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Endocrine Abstracts (2023) 97 028 | DOI: 10.1530/endoabs.97.028

BES2023 BES 2023 Section (29 abstracts)

A diagnostic conundrum in Bardet-Biedl syndrome: when genetics precede clinical diagnosis

Van Roy Nele 1 , Heerwegh Sylvester 1 , Husein Dashty 1 , Ruys Joke 2 & Coremans Peter 1

1Department of Diabetes and Endocrinology, VITAZ, Belgium.; 2Department of ophthalmology, VITAZ, Belgium

Introduction: Bardet-Biedl syndrome (BBS) is an autosomal recessive, monogenic syndrome of obesity, with an estimated prevalence of 1:160.000. BBS is caused by mutations in one of the twenty-six genes that play a role in the function of primary cilia (1). Early-onset obesity, post-axial polydactyly, retinitis pigmentosa, renal or genitourinary abnormalities, learning disabilities and hypogonadism are considered primary features. Diabetes, speech deficit, hearing loss, anosmia, cardiomyopathy, and hepatic fibrosis are described as secondary features. Diagnosis is clinical and modified diagnostic criteria: four primary features or three primary plus two secondary features are required (2). The role of genetic testing remains controversial.

Case presentation: Two 17 -year-old female monozygotic twins of Palestinian origin were referred for obesity. They were born in a consanguineous marriage. Both had normal birth weight, showed rapid weight gain during childhood, but no food-seeking behaviour. Issue A had a history of strabismus surgery, and removal of two supernumerary teeth. Issue B had previously consulted the emergency department for abdominal pain, due to cystitis and urinary retention. Initial contact revealed obesity class 1 (BMI 31.8 and 32.45kg/m²), an increased waist circumference, and no overt dysmorphic features. Because hormonal and metabolic screening came back negative, it was concluded as exogeneous obesity and a conservative weight-loss program was initiated. Issue A consulted the ophthalmology department 6 months later because of progressive deterioration of sight and photophobia. Comprehensive ophthalmological examination was consistent with retinitis pigmentosa. An exome-based RetNet panel, designed to screen for inherited retinal diseases, was analysed. A homozygous missense variant in exon 2/17 of the BBS2 gene on chromosome 16 (c.224T>G (p.Val75Gly)) was found, indicating BBS (likely pathogenic). After genetic testing, the patients were re-evaluated on the clinical diagnostic criteria of BBS (table 1a). Additional primary and secondary BBS features were identified, but they did not meet the full clinical criteria. However, given the results of genetic testing, diagnosis of BBS was considered confirmed. A trial with Dulaglutide was initiated, but no weight loss was observed and therapy was ceased after three months. The conservative treatment program was intensified and frequent follow up at the endocrine department was scheduled.

Table 1 Beales’ modified diagnostic criteria (2), applied to Issue A and B (a) and applied to Family 1 (4) and 2 (5), described in literature *
Issue AIssue BFamily 1Family 2
Primary features
Retinitis pigmentosa++++
Learning disabilities--+°
Renal abnormalities-+°+
Secondary features
Speech disorder/delay+-°°
Developmental delay--°°
Ataxia/poor coordination/imbalance--°°
Mild spasticity--°°
Diabetes mellitus--°°
Dental crowding/hypodontia/small roots/high arched palate++°°
Left ventricular hypertrophy/congenital heart disease--°°
Hepatic fibrosis--°°
*when a characteristic was present in more than half of the family members, it was considered as positive ° information could not be retrieved from the original article

Discussion: This case highlights two limitations of the diagnostic model of BBS. The first is inherently due to the high variability and progressive onset of the phenotype, leading to low sensitivity of the criteria at young age, and a significant delay in diagnosis. Although this was described for all primary features in literature, in this case it was most evident for obesity and retinitis pigmentosa (1). After the genetic diagnosis of BBS, the patients were re-evaluated, but a strict clinical diagnosis could not be made, highlighting the second limitation to Beales’ diagnostic model: the unclear role of genetic testing. Recent publications suggest that genetic testing can be used to confirm the clinical diagnosis (1, 3). In this case however, the genetic diagnosis of BBS preceded clinical diagnosis. To date, the identical homozygous single nucleotide variant c.224T>G (p.Val75Gly) in exon 2/17 of the BBS2-gene on chromosome 16 has been described in four families on ClinVar. Two of them have been described in literature (4,5) (table 1b). The confirmation of the diagnosis in our patients implies a fifth family identified, suggesting an upgrade in classification from ‘likely pathogenic’ to ‘pathogenic’ This may lead to earlier diagnosis and intervention.

Conclusion: The current standard for the diagnosis of BBS needs to be updated to clarify the role of genetic testing: due to evolution of the phenotype and the increasing availability of genetic testing, genetic testing may precede clinical diagnosis, leading to earlier diagnosis and intervention.

References: 1. Melluso A, Secondulfo F, Capolongo G, Capasso G, Zacchia M. Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook. Therapeutics and Clinical Risk Management. 2023;19:115-132.2. Beales P, Elcioglu N, Woolf A, Parker D, Flinter F. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. Journal of medical genetics. 1999;36(6):437-446.3. Moore SJ, Green JS, Fan Y, Bhogal AK, Dicks E, Fernandez BA, Stefanelli M, Murphy C, Cramer BC, Dean JC. Clinical and genetic epidemiology of Bardet Biedl syndrome in Newfoundland: A 22-year prospective, population-based, cohort study. American journal of medical genetics Part A.2005;132(4):352-360.4. Kwitek-Black AE, Carmi R, Duyk GM, Buetow KH, Elbedour K, Parvari R, Yandava CN, Stone EM, Sheffield VC. Linkage of Bardet-Biedl syndrome to chromosome 16q and evidence for non-allelic genetic heterogeneity. Nature genetics. 1993;5(4):392-396.5. Esposito G, Testa F, Zacchia M, Crispo AA, Di Iorio V, Capolongo G, Rinaldi L, D’Antonio M, Fioretti T, Iadicicco P, Rossi S, Franzè A, Marciano E, Capasso G, Simonelli F, Salvatore F. Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants. BMC Medical Genetics. 2017; 18(1):[10 p.]

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