Early development and adaptive functioning in children with Bardet-Biedl syndrome
Abstract
This study had two aims. Aim one investigated achievement of 10 developmental milestones in children with Bardet-Biedl syndrome (BBS). Aim one data were derived from retrospective responses by caregivers of individuals with BBS who are enrolled in the Clinical Registry Investigating Bardet-Biedl syndrome (CRIBBS). CRIBBS is a natural history registry acquiring serial observations. Aim two investigated early adaptive skills using the Adaptive Behavior Assessment System (ABAS-II 0–5) completed by caregivers of children with BBS aged from 0 to 5. There were 652 individuals with milestone information (with some variability based on availability of information for specific milestones), and 101 individuals (including 95 among the 652) with ABAS-II information. Results revealed wide-ranging delays in adaptive skills, particularly in the domain of Self-Care. Expressive language appears to be the most frequently delayed developmental milestone. We found a difference by BBS genotype wherein individuals with BBS1 had higher adaptive/developmental scores than individuals with BBS10. Age also carried a significant association with adaptive skills diverging farther from a normative trajectory as children with BBS progress through early childhood.
1 INTRODUCTION
Bardet-Biedl syndrome (BBS) is a rare genetic condition that affects about 1:100,000 patients in North America and Europe (Forsythe et al., 2018). It is an autosomal recessive ciliopathy impacting multiple body systems. To date, 27 BBS genes have been identified, with the majority of cases involving BBS1 and BBS10. Primary features of BBS include polydactyly, retinal degeneration resulting in progressive visual impairment, obesity, renal and genital abnormalities, and developmental and cognitive delays.
Both human and animal research of BBS suggest that cilia dysfunction plays an important role in brain development, although the exact mechanisms are not fully understood (Haq et al., 2019; Louvi & Grove, 2011). For example, Haq et al. (2019) found that in a mouse model, BBS dysfunction is associated with dendritic abnormalities in the central nervous system, which likely plays a role in developmental and cognitive features of BBS. There is also a suggestion that the relationship between genotype and phenotype is complex with variable clinical presentations based on genetic findings (Niederlova et al., 2019). While developmental delays are widely recognized as a feature of BBS, limited information is available about the degree and specific characteristics of the difficulties patients face.
Some investigations of adaptive functioning in individuals with BBS exist, although none to our knowledge examine the 5 and under age group specifically. Kerr et al. (2016) examined adaptive functioning in 24 individuals with BBS between the ages of 6 and 38 using the Scales of Independent Behavior-Revised. They found that 13% of participants were rated to have broadly average functional independence, 13% had moderately impaired independence skills, and 73.9% were severely impaired. Ten individuals (43.5%) were rated as broadly average in their social communication skills, 26% were moderately impaired, and 30.5% were severely impaired. For personal and community living skills, 60.9% and 65.2%, respectively, were rated to have severe impairments. Additional analyses revealed that verbal and visual–spatial intellectual skills were significantly correlated with a broad level of independence while visual acuity, visual fields, and BBS type (1, 10, or “other”) were not.
Brinckman et al. (2013) analyzed adaptive skill ratings from the Behavior Assessment System for Children for 13 participants with BBS ranging in age from 2 through 21. The mean adaptive skills T-score was 47.15 (mean = 50). There was a notable amount of variability with a standard deviation of 12.98. Unfortunately, these investigations largely represent the extent of formal assessments of adaptive functions in individuals with BBS. Our first aim is to describe achievement of 10 developmental milestones in children with BBS. The second aim is to characterize early adaptive skills in children with BBS (age 0–5) using the ABAS-II.
2 MATERIALS AND METHODS
2.1 Participants
Information for this study was drawn from the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS), an open-enrolling international database designed to record health information and outcomes in individuals with BBS on a yearly basis (ClinicalTrials.gov: NCT02329210). The present analysis included individuals with clinical features meeting established diagnostic criteria for BBS (Beales et al., 1999). Prior to patient inclusion in CRIBBS, informed consent was obtained from enrollees or their legal guardians. All registry procedures were approved by the Marshfield Clinic Health System Institutional Review Board. As a part of the registry, a senior research coordinator conducts yearly phone interviews updating health information. Participants or legal guardians are also asked to complete certain questionnaires.
