectual disability. If the described common neurological profile is followed closely, it is very unlikely that a neurodegenerative herediatry condition will be overlooked.

Alternative Conditions Suspected in Common Developmental Delay

Some of the clinical conditions that are frequently suspected in children with common developmental delay are: (1) Early fusion of anterior fontanel or hearing abnormality during infancy, (2) Absence seizure of childhood secondary to infrequent staring, (3) Acute onset of movements mimicking partial motor seizure, and (4). Gait difficulty later in childhood. Some of these children diagnosed as “High-functioning autism”.

Episodes of specific movements such as choreoathetosis or non-specific variable movements suggesting motor seizure are not uncommon in children with common developmental delay. Occurrence of these movements should not be seen as a regressive symptom.

Arguably, there are several conditions like neurofibromatosis or tuberous sclerosis which are associated with developmental delay, but they are primarily brought for evaluation other than developmental delay [32].

Clinical Assessment and Challenge

Previous literatures’ focus for neurodevelopmental assessment has been separate from common developmental delay. On other hand, physicians are often untrained for evaluating childrens’ IQ or genetic condition. There is a limited availability of trained neuropsychologists and medical geneticists. Even when they are available, costly genetic testing or unavailability of a particular test in particular geographical areas of the world limits their utilization.

Several methods of developmental assessement in different age groups of children have been used. Their sensitivity and specificity have been questioned [33].

Developmental delay in a single domain of development is rare. Detection of a motor developmental delay during early infancy presents another challenge. Delay in smile, lack of visual fixation and tracking, inability to turn from back to belly and vice versa , are all useful clinical clues for identifying developmental delay. An early preference of the arm for reaching out for an object or of the leg during crawling at before age 2 years suggest likely ipsilateral focal brain lesion.

The diagnosis of common developmental delay is based on clinical history and examination. For some, common developmental delay as a diagnostic entity may be unaccepatable. Frequently, parents state that the child has “no definite diagnosis”. In this situation, a symptom as a diagnosis with unknown etiology, is not limited to common developmental delay, it is commonly used in seizure disorder.

The history

Neurologically, once the child is brought for a developmental delay concern, a delayed developmental status should be assumed unless the evaluation suggests otherwise. It is unlikely that a developmentally normal child’s developmental status is of parental concern.

The first step is to explore and confirm the reasons behind parentals’ observation. Expected developmental milestones such as physical and mental abilities and child interactions should be evaluated. This step along with the standard tools will identify the domain and severity of the delay.

The second step is to assess the past developmental course. By asking if the child is now doing better or worse. The answer in children with common developmental delay is always, “The child is doing better”. The improvement in development domains should be documented. If the developmental course is uncertain and there is no urgency, a clinical follow up should take precedence over embarking on laboratory testing.

Amongst all domains, speech delay is probably the most commonly affected developmental domain, which occurs in isolation or in combination. Often, this is erroneously attributed to otitis media or the child being bilingual [34].

A new onset true seizure is the common presentation of children with common developmental delay who were unidentified previously. The third group of children presents after the manifestation of associated comorbidities. Infrequently, some parents seek neurological evaluation concerning the child’s quality of motor movement or performance, rather than the actual delays. These are clumsiness, awkward body or hand posturing during running or writing, respectively. Rarely, they present for assessment of persistent toe walking.

A history of frequent gagging, choking, and chronic constipation are commonly obtained in clinical practice. Particularly, the sleep disturbance has been reported in the literature [35]. The presence of such symptoms are non-specific but probably represents the entire spectrum of developmental disorders.

It should be noted that common developmental delay is characterized by a lack of specific medical, gentical, or neurological feature. A history deviant from proposed common neurological profile even in the absence of developmental regression should be a red flag for evaluation for a neurodegenerative disorder.

The examination

Examination by active observation plays a pivotal role particularly when an independent objective opinion regarding the developmental status of a child is confronted. A child’s quality of spontaneous motor and speech interactions is observed. Clinical motor signs suggesting developmental delay during early infancy include the quality or inability to support upright standing postion while held by armpits.

Later, inability to walk on heels without compensating at hips suggests upper motor neuron involvement. It is the most common objective sign which can be observed in children with common developmental delay. When in doubt, the child should be asked to take a squatting position. If Achilles tendon is tight, the child is unable to assume a full squatting position. If child continues to do so, he or she is likely to fall backward.

