Bardet-Biedel syndrome (BBS) is a rare autosomal recessive, genetically heterogeneous ciliopathy. Although the disease has been described in a patient with psoriasis, individuals with BBS are not known to be at risk of developing autoimmune disorders. Our objective was to describe a 14-year-old patient with BBS who presented with Crohn disease (CD), primary sclerosing cholangitis (PSC), and thyroiditis in the context of a cohort review at Sainte-Justine Hospital and to alert clinicians to the increased risk of autoimmune disorders in these patients. The cohort contained fifteen patients (9 boys), followed from 1968 to 2009 during a median period of 12 years (range 9 months–26 years). Three of the 15 patients (20%) developed a chronic autoimmune disease: one had juvenile rheumatoid arthritis; a second one had type 1 diabetes mellitus in association with Hashimoto thyroiditis and psoriasis; a third one developed CD, PSC, and Hashimoto thyroiditis. As chronic autoimmune diseases occurred in 20% of our cohort of children with BBS, it is appropriate to keep this association in mind during the followup.
Bardet-Biedel syndrome (BBS) is an autosomal recessive disorder, characterized by the following major criteria: early rod-cone dystrophy, polydactyly, obesity, hypogonadism, mental retardation, and renal abnormalities (including parenchymal cysts, calyceal clubbing, foetal lobulation, multicystic dysplastic kidneys, unilateral agenesis, renal calculi, vesicoureteric reflux, bladder obstruction, hydronephrosis, horseshoe kidney, and ectopic kidney) [
To date, BBS is genetically heterogeneous with 14 BBS genes responsible for 14 identified phenotypes [
Some case reports describe inflammatory conditions (such as psoriasis) in BBS patients but no patient with BBS and chronic autoimmune disorders, such as inflammatory bowel disease (IBD), primary sclerosing cholangitis (PSC), and Hashimoto thyroiditis (HT) has been reported to date. Herein, we report the case of an 14-year-old boy with BBS10 who developed Crohn disease (CD), PSC, and HT, and briefly review a cohort of 15 patients with BBS followed in our institution to assess if these patients with BBS are at increased risk of developing chronic autoimmune diseases.
A single centre, retrospective chart review of patients followed at Sainte-Justine Hospital from 1969 to 2007 was conducted after approval by the institutional Research Ethics Board. Charts were reviewed and following data were recorded: age, gender, date of birth, age at diagnosis, presenting criteria, results of genetic tests, duration of followup, presence of any chronic inflammatory, or autoimmune diseases. Appropriate descriptive statistics were used for the analysis of the cohort’s clinical features.
The charts of fifteen patients (9 boys), born between 1968 and 2002, were studied. The median followup was 12 years (range 9 months–26 years). Every patient was diagnosed as BBS based on severe obesity and at least 3 other major criteria, and results of genetic testing were available in 2 children.
During the followup, two children were transplanted for kidney failure at 14 and 16 years of age due to a BBS associated nephropathy. These patients developed progressive renal insufficiency secondary to multicystic dysplastic kidneys. No evidence of autoimmune nephropathy was observed in both children. Two patients died because of renal insufficiency: the first one on the waiting list for transplantation and the second one after renal transplantation due to surgical complications and vascular thrombosis. Currently, three children are still followed in our centre, while 10 patients have been transferred to adult care. Clinical characteristics of this cohort are reported in Table
Clinical characteristics of a cohort of 15 patients with Bardet-Biedl syndrome.
Patients | Date of birth | Gender | Molecular testing of BBS gene defect |
Follow-up period duration (years) | Associated chronic inflammatory or auto-immune disorders |
---|---|---|---|---|---|
1 | 8/03/1968 | F | No | 26 | / |
2 | 10/09/1970 | M | No | 17 | / |
5 | 9/10/1970 | F | No | 8.2 | / |
3 | 05/11/1973 | M | No | 21.5 | / |
4 | 9/07/1974 | F | No | 17 | / |
6 | 10/12/1977 | F | No | 16.1 | / |
7 | 11/01/1979 | F | No | 14.2 | / |
8 | 30/06/1980 | F | No | 15.3 | / |
9 | 8/12/1983 | M | No | 9.3 | / |
10 | 5/04/1984 | M | No | 8.1 | Juvenile rheumatoid arthritis |
11 | 16/06/1985 | M | No | 17.9 | Type 1 diabete mellitus, Hashimoto thyroiditis, Psoriasis |
12 | 22/04/1986 | M | No | 0.8 | / |
13 | 30/12/1988 | M | Yes (14) | 15.2 | / |
14 | 04/11/1997 | M | Yes (9) | 14 | Crohn's disease, primary sclerosing cholangitis, Hashimoto thyroiditis |
15 | 04/09/2002 | M | No | 9.3 | / |
F: female, M: male.