For Aim 1 of the study investigating achievement of 10 developmental milestones, 652 unique individuals had an informative response (Yes or No) in the database for at least one milestone question. The number of participants varied somewhat depending on the milestone as participants could refuse to answer or could mark that they did not know the answer. The developmental milestone questions are presumed to have been answered by the participants' caregivers who were involved from infancy. The sample was roughly split evenly by gender. Additional demographic information is available in Table 1. The mean participant age at which the developmental milestone information was asked was 15.9 with a standard deviation of 12.8 years and a range from 3 months to 68 years.
| Milestones cohort (652 participants) | ABAS II cohorta (101 participants) | |
|---|---|---|
| Sex | ||
| Male | 50.6% | 49.5% |
| Female | 49.4% | 50.5% |
| Age (years) | ||
| Minimum | 0.1 | 0.2 |
| Maximum | 68.6 | 5.9 |
| Median | 13.2 | 2.8 |
| Race and ethnicity | ||
| Asian | 5.4% | 7.9% |
| Black | 2.3% | 1.0% |
| Hispanic | 12.7% | 7.9% |
| White | 77.1% | 72.3% |
| Other | 15.0% | 13.9% |
| Unknown | 1.7% | 10.9% |
- a ABAS II cohort limited to Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) participants < 6 years at testing; 95 of 101 participants in the ABAS II cohort are also in the Milestones cohort.
For Aim 2 investigating adaptive functioning in children with BBS ages 0–5 using the ABAS-II, 101 individuals who had this information in the database were used (all but 6 of the 101 were among the milestone cohort). The age-appropriate ABAS-II is administered at the time of enrollment in the registry and every year after that. For some participants who were younger at the time of their first assessment, up to five ABAS-II forms were on file with additional information each year as the child grew and met milestones. Out of 101 individuals, 54% had one ABAS-II completed, 26% had two, 14% had three, and 6% had four or five. The mean age of assessment was 3.1 with a standard deviation of 1.5. Additional demographic information is presented in Table 1.
2.2 Materials
The ABAS-II questionnaire (Harrison and Oakland, 2003) assesses adaptive skills in individuals from birth to 89 years of age. It is a norm-referenced measure providing standardized scores across several adaptive domains. A parent or primary caregiver completes the infant and preschool age form (0 to 5). Therefore, participants were under the age of 6. The assessed skill areas include Communication (e.g., “Looks at others' faces when they are talking”), Community Use (e.g., “Recognizes own home in his/her immediate neighborhood”), Functional Pre-Academics (e.g., “Points to pictures in books when asked, for example, points to a horse or a cow”), Home Living (e.g., “Removes cookies, chips, or other food from a box or a bag”), Health and Safety (e.g., “Cries or whimpers when he/she does not feel well or is injured”), Leisure (e.g., “Plays with a single toy or game for at least one minute”), Self-Care (e.g., “Swallows liquids with no difficulty”), Self-Direction (e.g., “Shows interest in a toy or other object by looking at it for a few seconds”), Social (e.g., “Smiles when he/she sees parent”), and Motor (e.g., “Follows a moving object by turning head”). Parents/caregivers have to rate each behavior on a scale from 0 (is not able) to 3 (always or almost always when needed). In addition to Scaled Scores (mean = 10, SD = 3) for each skill area, the ABAS-II provides composite scores in four domains: Practical, Social, Conceptual, and General Adaptive Composite (mean = 100, SD = 15). The Practical domain provides a summary score for daily living skills and is composed of Self-Care, Health and Safety, Home Living, and Community Use skill areas. The Social domain describes interpersonal and social competence skills and is comprised of Social and Leisure skill areas. Self-Direction, Communication, and Functional Pre-Academics are skill areas included in the Conceptual domain, which rates general communication and early academic skills. The General Adaptive Composite is the overall summary score that combines all of the skill areas.
The developmental milestones information derives from a yearly questionnaire that is conducted by phone with CRIBBS participants and/or their caregivers. It is presumed that caregivers provided the information on developmental milestones, though perhaps indirectly in the case of older individuals with BBS. The questionnaire assesses various areas of health to provide an update on health status and changes. We used 10 developmental milestone questions that closely follow CDC milestones as described in Zubler et al. (2022). Timelines for milestones are determined by at least 75% of children achieving the milestone by a certain age. An example of a developmental question included in the CRIBBS questionnaire is, “By four months, did (name of individual) smile spontaneously at parents or caregivers?” The response options are “Yes,” “No,” “Don’t Know,” or “Not Applicable.” In this case, based on CDC data, at least 75% of children achieve this milestone by 4 months. The developmental milestone questions are not repeated if a response has been provided previously.
