Clinical Presentation and Co-Morbidities in Bardet-Biedel Syndrome: Case Series from a Single Centre

Abstract

Introduction:

Bardet–Biedl syndrome (BBS-OMIM 209900) is a rare genetic multi-system obesity syndrome with limited case reports from India. We describe a case series of BBS with varied clinical presentation and their co-morbidities.

Methods:

BBS was diagnosed based on the clinical criteria by Beales et al. Their clinical presentations including the presence of primary and secondary features, metabolic profile, and systemic complications were examined.

Results:

Eleven cases of BBS were analyzed over 9 years, of which the most common primary clinical manifestations were post-axial polydactyly and learning disabilities, noted in all individuals (100%). Retinitis pigmentosa and truncal obesity were present in 91% (10 out of 11). Clinical and biochemical features of hypogonadism and genital abnormalities were observed in 73% of individuals. Craniofacial dysmorphism and developmental delay were the more commonly observed secondary features, observed in 91%. Speech delay and brachydactyly/syndactyly were present in 73% of cases. Hyperactive behavioural disturbances and diabetes mellitus were noted in 45% and 18% of cases, respectively. Cataracts, hypertonia, dental malocclusion and cardiac anomalies (dextrocardia) were each observed in just one patient among the study population of 11 patients. The molecular genetics were analysed in two individuals.

Conclusion:

BBS is an extremely rare clinical syndrome with clinical heterogeneity at presentation. The appropriate diagnosis of syndromic obesity and an early multi-disciplinary intervention may improve their quality of life.

INTRODUCTION

The prevalence of childhood and adolescent obesity is increasing worldwide as well as in India, especially after the COVID-19 outbreak. The prevalence of obesity ranges from 20% to 30% as per ICMR studies in India.[1,2] Despite significant progress in understanding the molecular basis of obesity and body fat regulation, the genetic causes of obesity have not been fully elucidated. More than 95% of obesity is polygenic and determined by the aggregate effect of multiple common genetic variants.[3] As per the published Western literature, monogenic and syndromic obesity contributed to around 5% of the obese population.[4,5] Possible reasons for the very low prevalence in India are the failure to diagnose syndromic and monogenic obesity due to a lack of awareness among health professionals, as well as, the limited availability of molecular genetic testing.

Bardet–Biedl syndrome (BBS-OMIM 209900) is a clinically heterogeneous, autosomal recessive, non-motile ciliopathy, first described by ophthalmologists Laurence and Moon in 1866. BBS is often considered as two entities, namely Laurence–Moon syndrome (LMS) and BBS with overlapping clinical features. Important differentiating clinical features between these two are progressive spastic paraparesis and distal muscle weakness in LMS and polydactyly in BBS.[6] Both are classified as ciliopathy, and 20 BBS genes are involved in ciliary biogenesis and trafficking.

Because of the rarity of this condition, less awareness, varied clinical manifestations, and lack of a multi-disciplinary team approach, the diagnosis is often delayed in India. The delay in diagnosis leads to excess morbidity as well as mortality, related to renal impairment and metabolic dysfunctions. Very limited BBS case reports are available in India and most of them are from ophthalmological perspectives. Herewith, we describe a case series of BBS with varied clinical presentation and their co-morbidities from a single centre.

MATERIALS AND METHODS

This is a case series, from the obesity clinic of the Endocrinology Department of Government Rajaji Hospital, Madurai, a 4400-bed multi-specialty tertiary care referral hospital in Southern India. All individuals with clinical features of BBS syndrome diagnosed between January 2014 and December 2023 were included for analysis. Detailed history including birth history, parental consanguinity, and developmental milestones were obtained and they were examined in detail for the presence of primary and secondary features of BBS as per Beales et al.’s criteria.[7] Diagnosis was made based on the presence of four primary features or three primary features with two secondary features. Bodyweight and height were measured and body mass index (BMI) was calculated. Obesity in children and adolescents was defined as a BMI above the 27 adult equivalent line in the IAP-BMI 2015 chart for up to 18 years of age and a BMI of above 27 in adults after 18 years of age according to the World Health Organization (WHO) obesity criteria for Asians. They were subjected to fundus examination by an ophthalmologist and an intelligence quotient (IQ) assessment was conducted by a psychiatrist using the Binet–Kamat test.[8]

