Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype

Abstract

BackgroundKleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1.Case presentationWe describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom – abnormal antiepileptic drug metabolic response – could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large – 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911.ConclusionsThis is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.

New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review

“…In particular, double artery umbilical cord, increased nuchal translucency, oligohydramnios, fetus dismaturity in the 3rd trimester, and major malformations can be detected by prenatal US [Stewart et al, 2004;Chen et al, 2013;Hadzsiev et al, 2016;Huang et al, 2017]. In effect, increased nuchal translucency was detected in patient 1.…”

“…Reported anomalies include broad toes, syndactyly, clinodactyly, brachydactyly, and single palmar crease, with the latter 2 characteristics being predominant [Stewart et al, 2004;Neas et al, 2005;Kleefstra et al, 2006]. Patient 2 exhib- Stewart et al, 2004;Yatsenko et al, 2005;Kleefstra et al, 2006Kleefstra et al, , 2009Willemsen et al, 2012;Hadzsiev et al, 2016. ited a previously unreported foot feature, namely, postaxial polydactyly. Polydactyly is a congenital anomaly characterized by the presence of supernumerary toes or phalanges, with or without metatarsals; this anomaly may occur as an isolated feature or in association with particular genetic conditions [Temtamy and McKusick, 1978;Turra et al, 2007].…”

“…Overall, the children described in the present study have a mild presentation of KS, because they lack cardiovascular or renal involvement (present in 40-45% and 15-30% of KS subjects, respectively), genital anomalies (45-50% of males), skeletal malformations (30-50%), and gross ocular defects (45%). The described heart defects of KS children are primarily conotruncal malformations, such as tetralogy of Fallot or atrial septal defects/ ventricular septal defects, but patent ductus arteriosus/ foramen ovale, aortic coarctation, bicuspid aortic valve, aortic, mitral, or pulmonary valve stenosis, and tricuspid valve dysplasia also have moderate incidences [Stewart et al, 2004;Kleefstra et al, 2006Kleefstra et al, , 2009Willemsen et al, 2012;Hadzsiev et al, 2016]. Patient 1 presented with mild patent ductus arteriosus at birth, but this effect probably reflected prematurity, as suggested by its spontaneous remission within the first month of life.…”

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

“…Nevertheless, Kleefstra is considered a rare single gene trait, although the incidence may likely be underestimated due to lack of genetic testing. In addition, published reports clearly demonstrate a spectrum of phenotypes (Chen et al 2014;Segar et al 2015;Hadzsiev et al 2016;Schmidt et al 2016), most likely due to complexity of modifier genes.…”

EHMT1/GLP; Biochemical Function and Association with Brain Disorders

“…Finally, GLP has also been identified as a pathogenic CNV in patients with intellectual disability and early onset epilepsy [40]. Epilepsy is often associated with ID and developmental delay [38,40], and some patients with Kleefstra syndrome are also known to be comorbid with epilepsy [41].…”