Bardet‐Biedl syndrome: Weight patterns and genetics in a rare obesity syndrome

Summary Background Bardet‐Biedl syndrome (BBS) is a rare genetic disorder that severely inhibits primary cilia function. BBS is typified by obesity in adulthood, but pediatric weight patterns, and thus optimal periods of intervention, are poorly understood. Objectives To examine body mass differences by age, gender, and genotype in children and adolescents with BBS. Methods We utilized the largest international registry of BBS phenotypes. Anthropometric and genetic data were obtained from medical records or participant/family interviews. Participants were stratified by age and sex categories. Genotype and obesity phenotype were investigated in a subset of participants with available data. Results Height and weight measurements were available for 552 unique individuals with BBS. The majority of birth weights were in the normal range, but rates of overweight or obesity rapidly increased in early childhood, exceeding 90% after age 5. Weight z‐scores in groups >2 years were above 2.0, while height z‐scores approached 1.0, but were close to 0.0 in adolescents. Relative to those with the BBS10 genotype, the BBS1 cohort had a lower BMI z‐score in the 2‐5 and 6‐11 age groups, with similar BMI z‐scores thereafter. Children with biallelic loss of function (LOF) genetic variants had significantly higher BMI z‐scores compared to missense variants. Conclusion Despite normal birth weight, most individuals with BBS experience rapid weight gain in early childhood, with high rates of overweight/obesity sustained through adolescence. Children with LOF variants are disproportionally affected. Our findings support the need for earlier recognition and initiation of weight management therapies in BBS.

ciliopathy. 1 The centrality of obesity in the syndrome was recognized at least one century ago when the French physician Georges Louis Bardet submitted his 1920 thesis on hypothalamic obesity describing two French girls with polydactyly, obesity and retinitis pigmentosa. 2 Hungarian pathologist-endocrinologist Artur Biedl further defined the BBS phenotype 2 years later in his description of siblings with obesity, cognitive impairment, polydactyly, and genital anomalies. 3 Although the mechanisms for obesity in BBS remains incompletely understood, disruption of the hypothalamic leptin-melanocortin signaling pathway is evident, and BBS may provide insights into obesity in other monogenic and syndromic obesity disorders. 4,5 Rates of overweight and obesity in mixed populations of children and adults with BBS exceed 70%. [6][7][8][9] The majority of individuals with BBS have some level of excess body weight by adulthood; however, weight gain patterns in childhood and adolescence remain unclear.
Systematic examination of growth patterns in early life have not been rigorously examined, and gender-specific growth patterns are unexplored. At least 25 causative genes have been identified in BBS. [10][11][12] Previous reports document that truncating variants in BBS genes predict greater risk for severe chronic kidney disease and increased cardiovascular disease markers compared to missense variants. 13,14 Similar obesity genotype-phenotype correlations have not been explored in BBS. Rare disease registries employed to examine weight patterns and genotype-phenotype correlations could provide further insight into rare obesity syndromes. 15 In this study, we used a natural history registry to explore the prevalence of overweight and obesity in the largest known international pediatric BBS cohort. We examined BBS growth patterns in infancy, childhood, and adolescence. A second objective was to explore genotype and phenotype correlations with specific attention to the two most common BBS genotypes in North America, namely BBS1 and BBS10. Furthermore, we explored BBS variants based on their role in primary cilia function-the cellular organelle disrupted in BBS-and the role of loss of function variants in disease expression.

| Statistical Analyses
Data were analyzed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina). Participants were stratified by sex and grouped by age, with groups consisting of <2 years (not including birth weight), age 2-5 years, 6-11 years and 12-19 years. When a participant had more than one height/length and weight measurement within an age group, the median z-score was calculated and used in the analysis. Frequencies of overweight and obesity were calculated using both the WHO Child Growth Standards 16 and the International Obesity Task Force (IOTF) BMI cut-offs. 20 WHO standards define overweight as >2 SDs above the WHO Growth Standards median of weight-for-length for children under 5 years-of-age and > 1 SD above the WHO Growth Standards median BMI-for-age for children ages 5 to 19. Obesity is defined as >3 SDs above the WHO Growth Standards median for weight-for-height for children under 5 years-of-age and >2 SDs above the WHO Growth Standards median BMI-for-age for children ages 5 to 19. The IOTF uses BMI cut-offs for age and sex that correspond to adult overweight (BMI > 25 kg/m 2 ) or obesity (BMI > 30 kg/m 2 ). BMI z-scores (zBMI) were calculated using the WHO LMS method. 21 Comparisons of zBMI between boys and girls, as well as by genotypes, variant types, and protein groups, were evaluated with Kruskal-Wallis nonparametric tests stratified by age group. Two-tailed p values were considered significant at <0.05., without adjustment for multiple comparisons.

| RESULTS
This analysis included 453 length and weight measurements in 119 participants less than 2 years of age (not including birth weight), and height and weight measurements in 509 participants 2 years of age and older. We included 3674 height or length and weight measurements overall.
The majority of birth weights were normal with 376 (84%) under 4000 g. Of the 73 participants with a birth weight greater than 4000 g, 58 (79%) had a birth weight of 4000-4499 g, 14 (19%) had a birth weight of 4500-4999 g, and 1 participant (1.3%) had a birth weight of 5000 g or greater.
Of the 61 preterm births, 54 were moderately preterm (32 to 37 weeks), 6 were very preterm (28 to 32 weeks) and 1 was extremely preterm (less than 28 weeks). The majority of preterm births were appropriate for gestational age (69.5%), including 71.7% of moderately preterm and 50% of very preterm births. Large for gestational age occurred in 28.3% of the moderately preterm and 50% of the very preterm births. Small for gestational age occurred in 1 (1.9%) moderately preterm birth and in the only extremely preterm birth.

