QJM Advance Access published June 27, 2015 QJM: An International Journal of Medicine, 2015, 1–2 doi: 10.1093/qjmed/hcv114 Advance Access Publication Date: 29 May 2015 Case report
CASE REPORT
Bardet–Biedl syndrome in two siblings: a rare entity revisited H.N. Chakravarti, S. Ray, S.K. Chakrabarti, D. Biswas, S. Ghosh, S. Mukhopadhyay and S. Chowdhury From the Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata 700020, West Bengal, India Address correspondence to S. Ray, Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, 244, AJC Bose Road, Kolkata 700020, West Bengal, India. email: [email protected]
Bardet–Biedl syndrome (BBS) demonstrates highly variable expression, even among affected siblings, making the diagnosis difficult and often delayed and most patients are diagnosed in late childhood or early adulthood. The clinical diagnosis of BBS is based on the presence of at least four of five cardinal features: retinal dystrophy, polydactyly, obesity, hypogenitalism and renal disease. Significant weight gain begins in infancy and becomes a lifelong issue. Hypogonadism occurs more frequently in males than females and retinal dysfunction usually becomes apparent at age 7–8 years. Molecular investigations do not show clear phenotype–genotype correlations, therefore, the diagnosis is still made using clinical data. Characteristic retinal findings during fundoscopy may provide a clue towards diagnosis. A multidisciplinary management approach may be required in patients with BBS. The male sibling was the first child from a consanguineous marriage. This 12-year-old boy reported to us with complaint of underdevelopment of genitalia and inability to see at night. His height and weight were 138 cm and 55 kg (>97th percentile), respectively, with a resultant body mass index of 29 (>95th percentile) that indicated severe obesity. His 8-year-old sister presented with short stature, delayed developmental milestones and night blindness. Her height and weight were 116 cm and 36 kg, respectively, with a resultant body mass index of 26, which indicates obesity. Both of them had acanthosis nigricans around the neck. There was postaxial polydactyly with hexadactyly of all four limbs in both of them. The male sibling had
features of hypogenitalism with a low testicular volume of 2 ml and micropenis (stretched penile length (SPL) < 2.5 cm) (Figure 1A–D). The initial motor and developmental milestones of our cases were delayed. Mental development was lagging behind the normal range, with an I.Q. less than 70. Fundus examination showed atypical retinitis pigmentosa (RP) with vascular attenuation and salt–pepper type changes in both. Electroretinogram (ERG) showed grossly reduced amplitudes suggesting peripheral rod–cone dysfunction (Figure 1E and F). Hearing assessment of the siblings was normal. An ultrasound revealed fatty liver and normal kidney morphology. Electrocardiogram and echocardiogram were done to rule out underlying cardiac abnormalities and were normal. Parents were advised regarding probable morbidities and were also advised regular follow-up of their children to observe for renal dysfunction, diabetes and its management, if required.
Discussion Bardet–Biedl syndrome (BBS) is an autosomal recessive condition characterized by rod–cone dystrophy, postaxial polydactyly, central obesity, mental retardation, hypogonadism in males or genital abnormalities in females, and renal dysfunction.1 The prevalence of this group of disorders is 1 in 13 500 to 160 000 individuals depending on geographic location. The incidence is much higher in some populations with a high level of consanguinity.2 The characteristic combination of findings in BBS are rod– cone dystrophy (93–100%), polydactyly (58–69%), obesity (72– 88%), learning disabilities (41–62%), hypogenitalism in males (85–90%) or complex female genitourinary malformations and renal abnormalities (25–100%).1 Beales et al.3 have suggested
C The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. V
All rights reserved. For Permissions, please email: [email protected]
1
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Learning points for clinicians
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QJM: An International Journal of Medicine, 2015, Vol. 0, No. 0
male sibling (C), hypogonadism with micropenis and absence of secondary sexual characters in male sibling (D), fundus photography showing features of salt-andpepper pigmentary retinopathy (E), multifocal ERG (3-D plot): grossly reduced amplitudes of rod and cone responses with a relatively spared central response (F).