Most children with common developmental delay have normal or increased muscle tone. However, hypotonic type of common developmental delay is not uncommon. A generalized hypotonia in the context of normal or decreased deep tendon reflexes, congenital myopathies or congenital myasthenia should be considered.

A full ophthalmic examination for the status of the optic nerve and retina should be sought actively. Their abnormality will direct the investigation to white matter or grey matter disorders, respectively. The presence of corneal opacity in the context of coarsening of facial features directs investigation towards mucopolysaccharidosis.

Laboratory Investigation

Laboratory investigation and its extent for an etiologic diagnosis is personal to physicians. An etiologic diagnosis in common developmental delay is unlikely because the proposed common neurological profile makes the subject of common developmental delay homogenous by excluding the clinical markers suggestive of a specific etiology or diagnosis.

Almost all children with common developmental disorder with a common neurological profile do not require laboratory testing. Asymptomatic biochemical defects such as thyroid function test, if not done already, is tested universally.

A retrospective study selected nine clinical markers to improve the diagnostic yield of children with global developmental delay. These included sex, severity of global developmental delay, parental consanguinity, family history, behavioral problems, head size, facial dysmorphism, non-facial anomalies, and neurological deficits. Amongst 577 children, mild, moderate, and severe global developmental delay occured 63%, 33%, and 4%, respectively. An identifiable etiology was found in 53% with genetic disease being the most common (25%). For further diagnostic testing based on statistical analysis, they identified four clinical markers: (1) Severity of global developmental delay, (2) Behavioral problems, (3) Facial dysmorphism, and (4) Neurological deficits [36].

Who needs laboratory investigation? Any child who does not conform to the proposed common neurological profile should be a red flag for further investigation. The caution, a history where the child has lost previously acquired limited vocabulary or emergence of a new movement is not uncommon. These apparent regression do not qualify for a true regression and thus, no laboratory investigation is indicated.

Only few children with such a common neurological profile will need laboratory investigation. The indication for laboratory investigation include: (1) When the child’s developmental course is uncertain, (2) Chils has cerebral palsy–like syndrome, and (3) When the clinical evaluation indicates a medical or neurological condition. For example, in the presence of hyporeflexia at ankles suggesting white matter brain disease, skin marks suggesting neurocutaneous disorders, dysmorphism suggesting medical or neuro-genetical disorder, coarsening of facial features suggesting mucopolysacharidosis, involvement of optic nerve or retina suggesting leukodystrophy or grey matter disoders, respectively, In addition, the presence of specific neurological signs such as supranuclear gaze palsy suggestive of a specific neurodevelopmental disorders should prompt an magnetic resonance (MRI) of the brain [37].

In authors’ view, a universal routine testing or MRI of the brain in lack of clinical suspicion of a disease is unlikely to reveal a specific neurological diagnosis. The temptation to take such an approach should be avoided.

Neuroimaging

MRI of the brain is almost always preferred and most commonly performed procedure in the evaluation of children with developmental delay. The results in children with common developmental delay is either normal or reveals incidental finding.

The three most common findings are periventricular leukomalacia, arachnoid cyst, or Chiari malforamtion type I [38], which are unlikely findings in the context of a developmental regression. The presence of such findings in children with common developmental delay should assure the clinician that (1) The child does not have a neurodegenerative disorder, (2) His or her physical and mental abilities are likely to improve, and (3) This should obviate the need for further investigation.

Brain MRI is recommended in the presense of early preference in the use of limbs suggesting remote intrauterine stroke, dysmorphism, and abnormal head size or shape [39]. In the presence of early preference, MRI is likely to reveal asymmetrical periventricular leukomalacia, remote intrauterine stroke commonly in the distribution of middle cerebral artery or no cerebral abnormalities.

Electroencephalography

Presently, electroencephalography (EEG) is not recommended in evaluating the developmetal status of a child. However, during awake a slower than nomal background EEG activity for the age could be a useful marker to define developmetal delay status.

A case control study investigated EEG activity and its developmental course in ADHD and patients with typical developmental status. The study reported no difference in EEG activity between two groups. The study concluded “ A maturational deviation rather than a maturational delay may underlie a subgroup of ADHD. The author of the study questioned the clinical utility of conventional EEG for diagnosis of ADHD [40].

