Masatsune Itoh

Two cases of 22q11.2 deletion syndrome with anorectal anomalies and growth retardation.

Abstract Clinical features associated with the deletion of 22q11.2 are highly variable. Most are diagnosed by cardinal congenital heart disease or hypoparathyroidism. In cases without major features, an early accurate diagnosis of 22q11.2 deletion syndrome is difficult. Congenital anorectal malformations (ARM), which can be detected soon after birth, have been rarely reported in 22q11.2 deletion syndrome. We report two cases of 22q11.2 deletion syndrome with ARM who showed growth retardation. ARM was detected in both patients without congenital heart disease or hypoparathyroidism at early infancy and they were followed by pediatric surgeons. Later, failure to thrive or short stature became evident, and they consulted with pediatric endocrinologists who subsequently confirmed the diagnosis of 22q11.2 deletion by fluorescent in situ hybridization analysis. The combination of ARM and growth retardation may lead to an early diagnosis of 22q11.2 deletion syndrome.

An inherited disorder characterized by repeated episodes of bilateral ballism: A case report

This case report describes two siblings with a dyskinetic form of cerebral palsy who had repeated episodes of fever‐induced bilateral ballistic movements. The boy and his sister experienced the first episodes during early childhood. The movements developed over several hours and required rapid intervention. Electroencephalograms during the attacks showed no paroxysms, and brain magnetic resonance imaging scans revealed no lesions. The brother died of acute renal failure at age 5 due to rhabdomyolysis after his fifth episode of prolonged bilateral ballistic movements. This is the first report of an inherited disorder characterized by repeated episodes of violent movements.

Intermittent X-linked thrombocytopenia with a novel WAS gene mutation

X‐linked thrombocytopenia (XLT) is caused by mutations in the WAS gene and characterized by thrombocytopenia with minimal or no immunodeficiency. Patients with XLT usually exhibit persistent thrombocytopenia, and intermittent thrombocytopenia has been described only in two families. Here, we report a patient with intermittent XLT carrying a novel missense mutation (Ala56Thr). He showed residual expression of Wiskott–Aldrich syndrome protein in the lymphocytes and platelets. There appeared to be an association between normal platelet numbers and a post infectious state. Our findings further support the importance of analysis of Wiskott–Aldrich syndrome protein in male patients who exhibit fluctuating courses of thrombocytopenia. Pediatr Blood Cancer 2014;61:746–748.

A novel MEN1 mutation in a Japanese adolescent with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1; OMIM 131100) is an autosomal-dominant hereditary endocrine tumor syndrome. It is characterized by the combined development of anterior pituitary adenomas, adenomas or hyperplasia of the parathyroid glands, and gastroenteropancreatic neuroendocrine tumors (GEPNETs) in a single patient. Germline mutations in the menin gene (MEN1) account for the development of MEN1, and most of the MEN1 mutations are inactivating, which is consistent with the tumor-suppressing role of menin. More than 1000 different germline MEN1 mutations have been reported throughout the entire length of the coding and noncoding regions without significant clustering. Of all mutations, approximately 23% are nonsense mutations, 41% are frameshift deletions or insertions, 6% are in-frame deletions or insertions, 9% are splice-site mutations, and 20% are missense mutations (1). We describe herein a Japanese adolescent with MEN1 carrying a newly identified heterozygous missense mutation (p.Gly42Val) in MEN1.

AB076. Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis

Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder in ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy, including neonatal periods. More than 30 patients with this disorder have been reported and to our knowledge, their heterozygous parents and siblings have had no apparent ketoacidotic episodes. Over 5 years (2008–2012), we investigated several patients that presented with severe ketoacidosis and identified a heterozygous OXCT1 mutation in four of these cases (Case1 p.R281C, Case2 p.T435N, Case3 p.W213*, Case4 c.493delG). To confirm their heterozygous state, we performed a multiplex ligation-dependent probe amplification analysis on the OXCT1 gene which excluded the presence of large deletions or insertions in another allele. A sequencing analysis of subcloned full-length SCOT cDNA showed that wild-type cDNA clones were present at reasonable rates to mutant cDNA clones. Over the following 2 years (2013–2014), we analyzed OXCT1 mutations in six more patients presenting with severe ketoacidosis (blood pH ≦7.25 and total ketone body ≧10 mmol/L) with non-specific urinary organic acid profiles. Of these, a heterozygous OXCT1 mutation was found in two cases (Case5 p.G391D, Case6 p.R281C). Moreover, transient expression analysis revealed R281C and T435N mutants to be temperature-sensitive. This characteristic may be important because most patients developed ketoacidosis during infections. Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.

