Tethered cord syndrome in KBG syndrome.

Tethered cord syndrome (TCS) is characterized by leg pain and weakness, bladder and bowel dysfunction, orthopedic malformations such as scoliosis, and motor deficits caused by the fixation of the spinal cord to surrounding tissues. TCS is surgically treatable and often found in conjunction with other syndromic conditions. KBG syndrome is caused by variants in the ANKRD11 gene and is characterized by short stature, developmental delay, macrodontia, and a triangular face. The current study explores the prevalence of TCS in pediatric KBG patients and their associated signs and symptoms. Patients with KBG were surveyed for signs and symptoms associated with TCS and asked if they had been diagnosed with the syndrome. We found a high proportion of patients diagnosed with (11%) or being investigated for TCS (24%), emphasizing the need to further characterize the comorbid syndromes. No signs or symptoms clearly emerged as indicative of TCS in KBG patients, but some the prevalence of some signs and symptoms varied by sex. Male KBG patients with diagnosed TCS were more likely to have coordination issues and global delay/brain fog than their female counterparts. Understanding the presentation of TCS in KBG patients is critical for timely diagnosis and treatment.

KBG syndrome involving a single-nucleotide duplication in ANKRD11.

KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.