Adams–Oliver syndrome and familial MYH9 mutation

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  • Patient Reportsped_3466 407..433

    AdamsOliver syndrome and familial MYH9 mutation

    Tomomi Uyeda,1 Taketora Echizenya,3 Shuji Eto,1 Katsuki Ohtani,1 Takumi Sato,1 Tohru Takahashi,1 Etsuro Ito,1Susumu Yonesaka2 and Shinji Kunishima4Departments of 1Pediatrics and 2Health Sciences, Hirosaki University School of Medicine, Hirosaki, 3Department ofPediatrics, Iwate Prefectural Kitakami Hospital, Kitakami and 4Department of Advanced Diagnosis Clinical Research Center,National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Key words AdamsOliver syndrome, congenital heart defect, congenital scalp defects, MYH9, terminal transverse limb defects.

    AdamsOliver syndrome (AOS; OMIM 100300) is a rare condi-tion characterized by the combined occurrence of congenitalscalp defects and terminal transverse limb defects.1 The inherit-ance of AOS is autosomal dominant in most cases. Apart fromscalp and limb defects, there are a large number of abnormalitiesassociated with AOS. Although the pathogenesis of AOS is stillunclear, it is suggested that vascular abnormalities and throm-botic mechanisms during early embryogenesis may play animportant role in AOS.2,3

    MYH9 disorders are autosomal dominant platelet disorderscharacterized by the triad giant platelets, thrombocytopenia, andDhle body-like cytoplasmic granulocytes inclusion bodies.These disorders result from mutations in the MYH9 gene, whichencodes non-muscle myosin heavy chain II-A (NMHCIIA).4These disorders include MayHegglin anomaly, Sebastian, Fecht-ner, and Epstein syndrome and are also found to be responsible forseveral related disorders associated with deafness, nephritis andcataracts.5 Here we report on a patient with AOS associated withcardiovascular malformations and an MYH9 mutation.

    Case reportThe proband was the first child of non-consanguineous,Japanese parents. There was no family history of limb or scalpdefects or congenital heart disease. There was no exposure toany tetratogenic drugs or infections during embryonic develop-ment. The proband was born at 39 weeks of gestation with abirthweight of 2486 g. Physical examination at birth showedgeneralized cyanosis, a scalp defect (Fig. 1a), a transverse limbdefect on the right foot (Fig. 1b) and congenital dermal sinus onthe sacrococcygeal region, but no findings of amniotic band.There was a grade 2/6 systolic ejection murmur over the upperleft sternal border. Echocardiogram showed a secundum atrialseptal defect, a large ventricular septal defect, right ventricularoutflow tract obstruction, overriding of the aorta and anomalous

    origin of the right pulmonary artery. A selective right subclavianarteriogram demonstrated connection of the innominate arteryto the right pulmonary artery (Fig. 1c). These cardiovascu-lar anomalies were diagnosed as tetralogy of Fallot with anabnormal aorto-pulmonary vascular connection. Hearing loss,cataracts and developmental delay were apparently absent.Evaluation of kidneys on urinalysis and ultrasound showed noabnormal findings. G-banded lymphocyte chromosome analysisshowed a normal 46, XY karyotype. On laboratory testing theplatelet count was 27 000/mL. The proband had persistentthrombocytopenia without a bleeding tendency. On May-Grnwald-Giemsa staining of peripheral blood smears, giantplatelets and cytoplasmic inclusion bodies in granulocytes wereseen (Fig. 2a). Because of platelet morphological anomaly sug-gested the possibility of NMHCIIA, immunofluorescence analy-sis of neutrophils with anti-NMHCIIA polyclonal antibody wasperformed as described previously.6 An abnormal subcellularlocalization of NMHCIIA was detected as a punctuate pattern inevery observed neutrophil (Fig. 2c). Mutational analysis of exon38 and 40 of the MHY9 gene was performed as described pre-viously.7 Direct sequencing analysis showed an abnormal elec-tropherogram. Sequencing of cloned PCR products showed thatthe patient was heterozygous for a deletion of one G within the4G repeat at nucleotide 57705773 (5770delG), resulting in aframeshift that created a premature termination site (Fig. 2d).This substitution was not observed in normal individuals and inother patients with MYH9 disorders. The patients father, whohad thrombocytopenia and a laboratory finding of proteinuria,had the same mutation. The fathers peripheral blood smearsand immunofluorescence results were similar to the sons. Thefather did not have any findings of AOS.

