Investigating the borders of autism spectrum disorder: lessons from the former diagnosis of pervasive developmental disorder not otherwise specified

Introduction Autism Spectrum Disorder (ASD) diagnosis is relatively consensual in typical forms. The margins of the spectrum and their degree of extension, however, are controversial. This has far-reaching implications, which extend beyond theoretical considerations: first, peripheral forms of autism are more prevalent than central forms; second, we do not know how relevant typical-targeted recommendations are for atypical forms. In DSM-IV-TR, these margins of autism were studied within the category of Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS). In spite of its low reliability, this former diagnosis was of particular interest to shed light on the gray area of margins. The aim of this systematic is therefore to investigate the clinical characteristics of PDD-NOS in comparison with Autistic Disorder. Method A stepwise systematic PRISMA literature review was conducted by searching PubMed and Web Of Science databases to select corresponding studies. Results The systematic review included 81 studies comprising 6,644 children with PDD-NOS. Cross-sectional and longitudinal studies comparing PDD-NOS and AD showed that PDD-NOS corresponds to milder form of autism with less impact and less associated disorder, with the exception of schizophrenia and mood disorder. Discussion Our review challenges initial views of PDD-NOS, and shows the clinical relevance of this diagnosis when dealing with the margins of autism, and the de facto diversity included in the spectrum. However, in view of the many limitations of PDD-NOS (low reliability, instability through time, low acceptability), we suggest taxonomic changes in DSM-5: we introduce a new category based on three main dimensions related to socialization impairment, emotional lability and psychotic symptoms. Conclusion Our review argues for a distinction between AD and PDD-NOS on clinical characteristics and thus highlights the need to study the margins of autism. While the limitations of the PDD-NOS category made it irrelevant to investigate these margins from a research perspective, we believe that a multidimensional approach for mental health professionals taping socialization, emotion lability and psychotic symptoms would be interesting. Our review therefore encourage future studies to test relevant criteria for a new category and possibly identify developmental trajectories, specific interventions and treatments.


