Case Report: Managing Bardet-Biedl syndrome at a tertiary care centre

Introduction

Bardet–Biedl syndrome (BBS) is a rare ciliopathy with autosomal recessive inheritance.¹ BBS is prevalent all over the world in varying frequencies. Its prevalence in North America and Europe ranges from the 1:140000 to 1:160000 live births.² BBS is characterized by renal dysfunction, dystrophy of rods and cones, obesity, hypogonadism, post-axial polydactyly, learning difficulties and other minor features. Coexistence of clinical findings itself can consolidate the diagnosis of BBS. However, for the definitive diagnosis, sequencing of known disease-causing genes is needed.¹ Till date, about 21 BBS genes responsible for BBS have been identified including BBS1 - BBS20 and NPHP1 genes. The number of known BBS genes is likely to increase with the advancement in the genetic analysis via exome sequencing, and the study of more people in this population.³ Despite advancement in the diagnosis of BBS, the management of this syndrome is largely limited to the symptomatic treatment.³

Here, a patient with clinically diagnosed BBS who presented with complications including renal impairment, metabolic syndrome and blindness is described. His complications i.e., renal impairment and metabolic syndrome, and quality of life improved after starting him on the treatment and lifestyle modification. This case highlights the importance of timely diagnosis and treatment of clinical features and complication to improve the outcomes in patients with BBS.

Case report

A 42-year-old, unemployed South Asian man from Palpa District, Western Nepal came to our attention in medical outpatient department when he presented for his routine follow up for type 2 diabetes mellitus in November 2021. He was assisted by his mother as he was completely blind. His blood reports showed impaired renal function test. He was then further evaluated for his renal derangement. He was the eldest son among three siblings in the family. His mother denied the history of consanguinity. The mother said the patient had delayed development compared to other two siblings; he could speak monosyllables at the age of eighteen months, and two to three words at the age of three years which was delayed in comparison to other children of this age. He was found to have decreased vision when he was about four years of age, which was painless and progressive, and he was completely blind by the age of 10. He was admitted in school but could not continue his formal education beyond grade five, at the age of 11, because of his learning difficulties and vision problem. At the time of history taking, his visual acuity in both eyes was perception of light. He married at the age of 20 years and has two male children of 21 years and 20 years. Both of the children are doing well in college without any physical or mental impairment.

One year prior to this appointment, he visited a nearby clinic with the complaints of increased urinary frequency where he was diagnosed with type 2 diabetes mellitus and hypertension, and was started on oral hypoglycemic agent (tablet metformin 500mg per oral twice a day) and antihypertensive medication (tablet amlodipine 5mg per oral once a day).

On physical examination, his vital parameters were stable. He had central obesity and his waist circumference was 98 centimeters. His height was 152cm, weight was 74kg, and body mass index (BMI) was 32.0 kg/m². He had a moon shaped face, polydactyly on both feet, and right hand with history of amputation of the extra finger of the left hand during childhood at home by mother (Figures 1,2). His fundus examination showed the features of advanced retinitis pigmentosa with no evidence of diabetic retinopathy and hypertensive retinopathy.

Figure 1. Polydactyly of upper limb in Bardet-Biedl syndrome.

There is one extra finger in the right hand (red arrow).

Figure 2. Polydactyly in lower limbs in Bardet-Biedl syndrome.

There are extra toes in both feet (red arrows).

On laboratory reports, his blood counts and thyroid function test were within normal limits. His blood urea level was 54.6 mg/dl (15-45 mg/dl), serum creatinine level was 1.8 mg/dl (0.5-1.4 mg/dl), fasting blood glucose was 97 mg/dl (60-105 mg/dl), post prandial glucose was 156 mg/dl (70-140 mg/dl), and glycated hemoglobin level of 6.2% (3.8-5.8%). His urine microscopic examination was normal with spot protein creatinine ratio of 0.1 mg/mg. His intact parathyroid hormone level was raised i.e., 289.5 pg/mL (10-65 pg/mL) and serum uric acid level was 9.4 mg/dl (3.4-7.0 mg/dl). However, his serum calcium, phosphorous, albumin, sodium, potassium and vitamin D level were within normal limits. His liver function test showed aspartate transaminase level of 48 IU/L (0-46 IU/L), alanine transaminase level of 87 IU/L (0-40 IU/L) and alkaline phosphatase level of 168 U/L (30-120 U/L). In lipid profile plasma cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol were 180 mg/dl, 240 mg/dl, 40 mg/dl, 92 mg/dl, and 48 mg/dl respectively. His estimated glomerular filtration rate (eGFR) was 48 ml/min/1.73m².

On imaging studies, ultrasound of the abdomen and pelvis showed: fatty changes in liver grade-1 with normal liver size, loss of corticomedullary differentiation of bilateral kidneys with right kidney measuring 9.3x4.1 cm and left kidney measuring 8.9x5.0 cm, simple left renal cyst, and non-obstructing left nephrolithiasis (Figures 3,4). Two-dimension echocardiogram showed: mild enlarged left atrium of 42mm, normal left ventricle systolic function with ejection fraction of 65%, normal left ventricle diastolic function, no regional wall motion abnormalities, normal valves, and no intracardiac mass, thrombus, vegetation, pericardial effusion.

Figure 3. Ultrasound showing loss of corticomedullary differentiation in right kidney (red arrow).

RK: Right kidney

Figure 4. Ultrasound showing loss of corticomedullary differentiation and simple renal cyst in left kidney (red arrow).