    DiscussionThis is the first report of an AOS patient with an MYH9 mutation.Although the correlation between AOS and an MYH9 disordermay be coincidental, it is possible is that an MYH9 mutation maycontribute to the cardiovascular abnormalities observed in someAOS patients. For example, congenital cardiovascular and othervascular malformations including pulmonary hypertension, pul-monary arteriovenous malformation and hepatoportal sclerosis

    Correspondence: Tomomi Uyeda, MD PhD, Department of Pediatrics,Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki,Aomori 036-8563, Japan. Email: tomchin2@r15.7-dj.com

    Received 24 February 2010; revised 15 May 2011; accepted 18August 2011.doi: 10.1111/j.1442-200X.2011.03466.x

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    Pediatrics International (2012) 54, 407433

    2012 The AuthorsPediatrics International 2012 Japan Pediatric Society

  • have been reported to frequently occur in AOS patients.3 It issuggested that abnormalities in small vessel structures mani-fested during embryogenesis, and that thrombotic mechanisms,are involved in AOS. To identify the disease-causing genes,molecular analysis has been performed mainly to identify genesimplicated in skull and limb development within AOS families.None of the responsible genes for AOS has been identified atpresent. It is possible that genes that play a role in vasculogenesisand angiogenesis may also be good candidates for AOS, such asthe MYH9 gene, which encodes NMHCIIA, one of the isoformsof the non-muscle myosin heavy chain II (NMHCII). Accordingto the most recent findings, mutant NMHC-IIA aggregates andaccumulates in granulocytes to form cytoplasmic inclusionbodies, and thus dominant-negative effects serve as the molecularmechanism underlying the formation of such bodies. The pro-duction of giant platelets could be caused by expressed mutantmyosin, which has a loss of function and cannot participate in therecognition of cytoskeletal contractile structures. And the mac-rothrombocytopenia could be caused by impaired platelet releasedue to abnormal megakaryocyte fragmentation.8 In vertebrates,there are three different isoforms of NMHCII: NMHCIIA,NMHCIIB and NMHCIIC. These isoforms are expressed in mosttissues. Knockout mouse models for NMHCIIA and NMHCIIB

    have been generated. Embryonic lethality of NMHCIIA knock-out mice occurs at embryonic day 7.5, which is prior to tubularheart formation. In the NMHCIIB knockout mouse, however,heart defects are associated with looping abnormalities.9Replacement of NMHCIIB with IIA does not eliminate structuralheart defects in mice.10 These studies indicate that NMHCIIB isrequired for normal cardiac development. The role of NMHCIIAduring heart tube formation and vasculogenesis, and its relation-ship with NMHCIIB, however, are still unclear.

    In addition to a scalp defect and terminal transverse limbdefects typically seen in AOS, the present patient was diag-nosed with tetralogy of Fallot and an abnormal aorto-pulmonary connection. It is hypothesized that the scalp andlimb defects in the present patient are the result of vascularabnormalities manifested during embryogenesis. Although thefather of the present patient with the same mutation did nothave any findings of AOS, he had proteinuria. It is possible thatthe fathers proteinuria is associated with renal vasculogenesis.The phenotypic variations have been found even among iden-tical MYH9 mutations. They may result from genetic modifiers,age or environmental factors. Further analysis of candidategenes that play a role in cardiac looping, vasculogenesis andangiogenesis may provide further insight into the genetic abnor-malities that cause AOS.

    Fig. 1 Features of AdamsOliver syndrome in the present patient.(a) Scalp defect and (b) right foot with transverse limb defect. (c)Selective right subclavian arteriography showed abnormal vascularconnection to the right pulmonary artery, that is, abnormal aorto-pulmonary vascular connection.

    a (b)

    c (d)

    Fig. 2 Neutrophil and platelet morphology and sequence analysisof a patient with an MYH9 gene mutation. (a) Light micrograph ofMay-Grnwald-Giemsa-stained peripheral blood smear. A giantplatelet and an inclusion body in a neutrophil are indicated by anarrow and an arrowhead, respectively. (c) Immunofluorescencemicrograph of a neutrophil with anti-non-muscle myosin heavychain II-A antibody. Arrows, stained subcellular foci. (b,d) DNAsequence analysis of MYH9 in (b) a control and (d) the presentpatient. In the patient, an overlapping sequence pattern (doubleunderline) is obtained from direct sequence analysis of polymerasechain reaction (PCR)-amplified DNA fragments of exon 40. Aftercloning the PCR products, the mutation was confirmed to be a singlebase deletion of one G within the 4G repeat at nucleotide 57705773(5770delG; single underline in panel b).

    408 T Uyeda et al.

    2012 The AuthorsPediatrics International 2012 Japan Pediatric Society

  • References1 Adams FH, Oliver CP. Hereditary deformities in man due to

    arrested development. J. Hered 1945; 36: 37.2 Hoyme HE, Jones KL, Van Allen MI, Saunders BS, Benirschke K.

    Vascular pathogenesis of transverse limb reduction defects. J.Pediatr. 1982; 101: 83943.

    3 Girard M, Amiel J, Fabre M, Pariente D, Lyonnet S, Jacquemin1 E.AdamsOliver syndrome and hepatoportal sclerosis: Occasionalassociation or common mechanism? Am. J. Med. Genet. A 2005;135A: 1869.

    4 Kelly MJ, Jawien W, Ortel TL, Korczaf JF. Mutation of MYH9,encoding non-muscle myosin heavy chain A, in May-HegglinAnomaly. Nat. Genet. 2000; 26: 1068.