Introduction
Since 2013 and the DSM-5, the diagnostic category of Autism Spectrum Disorder (ASD) has included 2 behavioral dimensions which represent the core defining features of ASD ( 1): (a) communication and social interaction deficits on the one hand, and (b) repetitive behaviors and restricted interests on the other hand (1).The term "ASD" suggests that the core features of the disorder can be measured dimensionally and, that they fall along a continuum of severity.No diagnostic subtypes are listed (1); instead, specifiers are provided to indicate associated dimensions, such as intellectual and/ or language impairment, as well as the severity level of core ASD symptoms (2).Further, any known genetic or medical disorders are recorded and other co-occurring neurodevelopmental, mental, or behavioral disorders are indicated (2) to characterize subgroups.
In the DSM-5 (2), whatever the level of severity, even in the mildest forms, ASD symptoms are viewed as intrinsically autistic.However, to take one example, this conceptualization does not take into account the overlap between, on the one hand, some ASD symptoms, and on the other, Intellectual disability (3,4), language impairment (5,6), Attention Deficit/Hyperactivity Disorder (7,8) or schizophrenia (9,10).Moreover, mild ASD symptoms might be more akin to a natural variant of typical development than a formal disorder (11).Boundaries issues with typical development are also longitudinal, as has been shown in studies on "optimal outcome" or "Loss of Autism Diagnosis (LAD)" (12).These studies (13) focused on a group of individuals meeting criteria for ASD in childhood who no longer met them later in development.This definition entailed clear documentation of early ASD diagnosis, not meeting current diagnostic criteria (with ADOS scores similar to neurotypical peers with no history of ASD), and having overall cognitive, language, and social functioning standardized test scores within the average range (12).Confirmation that meeting criteria for ASD is not necessarily a lifelong state appears evident in the strikingly similar proportions (about 9%) of individuals experiencing LAD in prospective and retrospective studies (12).In line with the scope of our review, it is worth noticing that one study (14) showed that among ASD children included at age 2, those with PDD-NOS were significantly more likely than those with AD to move off the spectrum by age 4. ASD symptoms might be thus less specific than suspected in the DSM-5, especially in milder forms.
Envisioned in line with Kannner's (15) first description and seminal work, autism is relatively consensual in its typical forms (full syndrome) (16).However the margins of the spectrum and their degree of extension are controversial (17) because of overlaps with other dimensions and blurred boundaries with typical development.This question is much more than a theoretical issue, since peripheral or "marginal" forms of autism might be more prevalent than central forms (see below).Furthermore, one could question the usefulness and relevance of recommendations made for typical forms when facing atypical ones.Past conceptualizations (18) contrasted the more prototypical form of autism, called "Autistic Disorder (AD), " with the margins of autism studied within the Pervasive Developmental Disorder -Not Otherwise Specified (PDD-NOS) category.Is therefore of special interest to explore these margins through the lens of this former diagnosis.
The PDD-NOS diagnosis category was first introduced in 1987 (19) to contrast with typical forms for autism labeled "Autistic Disorder" (AD).The DSM-III-R (19) states that "this category should be used when there is a qualitative impairment in the development of reciprocal social interaction and of verbal and nonverbal communication skills, but the criteria are not met for autistic disorder, schizophrenia or schizotypal or schizoid personality disorder.Some people with this diagnosis will exhibit a markedly restricted repertoire of activities and interests, but others will not." In DSM-IV (20) and DSM-IV-TR (18), AD and PDD-NOS were included within the Pervasive Developmental Disorders (PDDs) that prelude ASD.PDDs also included Asperger Syndrome (AS), Childhood Disintegrative Disorder and Rett Syndrome (18,20).
In DSM-IV-TR (18), the PDD-NOS category included atypical autism, i.e., presentations that did not meet the criteria for AD because of late age of onset, atypical symptomatology, or subthreshold symptomatology, or all of these.These recommendations echoed Towbin's conceptualization (21) described in a reference textbook section published in 1997.He recommended the use of PDD-NOS in 4 indications: (a) as a temporary diagnosis when data are lacking or when the child is too young; (b) to designate a mild form of ASD; (c) in the case of late age of onset of autistic symptoms; (d) to depict a clinical picture with early symptom onset and impairment in social reciprocity (21).In terms of diagnostic use, the PDD-NOS, often envisioned as a diagnosis of subthreshold autism, seems to cover a wide range of clinical variability, sometimes referred to as heterogeneity; it would benefit from being studied in a more positive manner, by drawing on its clinical diversity (22).
Epidemiological studies show that at least half of PDD were PDD-NOS.In 2005, Fombonne (23) found a PDD-NOS prevalence of 37.1 per 10,000 for a PDD prevalence of 63 per 10,000 and an AD prevalence of 13 per 10,000.In 2010 in the United States, the results of the Centers for Disease Control and Prevention (CDC) showed a PDD prevalence of 14.6 per 1,000 in a population of 363,749 8-year old children (24).PDD-NOS were 46% of the PDD, AD 43% and AS 11%.Noticeably, between 2006 and 2010 the distribution of AD and PDD-NOS has not undergone substantial changes (24).The diagnosis of PDD-NOS had a low inter-rater reliability.The inter-rater reliability was good to excellent (k from 0.95 to 0.67) for the distinction between PDD and non-PDD.However, the disentanglement of different subtypes of PDD was much less reliable (k from 0.18 to 0.65) (25)(26)(27).The DSM-IV-TR criteria were therefore more successful in differentiating PDD (25) from other psychiatric disorders than in distinguishing between the three main subtypes of PDD, namely AD, PDD-NOS and AS (28).In line with these results, a study (29) tried to assess the variation between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders across 12 university-based sites.They found that clinical distinctions among categorical diagnostic subtypes of PDDs (AD, PDD-NOS and AS) were not reliable even across sites with welldocumented fidelity, using standardized diagnostic instruments (29).
In spite of its low reliability, the former diagnosis of PDD-NOS is very interesting to study the margins of autism because of both its conceptualization at the end of the spectrum, and its high prevalence.The aim of our systematic review is thus to investigate the clinical characteristics of PDD-NOS in comparison with AD.The objectives were therefore to study comparatively (in both diagnoses) synchronic and diachronic characteristics such as autism symptoms, cognitive function, daily impact, associated mental health or physical health condition and developmental trajectory from infancy to adolescence.The comparison is intended to address the distinction between the typical form and the margins of autism as well as the relevance of the PDD-NOS/AD distinction.Our study therefore aims to determine whether this distinction helps mental health professionals to account for diversity within the spectrum, and to identify divergent trajectories, better than the current ASD category.

