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Abstract：
BACKGROUND: paucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1β mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1β defect.
METHODS: A 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks\' gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1β gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control.
CONCLUSIONS: Alagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1β deficiency should also be ruled out, taking into consideration HNF1β mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.
METHODS: A 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks\' gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1β gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control.
CONCLUSIONS: Alagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1β deficiency should also be ruled out, taking into consideration HNF1β mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.
摘要：
背景：小叶间胆管的缺乏是肝活检在新生儿胆汁淤积的诊断工作中的重要观察。迄今为止,除了Alagille综合征,在4例具有HFN1β突变的胆汁淤积性新生儿中，已记录到小叶间胆管的综合征性缺乏。一种综合征表型，被称为肾囊肿和糖尿病综合征(RCAD)，已被确认。这通常以广泛的临床频谱为特征，包括肾囊肿,年轻人的成熟型糖尿病，胰腺外分泌功能不全，泌尿生殖系统异常和肝脏受累。在此，我们报告了一例由于HFN1β缺陷而导致小叶间胆管缺乏的新病例。
方法：一名5周大的男孩因胆汁淤积性黄疸入院，并伴有γ-谷氨酰转肽酶升高，临床检查无异常。他在妊娠38周时被剖腹产从不相关的父母那里分娩，出生体重2600克（第3百分位数）。筛查胆汁淤积性疾病，包括Alagille综合征,除超声心动图检查肺动脉轻度狭窄和怀疑胸蝶半椎骨外，均为阴性。超声检查发现高回声肾伴有多个双侧皮质囊肿，伴有蛋白尿的中度肾功能受损，多尿和代谢性酸中毒，暗示纤毛病.肝活检显示小叶间胆管缺乏，因此，Alagille综合征的诊断被重新考虑。尽管进行了肝胆汁淤积性疾病的遗传测试，但Alagille综合征（JAG1和NOTCH2）的结果为阴性，检测到HNF1β基因的从头错义突变。在18个月大时，我们的患者患有持续性胆汁淤积，并且他的瘙痒没有得到令人满意的控制。
结论：Alagille综合征可能不是决定胆汁淤积和肾功能损害新生儿小叶间胆管缺乏的唯一综合征，尤其是小于胎龄的新生儿。我们建议也应排除HNF1β缺乏症，考虑到HNF1β突变，连同Alagille综合征,在胆汁淤积新生儿的下一代测序策略中，肝活检时肾脏损害和/或小叶间胆管的缺乏。
方法：一名5周大的男孩因胆汁淤积性黄疸入院，并伴有γ-谷氨酰转肽酶升高，临床检查无异常。他在妊娠38周时被剖腹产从不相关的父母那里分娩，出生体重2600克（第3百分位数）。筛查胆汁淤积性疾病，包括Alagille综合征,除超声心动图检查肺动脉轻度狭窄和怀疑胸蝶半椎骨外，均为阴性。超声检查发现高回声肾伴有多个双侧皮质囊肿，伴有蛋白尿的中度肾功能受损，多尿和代谢性酸中毒，暗示纤毛病.肝活检显示小叶间胆管缺乏，因此，Alagille综合征的诊断被重新考虑。尽管进行了肝胆汁淤积性疾病的遗传测试，但Alagille综合征（JAG1和NOTCH2）的结果为阴性，检测到HNF1β基因的从头错义突变。在18个月大时，我们的患者患有持续性胆汁淤积，并且他的瘙痒没有得到令人满意的控制。
结论：Alagille综合征可能不是决定胆汁淤积和肾功能损害新生儿小叶间胆管缺乏的唯一综合征，尤其是小于胎龄的新生儿。我们建议也应排除HNF1β缺乏症，考虑到HNF1β突变，连同Alagille综合征,在胆汁淤积新生儿的下一代测序策略中，肝活检时肾脏损害和/或小叶间胆管的缺乏。
