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An unusual case of Bardet–Biedl syndrome presenting with type 1 diabetes mellitus

Ghosh, Suddhasattaa; Guha, Suparnaa; Basu, Sumitaa; Mukherjee, Dilip Kumara; Gupta, Riddhi Dasb

Middle East Journal of Medical Genetics: July 2012 - Volume 1 - Issue 2 - p 85–87
doi: 10.1097/01.MXE.0000414808.08492.ec
Case report
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Introduction Bardet–Biedl syndrome (BBS) is an autosomal recessive, heterogenous disorder with a wide variety of clinical presentations. Although minor associations with type 2 diabetes mellitus have been reported, the association of type 1 diabetes mellitus with BBS is an extremely uncommon occurrence.

Case report A 14-year-old boy, born out of a nonconsanguineous marriage, was admitted with a history of fever, vomiting, and abdominal pain for 3 days and impaired consciousness since morning. Examinations indicated the presence of hyperglycemia, metabolic acidosis, and the presence of urinary ketone bodies. Subsequently, C-peptide levels were found to be 0.8 mg/dl and screening for islet cell autoantibodies indicated positivity for GAD-65 and IA-2 autoantibodies. Once the patient had recovered from the hyperglycemic crisis, further investigations indicated that the boy had a short stature, truncal obesity, postaxial polydactyly of all four limbs, mental retardation, hypogonadism, and pigmentary retinopathy. The luteinizing hormone and follicle-stimulating hormone levels showed a prepubertal pattern with a suppressed testosterone level. Our patient had a 14-year-old twin brother with similar clinical features, except for the presence of a normal glycemic index. According to the clinical and laboratory evidence, both the brothers were diagnosed with BBS with associated type 1 diabetes mellitus in the index case.

Conclusion The association of type 1 diabetes mellitus with BBS presents an intriguing feature of the disease and should always be kept in mind in a patient with BBS presenting with hyperglycemia.

aDepartment of Paediatrics, Vivekananda Institute of Medical Sciences

bDepartment of Endocrinology, NRS Medical College and Hospital, Kolkata, West Bengal, India

Correspondence to Riddhi Das Gupta, MD, Department of Endocrinology, NRS Medical College and Hospital, 103/19 Nabalia Para Road, Kolkata 700008, West Bengal, India Tel: +091 8017144032; e-mail: riddhi_dg@rediffmail.com

Received February 29, 2012

Accepted March 19, 2012

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Introduction

Bardet–Biedl syndrome (BBS) is a rare, genetic multisystem disorder. It is a ciliopathy secondary to the basal body dysfunction (Runge et al., 1986). To date, 15 BBS genes have been cloned (BBS1–BBS15) (OMIM, ID: 209900). The main clinical features are rod–cone dystrophy with childhood-onset night blindness and visual loss, postaxial polydactyly, truncal obesity that manifests during infancy and remains problematic throughout adulthood, specific learning difficulties, male hypogenitalism, and complex female genitourinary malformations.

However, the presence of BBS in identical twins and the associated type 1 diabetes mellitus (DM) in one of them is an extremely rare occurrence and this combination is yet to be reported in the Indian literature.

Here, we discuss a case from the eastern part of India presenting with BBS in identical twin brothers and the presence of type 1 DM in the elder sibling.

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Case report

A 14-year-old boy, born out of a nonconsanguineous marriage, was admitted with a history of fever, vomiting, and abdominal pain for 3 days and impaired consciousness since morning. Examinations indicated that the patient was comatose, tachypneic, and febrile. Investigations indicated a total leukocyte count of 12 500, with a predominance of neutrophils (89%). Blood cultures were negative. Random plasma glucose was 469 mg/dl and urine for ketone bodies was positive. Arterial blood gas analysis showed a pH of 7.2, bicarbonate of 13 mmol/l, and serum sodium and potassium of 126 and 3.8 mmol/l, respectively. Subsequently, C-peptide levels were found to be 0.8 mg/dl and screening for islet cell autoantibodies indicated positivity for GAD-65 and IA-2 autoantibodies. Other routine investigations were essentially normal. A diagnosis of type I DM presenting with diabetic ketoacidosis was made. The patient was administered parenteral antibiotics and the Milwaukee Protocol of insulin regimen. Over the next 3 days, the patient improved gradually and could take oral feeds within a week. His laboratory parameters improved markedly and he was placed on a basal-bolus regimen of insulin and supportive management.

Once the patient had recovered from the hyperglycemic crisis, we proceeded with a thorough evaluation. He had a history of gradual dimness of vision, poor scholastic performance, and increased weight gain in the last 5 years. He complained of a small penile length in comparison with his peers. His perinatal and antenatal history was normal. But his initial motor and mental development milestones were delayed.