Materials and methods
This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines (PRISMA) (30).

Search strategy and selection criteria
A stepwise systematic literature review (30) was conducted by searching PubMed, MEDLINE, and Web Of Science databases for published peer-reviewed papers using the following keywords: "PDD-NOS" OR "Pervasive Developmental Disorder Not Otherwise Specified" from January first 1987 (the year of the DSM-III-R publication, introducing this diagnostic category for the first time) to June 16th 2022.The keywords were screened in the titles and abstracts.

Eligibility criteria Inclusion criteria
To be included in this review, the articles had to meet all following criteria: (a) include children and/or adolescents (31), (b) compare toddlers, children or adolescents with PDD-NOS with children with AD (c) be published in English, (d) use a quantitative design.RC and OP applied the eligibility criteria and screened the records to select included studies.

Exclusion criteria
The following exclusion criteria were used: (a) no reviews, comments or clinical cases, (b) methodological features: number of participants included in the AD or the PDD-NOS groups ≤10, adults included only, lack of comparison group, comparison with a group different from AD (e.g., AS), participants whose diagnosis has been confirmed by a classification other than the DSM-III or the DSM-IV, test validation studies, (c) epidemiological data in order to focus on mostly clinical well-characterized populations, (d) therapeutic trials, (e) anatomical, biological or fMRI studies (isolated, contradictory and/or non-replicated results) are (difficult to interpret), (f) language other than English, and (g) qualitative studies.

Outcome measures and data extraction
The following variables were extracted: First author (second, third author and journal if needed to distinguish from other studies); Year of publication; Sample Size; Age (mean ± SD); Sex (% Males); Functioning level when available and when age at inclusion (at baseline in longitudinal studies) > 6 y.o.(to assess comorbid ID); Objective; Design of the Study; Methods (only with longitudinal studies); Main assessment tools; Results.

Quality assessment
All included studies were observational, with a similar comparative framework.Quality assessments in such observational studies is controversial, with no clear agreement on rating methods (32).We therefore did not assess quality.

Database
Our search from 1987 to 2022, undertaken on June 16th 2022, found 510 articles on PubMed and 431 on Web of Science.After manually removing all duplicates, 681 references remained.Based on their titles and abstracts, 256 papers were excluded for lack of relevance as they displayed no separate groups for AD and PDD-NOS.Most of these articles focused on PDDs (not PDD-NOS), ASD or grouped PDD-NOS, AD and/or AS into common groups.Other articles studied PDD-NOS in specific groups such as X-Fra, cerebral palsy, Down Syndrome... Our search strategy yielded 425 full-text articles assessed for eligibility.After conducting a full-text analysis of all these papers and excluding those not meeting our inclusion criteria, we ended up with 81 relevant studies, 67 of which were cross-sectional and 14 longitudinal.

Studies
A total of 6,644 children with PDD-NOS and 11,156 children with AD were included.47 studies were from the United States (58%), 12 from Netherlands (15%), 5 from Turkey (6%), 3 from Italy (4%), and 3 from Sweden (4%) The mean age in each group (when available) was 5.85 and 5.84 years, respectively.The mean age was low because many studies included toddlers or/and pre-schoolers with PDD-NOS (52%).Sex was not systematically specified in each group.Based on available data, PDD-NOS groups comprised 75.1% of males.IQ was not always specified, in particular in studies in toddlers or preschoolers.Based on available IQ measures, average IQ was 81.93.
Within the 67 selected cross-sectional studies, we distinguished those relating to (a) autism symptoms (22 studies), (b) perinatal, developmental and functional aspects (31 studies), (c) associated mental health conditions (14 studies) and (d) associated physical health conditions (6 studies).We chose these categories in part because they best served our goal, of investigating the clinical characteristics (autism symptoms, associated conditions/dimensions, developmental trajectories and adaptive behavior) of PDD-NOS in comparison with AD, and in part because they were those that best matched selected studies.All cross-sectional studies could be included in these three categories.As explained above, 14 longitudinal studies were also selected (Figure 1).
The mean age of onset of parental concerns in the group with AD was comparable to that reported in the PDD-NOS group (53).These parental concerns in PDD-NOS referred to non-specific problems linked to sleeping, eating, and level of activity (53).