Fasting and postprandial blood glucose, 75 g of oral glucose tolerance tests (GTT), HbA1c, blood urea and serum creatinine, liver function tests, free T4, thyroid-stimulating hormone (TSH), luteinising hormone (LH), follicle-stimulating hormone (FSH) and testosterone levels for male and oestradiol levels for females (Cobas e411 analyser; Roche Diagnostics, Manheim, Germany) were conducted in all BBS. Genetic analysis was conducted by using next-generation genome sequencing in selected cases.

Ethical aspect

The study protocol was approved by the Institutional Ethical Committee, Madurai Medical College, Madurai, CDSCO Reg. no. ECR/1365/Inst/TN/2020 and DHR reg no. EC/NEW/INST/2022/TN/0059, dated 30.11.2023. Clinical images were acquired after the written informed consent of their parents and assent from the children and the use of the patient data for research and educational purposes as per the guidelines laid down in the Declaration of Helsinki (1964).

RESULTS

Eleven individuals were diagnosed with BBS over 9 years [Figure 1a and b] with a male-to-female ratio of 1:1.2 and an age range from 14 to 25 years. The mean age at presentation was 16.2 ± 3.0 years. Parental consanguinity was noted in six (54.5%) cases. Baseline anthropometric parameters are summarised in Table 1. Among the primary clinical features, post-axial polydactyly and learning disabilities were noted in all BBS (100%). All children had mild to moderate intellectual disability, learning difficulties with poor scholastic performances with a mean IQ of 62 ± 8. Among the secondary clinical features, developmental delay and craniofacial dysmorphism were observed in 10 (91%) cases, [Figure 2]. Primary and secondary clinical features are summarised in Table 2. Diabetes mellitus was observed in 2 of the 11 cases (18%), of which one was insulin-requiring and the other was controlled with oral anti-diabetic drugs. All five males had a lack of secondary sexual characteristics and hypogonadism with a hormonal profile suggestive of hypogonadotropic hypogonadism. Among six female cases, three had normal pubertal progression, and the remaining three had delayed puberty. One male patient had a renal anomaly in the form of a horseshoe kidney and the second one (female) had chronic kidney disease and died at the age of 27 years. Genetic analysis reports were available in two children and were positive for the BBS1 and BBS2 genes respectively and the nature of mutation is summarised in Figure 3. We have not observed any cardiac anomalies, hepatic diseases, diabetes insipidus, or Hirschsprung diseases in the study population.

Figure 1.

a and b: varied clinical manifestations of syndactyly and polydactyly of hands and feet

Table 1.

Baseline and anthropometric characteristics

Case no	Age (years)	Sex (M/F)	Weight (kg)	Height (cm)	BMI
1	14	F	66	148	30.1
2	16	M	82	158	32.8
3	16	M	84	162	32.0
4	14	F	78	154	32.9
5	17	M	88	154	37.1
6	17	M	76	146	35.7
7	25	F	56	152	24.2
8	17	F	80	158	32.0
9	14	M	52	150	23.1
10	14	F	68	149	31.1
11	15	F	76	152	32.9

Figure 2.

Characteristic facies of BBS with polydactyly

Table 2.

Prevalence of primary and secondary features of BBS

Primary features
Feature	n (11)	%
Retinal dystrophy	10	91
Post–axial polydactyly	11	100
Truncal obesity	10	91
Hypogenitalism	8	73
Renal malformations	1	9
Learning disabilities	11	100
Secondary features
Speech delay/disorder	8	73
Developmental delay	10	91
Craniofacial dysmorphism	10	91
CVS anomalies	1	9
Hypertonia	1	9
Cataract	1	9
Brachydactyly/syndactyly	8	73
Behavioral disorders	5	45
Diabetes mellitus	2	18
Dental mal-occlusion	1	9

Figure 3.