LK: Left kidney

A diagnosis of the Bardet-Biedl syndrome was made based on the modified diagnostic criteria for BBS (Table 1).⁴ The patient and his family members were counselled about the disease and the patient was started on supportive care. He was started on oral hypoglycemic agent (tablet linagliptin 5mg PO OD), angiotensin receptor blocker (tablet telmisartan 40mg PO HS), calcium channel blocker (tablet amlodipine 2.5mg PO OD), xanthine oxidase inhibitors (tablet febuxostat 40mg PO OD), HMG-CoA reductase inhibitors (tablet atorvastatin 10mg PO HS), oral N-acetylcysteine (600 mg PO BD), and cholecalciferol (60000 IU once a week). As he met the criteria of metabolic syndrome, he was advised to perform daily exercises and consume low calorie diet for reducing his BMI. He was advised to follow a renal diet and asked to avoid over the counter medications. He was followed every two months and danger signs of renal failure were explained. After receiving treatment and adhering to the lifestyle modification for six months, he lost four kilograms of bodyweight. His laboratory parameters improved to blood urea level of 21 mg/dl, serum creatinine level of 1.2 mg/dl, serum uric acid level of 6.0 mg/dl and normal range of liver enzymes.

Discussion

Ciliopathies refer to shared disorders due to loss of cilia and/or its dysfunction leading to various systemic manifestations in humans, BBS being one of them. Ciliopathies affects the various ciliated organ system causing a wide range of manifestations. Among the 21 recognized BBS genes, BBS1 and BBS10 are the two main genes that are involved in more than 20% of the cases. Bardet–Biedl genes encode BBSomes, proteins that aid in generation and function of primary cilia.⁵

Diagnosis of BBS is done on the basis of phenotypic presentation of the disease and the disease manifestation varies among the patients remarkably. There are multiple primary and secondary features of BBS which have been summarized among patients of various age groups.³ The primary features of BBS include retinal abnormalities, obesity, polydactyly, hypogonadism, renal anomalies, and learning difficulties.¹ Secondary features include speech disorder/delay, strabismus/cataracts/astigmatism, brachydactyly/syndactyly, developmental delay, polyuria/polydipsia (nephrogenic diabetes insipidus), ataxia/poor coordination/imbalance, mild spasticity (especially lower limb), diabetes mellitus, dental crowding/hypodontia/small roots/high arched palate, left ventricular hypertrophy/congenital heart disease, hepatic fibrosis.¹ Many patients at birth have only polydactyly and other clinical features arise as the patient grows.³

In BBS the major cause of morbidity and mortality is renal failure causing 25% mortality by the age of 44 years.⁵ Renal disease is prevalent among 53-82% of patient with BBS. Spectrum of the renal anomalies varies from polycystic kidney disease (most common), renal dysplasia, hydronephrosis, scarred or atrophic kidneys, loss of corticomedullary function, and renal involvement secondary to metabolic syndrome.⁶ The main management of BBS currently focuses on the symptomatic treatment of the patient to reduce the harmful effects of various manifestations on the organ systems of the patient, especially on the kidneys and eyes.^3,6 Renal failure in BBS is managed as in other situations with the use of supportive therapy and renal replacement therapy if necessary.⁵ In our case, we managed the deranged renal function of the patient using the same multidisciplinary approach as we do in other cases of renal impairment.

Early detection of this pleiotropic disease plays an indispensable role in its management. Patients with BBS need a multidisciplinary approach by a team of pediatricians, nephrologists, orthopedic surgeons, endocrinologists, psychologists, cardiologists, ophthalmologists, dental specialists, speech and language therapists, dietitians, geneticists and patient support group representatives. This multifaceted approach with annual review of the patient can provide a plan to individualize risk stratification for particular system like renal and endocrine system. In addition, genetic assessment gives the chance to secernate patients according to genotype, hence the need to follow up according to the natural progression of BBS can be insisted.^5,6 Moreover, the affected individual and their family members can benefit from the genetic counseling.^7,8

In future, genetic therapies will foresee considerable obstacles and challenges due to numerous disease-causing genes and private mutations seen in a particular single family. Potential genetic therapies for the management of BBS in the near future might include gene therapy, readthrough therapy, exon skipping therapy and genome editing. Other non-genomic therapies that can be available in future encompasses targeted drug therapy and drug repurposing.⁶ Despite extensive research in gene therapies, early diagnosis and symptomatic treatment remains the mainstay of the management of BBS for now.

This case highlights the importance of identifying patients with BBS and screening them for the possible complications including renal dysfunction, metabolic syndrome, and retinitis pigmentosa. Early identification and proper management of complications can halt the progression of complications and can improve the quality of life of patient, as in this case.

However, in this case, we couldn’t perform genetic analysis to find the responsible gene because of the unavailability of the resources. In addition to this, as BBS is associated with many gene mutations, has various clinical features, and many complications, a result from this single case report might not be applicable to all patients with BBS. Hence an individualized approach might be necessary for the optimal management of BBS patients.

Conclusion

Bardet-Biedl syndrome is a rare genetic disease with various clinical manifestations. As this condition is rare, diagnosis can be easily overlooked by medical professionals. Management of BBS is symptomatic and requires a multidisciplinary approach. Gene therapy, which is evolving swiftly as a treatment modality in BBS, is challenging owing to the complexity and variability of the genes involved. As renal manifestations including renal failure are the major causes of morbidity and mortality in BBS, they should be screened for early diagnosis and managed accordingly. Hence, timely identification and proper treatment of people with BBS can improve their survival and quality of life.

Consent

Verbal informed consent was taken from patient and written informed consent was taken from his mother for the publication of the article and associated images.