Perinatal, developmental and functional aspects
Three studies (54)(55)(56) showed distinct perinatal risk factors in PDD-NOS in comparison with AD (Table 2).However, involved factors differed: hyperbilurinemia (55), higher exposure to smoking during pregnancy (56), threatened abortion, a labor duration of less than 1 h, cephalopelvic disproportion, and deliverance by an elective or emergency cesarean section (54).Even if perinatal risk factors might differ, odds ratios for birth defects were similar for AD and PDD-NOS (57).
Early development was less impacted in PDD-NOS with respect to AD (Table 2).Pointing was less impaired in PDD-NOS than in AD (33, 58).Skill loss was less frequent in PDD-NOS (58,59).Children with AD began crawling significantly later than those with PDD-NOS (60).Using the Revised Educational Profile, Portoghese et al. showed that all behavioral areas and almost all assessed developmental domains (with the exception of the cognitive verbal) were more severely impaired in the AD group than in the PDD-NOS group (61).Children with AD and ID displayed a Visual Rooting Reflex more often than children with PDD-NOS and ID (62), suggesting less severe neurological impairments.
The investigation of language development in PDD-NOS in comparison with AD did not show any difference or particularity (63, 64) (Table 2).Also, fine and gross motor development did not differ between the 2 groups (35,65).However, Ghaziuddin et al. found lower clumsiness in PDD-NOS (66).
Regarding socio-emotional development, social cognitive performance did not differ between both groups (67).One study shows a distinct profile of emotional information treatment in PDD-NOS in comparison with AD (68) (Table 2).
Quality of life of children and parents was less impaired in the PDD-NOS groups (33, 80) (Table 2).
Only one study showed an impact of sex on AD vs. PDD-NOS (81).
Anxiety led to contradictory results (Table 3).Anxiety has been shown to be higher in the AD group (83,85,89) or in the PDD-NOS group (90).A study investigated the interaction between diagnosis (AD or PDD-NOS) and communication deficits (91).Children with AD experienced less anxiety as communication deficits increased while children with PDD-NOS experience more anxiety as communication deficits increased highlighting distinct type of interaction (91).
Chien et al. showed that children with PDD-NOS had a higher risk for developing Schizophrenia Spectrum Disorder, Bipolar Disorder, Major Depressive Disorder than those with AD (92).These results concur with another study comparing youth with ASD attending a specialty clinic to those attending a general psychiatry clinic (88).The latter group suffered from a greater burden of psychopathologies (Major Depressive Disorder and psychosis), higher levels of dysfunction and more pharmacotherapy [cf Carigi et al. (33); Table 3].

