Motor-Dominant Peripheral Neuropathy, Polydactyly, Mental Retardation, Kidney Failure, Diabetes Mellitus, and Developmental Delay in the Absence of Retinal Dystrophy: Spectrum of Bardet-Biedl Syndrome (BBS)

Hiroyuki Morita1,2,*, Yoshinori Sato1, Yoshihiro Wakayama3, Masahiko Ayaki4, Sho Hirase2, Junko Takagi2, Kazuo Otake2, Kiyoko Inui1, Yoshihiko Inoue1, Ashio Yoshimura1 and Fumihiko Koiwa1 1Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan 2Division of Endocrinology and Nutrition, Department of Internal Medicine, Aichi Medical University School of Medicine, Japan 3Division of Neurology, Department of Medicine, Showa University Fujigaoka Hospital Japan 4Department of Ophthalmology, Showa University Fujigaoka Hospital, Japan

at term to double first cousin parents with uneventful prenatal periods. At three months of age, he underwent initial surgery for postaxial polysyndactyly. He started walking by himself at the age of 12 months. He had mental and growth retardations in childhood. His skeletal ages at the chronological ages of 3.5 and 12.25 years were 1.25 and 8.5 years, respectively. At 8 years of age, he underwent surgery for unilateral cryptorchidism. His parents stated he was obese and had round face in his childhood. He had gone through a total of four surgical operations for polysyndactyly.
An X-ray photograph of the hands taken in the fourth decade of life clearly shows an abnormality of the DIP joint and phalanges (ossa digitorum manus) of the first finger (Figure 1). At 15 years of age, he was diagnosed with type 2 diabetes mellitus (DM): his height, weight and IQ were 143.2 cm (-3.8 SD), 39.0 kg (-1.8 SD) and 66, respectively. Although his blood sugar control was poor, his behavioral problems had prevented him from receiving insulin therapy until he came to our institute at the age of 28 years.

Family History
The patient's parents are double first cousins who came from Yamanashi prefecture in Japan. He has an elder brother who has no BBS phenotypes. His maternal grandmother and grandfather had diabetes mellitus and cerebral infarct, respectively. His paternal grandmother had cardiovascular disease (details unknown) and had brothers who were short of stature (140-150 cm).

Discussion
A BBS patient requires 4 primary features, or 3 primary features plus at least 2 secondary features [2,9]: Our patient has at least 3, and possibly 4, primary features; polydactyly, renal abnormalities, learning disability, and obesity. We are not sure if latent hypogonadism and calcification of deferent duct that he has should qualify as another primary feature; "hypogonadism in males". Nevertheless, it is fair to claim he is diagnosed with BBS, because he has at least 2 secondary features; diabetes mellitus and developmental delay [2,9]. Particular emphasis is placed on eye phenotype in diagnosis of BBS [10]. Retinal dystrophy, rod-cone dystrophy, or related eye disorders are present in 100% of patients in some reports [7,[11][12][13]. Although it was present in slightly less than 100% in other reports, those who did not have the eye disorder were children [8,9]. In one Chinese report, retinitis pigmentosa was found only in 72.3% of the patients [14]. This lower incidence may have been due to a young mean age of 15.8 years in study cohort. Typically, BBS patients develop ocular problems in the second and third decade of life [15]. Our patient is over 30 years of age, and it is very unusual for BBS patients of this age not to have any of the above-mentioned eye phenopypes. BBS genes encode cilium proteins, of which there are reported links with retinal dystrophy [2,5].
Rod-cone dystrophy may be caused by trafficking abnormalities across the defective modified cilia that connects to the inner and outer segments of photoreceptors leading to apoptosis [16]. motor-dominant peripheral neuropathy [9]. Sensory dominant peripheral neuropathy is much more common in DM [17]. There are 2 groups BBS patients with renal failure, the first one includes patients with renal and urinary tract abnormalities diagnosed early in life, and the second one includes adult BBS patients with no clear information on the onset of CKD (18). Our patient belongs to the second group. End-stage renal disease due to diabetic nephropathy