New Mutation Identified in Bardet-Biedl Patient With Concurrent Rare Disease

Aisha I Abdullah PhD avatar

by Aisha I Abdullah PhD |

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A study has described a rare case of a girl with Bardet-Biedl syndrome (BBS) caused by a newly identified mutation, who also developed a second rare disorder — Legg-Calvé-Perthes disease (LCPD) — that affects the hips.

This is only the second documented case of a patient diagnosed with both BBS and LCPD, researchers said.

The case study, “Legg-Calvé-Perthes disease in a patient with Bardet-Biedl syndrome: A case report of a novel MKKS/BBS6 mutation,” was published in the journal Clinical Case Reports.

BBS is a ciliopathy, a genetic disorder caused by dysfunction of cilia, which are hair-like structures involved in sending messages between nearly all cells.

People with BBS typically gain weight, leading to obesity and abnormalities in the structure and function of the retina (eyes), hands, genitals, and kidneys. BBS is caused by mutations in as many as 21 different genes, called BBS genes, which regulate normal cilia function.

In the case study, researchers in Japan report on a newly identified mutation in the MKKS/BBS6 gene in a 12-year-old patient with both BBS and LCPD. She was the first child of healthy, nonconsanguineous parents, and her family history did not include genetic conditions.

At birth, she showed synpolydactyly in the lower limbs, meaning extra and fused toes, which is a typical sign of BBS. The girl started exhibiting gradual growth retardation, and was referred to the researchers’ institution at age 4 due to continued growth impairment and various malformations, including those in the face and teeth.

Ciliopathies impact many different tissues and organ systems, making diagnosis difficult. In this case, the patient was initially misdiagnosed with a skeletal ciliopathy called Weyers acrofacial dysostosis. However, congenital anomalies of the hands and feet, a trend toward obesity, and retinitis pigmentosa made the team suspect BBS.

“Because the skeletal ciliopathies generally lack of retinal involvement, clinicians should pay attention to visual acuity in addition to the presence of night blindness and peripheral visual field defects indicative of retinal abnormalities when encountering patients with suspected skeletal ciliopathies,” the researchers wrote.

Using whole-exome and conventional DNA sequencing, the team identified a previously unreported mutation (named NM_018848:c.589G>T:p. Gly197*) in both copies of the MKKS/BBS6 gene.

The girl also exhibited symptoms characteristic of LCPD, including a limp without an underlying injury at age 8, limited range of motion in the hip, as well as sclerosis (stiffening of tissue) and abnormal formation of the top of the thigh bone, called the femoral head. Her LCPD diagnosis was confirmed through MRI.

The patient was treated by osteotomy (cut or removal of a piece of a bone), a standard method in children with LCPD. She gradually became obese, and was allowed full weight-bearing, or the amount of weight she could support, on her legs 10 months after surgery. Four years after her LCPD diagnosis, she exhibited a misshapen and misaligned femoral head.

At the last follow-up, the girl was clinically asymptomatic, with normal range of motion and no pain in the right hip, and without apparent gait abnormalities.

Although the researchers could not fully determine if BBS directly impacted LCPD in this patient’s case, “combined pelvic and femoral osteotomy or triple pelvic osteotomy … during the early phase of the disease may be preferable for patients with a ciliopathy,” they wrote.

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