Associated physical health conditions
Studies showed less sleep disorders in the PDD-NOS-group (33, 93, 94) but another did not (35) (Table 4).Feeding disorders were less common in the PDD-NOS group than in the AD group (35,93,94).However, one study did not confirm this result (85) (Table 4).
Parmeggiani et al. showed that pathological neurological examination, cerebral lesions, abnormal EEG background activity and associated genetic pathologies were more common in PDD-NOS.Moreover, Epilepsy seizure in PDD-NOS had an earlier onset (2 years 8 months) and a better outcome (95).
Cognitive development was less impaired in PDD-NOS (Osada et al., Takeda et al., Thurm et al.) (101-103).However, another study did not show such a better outcome in this group (96).
As a whole, autistic symptoms were lower in the PDD-NOS group than in the AD group (96, 101) (Table 5).More specifically, studies showed better communication and socialization skill outcomes in PDD-NOS than in AD (103-105).Kim et al. 's study showed that the likelihood of having restrictive and repetitive behavior was the same for both AD and PDD-NOS groups; though the rated severity of these The ADI-R 3   The ADOS 4   The CARS 5   The Griffith's Mental       (SD). 2 Developmental Quotient. 3Autism Diagnostic Interview -Revised. 4Autism Diagnostic Observation Schedule. 5Child Autism Rating Scale. 6Baby and Infant Screen for Children with aUtIsm Traits. 7Schedule for Affective Disorders and Schizophrenia for School-Age Children. 8Vineland Adaptive Behavior Scale. 9Autistic Behavior Checklist.(SD). 2 Clinical Global Impression Severity Scale. 3 Autism Diagnostic Observation Schedule. 4Vineland Adaptive Behavior Scale. 5Baby and Infant Screen for Children with aUtIsm Traits.      1 (SD). 2 Development Quotient. 3 Schedule for Affective Disorders and Schizophrenia for School-Age Children. 4Baby and Infant Screen for Children with aUtIsm Traits. 5Autism Diagnostic Observation Schedule.Seizure outcome was better in AD 1 (SD) 2 Developmental Quotient. 3Baby and Infant Screen for Children with aUtIsm Traits. 4Autism Diagnostic Observation Schedule. 5Childhood Autism Rating Scale.The ADOS-G 4   The CARS 5   The VABS 6   The Mullen

Learning
The       (SD). 2 Autistic Behavior Checklist. 3Clinical Global Impression Severity Scale. 4 Autism Diagnostic Observation Schedule. 5Child Autism Rating Scale. 6Vineland Adaptive Behavior Scale. 7Autism Diagnostic Interview -Revised.Regarding functional outcome, a study form Norway (107) showed that the disability pension award at adulthood was the only outcome measure differing significantly between the AD and PDD-NOS groups previously included during childhood.
Within the PDD-NOS group, worse outcome was associated with ID, lesser birth weight and older age at diagnosis (108).Moreover, a better psychosocial functioning during childhood predicted a lower rate of disability pension award in the PDD-NOS group (107).