The developmental status of children in the study was unstated. The majority of children with ADHD do have developmental delay was reported by another study [41]. In this study, developmental delay was defined as delayed milestones according to the Denever II, which is a screening tool.

Nonetheless, a video-EEG is particularly useful in documenting the lack of ictal EEG abnormality in case of children with developmental delay who develop unexplained abnormal movements.

Specialized tests

The following tests should be performed selectively in very limited number of cases.

Inborn errors of metabolism: The purpose is to identify the earliest possible treatable cause of an inborn error of metabolism [42]. This includes serum lactate, pyruvate, ammonia, creatine kinase, quantative serum aminoacids and urinary organic acids, or urinary mucopolysaccharides. This test should be reperformed in the absence of a universal screening result or in the presence of clinical suspicion.

Chromosomal microarray DNA test: Amongst genetic tests, chromosomal microarray has become a first-line test for evaluation of children with global developmental delay. The G-banded karyotype is frequently utilized as an adjunct to the microarray. Most recently, the clinical availability of whole-genome and whole-exome sequencing has opened new possibilities for the evaluation of children with global developmental delay [43].

A retrospective study of microarray analysis in 82 children was carried-out in childen with epilepsy, speech delay, motor impairment, or autism. The clinical variable included mental retardation / delay 73 (89%), autism 16 (19.5%), learning disability 14 (17%), motor impairment 59 (72%), hypotonia 35 (42.7%), dysmorphic features 20 (24.4%), and epilepsy 22 (26.8%). All patients exhibited a normal karyotype. Microarray analysis was abnormal in 20 (23.5%). Deletions comprised 74% of all abnormalities. Patients with ≥ 4 clinical variables demonstrated a 30.5% incidence of abnormal chromosomal microarray findings, compared to 8.7% of patients with ≤ 3 clinical variables (P = 0.039, χ² test) [44].

It should be noted that chromosomal microarray may be abnormal in children with normal karyotype and unlike common deveopmental delay, the subjects in this study included autism, mental retardation, and dysmorphic feature. The presence of dysmorphic features, congenital abnormality, features suggestive of a specific hereditary disease, or gender in specific disorders increase yields for microarray abnormality [45].

Nonetheless, in some children with common developmental delay, microarray analysis may reveal abnormality of unknown significance. In the future, chromosomal microarray is likely to replace karyotying and thus, be used routinely. Contrartary to the perception that this approach is more expensive, microarray would be cost-effective as a first genetic test in the clinical evaluation of children with global developmental delay [46].

Fragile X DNA testing is recommended in the initial evaluation, however it is normal in children with common developmental delay.

Any genetic testing beyond microarray analysis should be done in consultation with a medical geneticist, unless physician has suspected or identified clinically a specific condition.

Other specific tests

Laboratory testing for a specific neurological disorder affecting development, such as Rett syndrome, leukodystrophies, mucopolysaccharidoses, or other disoders should be performed in the clinical context suggestive of the individual disorder. The diagnostic work up for hereditary neurodegenerative disorders is complex. The pattern and extent of white matter on MRI of the brain may suggest a clinical diagnosis and guide a particular test in confirmation the diagnosis.

Diagnosis

Developmental delays with presumed etiology

Common developmental delay should be differentiated from impairments caused by acquired conditions, which include being premie (gestational age less than 37 weeks), adverse perinatal events such as hypoxic ischemic event, congenital infection, fetal alcohol syndrome, and cerebral malformations. Developmental delay caused by these etiologies has a non-regressive course and children’s developmental milestones is likely to improve overtime.

Cerebral palsy-like syndrome

Cerebral palsy-like syndromes are rare and should be considered actively if cortical motor involvement occurs in the absence of cognitive delay.

In the presence of dystonic cerebral palsy, look for doparesponsive childhood-onset dystonia [47]. In the presence of paraplegia, evaluate for arginase deficiency. In the presence of hemiparesis with or without migraine, evaluate for MELAS, and in the presence of quadriplegia, mucolipidosis type IV or Niemann- Pick disease type C should be considered. Niemann-Pick disease type C should be suspected in the presence of difficulty when going to down staires suggesting supranuclear vertical gaze palsy [48]. Mucolipidosis type IV is suspected in the presence of diminishing vision secondary to corneal opacity or non-correctible iron deficiency anemia despite an appropriate therapeutic dose and duration of iron administration [49].