Three patients developed inflammatory disorders (Table
This patient, born in 1997, is the only child of nonconsanguineous French Canadian parents. There is no familial history of chronic autoimmune disease. The father is healthy and tall (198 cm, +1.5 standard deviation) and the mother has a huge naevus flammeus of the left facies and partial deafness suggesting Sturge-Weber syndrome but was not investigated. At the age of 29 years, a first pregnancy required a therapeutic abortion for foetal anencephaly and an abnormal thorax as well as renal cysts. The family pedigree is presented in Figure
Familial pedigree of the reported patient. The patient has nonconsanguineous French Canadian parents without history of inflammatory bowel disease. First-degree relatives are healthy except the mother who presents with renal cysts, possible Sturge-Weber syndrome, and previous abortion secondary to foetal anencephaly and abnormal thorax.
At the age of 40, after an uneventful pregnancy with prenatal diagnosis of foetal bilateral renal polycystic disease, the mother had an uneventful delivery. The full-term male newborn, weighing 3.2 kg, presented with superior and inferior postaxial polydactyly, an incomplete foreskin, a naevus flammeus on the neck, a flattened angioma on the philtrum and on the nose, and a mild erythema on the left eyelid. The renal US confirmed the prenatal diagnosis revealing bilaterally increased kidneys (57–60 mm of longitudinal length) with hyperechogenic and ill differentiated cortical and medullar areas, and the presence of several cysts.
Early in life, the child presented a developmental delay: crawling at 18 months, sitting at 24 months, speech acquisition after 3 1/2 years. The body mass index (BMI) was also abnormally increased early in life (31 and 32 at 2 1/2 and 5 years old, resp.). In 2006, at 9 years of age, the suspected diagnosis of BBS was confirmed (homozygous
Recently, this adolescent presented with persistently increased levels of serum aminotransferases: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at 101 and 67, respectively, and gamma-glutamyl transpeptidase. (GGT) at 59 U/L during a 6-months period without any clinical sign or complaint. In our hospital, the upper limit for normal ALT, AST, and GGT is 25–34 U/L, 43–70 U/L, and 3–43 U/L, resp.). Etiologies of hepatitis were systematically explored. In particular, we thoroughly ruled out usual infectious causes (Hepatitis A, B, C, and D viruses, Epstein-Barr virus, cytomegalovirus, adenovirus, herpes group viruses, parvovirus, and echoviruses), Wilson disease, and autoimmune hepatitis. Toxic causes related to 6-mercaptopurine treatment were also excluded by weaning him off the treatment for a prolonged time. A magnetic resonance cholangiography was performed and revealed features compatible with PSC, in particular peripheral areas of high T2-weighted signal intensity in the liver parenchyma, intrahepatic bile ducts strictures, and secondary dilatation. In addition, peri-portal edema and peri-portal inflammation have also been observed as regions of low signal intensity on T1-weighted images and as intermediate signal between liver and bile on T2-weighted images. These abnormalities were highly suggestive of a diagnosis of PSC. A liver biopsy was proposed but parents declined this option. The patient has been treated with ursodeoxycholic acid treatment (500 mg twice a day) and serum aminotransferases have normalized. Currently, he is free of any symptoms or signs of chronic hepatopathy.
Development of 3 autoimmune diseases over a 14-year period in one patient led us to ask whether other BBS patients were at risk of developing chronic inflammatory and autoimmune disorders, especially IBD, and to review the cohort of BBS patients in our hospital.
BBS is estimated to occur in 1/125.000 to 160.000 inhabitants of European countries and in 1/13.500 to 1/17.500 people of Middle East countries and Newfoundland [
The genetic defect found in the reported patient is a frameshift mutation on chromosome 12q21.2, described in almost 50% of patients with
In conclusion, we described a patient with BBS, ileal CD without family history of IBD, PSC, and Hashimoto thyroiditis, and found a 20% prevalence of chronic inflammatory or autoimmune diseases in our cohort of patients with BBS. These observations should encourage physicians to explore carefully and rule out chronic inflammatory or autoimmune disorders, including IBD, in the followup of BBS patients.
The authors declare that they have no conflict of interests, and they agree with the Hindawi Copyright and Licence Terms.
The authors thank Professor Claude Roy (from the Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Hospital Sainte-Justine, Université de Montréal, Québec, Canada) for his helpful comments and valuable assistance in the review of this work. Pr Claude Roy has no conflict of interests.