Discussion
We conducted a systematic review of PDD-NOS in comparison with AD.Cross-sectional and longitudinal studies comparing PDD-NOS and AD showed a clear trend for lower communication and socialization impairment in children with PDD-NOS.Results on restrictive and repetitive behaviors were more contradictory.Early development was less impacted in PDD-NOS as well as the quality of life of children and families.Children with PDD-NOS showed less challenging behavior than those with AD.Schizophrenia and mood disorders appeared to be higher in PDD-NOS whereas feeding and sleep disorders tend to be less prevalent.
With regard to our results, PDD-NOS appeared as category both quantitatively and qualitatively distinct from AD.In a quantitative perspective, PDD-NOS was a lesser variant of autism with respect to the trajectory of autism symptoms, some associated mental and physical health conditions, or quality of life.This perspective is consistent with the spectrum approach of the DSM-5 (2) and a possible continuum between AD and PDD-NOS within ASD.However, in a qualitative perspective, PDD-NOS differed from AD because of higher associated schizophrenia and mood disorders.These results were unexpected with respect to a spectrum approach and suggest specific links between the margins of autism and other psychiatric dimensions.Our review coheres with Tsai and Ghaziuddin's review (109) which concluded that the literature appeared to suggest that PDDNOS can be separated from AD, and, therefore, does not seem to lie on a "continuum" with that disorder.These authors recommended systematic research to settle the issue and that PDDNOS should be regarded as a separate category to facilitate ongoing research (109).In contrast, a recent systematic review on PDD-NOS (110) concluded that in regard of the limited consistency, sensibility, and stability of this disorder, it would be more consistent to include this diagnosis within ASD.Noticeably, the authors still recommended to collect information from professionals on adults who received a PDD-NOS diagnosis in childhood.
Our search on PubMed found 510 references.On the same period, from 1987 to 2022, the term "Autistic disorder" gave 24,639 references.PDD-NOS was thus referenced 48 times less than AD, and was therefore much less studied.However, the high prevalence of the PDD-NOS category demonstrates its high clinical relevance.This clinical importance of PDD-NOS in psychiatry was also emphasized by a study comparing youth with PDDs attending a specialty clinic for autism with those attending a general psychiatry clinic (88).More autism clinic youth met criteria for AD; more of those referred to the psychiatry clinic met the criteria for PDD-NOS (88).The discrepancy between the past clinical use of the PDD-NOS category and the scarcity of research in the field (in comparison with AD) might be due to the difficulty of studying the margins of autism because of their heterogeneity and complexity -which our review aimed to underline.PDD-NOS therefore illustrated a gap between clinical and research issues and the need to address heterogeneity from a research perspective.Based on research rather than clinical consideration of the PDD-NOS, the DSM-5 missed the complexity of the margins and opted for a continuum approach and ASD.
With regard to the 4 recommendations proposed by Towbin on the use of the PDD-NOS diagnosis category ( 21), it appears that, firstly, although PDD-NOS is related to earlier developmental disorders, the age of parental concern does not differ between AD and PDD-NOS.The latter result suggests that the PDD-NOS is not commonly used in the case of a later age of onset of autistic symptoms.Towbin (21) and Mandy et al. (35) suggested that PDD-NOS depicted a clinical picture with early onset of symptoms, an impairment in social reciprocity and less to no restrictive and repetitive behaviors.We showed, however, the lack of clear support to the claim of lesser frequency of restrictive and repetitive behaviors in PDD-NOS.Towbin also recommended using PDD-NOS as a temporary diagnosis when data are lacking or when the child is too young (21).This recommendation concurs with less diagnostic stability in PDD-NOS in infants and pre-schoolers, as is shown by our results.Finally, our review mostly supports the recommendation referring to PDDS-NOS as a lesser variant of autism with respect to the trajectory of autism symptoms, associated mental and physical health conditions, or quality of life.
Chien et al. showed that PDD-NOS was more associated than AD with schizophrenia and mood disorder (92).This result concurs with Joshi et al. 's study comparing youth with PDDs attending a specialty clinic for autism to those attending a general psychiatry clinic (88).General psychiatry clinic youth with PDDs (with more PDD-NOS than AD) suffered from more Major Depressive Disorder and psychosis.This result echoes the results of the Sporn et al. 's retrospective study, showing that 25% of the 76 patients who reported early onset schizophrenia had a diagnosis of PDDs during their childhood, with a clear predominance of PDD-NOS (111).In a reference sample of childhood onset schizophrenia, Rapaport et al. also found a high frequency of PDD-NOS (112).
The importance of associated psychosis and mood disorder in PDDs also echoes past syndromic conceptualization such as Multiple Complex Developmental Disorder (MCDD) (113), Pathological Demand Avoidance (PDA) (114) or Multi-Dimensional Impairments (MDI) (115) which linked social impairment, emotional lability and signs of psychosis (without a diagnosis of early onset schizophrenia).These signs of psychosis referred to thought disorder (MCDD), delusions (MCDD), poor ability to distinguish fantasy from reality (MDI, PDA).It is important to stress that MCDD and PDA were initially coined to deal with heterogeneity within PDD-NOS.However, both syndromes were not limited to the PDD-NOS category (116,117).
The results of our review highlight that PDD-NOS was of great interest because of its high prevalence and clinical relevance.This diagnosis was useful to take into account milder forms of autism.However, it was less reliable and less stable through time than AD.Moreover, a qualitative study emphasized (118) that the autistic community might not acknowledge this diagnosis.This study was a phenomenological analysis of discussion forum dialog among 76 adult participants with self-reported diagnosis of AD and AS but not PDD-NOS (118).Participants constantly agreed that PDD-NOS should be removed in the DSM-5.Several participants expressed concern that the PDD-NOS diagnosis was not specific and reliable enough.They called the diagnosis "a junk category, " "a receptacle" (118).
Our review emphasized lower socio-communication impairments in PDD-NOS than in AD.In DSM-5, ASD diagnosis required three criteria out of three in this domain, namely deficits in socialemotional reciprocity, deficits in nonverbal communicative behaviors used for social interaction and deficits in developing, maintaining, and understanding relationship (2).To diagnose PDD-NOS, only two of them was required (18).It might therefore be suspected that the social and communication deficit characteristic of PDD-NOS wasn't important enough for it to remain in the autism spectrum.A review and meta-analysis (119) showed that 70% of PDD-NOS did not meet the criteria for ASD.Another hypothesis postulated that PDD-NOS might belong to the Social Communication Disorder (SCD) diagnosis category.However, this category must meet all three criteria for the social-communication domain, as in ASD (2).Thus, it appears that PDD-NOS has been excluded from ASD and SCD.
Our review challenged initial views of PDD-NOS and showed that this diagnosis mostly included milder forms of autism.PDD-NOS was very clinically relevant to deal with the margins of autism and the diversity within the spectrum.However, PDD-NOS encountered too many limitations (low reliability, instability through time, low acceptability) to be retained in the DSM-5.The fact is that many PDD-NOS did not join either ASD or SCD.Thus, in order to take into account past research on PDD-NOS and the margin of autism, we argue for the creation of a new category alongside ASD and SCD, based on three main dimensions related to socialization impairment, emotional lability and psychotic symptoms and coined on PDA, MCDD and MDI.Criteria for this new category could be selected from the most valid criteria for these three syndromes and tested against the ASD criteria, to ensure that they are truly distinct.In our view, this new category would provide an opportunity for mental health professionals, along with SCD and ASD, to better take into account the neurodevelopmental disorders that have an impact on the development of social communication and its heterogeneity.From a clinical point of view, this new category would trigger the search for associated psychotic symptoms or emotional lability that might currently be understudied by professionals.In addition, new developmental trajectories, specific interventions and treatments could be identified, which would in turn make it possible to better inform and help the people concerned and their families.

