Interstitial deletions of 7q11.23 cause the well-known Williams–Beuren Syndrome (WBS) (MIM 194050), while micro-duplication of the same region leads to 7q11.23 duplication syndrome (Dup7). WBS was first described in 1961 by J.C.P. Williams (1) and since the moment in which this non-allelic homologous recombination was reported, it has been supposed that a syndrome with the opposite picture would have existed, even though there were still no information about the phenotype. The first case of Dup7 was described only in 2005, when Somerville and colleagues tested a patient who showed severe expressive speech delay – a feature that was opposite to the linguistic characteristics seen in WBS (2).

In principle, microdeletions and micro-duplications of this specific region on the long arm of chromosome 7 were supposed to occur at the same frequency. However, while the prevalence of WBS is 1 in 7.500 live births, the prevalence of Dup7 is still unknown. It has been proposed that de novo prevalence of Dup7 could be 1/12.000, while parental transmission prevalence 1/7.500 live births (3).

The comparison between WBS and Dup7 phenotypes may represent a unique opportunity to better understand the brain functions in which the 7q11.23 section is involved.

Suggestive findings of WBS can be heterogeneous, however, they generally include characteristic “elfin-like” facial features (i.e., periorbital fullness, a stellate/lacy iris pattern, large ear lobes, wide mouth, prominent lips), feeding difficulties in childhood and cardiovascular diseases (usually supravalvar aortic stenosis) and ocular, endocrine and gastrointestinal abnormalities (4). Furthermore, people with WBS share a distinct neuropsychological, cognitive and behavioral phenotype, which counts mild to severe intellectual disability (ID), developmental delay (5), severely impaired visual spatial abilities (i.e., preferential processing of local forms and details; deficits in face processing) (6), anxiety problems, enhanced social motivation (i.e., “hypersociable behaviors,” lack of “stranger danger”) (7), and socio-communicative problems (deficits in shared attention, the understanding of social relationships, etc.) (8). In addition, people with WBS exhibit a characteristic linguistic profile, with receptive skills usually more impaired than expressive ones (9). On the other side, even though language skills have always been considered a strength in the WBS profile, they fail during everyday life-communication and community living, as studies on adaptive functioning showed (10, 11), in particular in adolescence (11).

Children with the reciprocal microduplication do not share distinct physical features, even if some recurring characteristics have been reported, including macrocephaly, broad prominent forehead, elongated palpebral fissures, short philtrum, thin lip vermilion and microstomia (12, 13). Furthermore, children with Dup7 may exhibit developmental delay and ID (usually in the mild range), behavior problems (selective mutism, anxiety disorders), ADHD (Attention Deficit Hyperactivity Disorder) and extreme shyness around strangers (14); moreover, individuals with Dup7 demonstrate language delay, with wide variability ranging from mild to severe expressive impairment (2). The receptive abilities seem to be considerably better than the expressive vocabulary (15).

The comparison of WBS and Dup7 represents an outstanding possibility for the neurobehavioral characterization of the 7q11.23 section. For instance, some “common,” “mitigated,” and “inverted” features have already been revealed. Common features between the two syndromes include anxiety problems and the presence of autistic features. Mitigated characteristics count ID and adaptive impairment, usually mild in children with Dup7 when compared to the ones with WBS. Instead, social motivation and verbal skills are usually considered as inverted characteristics (16, 17). In fact, while children with WBS are described as hyperverbal, hyper-sociable and with relatively spared expressive skills, children with Dup7 usually show selective mutism, social anxiety and impairment in expressive skills. Visuospatial cognition skills seem to be inverted too (spared in patients with Dup7 and impaired in WBS patients) (17).

In order to provide a more realistic clinical picture and then a logical basis for individualized supports, over the last two decades assessment of cognitive functioning has been integrated with measurement of adaptive functioning, which is more representative of behavior during everyday life. Indeed, AAIDD (American Association on Intellectual and Developmental Disabilities) postulates that “ID is characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills. This disability originates before age 18” (18). Therefore, adaptive behaviors should be always evaluated during ID assessment.