2.3 Statistical analyses
Descriptive summaries are presented to characterize the BBS cohort with regard to achievement of developmental milestones and adaptive functioning based on the ABAS-II scores. Estimated percentages achieving milestones are presented with 95% confidence limits and p-values for Fisher's exact test comparing groups. Comparisons of milestone achievement rates and ABAS-II scores among individuals with BBS1 and BBS10 are compared using mixed linear models to allow for repeated measures within individuals, and these models include covariate adjustment for age. Comparisons are reported as statistically significant at the common 5% level (p < 0.05) without adjustment for multiple comparisons (Perneger, 1998).
3 RESULTS
3.1 Developmental milestones
Since CDC determines timelines for milestones based on a percentage of children (at least 75%) achieving the milestone by a certain age, this is how we present the 10 developmental milestones for children with BBS (Table 2). According to parent/caregiver responses for the full cohort, by the age of 4 months, 83% of children with BBS were reported to hold their head up steady and unsupported. Sixty-nine percent of children with BBS walked by the age of 18 months. Sixty-four percent used a spoon to feed themselves by 18 months and 61% began to run by age two. With regard to social and cognitive milestones, by the age of 4 months, 83% of children with BBS would smile spontaneously at parents or caregivers. By the age of 9 months, 72% were reported to play peek-a-boo or other interactive games. By the age five, 74% were reported to be able to print some letters or numbers. For speech milestones, 84% of children with BBS were reported to use gestures or pointing to indicate a want or a need before age 2. Fifty-four percent spoke their first word before 1 year old and 50% could put two words together before 2-years-old.
| Reports within 24 months of Milestone reference age | ||||||
|---|---|---|---|---|---|---|
| Full cohort (Total N = 652) | (Total N = 179) | |||||
| 95% confidence | 95% confidence | |||||
| Milestone | N | % | Interval | N | % | Interval |
| By 4 months, smile spontaneously at parents or caregivers? | 617 | 83.5 | (80.5, 86.4) | 65 | 89.2 | (81.7–96.8) |
| By 4 months, hold his/her head up steady, unsupported? | 613 | 82.9 | (79.9, 85.9) | 64 | 79.7 | (69.8–89.5) |
| By 9 months, play peek-a-boo, or other interactive games? | 600 | 71.8 | (68.2, 75.4) | 75 | 57.3 | (46.1–68.5) |
| By 18 months, walk alone without hands held? | 623 | 69.3 | (65.7, 73.0) | 92 | 71.7 | (62.5–80.9) |
| By 18 months, use a spoon to feed self? | 603 | 64.2 | (60.4, 68.0) | 92 | 45.7 | (35.5–55.8) |
| By 2 years, begin to run? | 608 | 61.3 | (57.5, 65.2) | 105 | 66.7 | (57.6–75.7) |
| By 5 years, begin to print some letters or numbers? | 565 | 73.8 | (70.2, 77.4) | 111 | 61.3 | (52.2–70.3) |
| Speak first word before 1-year-old? | 600 | 54.2 | (50.2, 58.2) | 78 | 41.0 | (30.1–51.9) |
| Put two words together before 2-years-old? | 581 | 49.6 | (45.5, 53.6) | 98 | 18.4 | (10.7–26.0) |
| Use gestures or point to indicate a want or need, before 2-years-old? | 605 | 83.8 | (80.9, 86.7) | 104 | 75.0 | (66.7–83.3) |
In examining the developmental milestones by gender, Fisher's p-value was significant only for printing letters or numbers by age five (p = 0.03) with a higher percentage of girls reported to achieve this milestone by age 5 (78% vs. 70% in boys).
Table 2 also presents the milestone data limiting recall duration by including only those individuals for whom milestones were reported within a 2-year window of when the milestone was expected to be achieved by the majority of typically developing children. This resulted in a subgroup of 179 total individuals, with the numbers evaluated varying substantially depending on the milestone and reference age. In a qualitative comparison of percentages of Yes responses (signifying that the milestone has been achieved), the percentage for the subgroup was higher for three milestones and lower for seven. The most significant differences were in milestones addressing language development, printing letters/numbers, using a spoon, and playing interactive games like peek-a-boo. In the subgroup, a lower percentage of children was reported to accomplish those milestones by the reference age. In examining the pattern of milestone achievement, speech milestones (single words and tying words together) have consistently the lowest percentages across the whole cohort and the subgroup.