| Overweight/Obesity
The participants in each age group who had obesity, overweight, or did not have obesity or overweight were determined using the WHO Child Growth Standards (Table 1A) and IOTF Standards (Table 1B). In categories above age 2 years, obesity is common using either standard. Only the WHO standards include reference for children under the age of 2. In those under 2 years, 23% of participants had obesity and 56% had overweight or obesity. The prevalence of obesity or overweight increased in the 2-5 age group to 79%, with 60% having obesity. Over 70% of all age groups had obesity using the IOTF standards with the prevalence of overweight or obesity ranging from 86% to 95%.

| Length or height z-scores by age group
The length or height z-scores by age group are shown in Figure 1A. The height z-scores for all age groups <12 years were above average, with the median length or height z-scores ranging from 0.5 to 1 and no significant differences between girls and boys. The height z-scores for the 12-19 age group were closer to 0. There was a significant difference in height z-scores between girls and boys for the 12-19 any age group; boys had significantly higher z-scores than girls did (Kruskal-Wallis P = .0076). Note: Data expressed as n (%). a The less than 2 years age group does not include birth weight. Without overweight/obesity, overweight, and obesity defined using the World Health Organization weight status categories 16 (Table 1A) and the International Obesity Task Force 20 (Table 1B). Weight status categories are based on zWFL for less than 2 years age group and zBMI for ages 2 and above.

| Body mass index z-scores by age group
The BMI z-scores by age group are shown in Figure 1B. The median z-scores for all age groups were above 2. The highest median z-scores were in the 2-5 age group. The only between sex difference was in BMI z-scores for the 12-19 age group; girls had significantly higher z-scores than boys did (Kruskal-Wallis P = .0180).

| Body mass index scores in BBS1 and BBS10 cohorts
Biallelic pathogenic variants in BBS1 (n = 144) and BBS10 (n = 86) were the most common cause of BBS in our cohort. Comparisons of zBMI by age group, in patients with pathogenic variants in BBS1 and BBS10, are shown in Figure 2A.

| Body mass index scores and variant classification
Comparisons of z-score for BMI by age group and variant type are shown in Figure 2C. BBS is usually inherited in an autosomal recessive manner. Individuals with two pathogenic variants in one BBS gene were used for this analysis. There were significant differences within each age group age 2 and older. In

| DISCUSSION
We examined the growth and obesity patterns in the largest international cohort of children with the rare obesity syndrome, BBS. As expected, we confirmed that obesity is a highly prevalent disease phenotype in this cohort, but several new insights were observed. Intrauterine growth appeared normal in this population, with the majority of infants delivered at term with a birth weight <4000 g. Rapid weight gain ensued during early childhood though. Of BBS children, >55% were overweight or with obesity by 2 years-of-age, and accelerated weight gain was particularly evident in pre-school ages. This very early onset of obesity observed in BBS children <6 years old is atypical of childhood obesity and should raise consideration of diagnostic screening for BBS and other rare obesity syndromes.
Obesity and overweight was ubiquitous across the pediatric life span and was present in more than 90% of individuals with BBS over 6 years-of-age. Like common childhood obesity, children with BBS in the 2-5 age group and the 6-11 age group tended to be somewhat taller than average, with median height z-scores ranging from 0.7 to 1.0, but height is largely normalized by adolescence. 22 30 whereas the average length and height z-score in this report and previous reports is within a normal to above average range in children with BBS. These patterns, while helpful, underscore the need to consider comprehensive evaluation, including genetic investigation, in children exhibiting early onset obesity. 31 Our study also provides insight into the correlation of genotype and phenotype in a rare, genetically heterogeneous obesity syndrome.

Previous investigators suggested a milder obesity phenotype in BBS1
compared to other BBS genotypes. 8,9,32 The present study confirms lower BMI z-scores during childhood in the BBS1 cohort compared to the BBS10 cohort; however, the difference abates by adolescence. Our study examining childhood weight patterns in BBS has limitations.

MKKS
Obesity is a multi-factorial disease, even in syndromic and monogenic disorders. 5,31,34 Potential contributing factors such as socioeconomic, cultural, and racial parameters were not examined in this study. The impact of disease identification resulting in lifestyle modification was not examined in this report. Likewise, appetite altering medications and co-morbidities-including diabetes mellitus and solid organ transplantation-were not considered. Type 1 diabetes was present in only one participant, while type 2 diabetes is uncommon prior to adulthood in the BBS population, unlike Alström syndrome. 30 We have previously reported the accelerated obesity trends in renal transplant recipients with BBS. 48 The present study utilized height/length and weight measurements primarily obtained at healthcare encounters, with some self-reported values, and do not reflect the precision in single center prospective studies. Finally, our study examined only biallelic BBS variants and did not capture the potential additive effect of other ciliopathy genes or other obesity-associated genes that may modulate disease severity.
In conclusion, obesity is a disease of dominant concern in the health of children with BBS. BBS growth patterns appear to be characterized by appropriate gestational length and weight, followed by disproportionate weight gain with rapid onset of overweight or obesity in early childhood and persisting through adolescence. Children with loss of function variants in BBS genes appear to be at the highest risk for severe obesity, consistent with other BBS phenotypes previously described. Our findings support the importance of exploring effective obesity therapies in individuals with BBS during early childhood.

ACKNOWLEDGEMENTS
Supported by the Bardet-Biedl Syndrome Foundation.