To our knowledge there are no studies comparing adaptive functioning of the above mentioned rare genetic conditions, therefore the main aim of this cross-syndrome study is to compare the adaptive functioning of two relatively small samples of children with molecularly confirmed diagnosis of WBS and Dup7, matched for chronological age and IQ.

The comparison between adaptive profiles in these syndromes could allow having further information on “common,” “mitigated,” and “inverted” features as expressed in daily life and to better understand if the reciprocal duplication of the region deleted in WBS leads to a different adaptive functioning or if on the contrary the two syndromes have a comparable phenotype. Based on previous studies, we expect to find significant differences in socialization domain and expressive subdomains, where children with WBS should reach better scores.

Despite on the greater or lesser knowledge on adaptive functioning on WBS and Dup7 alone, no cross-syndrome comparisons examining adaptive behavior have been carried out. However, delineating adaptive trends and potential phenotypic specificity between rare genetic syndromes is crucial to improve clinical-functional diagnosis and develop novel early interventions.

This brief report is the first attempt to investigate differences on adaptive functioning in two small samples of children with deletions of 7q11.23 and with microduplications of the same region.

Results showed that non-significant difference emerged between the two groups in domains, subdomains and in Adaptive Behavior Composite. These results are somehow unexpected, given the differences highlighted in the previous studies on neuropsychological and psychopathological features of the two syndromes [i.e., (15)]. On the other side, it has to be taken into account that the absence of significant results could be due to the small sample size; effectively, we selected a group of nine WBS to compare with a group of eight Dup7. Since these syndromes are particularly rare and considering the methodological decision to match individuals not only for age, but also for IQ, our sample size was inevitably small. This specification has to be considered when interpreting results.

Our findings could suggest that differences between these conditions could be due to other features such as cognitive level rather than to the genotype. Previous observation reporting that children with WBS usually have a worsening functioning in adaptive skills when compared to children with Dup7 could depend on the widest presence of severely cognitive impairment in population of individuals with WBS (14). However, when children with WBS are matched with Dup7 for chronological age and IQ, these differences in adaptive level seems to disappear.

Analysis of domains and subdomains also revealed interesting information. The absence of difference in Socialization was not expected. The inverted hyper-sociable (WBS) versus inhibited/social anxious behaviors (Dup7) profile, which has been reported in previous studies, in our groups seems not to conduct to different patterns in establishing relationships with peers and adults.

Furthermore, even though in our sample there is not a significant difference in Communication domain and subdomains between WBS and Dup7, expressive subscale of WBS seems to be more preserved than the one of Dup7, consistently with literature considering expressive skills of children with WBS and Dup7 as opposite (relatively preserved in WBS and severely compromised in Dup7). However, reminding that both populations exhibit a performance below 2 SD in each subdomain of Communication, a possible interpretation could be that children with Dup7 are not so more impaired in expressive skills than the ones with WBS as usually thought. For this reason, assessment of speech and language characteristics should include also other information; in fact, high level of social anxiety and selective mutism, as well as Disruptive Behavior Disorders (typical of children with Dup7), could at least partially account for this discrepancy. Moreover, while children with WBS are generally compliant with the examiner, children with Dup7 may show oppositional or inhibited behaviors that could lead to a poorer performance in structured evaluations. Generalized anxiety could contribute to the worsening of performance on language tests as well.

On the other side of the coin, children with WBS, which expressive abilities seem to be less impaired, when are evaluated with structured scales, show their real difficulties. For instance, they perform worse than people with Dup7 on tests that measure pragmatic and receptive skills that in WBS are usually more impaired than in Dup7. However, since VABS II do not deeply investigate pragmatic issues, potential significant differences may have not been emerged.

One previous study documented that communication skills measured by VABS II decrease during adolescence period in concomitance with enhancement of social demands, because of a specific worsening of receptive subdomain probably related to pragmatic skills (11). Due to the different language profiles, we would have expected differences between our two groups in the subdomains of communication but this did not happen. However, it should be noted that in our two samples the average age was about 10 years, so it cannot be excluded that the difference was not found due to the young age of our patients.