When BBS1 and BBS10 genotypes were compared (Table 3), there was a significant difference in some motor skills, including holding their head up unsupported by 4 months (p = 0.03; 91% in BBS1 group and 82% in BBS10 group), using a spoon to feed themselves by 18 months (p = 0.02; 74% in BBS1 group and 59% in BBS10 group), and running by age two (p = 0.01; 70% in BBS1 group and 54% in BBS10 group).
| BBS1 (N = 168 total subjects) | BBS10 (N = 105 total subjects) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 95% confidence interval | 95% confidence interval | ||||||||
| Milestone | N | % Yes | Lower | Upper | N | % Yes | Lower | Upper | p-value |
| By 4 months, smile spontaneously at parents or caregivers? | 162 | 88.3 | 83.3 | 93.2 | 102 | 82.4 | 75.0 | 89.8 | 0.159 |
| By 4 months, hold his/her head up steady, unsupported? | 163 | 91.4 | 87.1 | 95.7 | 101 | 82.2 | 74.7 | 89.6 | 0.031 |
| By 9 months, play peek-a-boo, or other interactive games? | 159 | 76.1 | 69.5 | 82.7 | 98 | 73.5 | 64.7 | 82.2 | 0.854 |
| By 18 months, walk alone without hands held? | 163 | 78.5 | 72.2 | 84.8 | 98 | 68.4 | 59.2 | 77.6 | 0.070 |
| By 18 months, use a spoon to feed self? | 160 | 74.4 | 67.6 | 81.1 | 93 | 59.1 | 49.1 | 69.1 | 0.024 |
| By 2 years, begin to run? | 158 | 69.6 | 62.4 | 76.8 | 97 | 53.6 | 43.7 | 63.5 | 0.011 |
| By 5 years, begin to print some letters or numbers? | 152 | 80.3 | 73.9 | 86.6 | 90 | 83.3 | 75.6 | 91.0 | 0.462 |
| Speak first word before 1-year-old? | 157 | 57.3 | 49.6 | 65.1 | 98 | 55.1 | 45.3 | 64.9 | 0.811 |
| Put two words together before 2-years-old? | 154 | 53.9 | 46.0 | 61.8 | 90 | 52.2 | 41.9 | 62.5 | 0.999 |
| Use gestures/point to indicate a want/need, before 2-years-old? | 158 | 88.0 | 82.9 | 93.0 | 94 | 81.9 | 74.1 | 89.7 | 0.236 |
3.2 ABAS II (parent/primary caregiver form for ages 0–5)
Mean Scaled Scores for each skill area, as well as Composite Scores, are presented in Table 4. All of the Scaled and Composite score means for individuals with BBS were significantly lower than the corresponding normative mean (p < 0.001), with relatively wide standard deviations, reflecting the variability of scores in this population. The highest mean Scaled Scores were in skill areas of Leisure and Self-Direction (7.2 and 7.1, respectively). Clinically, these would be interpreted to be in the low average range compared to similarly-aged peers in the normative sample. The lowest score was in the area of Self-Care (4.1), which is nearly two standard deviations below the mean.