Limitations
The first limitation of our study comes from the terms selected for the database search.Few studies directly addressed differences between PDD-NOS and AD.However, when the DSM-IV-TR was in use, some studies included participants with PDDs including those with AD, PDD-NOS or another PDD subtype often compared to controls.In the latter case, PDD-NOS was only mentioned in the abstract or in the title when there was a difference within PDDs subgroups.That is why we may have over-selected references showing a difference between PDD-NOS and AD, and under-selected negative studies that did not.The second limitation is that we studied all clinical features of PDD-NOS.For example, some characteristics such as quality of life were rarely studied and were only related to two references.The third limitation is sample overlap between studies, as 25% of the studies were from Matson et al.Finally, our results cannot be extended to females with PDD-NOS, individuals with PDD-NOS and ID, or adults with PDD-NOS.

Conclusion
Our systematic review shows that PDD-NOS corresponds to milder form of autism with less impact and less associated disorder, with the exception of schizophrenia and mood disorder.Our review challenges initial views of PDD-NOS, echoes past syndromic conceptualizations such as MCDD, PDA or MDI, and argues for a quantitative and qualitative distinction between AD and PDD-NOS.The PDD-NOS diagnosis was very clinically relevant to deal with the margins of autism and the diversity within the spectrum, and therefore massively used by professionals in the field.However, PDD-NOS had many limitations (low reliability, instability through time, low acceptability) and was therefore understudied, thereby generating a discrepancy between clinical and research issues.Thus, in order to overcome this gap and to take into account past research on PDD-NOS, we suggest taxonomic changes in DSM-5, through the introduction of a new category based on three main dimensions: socialization impairment, emotional lability and psychotic symptoms.Future studies are therefore needed to test relevant criteria for this new category and possibly identify developmental trajectories, specific interventions and treatments.

TABLE 1
Autism symptoms in PDD-NOS in comparison of AD.

TABLE 2
Perinatal, developmental and functional aspects in PDD-NOS in comparison of AD.

TABLE 3
Associated mental health conditions in PDD-NOS in comparison with AD.

TABLE 4
Associated physical health conditions in PDD-NOS in comparison with AD.

TABLE 5
Longitudinal studies comparing developmental trajectories in AD and PDD-NOS.