Bronchial isomerism in a Kabuki syndrome patient with a novel mutation in MLL2gene

Abstract

BackgroundKabuki syndrome (KS) is a rare, multiple congenital anomalies/intellectual disability syndrome caused by mutations of MLL2 gene, which codifies for a histone methyltrasferase that regulates the embryogenesis and the tissue development. Left-bronchial isomerism is a rare congenital abnormality that can be defined as the absence of the normal lateralizing features which distinguish right and left-sides in the lungs. To date, this is the first report of left-bronchial isomerism in association with KS.Case presentationA one-month-old Caucasian male patient underwent our attention for microcephaly, dysmorphic features (long palpebral fissures, eyebrows with sparse lateral third, everted lower eyelids, blue sclerae, large dysplastic ears, lower lip pits), persistent fetal fingertip pads, short stature, heart defects (interventricular defect and aortic coarctation), unilateral cryptorchidism, hypotonia and delay in gross motor skills. These features suggested a diagnosis of KS and a molecular analysis confirmed a novel frame-shift mutation in the exon 11 of MLL2 gene. Subsequently, given recurrent respiratory infections with a normal immunological status, he underwent a chest CT scan that showed a left bronchial isomerism.ConclusionWe report a patient affected by KS, with a novel MLL2 mutation and an atypical phenotype characterized by left-side bronchial isomerism. Interestingly, genes involved in the heterotaxia/isomerism such as ROCK2 and SHROOM3 are known to interact with MLL2 gene. In order to achieve a correct diagnosis and an appropriate therapy, the presence of pulmonary anatomical variations should be investigated in KS patients with respiratory signs not associated to immunological deficiency. Finally, our findings support the hypothesis that the mutations leading to a complete loss of function of MLL2 gene is often associated with complex visceral malformations.

Congenital heart defects in molecularly proven Kabuki syndrome patients

“…Pathogenetic variants in KMT2D (MLL2) gene were detected in 27 patients, and a deletion of part of KDM6A gene in an additional patient which was previously reported by Lederer et al () (Table ). Previously published Kabuki syndrome subjects are patients 2,3 (Dentici et al, ; Micale et al, ), 5 (Cappuccio et al, ; Dentici et al, ), 6,7,9,21 (Dentici et al, ), 26 (Roma et al, ) (Table ). Patient 2 (Table ) had 47,XXY karyotype, additionally to the variant in KMT2D (MLL2) .…”

Mutation Update for Kabuki Syndrome GenesKMT2DandKDM6Aand Further Delineation of X-Linked Kabuki Syndrome Subtype 2

“…We searched the HGMD database for mutations in KMT2D and KDM6A and, additionally, conducted a search for further mutations described in original articles in PubMed using the terms "Kabuki syndrome", "MLL2 mutation", and "KMT2D mutation" in different combinations. We examined the clinical and molecular information available from the retrieved 21 mutation screening studies [Ng et al, 2010;Hannibal et al, 2011;Li et al, 2011;Micale et al, 2011;Paulussen et al, 2011;Banka et al, 2012;Courcet et al, 2013;Lindgren et al, 2013;Makrythanasis et al, 2013;Miyake et al, 2013aMiyake et al, , 2013bCheon et al, 2014;Micale et al, 2014;Subbarayan and Hussain, 2014;Dentici et al, 2015;Lin et al, 2015;Lindsley et al, 2015;Liu et al, 2015;Morgan et al, 2015;Van Laarhoven et al, 2015;Paděrová et al, 2016] and 19 molecularly proven case reports [Kokitsu-Nakata et al, 2012;Riess et al, 2012;Tanaka et al, 2012;Zarate et al, 2012;Brackmann et al, 2013;Kim et al, 2013;Ratbi et al, 2013;Zaidi et al, 2013;Cappuccio et al, 2014;Giordano et al, 2014;Soden et al, 2014;Schulz et al, 2014;Takagi et al, 2014;Verhagen et al, 2014;Gohda et al, 2015;McVeigh et al, 2015;…”

Coexistence of Kabuki Syndrome and Autoimmune Thyroiditis

“…The main causes of KS are point mutations with large intragenic deletions and duplications of the histone methyl transferase MLL2 gene ( 1 , 4 , 5 ). We detected a de novo heterozygous p.R2471* (c.7411C>T) mutation in this patient.…”