These considerations could suggest that assessment of language skills should always include batteries that measure pragmatic and daily-life usage of language. Likewise, evaluations should be conducted in a wider period in order to allow children with Dup7 to become more familiar with the clinical setting. In fact, only a more comprehensive evaluation could be able to clarify the reasons of eventual differences in language between those populations.

Furthermore, a slightly trend toward significance was found in Daily Life Skills – Personal Subdomain, which may indicate that WBS people probably show more difficulties in eating, dressing, self-care and personal hygiene than individuals with Dup7. Another difference, even though not achieving acceptable levels of statistical significance, was observed in Daily Life Skills – Community Subdomain, which may imply that WBS perform worse than Dup7 group in the ability to use money, to order food, to use technology and to read a clock. These tiny differences could be due to the visuo-spatial and coordination deficits largely described in WBS population [i.e., (30)].

Concerning within groups’ comparisons, analysis of VABS-II domains did not show significant differences in Dup7 group. Previous studies underlined that Dup7 profile is characterized by a weakness in language abilities, in particular in expressive skills (15). Our results, even though failing to reach statistical significance, are consistent with this finding, in fact in Dup7 group Communication Domain is the most impaired than other domains (Communication MED = 53, M = 53.38; Socialization MED = 69, M = 70.75; Daily Living Skills MED = 65.5, M = 66.25).

Taking into account WBS population, research has demonstrated that WBS is associated with deficits in adaptive functioning (31), where adaptive profile of children with WBS seems to be characterized by relative strengths in the Socialization and Communication domains and challenges in Daily Living Skills and Motor functioning (32). Our study is consistent with this line of evidence, in fact performance on Socialization Domain was significantly higher than Daily Living Skills one. This may indicate that the hyper-sociable behavior and the apparent expressive skills of WBS people may hide their real difficulties in adaptive functioning.

In conclusion, this pilot investigation suggests that, when matched for chronological and cognitive level, children with WBS and Dup7 share more similarities than thought. Differences that usually emerge in the clinical evaluation of expressive language and social motivation seem not to come up in the daily abilities to communicate and socialize with meaningful others. Then, differences popped out in previous indirect comparisons could be due to general and non-specific factors such as cognitive level, which is more severely impaired and inhomogeneous in individuals with WBS than in the ones with Dup7, rather than on syndrome-specific features. Therefore, this evidence could suggest that interventions for patients with WBS and Dup7 should target the same adaptive skills across all domains.

Our study has some limitations. First, the relatively small sample size may have not allowed to detect differences present in the general populations. Future studies on wider groups are then required to better compare the adaptive profiles of children with WBS and Dup7. Second, since adaptive behavior may change on the basis of different factors such as early interventions, it could be interesting to evaluate if other aspects influence the performance on VABS-II. Third, as we used developmentally appropriate cognitive assessment, different tests have been used to measure cognitive/developmental levels (i.e., Wechsler Scales and Leiter-3) that may have led to a heterogeneous evaluation. Then, future cross-syndrome studies should include a larger sample size and matched patients for the greatest number of features possible.

To conclude, using a cross-syndrome comparison approach revealed partially overlapping profiles in WBS and Dup7, despite the two groups being considerate opposite syndromes. However, as a whole, the two disorders remain distinct in the severity of their core difficulties. This study has some limitations, given the relatively small sample of evaluated subjects. Future studies on larger number of individuals with 7q11.23 deletion and duplication are necessary to support our data and deeper analysis is required to better investigate their adaptive functioning and to design innovative specific diagnostic measures and early novel interventions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Bambino Gesù Children’s Hospital number of protocol 1125. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

PA and FS conceived the study. PA, FS, and FAMM wrote the manuscript. CC and FAMM analyzed the data and assisted in the interpretation of findings. SV, PA, PB, and MLD critically reviewed the manuscript. All authors are agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, they provide intellectual input and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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