KBG syndrome patient due to 16q24.3 microdeletion presenting with a paratesticular rhabdoid tumor: Coincidence or cancer predisposition?

Abstract

KBG syndrome is a rare autosomal dominant disorder caused by constitutive haploinsufficiency of the ankyrin repeat domain-containing protein 11 (ANKRD11) being the result of either loss-of-function gene variants or 16q24.3 microdeletions. The syndrome is characterized by a variable clinical phenotype comprising a distinct facial gestalt and variable neurological involvement. ANKRD11 is frequently affected by loss of heterozygosity in cancer. It influences the ligand-dependent transcriptional activation of nuclear receptors and tumor suppressive function of tumor protein TP53. ANKRD11 thus serves as a candidate tumor suppressor gene and it has been speculated that its haploinsufficiency may lead to an increased cancer risk in KBG syndrome patients. While no systematic data are available, we report here on the second KBG syndrome patient who developed a malignancy. At 17 years of age, the patient was diagnosed with a left-sided paratesticular extrarenal malignant rhabdoid tumor. Genetic investigations identified a somatic truncating gene variant in SMARCB1, which was not present in the germline, and a constitutional de novo 16q24.3 microdeletion leading to a loss of the entire ANKRD11 locus. Thus, KBG syndrome was diagnosed, which was in line with the clinical phenotype of the patient. At present, no specific measures for cancer surveillance can be recommended for KBG syndrome patients. However, a systematic follow-up and inclusion of KBG syndrome patients in registries (e.g., those currently established for cancer prone syndromes) will provide empiric data to support or deny an increased cancer risk in KBG syndrome in the future.

Natural history of KBG syndrome in a large European cohort

“…Seven patients (patients 7, 8, 9, 13, 20, 26, 38 in Supplementary Material, Table S1 ) out of the 44 evaluable individuals (15,6%), did not display ID. Severe ID was identified only in two patients with concomitant genetic conditions ( 12 , 16 ), namely maternal 15q11.2 deletion and paternal inherited exostosis due to EXT1 mutation , respectively. About 18% of patients presented hypotonia at birth or at the first evaluation.…”

“…Epilepsy was present in 26.5% of patients (13/49) and mostly correlated with cerebral anomalies at the MRI. Indeed, out of 13 patients who developed seizures, eight presented brain anomalies, in three of them ( 12 , 25 , 26 ) no cerebral alteration was detected by brain imaging and in two of them no MRI was performed. Electroencephalography (EEG) often revealed mild non-specific background abnormalities with modest voltage asymmetry, slow background activity (patient 2, 8, 47) or an irregular brain activity during sleeping (patient 41).…”

“…Interestingly, ANKRD11 is frequently affected by loss of heterozygosity in cancer, and it is supposed to enhance the tumour-suppressive function of TP53 oncogene ( 19 ). It has been speculated that ANKRD11 haploinsufficiency may lead to an increased cancer risk in KBGS patients but only one patient with a 16p24.3 deletion involving ANKRD11 developed a paratesticular rhabdoid tumour ( 12 ).…”

Case Report: Two Newly Diagnosed Patients With KBG Syndrome—Two Different Molecular Changes

“…ANKRD11 expression was shown to be downregulated in breast cancer cell lines. Moreover, Behnert et al (29) reported a 17-year-old patient who was diagnosed with a left-sided paratesticular extrarenal malignant rhabdoid tumor. Genetic testing identified a constitutional de novo 16q24.3 microdeletion leading to the loss of the entire ANKRD11 locus.…”

Two case reports of KBG syndrome with Dandy‐Walker variant

“…Noriko Fuke, 1 Sae Nishisho, 1 Aya Tanaka, 2 Ryuichi Shimono 2 and Takashi Kusaka 1 Department of 1 Pediatrics, 2 Pediatric Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan Key words ascites, pharmacotherapy resistance, pleuroperitoneal communication, quality of life.…”