タイトル厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

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厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

748 Y.-H. Gu et al. / Brain & Development 34 (2012) 746?749Table 1Spectrum of congenital malformations (CMs) and mutations in the ATP7A gene in 14 patients with classical MNK.PatientnumberCongenital malformationsCause of deathAge at death(Month)1 Higher arched palate, congenitalmicroblepharia, entropion, flat occiput,and single transverse palmer crease2 Higher arched palate, micrognathia,patent ductus arteriosus, and accessoryspleen3 Higher arched palate and singletransverse palmer crease4 Higher arched palate and undescendedtestis at birth5 Higher arched palate, hypertrophicpyloric senosis and hydrocele6 Single transverse palmer crease,congenital microblepharia and flatocciput, hypoplastic corpus callosum,aplasia of inferior vermis7 Cystic malformation in white matter ofbrainMutation in the ATP7A gene[References]Unknown 17.0 IVS20+5G>A [7,9]Sudden death 34.5 2491insA (F781FS826X)Bladder32.53101C>T (R986X) [7?9,12]hemorrhageUnknownUnknown1730G>T (E529X) [7?9]Alive ? Not found, 46 XY [15]Stomachhemorrhage57.5 IVS9+12insAATTG [9]Infectious disease 22.5 2429-2430delTT (S761FS770X) [9]8Congenital complete A?V blockSudden death45.0IVS9+5G>C [8,9]9MicrophallusSudden death13.0Not found10Club footInfectious disease19.54177T>A and 4178A>T (S1344R andI1345F) [7,9]11Cystic malformation in lungInfectious disease22.51474delC [9]12MicrognathiaInfectious disease43.02298-2299insAluYa5a2 [9,10]13Cystic malformation in arachnoid materAlive?Not detected yet14Cerebellar hypoplasiaInfectious disease186.0Not foundCM (Patient 7 in Table 1), died at 22.5 months due tosepsis and overall bad health from a tumoral lesion inhis stomach. His older brother did not have any CMs,but died at 69 months of age from an infectious disease.No relationship was found between CMs and geneticmutation (Table 1).4. DiscussionIn OMIM (http://omim.org/entry/309400) head andneck of MNK patients were described as microcephaly,brachycephaly, Wormian bone and pudgy cheeks. Hornet al. mentioned high-arched palate as one of the MNKsymptoms [17]. However, to date, CMs in MNKpatients have not been reported details yet. This is thefirst documentation of CMs in MNK patients in detail.This information can be added to what we know aboutMNK patients, which is that they often exhibit kinkyhair, hypopigmentation, a higher arched palate, micrognathia,flat occiput and single transverse palmer crease.These minor and major anomalies presenting at birthare as clues for early diagnosis of MNK.In this study, higher arched palate was mostobserved, and micrognathia and flat occiput were alsoobserved. Along with the fact that microcephaly,brachycephaly, and pudgy cheeks described in MNKpatients, it is considered that abnormal craniofacialgrowth and development occurred during pregnancy,although flat occiput was often considered as subjectivejudgment.The main causes of death among MNK patients withor without CMs were infectious disease and abnormalitiesof connective tissues, such as hemorrhage and ruptureof abdominal aorta (Tables 1 and 2). However,sudden death occurred in MNK patients with CMs only,especially in patients with congenital heart disease(Table 1). Moreover, MNK patients often exhibit connectivetissue complications associated with lower activitiesof copper enzymes, such as osteoporosis, bladderdiverticula, gastroesophageal reflux disease, whichrequire surgical treatment [14,18,19]. It was reportedthat micrognathia made intubation and anesthesiaextremely problematic [18,19], such that surgical interventionfor MNK patients with CMs is avoided or difficult,although micrognathia was a minor CM. MNK is arare disease, although we did not have enough numberof patients to do statistical analysis, it was easy tounderstand that some CMs, such as congenital heart diseaseand micrognathia, lead to an inevitably shorter lifespanin these patients compared to patients withoutCMs. Pediatricians should pay extra attention to complicationsand CMs when treating MNK patients.As some MNK patients do not have mutations in theATP7A gene (Table 1) [7?9,11], we wonder if CMs in8