    5 Arrondel C, Vodovar N, Knebelmann B et al. Expression of thenonmuscle myosin heavy chain IIA in the human kidney andscreening for MYH9 mutations in Epstein and Fechtner syn-dromes. J. Am. Soc. Nephrol. 2002; 13: 6574.

    6 Kunishima S, Matsushita T, Kojima T et al. Immunofluorescenceanalysis of neutrophil nonmuscle myosin heavy chain-A

    (NMMHCA) in MYH9 disorders: Association of subcellular local-ization with MYH9 mutations. Lab. Invest. 2003; 83: 11522.

    7 Kunishima S, Matsushita T, Kojima T et al. Identification of sixnovel MYH9 mutations and genotype-phenotype relationships inautosomal dominant macrothrombocytopenia with leukocyteinclusions. J. Hum. Genet. 2001; 46: 7229.

    8 Kunishima S, Hamaguchi M, Saito H. Differential expression ofwild-type and mutant NMMHC-IIA polypeptides in blood cellssuggests cell-specific regulation mechanisms in MYH9 disorders.Blood 2008; 111: 301523.

    9 Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS.Defects in cell adhesion and the visceral endoderm following abla-tion of nonmuscle myosin heavy chain II-A in mice. J. Biol. Chem.2004; 279: 41 2636.

    10 Bao J, Ma X, Liu C, Adelstein RS. Replacement of nonmusclemyosin II-B with II-A rescues brain but not cardiac defects in mice.J. Biol. Chem. 2007; 282: 22 10211.

    White-matter damage in a neonate with disseminated herpes simplexvirus infectionped_3428 409..435

    Karin Kojima, Naoto Takahashi, Yukari Yada, Yasunori Koike, Miyuki Matano, Yumi Kono and Mariko Y. MomoiNeonatal Intensive Care Unit, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan

    Key words cyclosporine A, cytokine, herpes simplex virus, neonate, white-matter damage.

    Neonatal disseminated herpes simplex virus (HSV) infection hasa high incidence of mortality and morbidity. Meningoencephali-tis is a common component of the disease, occurring in about6075% of patients, and many survivors show neurologicalimpairment.1 Hemophagocytic lymphohistiocytosis (HLH) is adisease caused by hypercytokinemia in the setting of immunedysregulation and can occur secondary to several infections.Suzuki et al. reported from a Japanese nationwide survey thatHSV was the causative organism in six of nine neonatal patientswith infection-associated HLH and four of these patients died.2

    We encountered a neonatal patient with HLH secondary toHSV infection. Although the patient had no evidence of viralinvolvement of the central nervous system (CNS), she showedwhite-matter damage. We will discuss the pathophysiology ofbrain damage in neonatal HSV infection with HLH.

    Case reportA female infant was born vaginally at 40 weeks gestation toa 23-year-old primigravida. The pregnancy and delivery were

    uncomplicated. The patients birthweight was 2785 g, and Apgarscores were 8 and 9 at 1 and 5 min, respectively. On the 3rd dayof life, the infant suddenly developed a high fever (38.5C), andthe white blood cell (WBC) count and C-reactive protein levelwere elevated at 18 660/mL and 57.9 mg/L, respectively. On the5th day of life she demonstrated elevated serum levels of aspar-tate aminotransferase (AST) at 1278 IU/L and alanine ami-notransferase (ALT) at 269 IU/L, and she was transferred to ourneonatal intensive care unit.

    The patients clinical course is shown in Figure 1. On admis-sion she appeared irritable and her activity was poor. Her liverwas enlarged to 1.5 cm below the right costal margin, but she didnot show splenomegaly. She had a low WBC count (3500/mL)and a low platelet count (102 000/mL). She showed a low fibrino-gen level (43 mg/dL) and an elevated level of fibrin degradationproducts (54.7 mg/dL). Her serum triglyceride level was normal(76 mg/dL). The serum AST and ALT levels had increasedfurther (2271 IU/L and 308 IU/L, respectively). Hyperferritine-mia (22 691 ng/mL) was also present. The cerebrospinal fluid(CSF) showed a cell count of 1/mL, protein level of 56 mg/dL,and a glucose level of 34 mg/dL. We suspected HSV infectionand started intravenous acyclovir (Zovirax) administration at40 mg/kg/day on an empirical basis. HSV DNA was detected inserum taken at admission on polymerase chain reaction, but not

    Correspondence: Naoto Takahashi, MD, Department of Pediatrics,Jichi Medical University School of Medicine, 3311-1, Yakushiji,Shimotsuke, Tochigi 329-0498, Japan. Email: naoto-t@jichi.ac.jp

    Received 3 March 2011; revised 7 June 2011; accepted 1 July 2011.doi: 10.1111/j.1442-200X.2011.03428.x

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    2012 The AuthorsPediatrics International 2012 Japan Pediatric Society

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