Details of genetic variants of the BBS gene

DISCUSSION

Bardet–Biedl syndrome (BBS) is a rare monogenic ciliopathic disease with an autosomal recessive mode of inheritance and an estimated incidence of 1 in 65,000–1,60,000. Due to the high prevalence of consanguineous marriages in India, with huge clinical and genetic heterogeneity of BBS, there may be a higher incidence than reported.[9] In the present study, consanguinity was noted in 55% of individuals. A slightly higher male prevalence (1.3:1) with a mean age of diagnosis at 9 years was observed by Beales et al.[10] However, we found a slight female prevalence (1.2:1), and a delay in diagnosis with a mean age at diagnosis of 16.2 years.

The most common mode of presentation was visual impairment due to red-cone dystrophy. We observed retinitis pigmentosa in 91% of cases, which is similar to the observation by Weihbrecht et al.,[11] where they noted 94% prevalence. The visual defects of BBS usually start with diminished night vision (nyctalopia) since early childhood, followed by loss of colour discrimination due to the development of retinitis pigmentosa and progressive visual loss with optic atrophy.[12] The other less common manifestations are refractive errors, strabismus, cataracts and astigmatism. Electroretinography (ERG) and visual evoked potentials (VEP) will show significant findings after the age of 5 years. The affected individuals often become legally blind (visual acuity <6/60) by the second or third decade of life. Retinal disease is the highly penetrant feature of BBS, affecting up to 100% of individuals in some studies.[13]

Central obesity usually develops at 2–3 years of age despite normal birth weight. Studies have shown that various mechanisms are involved in the development of central obesity, including altered neuro-endocrine signalling from ciliated neurons to adipose tissues, impaired leptin receptor signalling, leptin resistance and impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway. Setmelanotide, an MC4R agonist, was approved by the US FDA in 2022 for chronic weight management in patients with BBS ≥6 years old. Setmelanotide is associated with greater weight loss and hunger reduction in BBS.[14] Overt diabetes is less common, and most are manageable by lifestyle measures alone.[15] There is impaired insulin secretion as well as insulin receptor trafficking results in insulin deficiency as well as resistance.[16,17] In the present study, of the 11 BBS, 2 had diabetes mellitus. One had obesity at presentation and later developed significant weight loss with insulin-requiring diabetes. Another individual was obese with severe insulin resistance and had good glycaemic control with oral anti-diabetic medications alone.

Polydactyly is a congenital anomaly; it is a useful diagnostic clue and helps to suspect BBS even at birth with 60-80% prevalence among BBS.[17] We observed, post-axial polydactyly in all individuals (100%). Postaxial polydactyly are additional digits usually found on the ulnar side of the hand and/or fibular side of the foot, more commonly observed in the toes rather than fingers. The presence of finger polydactyly disturbed many school-going children and three of our BBS underwent surgical procedures to remove extra digits. The other less common features were brachydactyly, syndactyly, clinodactyly and sandal gap between I and II toes.

Weihbrecht et al.,[11] reported hypogonadism in 59%, whereas we observed hypogonadism in 72.7% of cases. The hormonal profiles of all five males were suggestive of hypogonadotropic hypogonadism, of which three had grade III gynecomastia. All were treated with injectable testosterone therapy. Among six female cases, three had normal pubertal progression; however, one of them developed premature ovarian insufficiency. The remaining three had delayed puberty and oestrogen therapy was initiated. Male hypogonadism can be clinically suspected at birth with cryptorchidism/micropenis, whereas in females, it may not be apparent until the age of puberty.[18] The reported pelvic urogenital anomalies in females are hypoplastic, duplex uterus, hypoplastic fallopian tubes/ovaries, septate vagina, partial/complete vaginal atresia, absent vaginal/urethral orifice, persistent urogenital sinus and vesicovaginal fistula.