Physical examination indicated a height of 130 cm (<3rd percentile), weight of 30 kg (<50th percentile), truncal obesity, and the presence of digital abnormalities in the form of postaxial polydactyly of all four limbs (Figs 1 and 2). Neurological examination showed that the child had an intelligence quotient of 36 (by psychometric testing) and an intellectual impairment of 75%. Ophthalmological evaluation showed the presence of pigmentary retinopathy (Fig. 3) with low visual acuity (6/30) and myopia of two dimensions in both eyes. The other neurological examinations were normal. Examination of the genitourinary system showed that the stretched penile length was 3 cm (micropenis) and the testes were bilaterally 2 ml (prepubertal) in volume as measured by an orchidometer and was in Tanner stage I (Fig. 4).

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Laboratory investigations indicated a prepubertal pattern of luteinizing hormone and follicle-stimulating hormone levels with a suppressed testosterone level suggestive of hypogonadotropic hypogonadism. The thyroid function tests and the basal and stimulated growth hormone levels were normal. Ultrasonography abdomen (with kidney ureter bladder) was normal; echocardiography and BAER study did not show any significant abnormality. All other investigations were found to be normal.

Our patient had a 14-year-old twin brother with a similar presentation of nystagmus and pigmentary retinopathy, mild central obesity, male hypogonadism (microtestis and microphallus on genital examination), mental retardation, and postaxial polydactyly of all four limbs. His laboratory data were essentially similar, except for the presence of a normal glycemic index.

According to the clinical and laboratory evidence, our patient was diagnosed with BBS with type I DM. His brother was also diagnosed with BBS but was euglycemic.

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Discussion

The variable manifestations of BBS were initially described by Bardet and Biedl in 1920. It is clearly different from a condition reported by Lawrence and Moon in 1865. BBS is genetically heterogeneous, with 15 BBS genes identified to date (OMIM, ID: 209900). Although the cellular mechanisms that underlie BBS remain unclear, it is now clear that all of the known BBS proteins are components of the centrosome and/or the basal body and have an impact on ciliary transport (Hichri et al., 2005). BBS is a rare disorder, affecting only about one in 150 000 individuals in North America and Europe. However, among Arabs, the prevalence rate is much higher, at about one in 13 500 individuals, suggesting a founder effect (Katsanis et al., 2001).

BBS is characterized by the following major associations: early-onset retinal dystrophy, obesity, limb-abnormalities, mental retardation, hypogonadism, and renal disease. In addition to the major diagnostic features of BBS, multiple minor features have been also documented in patients at varying frequencies. These include developmental delay, speech and language deficit, psychosis, facial dysmorphism, multiple pigmented nevi (10 patients, of whom eight were females, with multiple widespread pigmented nevi), neurological abnormalities, hearing loss, metabolic and endocrine disturbances including DM, cardiovascular anomalies, disturbances of dentition and liver function, atresia ani, and Hirschsprung disease.

The Arab literature has a number of reports of BBS in siblings. Al-Arrayed and Al-Arrayed (1991) reported a consanguineous Bahraini family in which two male siblings were affected by BBS (Al-Arrayed and Al-Arrayed, 1991). Farag and Teebi (1988) reported the presence of BBS in an Arab family with three female siblings including twins (Farag and Teebi, 1988). The helpful marker in the determination of zygosity was found to be concordant for benign acanthosis nigricans in the twins. Wright et al. (1994) studied 26 Bedouin families with at least two members affected with BBS to examine the disease linkage to 16q21 and 11q13 regions using markers covering chromosomes 2, 3, 17, and 18. Assuming homogeneity, the investigation of the 57 affected members indicated evidence of linkage to the D11S527 locus and an LOD score of 2.72 was obtained at a recombination fraction of 0.11 (Fujita et al., 1996). Balci (2007) reported a Saudi Arabian family with three cases of BBS, two of whom were presumably identical twins (Balci, 2007). However, reports of the disease in identical twins are very rare from other regions of the world.

The association of BBS with type I DM is another unique and extremely rare occurrence worldwide. To date, only Escallon et al. (1989) have reported a family with the BBS and DM. Two affected brothers and one affected sister were examined. Of the three, the 18-year-old brother was obese, had mental retardation, and had pigmentary retinopathy and insulin-dependent DM (Escallon et al., 1989). Whether the association of type1 DM with BBS is causal remains to be explored. Given the highly pleomorphic genetic make-up of BBS and the extremely strong influence of genetic mutations on the causality of type 1 diabetes, the association between the two cannot be dismissed as mere coincidence. However, animal studies on this issue are not forthcoming, neither is evidence from humans adequate. Further genetic studies in future might provide a clue to this intriguing association.

Our case is thus unique because of the extremely rare association of BBS with type I DM in one of the two affected twin brothers. We believe that our case is the first of its kind to be reported from India and this extremely uncommon association adds a new dimension to the pleomorphic nature of this rare genetic syndrome.

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Conclusion

Close monitoring of the glycemic parameters in patients with BBS from an early age is highly recommended and the possibility of type I DM should always be kept in mind in a patient with BBS presenting with hyperglycemia.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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References

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Keywords:

Bardet–Biedl syndrome; identical twin brothers; polydactyly; retinopathy; type 1 diabetes mellitus

© 2012 Middle East Journal of Medical Genetics