that the presence of four primary or three primary plus two secondary features is diagnostic. Other features include hepatic fibrosis, diabetes mellitus, reproductive abnormalities, short stature, developmental delay and speech deficits. Although the exact pathogenesis of BBS is unknown, a defect in one of 15 genes (BBS1–BBS15) involved in ciliary function can lead to BBS, now regarded as one of the ‘ciliopathies’.4,5 Obesity is a common feature in almost all the patients. Birth weight is usually normal in individuals with BBS. The distribution of adipose tissue is more prominent in the trunk and proximal limbs in adulthood.3,6 Retinopathy occurs in 90% of the patients. Retinal dysfunction usually becomes apparent at age 7–8 years, when night blindness gradually starts.3 Hypogonadism in females results in failure of development of secondary sexual characteristics and delayed menarche. Males have micropenis at birth, with small volume testes. Progressive renal damage occurs in BBS and can lead to end-stage renal disease necessitating renal replacement therapy or transplantation.4 The management of BBS is supportive and it includes training and rehabilitation for blind patients and for those with specific learning disabilities. There is no proven effective treatment to either prevent or improve the outcome in vision.
Conclusion BBS demonstrates highly variable expression, even among affected siblings, making the diagnosis difficult and often delayed and most patients are diagnosed in late childhood or early adulthood. Developmental delay can present in early childhood
and visual impairment is generally detected in teen years. The disease is incurable, and therefore, persists as a chronic condition. However, timely symptomatic treatment ensures a good prognosis. Conflict of interest: None declared.
References 1. Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC, Johnson G, et al. The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 1989; 321:1002–9. 2. Klein D, Ammann F. The syndrome of Laurence-MoonBardet–Biedl and allied diseases in Switzerland. Clinical, genetic and epidemiological studies. J Neurol Sci 1969; 9: 479–513. 3. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet 1999; 36:437–46. 4. Guo D, Rahmouni K. Molecular basis of the obesity associated with Bardet–Biedl syndrome. Trends Endocrinol Metab 2011; 22: 286–93. 5. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 2003; 425:628–33. 6. Grace C, Beales P, Summerbell C, Jebb SA, Wright A, Parker D, et al. Energy metabolism in Bardet–Biedl syndrome. Int J Obes Relat Metab Disord 2003; 27:1319–24.
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Figure 1. Sibling pair having truncal obesity and acanthosis (A), postaxial polydactyly with hexadactyly of hands in male sibling (B), postaxial polydactyly of feet in fe-
CASE REPORT
Bardet–Biedl syndrome in two siblings: a rare entity revisited H.N. Chakravarti, S. Ray, S.K. Chakrabarti, D. Biswas, S. Ghosh, S. Mukhopadhyay and S. Chowdhury From the Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata 700020, West Bengal, India Address correspondence to S. Ray, Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, 244, AJC Bose Road, Kolkata 700020, West Bengal, India. email: [email protected]
Bardet–Biedl syndrome (BBS) demonstrates highly variable expression, even among affected siblings, making the diagnosis difficult and often delayed and most patients are diagnosed in late childhood or early adulthood. The clinical diagnosis of BBS is based on the presence of at least four of five cardinal features: retinal dystrophy, polydactyly, obesity, hypogenitalism and renal disease. Significant weight gain begins in infancy and becomes a lifelong issue. Hypogonadism occurs more frequently in males than females and retinal dysfunction usually becomes apparent at age 7–8 years. Molecular investigations do not show clear phenotype–genotype correlations, therefore, the diagnosis is still made using clinical data. Characteristic retinal findings during fundoscopy may provide a clue towards diagnosis. A multidisciplinary management approach may be required in patients with BBS. The male sibling was the first child from a consanguineous marriage. This 12-year-old boy reported to us with complaint of underdevelopment of genitalia and inability to see at night. His height and weight were 138 cm and 55 kg (>97th percentile), respectively, with a resultant body mass index of 29 (>95th percentile) that indicated severe obesity. His 8-year-old sister presented with short stature, delayed developmental milestones and night blindness. Her height and weight were 116 cm and 36 kg, respectively, with a resultant body mass index of 26, which indicates obesity. Both of them had acanthosis nigricans around the neck. There was postaxial polydactyly with hexadactyly of all four limbs in both of them. The male sibling had
features of hypogenitalism with a low testicular volume of 2 ml and micropenis (stretched penile length (SPL) < 2.5 cm) (Figure 1A–D). The initial motor and developmental milestones of our cases were delayed. Mental development was lagging behind the normal range, with an I.Q. less than 70. Fundus examination showed atypical retinitis pigmentosa (RP) with vascular attenuation and salt–pepper type changes in both. Electroretinogram (ERG) showed grossly reduced amplitudes suggesting peripheral rod–cone dysfunction (Figure 1E and F). Hearing assessment of the siblings was normal. An ultrasound revealed fatty liver and normal kidney morphology. Electrocardiogram and echocardiogram were done to rule out underlying cardiac abnormalities and were normal. Parents were advised regarding probable morbidities and were also advised regular follow-up of their children to observe for renal dysfunction, diabetes and its management, if required.
