Christesen Henrik Thybo, Christensen Lene Gaarsmand, Löfgren Åsa Mattsson, Brøndum-Nielsen Karen, Svensson Johan, Brusgaard Klaus, Samuelsson Sofie, Elfving Maria, Jonson Tord, Grønskov Karen, Rasmussen Lars, Backman Torbjörn, Hansen Lars Kjaersgaard, Larsen Annette Rønholt, Petersen Henrik, Detlefsen Sönke
Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark.
Dept. of Pathology, Odense University Hospital, Odense, Denmark.
Eur J Med Genet. 2020 Jan;63(1):103632. doi: 10.1016/j.ejmg.2019.02.004. Epub 2019 Feb 21.
Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years' age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.
镶嵌型全基因组父源单亲二体（GW-pUPD）是一种罕见的疾病。多位点印记缺陷（MLIDs）的表型表现尚不清楚。我们报告了一名明显无综合征的婴儿，患有严重先天性高胰岛素血症（CHI），18F*-多巴PET/CT显示胰腺弥漫性显像，最终导致近乎全胰腺切除术。组织学表现不典型，内分泌细胞显著增生，占胰腺组织的70%以上，并有一个小的胰腺母细胞瘤。对CHI进行的常规血液和切除胰腺组织的基因分析均正常。两岁时出现贝克威思-维德曼综合征（BWS）体征，五岁时切除了伴有局灶性结节性增生的肝肿瘤和肾上腺肿瘤。使用微卫星标记在11p15检测到pUPD，随后在整个11号染色体上也检测到。对13、18、21号染色体和X染色体进行特异性DNA序列扩增的定量荧光PCR表明存在GW-pUPD。一个包含21条染色体上303个单核苷酸多态性（SNP）的二代测序panel显示血液和胰腺组织中均存在pUPD。GW-pUPD的镶嵌分布在血液和口腔拭子中为31%至35%，在切除的胰腺中为74%，在非肿瘤性肝活检中为80%，在肝局灶性结节性增生和肾上腺肿瘤中为100%。MLID特征包括短暂的结合胆红素血症以及BWS（pUPD6）所致的无巨大儿表现；随访中出现天使综合征（pUPD15）的行为和精神运动表现。总之，明显无综合征的严重CHI患者的非典型胰腺组织学可能是BWS和GW-pUPD所致多综合征CHI的首要线索。组织间镶嵌程度的差异解释了表型。
