Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome

Abstract

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.

Figure 1

Results of the BBS2, BBS4, and BBS6 mutation screening. The pedigrees and mutations are indicated. The black symbols indicate the affected cases. Below each pedigree, sequence chromatographs are shown. In family BOU, the results of the RT-PCR study confirming the deletion of three BBS4 exons in proband 5b (E) and the results of haplotype analysis at the BBS4 locus (F) are shown.

Figure 2

Histological sections (hematoxylin/eosin) of kidneys and livers of fetuses carrying BBS mutations. Case 8 shows normal kidney histology. Cases 1 and 4 show medullary cysts, whereas cases 3, 6, and 2b show kidneys “Meckel-like” lesions. The liver shows moderate portal fibrosis in cases 3 and 2b.