Discussion Bardet–Biedl syndrome (BBS) is an autosomal recessive condition characterized by rod–cone dystrophy, postaxial polydactyly, central obesity, mental retardation, hypogonadism in males or genital abnormalities in females, and renal dysfunction.1 The prevalence of this group of disorders is 1 in 13 500 to 160 000 individuals depending on geographic location. The incidence is much higher in some populations with a high level of consanguinity.2 The characteristic combination of findings in BBS are rod– cone dystrophy (93–100%), polydactyly (58–69%), obesity (72– 88%), learning disabilities (41–62%), hypogenitalism in males (85–90%) or complex female genitourinary malformations and renal abnormalities (25–100%).1 Beales et al.3 have suggested
C The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. V
All rights reserved. For Permissions, please email: [email protected]
1
Downloaded from by guest on November 13, 2015
Learning points for clinicians
2
|
QJM: An International Journal of Medicine, 2015, Vol. 0, No. 0
male sibling (C), hypogonadism with micropenis and absence of secondary sexual characters in male sibling (D), fundus photography showing features of salt-andpepper pigmentary retinopathy (E), multifocal ERG (3-D plot): grossly reduced amplitudes of rod and cone responses with a relatively spared central response (F).
that the presence of four primary or three primary plus two secondary features is diagnostic. Other features include hepatic fibrosis, diabetes mellitus, reproductive abnormalities, short stature, developmental delay and speech deficits. Although the exact pathogenesis of BBS is unknown, a defect in one of 15 genes (BBS1–BBS15) involved in ciliary function can lead to BBS, now regarded as one of the ‘ciliopathies’.4,5 Obesity is a common feature in almost all the patients. Birth weight is usually normal in individuals with BBS. The distribution of adipose tissue is more prominent in the trunk and proximal limbs in adulthood.3,6 Retinopathy occurs in 90% of the patients. Retinal dysfunction usually becomes apparent at age 7–8 years, when night blindness gradually starts.3 Hypogonadism in females results in failure of development of secondary sexual characteristics and delayed menarche. Males have micropenis at birth, with small volume testes. Progressive renal damage occurs in BBS and can lead to end-stage renal disease necessitating renal replacement therapy or transplantation.4 The management of BBS is supportive and it includes training and rehabilitation for blind patients and for those with specific learning disabilities. There is no proven effective treatment to either prevent or improve the outcome in vision.
Conclusion BBS demonstrates highly variable expression, even among affected siblings, making the diagnosis difficult and often delayed and most patients are diagnosed in late childhood or early adulthood. Developmental delay can present in early childhood
and visual impairment is generally detected in teen years. The disease is incurable, and therefore, persists as a chronic condition. However, timely symptomatic treatment ensures a good prognosis. Conflict of interest: None declared.
References 1. Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC, Johnson G, et al. The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 1989; 321:1002–9. 2. Klein D, Ammann F. The syndrome of Laurence-MoonBardet–Biedl and allied diseases in Switzerland. Clinical, genetic and epidemiological studies. J Neurol Sci 1969; 9: 479–513. 3. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet 1999; 36:437–46. 4. Guo D, Rahmouni K. Molecular basis of the obesity associated with Bardet–Biedl syndrome. Trends Endocrinol Metab 2011; 22: 286–93. 5. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 2003; 425:628–33. 6. Grace C, Beales P, Summerbell C, Jebb SA, Wright A, Parker D, et al. Energy metabolism in Bardet–Biedl syndrome. Int J Obes Relat Metab Disord 2003; 27:1319–24.
Downloaded from by guest on November 13, 2015
Figure 1. Sibling pair having truncal obesity and acanthosis (A), postaxial polydactyly with hexadactyly of hands in male sibling (B), postaxial polydactyly of feet in fe-