| 95% confidence interval | ||||
|---|---|---|---|---|
| Skill areas | n | Mean score | Lower | Upper |
| Communication | 101 | 5.7 | 5.1 | 6.4 |
| Community use | 94 | 6.0 | 5.3 | 6.7 |
| Functional pre-academics | 94 | 6.6 | 5.8 | 7.4 |
| Home living | 94 | 6.2 | 5.4 | 6.9 |
| Health and safety | 101 | 6.2 | 5.5 | 6.8 |
| Leisure | 100 | 7.3 | 6.6 | 8.0 |
| Self-care | 101 | 4.1 | 3.7 | 4.6 |
| Self-direction | 101 | 7.1 | 6.5 | 7.7 |
| Social | 101 | 6.2 | 5.5 | 6.9 |
| Motor | 100 | 5.8 | 5.2 | 6.5 |
| 95% confidence interval | ||||
|---|---|---|---|---|
| Composite | n | Mean score | Lower | Upper |
| General adaptive | 101 | 72.6 | 68.8 | 76.4 |
| Conceptual | 101 | 77.0 | 73.3 | 80.6 |
| Social | 101 | 79.6 | 75.8 | 83.3 |
| Practical | 101 | 72.1 | 68.3 | 75.9 |
To examine adaptive functioning by BBS genotype, analyses were limited to the most common BBS genotypes 1 and 10 (Table 5). Due to the fact that some of the participants had several ABAS-II forms completed, we used repeated measures analysis (mixed linear model) with a covariate adjustment for age because the ages at the first available ABAS-II form were significantly lower in participants with BBS10 compared to BBS1 (p = 0.02). Results for this analysis are demonstrated in Table 5. Qualitatively examining the standard scores, it is noticeable that individuals with BBS10 have lower scores on all composite and scaled scores. The analysis revealed that the GAC was significantly higher for individuals with BBS1 compared to BBS10 (80.9 and 67.4, p = 0.004). Similarly, individuals with BBS1 had higher scores in other composite areas (Conceptual, Social, and Practical). In examining the Scaled Scores, there were significant differences on 6 out of the 10 skill areas, again with a clear pattern of individuals with BBS1 having higher scores than individuals with BBS10. The most significant differences were found in areas of Health and Safety and Motor. Other areas that were significantly different included Communication, Community Use, Leisure, and Social.
| BBS1 | BBS10 | |||||
|---|---|---|---|---|---|---|
| Skill areas | n | Adjusted mean SS | n | Adjusted mean SS | Gene p | Age p |
| Communication | 44 | 6.9 | 54 | 5.2 | 0.024 | 0.043 |
| Community use | 40 | 7.1 | 44 | 5.4 | 0.022 | 0.061 |
| Functional pre-acad. | 40 | 7.2 | 45 | 6.7 | 0.548 | 0.538 |
| Home living | 40 | 7.0 | 46 | 6.4 | 0.445 | 0.931 |
| Health and safety | 44 | 7.7 | 54 | 5.2 | <0.001 | <0.001 |
| Leisure | 44 | 8.7 | 54 | 6.7 | 0.020 | <0.001 |
| Self-care | 44 | 4.7 | 54 | 3.8 | 0.123 | <0.001 |
| Self-direction | 44 | 8.2 | 54 | 6.9 | 0.081 | 0.033 |
| Social | 44 | 7.2 | 54 | 5.4 | 0.029 | 0.008 |
| Motor | 43 | 7.4 | 51 | 4.8 | 0.003 | 0.895 |
| Composite | n | Adjusted mean score | n | Adjusted mean score | Gene p | Age p |
|---|---|---|---|---|---|---|
| General Adaptive | 44 | 80.9 | 54 | 67.8 | 0.004 | <0.001 |
| Conceptual | 44 | 83.7 | 53 | 75.5 | 0.037 | 0.016 |
| Social | 44 | 86.6 | 53 | 75.8 | 0.020 | <0.001 |
| Practical | 44 | 77.9 | 54 | 68.8 | 0.027 | 0.001 |
In a repeated measures analysis of scaled scores for the entire sample of individuals with BBS, the effects of gender (male/female) were not significant (p = 0.187) but the effects of age were (p < 0.001). To characterize this in another way, the mean of all scaled scores was 7.9 for children 0–1, 5.7 for children 2–3, and 4.7 for children 4–5. If the analysis is broken down between individuals with BBS1 and BBS10, the effect of age remains significant, although less so in the BBS1 sample (p = 0.033 for BBS1 and p < 0.001 for BBS10). The effects of age appear to be most significant for skill areas of Health and Safety, Leisure, Self-Care, and Social.
4 DISCUSSION
The study examined early developmental milestones in a large sample (652) of individuals with BBS derived from CRIBBS. The second aim of the study was to examine early adaptive skills in a smaller subset of participants ranging in age from 0 to 5 using the ABAS-II. Our goal is to expand knowledge regarding cognitive, adaptive, and behavioral characteristics of individuals with BBS through a series of subsequent investigations based on information contained in CRIBBS. To our knowledge, this study includes the largest number of individuals with BBS compared to previously published studies. It is also the first study to specifically examine early development up to the age of 6.