Conditions with loss of acquired developmental milestones

Specific syndromes, such as Rett syndrome or Menkes disease, are diagnosed based on their specific neurological features in the background of developmental regression. It should be noted that the majority of disorders affecting regression are the result of neurometabolic disorders of enzyme defect. Thus, these children are born normal delivery at full-term and have no dysmorphisms. The age at which the disease manifests depends upon the residual enzyme acitivity, lesser the active enzyme the younger the onset and severe is the disease.

The clinical diagnosis of children with a common developmental delay should be based on described common neurological profile (Table 3).

Table 3: Lists common neurologicalprofile for full-term children with developmental delay of unknown etiology without regression

A study analyzed the clinical characteristics of children with primary delayed language development (n = 183) and a language delay as a part of a global developmental delay (n = 467). They reported no perinatal risk factor difference in these two groups. Children with global developmental delay had much more delayed acquisition of independent walking and more frequent EEG abnormalities. The positive family history of delayed language development was prevalent in children with primary delayed language development (p < 0.01). They concluded that the linguistic profiles of children with language delay could not differentiate between primary and global delayed language developments [50].

Common Comorbidity

Common developmental delay is not a temporary diagnosis. This diagnosis has future consequences of poor qualitative physicial and educational performances. The exact prevelance and the type of comorbities are unknown. In general, developmental delay irrespective of the etiology is associated with a lifelong associated co-morbidities, which include a learning disability, behavioral problem, or seizure disorder.

Common Management Strategy

The goal of therapy is to optimize physical and mental activity. The common neurological therapies are; (1) Reassurance, (2) Early intervention, and (3) Managing the concurrent or future risks for behavioral problem, learning disability, and epilepsy.

An early clinical diagnosis is desirable to institute an early intervention [51].

Clinical evidence suggests that an early intervention during early infancy has a positive effect on cognitive and speech development, social skills, behavior, and school performance [52, 53].

A long term oral drug therapy with gamma-aminobutyric acid (Baclofen) or periodic injections of onabotulinumtoxin A (Botox) for children with spasticity may be needed [54-56].

Neurological Outcome

Preschool children diagnosed with global developmental delay and language impairment were reassessed by Battelle Developmental Inventory and functional outcome was measured by Vineland Adaptive Behavior Scale. The proportion of children falling below meaningful cut-offs was significantly higher in global developmental delay. The developmental and functional deficits persisted in both subgroups of children [57].

At the first encounter of clinical diagnosis, risk for comorbidities that present later in life should be discussed. The parents should be reassured of medical health wellness of their child.

Litigation

Delay in diagnosis or missing a specific neurodevelopmental disorder can be avoided by adherence to the common neurological profile and identifying a specific feature suggestive of a particular disease that may require appropriate neurological work-up.

Future

The developmental delay related studies should define developmental status of their subjects carefully. Future studies statistically analyse the proposed neurological profile in making the clinical diagnosis of children with common developmental delay.

Summary

Most children with common developmental delay are “unnoticed” in general population. They have variable presentations. Rapidly expanding knowledge in the setting of a busy neurological practice demands a clear clinical understanding of the presented developmental problems and its course.

The children with common developmental delay described above are a relatively homogenous population of term children with developmental delay of unknown etiology without regression. A lack of specific neurological symptomatology differentiate them from other developmental delay groups.

Based on the past studies, this is the very first report of a common neurological profile in full-term children with common developmental delay. The use of the term “common developmental delay” differentiates the diagnosis from the domains of disability and comorbidity of children with developmental delay. The proposed common neurological profile will empower clinicans in making a clinical diagnosis for common developmental delay.

Once recognise, no laboratory investigations are needed. At times, normal results incite further anxiety and thus, more testing. As a result, a legal implication of delay in diagnosis and management can be avoided. Management strategies incudes parental reassurance, early intervention, and future management of comorbidities, namely epilepsy, behavioral problem, and a learning disability.

Acknowledgement

The authors thank to Jason Green, DO for his critical review of this manuscript draft.

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