Sunday, December 30, 2018

KBG syndrome

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Morel Swols D, Tekin M. KBG Syndrome. 2018 Mar 22. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from

KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.

The diagnosis of KBG syndrome is confirmed in a proband by detection of either a heterozygous pathogenic variant in ANKRD11 or deletion of 16q24.3 that includes ANKRD11.

Treatment of manifestations. Surgical corrections and/or speech therapy for palatal anomalies; nasogastric tube feeding in infants; pharmacologic treatment for gastroesophageal reflux disease; pressure-equalizing tubes and/or tonsillectomy/adenoidectomy for chronic otitis media; consideration of amplification for hearing loss; consideration of growth hormone therapy for short stature and medication to arrest puberty for premature pubertal development; standard treatment of seizure disorder, undescended testis in males, congenital heart defects, strabismus / refractive errors, and developmental disabilities. Surveillance. Routine monitoring of hearing, vision, growth, pubertal status (in prepubertal individuals), and cognitive development. Agents/circumstances to avoid. Ototoxic drugs should be avoided because of the risk for hearing loss. Pregnancy management. Pregnancy management should be tailored to the specific features in the affected woman. For example, involvement of a cardiologist and maternal fetal medicine physician for a pregnant woman with a history of a congenital heart defect; control of seizures during pregnancy for those with a seizure disorder.

Recurrence risk for sibs of a proband with KBG syndrome depends on the genetic alteration: Deletion of 16q24.3 (~75% of reported pathogenic variants are de novo and the remainder are inherited in an autosomal dominant manner.) ANKRD11 sequence variants (~66% of reported pathogenic variants are de novo and the remainder are inherited in an autosomal dominant manner.) Prenatal testing and preimplantation genetic diagnosis are possible if the causative genetic alteration has been identified in an affected family member.

De Bernardi ML, Ivanovski I, Caraffi SG, Maini I, Street ME, Bayat A, Zollino M, Lepri FR, Gnazzo M, Errichiello E, Superti-Furga A, Garavelli L. Prominent and elongated coccyx, a new manifestation of KBG syndrome associated with novel mutation in ANKRD11. Am J Med Genet A. 2018 Sep;176(9):1991-1995.

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon-intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.

Behnert A, Auber B, Steinemann D, Fr├╝hwald MC, Huisinga C, Hussein K, Kratz C, Ripperger T. KBG syndrome patient due to 16q24.3 microdeletion presenting with a paratesticular rhabdoid tumor: Coincidence or cancer predisposition? Am J Med Genet A. 2018 Jun;176(6):1449-1454.

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.

Monteiro JP, Rijo D, Pereira R, Guerra M. Isolated tricuspid valve Staphylococcus lugdunensis endocarditis in patient with a KBG syndrome. Rev Port Cir Cardiotorac Vasc. 2018 Jan-Jun;25(1-2):91-93. Abstract in English, Portuguese

Both KBG syndrome (approximately 50 patients worldwide) and isolated tricuspid valve Staphylococcus lugdunensis endocarditis are very rare entities. The KBG syndrome is a multiple congenital anomaly characterized by short stature, distinctive craniofacial features, and neurologic/developmental/cognitive delay and is only associated to congenital heart defects in 9% of patients. Staphylococcus lugdunesis is an aggressive cause of infective endocarditis. Herein is described a case of a patient presenting both diseases, despite the absence of any known infection, congenital heart defect, heart device or any other entry port which could explain this scenario. The unusual findings in this young patient raised questions regarding the, as-yet unexplained, etiopathogenesis of the KBG syndrome, the possibility of it being related to this rare and concerning clinical presentation and the unclear and undefined management and surgical approach associated to right side endocarditis.

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