Contents Vol. 149, 2016

Plant cytogenetics and genomics Andreas Houben Institute of Plant Genetics and Crop Plant, Research (IPK) Corrents-Str. 3 Gatersleben, D–06466 (Germany) Tel. (+1) 785 532 2364; Fax (+1) 785 532 5692 E-mail: houben@ipk-gatersleben.de Tumor cell genetics and cancer cytogenetics Ad Geurts Van Kessel Department of Human Genetics University Hospital P.O. Box 9101 NL–6500 HB Nijmegen (The Netherlands) Tel. (+31) 24 361 4107; Fax (+31) 24 354 0488 E-mail: a.geurtsvankessel@antrg.umcn.nl

Angelman Syndrome Caused by Chromosomal Rearrangements: A Case Report of 46,XX,+der(13)t(13;15)(q14.1;q12)mat,-15 with an Atypical Phenotype and Review of the Literature

Less than 1% of the cases with Angelman syndrome (AS) are caused by chromosomal rearrangements. This category of AS is not well defined and may manifest atypical phenotypes. Here, we report a girl with AS due to der(13)t(13;15)(q14.1;q12)mat. SNP array detected the precise deletion/duplication points and the parental origin of the 15q deletion. Multicolor FISH confirmed a balanced translocation t(13;15)(q14.1;q12) in her mother. Her facial appearance showed some features of dup(13)(pter→q14). Also, she lacked the most characteristic and unique behavioral symptoms of AS, i.e., frequent laughter, happy demeanor, and easy excitability. A review of the literature indicated that AS cases caused by chromosomal rearrangements can be classified into 2 major categories and 4 groups. The first category is paternal uniparental disomy 15, which is subdivided into isodisomy by de novo rob(15;15) and heterodisomy caused by paternal translocation. The second category is the deletion of the AS locus due to maternal reciprocal translocation, which is subdivided into 2 groups associated with partial monosomy by 3:1 segregation and partial trisomy by adjacent-2 segregation. Classification into these categories facilitates the understanding of the mechanisms of chromosomal rearrangements and helps in accurate diagnosis and genetic counseling of these rare forms of AS.

A novel frameshift mutation in the TRPS1 gene caused Tricho-rhino-phalangeal syndrome type I and III in a Japanese family.

Tricho-rhino-phalangeal syndrome (TRPS) is a heritable congenital syndrome characterized by craniofacial and skeletal abnormalities. TRPS is an autosomal dominant syndrome with high penetrance and wide phenotypic variability. TRPS is classified into three subtypes; TRPS types I (TRPS I; OMIM 190350) and III (TRPS III; OMIM 190351) have distinct clinical manifestations that often correspond to distinct mutations in the TRPS1 gene. Patients with either TRPS I or III have sparse scalp hair, a nose with a bulbous tip, and skeletal abnormalities including cone-shaped epiphyses at the phalanges and short stature (1). Skeletal malformations in patients with TRPS III are more severe than that in patients with TRPS I (2). TRPS type II (TRPS II; OMIM 150230) is caused by a contiguous gene deletion involving TRPS1 and EXT1. Several genotype-phenotype relationship studies on TRPS indicate that TRPS III is at the most severe end of the TRPS clinical spectrum and TRPS I is at the least severe end (3). Here, we describe a Japanese family with two TRPS cases with intra-familial phenotypic variability (TRPS I and TRPS III). Both cases were associated with a single newly described frameshift mutation in TRPS1.