ABSTRACT
OBJECTIVE: to report the first case series of Brazilian children diagnosed with Kleefstra syndrome, present a possible phenotype expansion to the syndrome and to raise physicians' awareness for this rare disease. RESULTS: seven patients with confirmed KS were evaluated, including 5 males and 2 females. Abnormal prenatal findings were observed in 4 patients. Most patients were born at term, with normal birth measurements. All patients had neurodevelopmental delay and 6 evolved with intellectual disability. Hearing loss was present in 57.1% of patients and 28.7% had congenital heart disease. In males, cryptorchidism was present in 75%. Despite the facial dysmorphisms, only 2 out of 7 patients had a pre-test clinical suspicion of KS. One specific patient presented bilateral agenesis of the semicircular canals, a very rare ear manifestation in Kleefstra syndrome, representing a possible phenotype expansion of the syndrome. CONCLUSION: this report aims to promote awareness among physicians evaluating patients in a context of neurodevelopmental delay or congenital malformations, especially congenital heart defects. We also highlight a possible phenotype expansion of the syndrome, with a case of semicircular anomaly, not reported in this syndrome so far.
Subject(s)
Chromosome Deletion , Craniofacial Abnormalities , Intellectual Disability , Phenotype , Semicircular Canals , Humans , Male , Female , Intellectual Disability/genetics , Intellectual Disability/pathology , Brazil , Craniofacial Abnormalities/pathology , Craniofacial Abnormalities/genetics , Child , Child, Preschool , Semicircular Canals/abnormalities , Semicircular Canals/pathology , Heart Defects, Congenital/pathology , Heart Defects, Congenital/genetics , Chromosomes, Human, Pair 9/genetics , InfantABSTRACT
BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder caused by pathogenic variants in VHL gene. The common manifestations include hemangioblastomas (HB) of the central nervous system (CNS) and retina (RH); pheochromocytoma (PHEO); clear cell renal cell carcinoma (ccRCC); pancreatic and renal cysts (PRC) and pancreatic neuroendocrine neoplasm (PNEN). METHODS: The first characterization of VHL in Brazil was published in 2003 and included 20 families with a history of VHL. The aim of this study was to expand the previous Brazilian cohort to include more families, as well as to collect prospectively both clinical and molecular characteristics of patients with VHL to build the VHL Brazilian Registry (VHLBR). Patients with VHL were selected through review of data from medical records of experts and from social networks of support for families with VHL in Brazil. RESULTS: A total of 142 subjects representing 62 unrelated Brazilian families with VHL were registered. The mean age of VHL onset was 28.78 years old and 128 individuals (90.1%) had at least one VHL-related lesion. CNS HB was the most common manifestation occurring in 91 (71%) patients, followed by multiple PRC (48.4%), RH (39.8%), ccRCC (28.9%), PHEO (12.5%) and PNEN (7.8%). Of the 97 subjects whose presence of VHL variants was confirmed, 51 (52.6%) had missense variants, 22 (22.7%) large deletions, 10 (10.3%) frameshift, 7 (7.2%) splice site, 4 (4.1%) nonsense and 3 (3.1%) in-frame deletions. Regarding surveillance, 115 (81%) participants had at least one physician responsible for their outpatient follow-up; however, 69 (60%) of them did not report a regular frequency of tests. CONCLUSION: We built the largest prospective VHLBR with organized collections of clinical and genetic data from families with VHL, which will be helpful to guide policies for VHL care and oncogenetics in Brazil. Although there have been improvements in diagnosis and clinical screening methods, VHL care in Brazil is still deficient, especially regarding surveillance and regular medical appointments with experts.