- With regard to developmental milestones, expressive language delays were found most frequently in children with BBS compared to motor and social/communication milestones available for analysis. This was true even when we limited the recall duration by evaluating subgroups with reports within 2 years of the milestone reference age.
- When developmental milestones were compared in subsets of participants divided by BBS genotype (BBS1 and BBS10), a lower percentage of participants with BBS 10 was rated to achieve independent head holding by 4 months, unsupported walking by 18 months, self-feeding with a spoon by 18 months, and running by 2. There was no significant difference between the two genotypes on speech milestones.
- Overall, there are significant differences in early adaptive skills between children with BBS and normative samples. Based on ABAS-II ratings, Self-Care is the most affected area of early adaptive skills.
- Individuals with BBS10 tend to have lower early developmental/adaptive skills compared to individuals with BBS1.
- Adaptive skill ratings tend to be higher at a younger age compared to older age within the 0–5 range.
Overall, when summary scores are considered, such as those provided by the ABAS-II 0–5, children with BBS receive significantly lower ratings in all summary measures of development, including the General Adaptive, Conceptual, Social, and Practical Composites. Leisure and Self-Direction skill domains represented relative strengths, although they were still on average one standard deviation below the mean (approximately 16th percentile). The Self-Care domain represented a relative weakness with a mean scaled score around the second percentile for age. The developmental milestone data provides a more granular look at specific areas of development. Language development, such as saying first words around age one and tying two words together around age two, appear to be the most frequently observed delays with around 50% of children with BBS reaching these milestones by age one and two, respectively, compared to 75% of typically developing children according to CDC guidelines. Based on the milestone analysis, a greater percentage of children with BBS10 had a delay in their ability to independently support their head, walk, run, and feed themselves with a spoon compared to children with BBS1. Analysis of ABAS-II Motor skill area between the two groups revealed a highly significant difference with children with BBS1 obtaining significantly higher ratings of motor skills compared to children with BBS10. There were no significant differences in participants with BBS1 and BBS10 in achievement of speech milestones. However, when the ABAS-II Communication skill area was compared in children with BBS1 and BBS10, there was a significant difference with BBS1 group receiving higher ratings than BBS10 group. We can cautiously interpret this as meaning that more children with BBS10 have delays in motor development compared to children with BBS1 based on both ways of looking at the information. The case with speech development is less clear but it appears that children with BBS10 potentially demonstrate similar or greater rates of speech delay compared to children with BBS1.
Through both ABAS-II 0–5 and milestone data analysis, a pattern emerged of generally lower adaptive skills in individuals with BBS10. Kerr et al. (2016) did not find that BBS gene type was associated with a broad level of independence but their sample consisted of only 24 individuals. In a more recent meta-analysis of genotype–phenotype associations in BBS, Niederlova et al. (2019) showed that there were significant differences in clinical presentation in different types of BBS. For example, they found that polydactyly was more frequent in BBS10 compared to BBS1. Since this is a feature visible at birth, this may help explain why individuals with BBS10 were on average identified earlier than individuals with BBS1 in our CRIBBS database. The same study revealed that individuals with BBS1 were reported to have a lower “syndromic score” than individuals with BBS2 or BBS7. The “syndromic score” consisted of the number of five core symptoms an individual has (retinal dystrophy, obesity, polydactyly, cognitive impairment, and renal anomalies) divided by 5. The authors concluded that individuals with BBS1 had milder disease compared to individuals with BBS10, which was mainly driven by lower prevalence of polydactyly and renal anomalies in individuals with BBS1. The current study extends these conclusions to suggest that there are differences in developmental and adaptive functioning based on genotype. Data from the ABAS-II 0–5 revealed that all composite scores, including the overall General Adaptive Composite, were significantly higher in individuals with BBS1 compared to BBS10. In six out of ten specific skill areas, there was a significant difference consistently showing higher scores in participants with BBS1. The most significant differences were observed in domains of Health/Safety and Motor. The developmental milestone data further supported this pattern. For example, 82% of individuals with BBS10 were able to hold their head up unsupported by 4 months versus 91% with BBS1. Seventy-four percent of individuals with BBS1 were rated as able to run by age 2 whereas the percentage was 59% in participants with BBS10.