In our study, out of 11 cases, 1 male had a horseshoe kidney with normal renal function, and another female had progressive renal dysfunction and died of its complications. The renal involvement in BBS is highly variable. It can be structural anomalies, hydronephrosis, cystic tubular diseases, vesicoureteral reflux, interstitial nephritis, glomerulosclerosis, or progressive renal parenchymal disease.[19] Structural kidney disease includes horseshoe, ectopic, duplex, absent kidneys, or dysplastic cystic disease. Chronic kidney disease (CKD) is a major cause of morbidity and mortality in BBS. As per the previously reported literature, there is a significantly increased risk of CKD in patients carrying BBS 1, 2, and 10 gene mutations.[19]

The prevalence of secondary features of BBS varied among the reported literature. Hearing issues, ataxia, poor coordination and mild hypertonia have been described. Speech disturbances including receptive/expressive speech delay and articulation defects are also observed. Behavioural and psychiatric abnormalities are also reported. Significant intellectual disability is a prominent feature and cognitive impairment is present in 60–66% of individuals.[20] Developmental delay in all domains is common.[21,22] In our study, we are reporting IQ with a mean/SD of 62 ± 8.

Dysmorphic craniofacial features observed in individuals with BBS include brachycephaly, macrocephaly, narrow forehead, short and narrow, down-slanted palpebral fissures, deep and widely set eyes, large ears, long and smooth philtrum, depressed nasal bridge, malar flattening and retrognathia. Various oral/dental abnormalities reported are hypodontia/microdontia, dental crowding, short roots/taurodontism, posterior crossbite, enamel hypoplasia and high-arched palate. Congenital heart defects associated are atrioventricular septal defects and vascular anomalies including bilateral persistent superior vena cava and interrupted inferior vena cava.[23]

Because BBS is a multi-system disease with heterogeneous involvement, the prognosis depends on the severity of the organ involved. Renal impairment is the major cause of mortality, and some of them presented with end-stage kidney disease. Despite the various systemic manifestations, an ophthalmologist is the first line of contact among many BBS individuals. Hence, holistic care of BBS requires a multidisciplinary team consisting of a pediatrician, ophthalmologist, endocrinologist, nephrologist, orthopedic surgeon, cardiologist, dental specialist, speech therapist and audiologist. These patients should undergo regular multi-systemic and metabolic surveillance at periodic intervals.[24] Because vision loss is non-preventable, early educational planning based on the visual condition is the key cornerstone to improving the quality of life in BBS.

Twenty-six different genes (BBS1BBS22), CEP19, NPHP1, SCAPER and SCLT1 have been mapped to date for BBS with variable expression and incomplete penetrance. The autosomal recessive mode of inheritance was commonly observed with oligogenic inheritance occasionally,[25,26] BBS1 and BBS10 genes contribute to 40%–50% of European BBS, whereas a higher prevalence of BBS3 and BBS9 genes has been observed in Asians. BBS1 and BBS10 mutations accounted for only 7% and 10% of the Indian population, respectively.[27,28] However, in the present study, we reported BBS1 and BBS2 gene biallelic variants in two different cases. One had a homozygous novel, missense variation in exon 10 of the BBS1 gene and the other had a pathogenic, homozygous, nonsense variant in exon 11 of the BBS2 gene that results in a stop codon and premature truncation of the protein at codon 413. The BBS1 genetic mutation is less syndromic with less penetrance of renal anomalies and polydactyly when compared to BBS2. Obesity phenotype is mild in BBS2 when compared to BBS1.[7,29]

The strength of the present case series is the pictorial depiction of BBS cases in a single centre with varied clinical manifestations and presented to a different specialty. To the best of our knowledge, all previously reported cases of BBS in India, from the ophthalmological perspective, rarely focused the systemic co-morbidities. The limitation is molecular genetic analysis to validate the genes involved were available only in two study subjects.

CONCLUSION

BBS is an extremely rare clinical syndrome with varied systemic presentation. The combination of postaxial polydactyly, blindness, learning disabilities and obesity in an individual should alert the possibility of BBS. Early diagnosis of this complex disorder and lifestyle modification, periodic monitoring of metabolic and renal parameters with appropriate interventions by a multidisciplinary team will improve their quality of life among them.

Authors contribution

SS was involved in concept, design and idea of the study, SP prepared the manuscript, JS contributed in data collectin, KK was involved in opthalmic evaluation of study subjects and VG was in IQ assessment of study subjects.

Conflicts of interest

There are no conflicts of interest.

Data availability

The data that supports the findings of this study is available on request from the author.

Funding Statement

Nil.