A pattern of higher adaptive scores for younger participants and lower for older participants (within the 0–5 age range) was observed in the ABAS-II data. Rather than representing a decline, this likely represents a separation of children with BBS into a different developmental trajectory compared to typically developing children. In other words, as adaptive tasks become more complex, children with BBS on average have greater difficulty meeting the expected timelines. This has been referred to as “developmental divergence” in some literature (Will et al., 2019).
Analysis for gender differences was not significant within the entire sample on ABAS-II 0–5. For the developmental milestones, a greater percentage of girls with BBS were able to acquire early literacy skills (printing of some letters or numbers) by age 5 compared to boys with BBS. The significance of this is unclear. Some research suggests that girls in the general population do better than boys on measures of early literacy. However, this relationship is complex and is mediated by other factors, such as socioeconomic status and educational opportunities (Lee & Otaiba, 2015). What emerged from our analysis is that BBS type appeared to be more impactful in terms of adaptive skills than gender.
Limitations of this project include the retrospective nature of the data. Many individuals with BBS are not diagnosed with the syndrome until mid-childhood or adolescence, which means that parents/caregivers often report early developmental milestones based on their recall. This introduces a potential source of error. Research examining retrospective reporting of developmental milestones and symptoms has revealed a significant amount of complexity and intervening factors that influence the accuracy of the report. Some retrospective parental reporting has been found to be quite accurate (Natland et al., 2012). This is particularly the case for “hard” milestones, such as first steps. It should not be assumed that parents tend to retrospectively provide a more positive report of their children's development than what it actually was. In fact, there are well-documented “telescoping effects” that can result in forward telescoping (reporting milestones being achieved later than they actually happened) and backward telescoping (reporting milestones to be achieved earlier than they were actually achieved; Ozonoff et al., 2018). It has been reported that parents of children who continue to have developmental and adaptive challenges are more likely to engage in forward telescoping (Hus et al., 2011). We aimed to present the milestone data in two different ways for readers to consider (Table 2). The advantage of considering the entire sample is that a larger number of participants likely helps to alleviate some of the variability in retrospective reporting. Based on the discussion above, data from the 179-participant subset (for whom milestones were reported within 2 years of target achievement) should be interpreted with caution as there are confounding variables that could be influencing the data, such as earlier age at diagnosis, earlier enrollment in the registry, and BBS genetic subtype. For example, factors that could be involved in earlier enrollment in the registry may include greater developmental delays resulting in an earlier diagnosis, which may skew the data in the direction of greater delay for the younger subset. An additional point to consider is that the broad age range in the study creates the possibility that access to diagnosis and early interventions/resources varied among participants, thus conceivably influencing developmental milestones and early adaptive skills. The limitations of retrospective data certainly need to be kept in mind in interpreting the findings of this project. The goal was to identify informative trends and patterns, as well as develop hypotheses for prospective investigations.
Knowing that developmental and adaptive functioning delays are observed early in children with BBS, earlier identification and intervention should be important goals to improve outcomes for individuals with BBS. Furthermore, while deriving data from the CRIBBS allowed us to have a relatively large sample size, there is likely a selection bias with regard to who becomes involved in the database and who completes the telephone interviews and questionnaires. Even with the large sample, we did not have enough individuals with various BBS genotypes besides BBS1 and BBS10 to complete meaningful statistical analyses. As this and other recent research have suggested, BBS phenotype seems to vary based on the genotype, making this an important area of future study. Knowing which clinical conditions are more likely to be associated with certain genotypes could help clarify prognosis, direct more careful personalized care, and provide targeted intervention. This work also highlights the importance of early and baseline assessment of developmental, adaptive, and behavioral features using standardized assessment methods in all children diagnosed with BBS. This would help track developmental trajectories in a more consistent and systematic manner, allowing for targeted intervention and evaluation of progress/improvement in both clinical and research settings.
AUTHOR CONTRIBUTIONS
Ekaterina Keifer: Conceptualization, methodology, project administration, supervision, writing-original draft preparation. Richard Berg: Conceptualization, methodology, data curation, formal analysis, visualization, writing-review and editing. Jesse Richardson: Conceptualization, data curation, resources, software, project administration. Robert Haws: Conceptualization, resources, writing-review and editing.
ACKNOWLEDGMENTS
The authors are grateful to David S. Puthoff, PhD for his careful review of the manuscript.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data are available upon request from the corresponding author. The data are not publicly available due to privacy and ethical considerations.
