Renal tubular dysgenesis with atypical histology and in-utero exposure to naproxen sodium

Renal tubular dysgenesis (RTD), a rare, lethal, autosomal recessive disorder, is characterised by short and poorly differentiated proximal convoluted tubules associated with oligohydramnios, Potter sequence and neonatal death from respiratory failure. We report an unusual case of neonatal anuria owing to RTD with normally formed lungs, in-utero exposure to naproxen sodium and atypical histology in that the glomeruli were not as crowded as usually seen in RTD. When there is anuria in an infant following birth in the context of a normal renal ultrasound and an absence of objective evidence of perinatal hypoxia, RTD should be considered.     

Neonatal haemochromatosis associated with gastroschisis

We describe, to our knowledge, the first case of progressive neonatal liver failure due to neonatal haemochromatosis (NH) occurring in an infant with a gastroschisis and review the literature regarding these two conditions. A 1,665 g male infant with antenatally diagnosed gastroschisis was born with a severe coagulopathy, anaemia, thrombocytopenia, hypoglycaemia and jaundice. He developed progressive liver failure, complicated by necrotising enterocolitis. Serum ferritin was elevated at 1,459 μg/L. He died on day 40 and a limited post-mortem examination confirmed significant hepatic siderosis with fibrosis and cholestasis, and siderosis of the pancreas. Although no genetic aetiology for gastroschisis has been identified, an occasional inherited tendency has been observed. There is also evidence to support an autosomal recessive inheritance in NH.     

Renal Tubular Dysgenesis: A Description of Early Renal Maldevelopment in Siblings

A family is described in which three siblings, born after pregnancies complicated by oligohydramnios, developed renal abnormalities. In the first infant, of 38 weeks gestation, histologic changes were nearly identical to those found in renal tubular dysgenesis (RTD), a recently identified disorder characterized by the absence of recognizable renal proximal tubules. Additional findings include bilateral renal vein thrombosis and marked calvarial bone hypoplasia. The other two gestations were 20 and 22 weeks long. Renal histology in these cases showed nonspecific abnormalities with focal tubular dilatation, decreased tubule formation, and increased interstitial connective tissue. Clearly recognizable proximal tubules were present, though decreased in number. The latter two gestations described herein are the earliest examined in a family with RTD and the renal abnormalities may represent early changes seen in this disorder.     

Renal Tubular Dysgenesis in Twin-Twin Transfusion Syndrome

In twin-twin transfusion syndrome (TTTS), the disparity in circulation is reflected in discordant fetal growth, urine output, and amniotic fluid accumulation. The effect of uneven shunting of the growth factor and nutrient-rich vasculature on development and differentiation of the kidney has not been well studied. We analyzed renal tubular growth and differentiation in 25 fetal autopsies with TTTS (13 donors and 12 recipients, including 9 sibling pairs) between 18 and 33 weeks gestation. Immunohistochemical markers for fumarylacetoacetate hydrolase (FAH), Leu-M1, and Lotus tetragonolobus (LTA) were used to identify proximal convoluted tubules, and epithelial membrane antigen (EMA) was used to demonstrate distal convoluted and collecting tubules. FAH appeared to be more specific and reliable than either Leu-M1 or LTA in the identification of proximal tubules. Donors tended to demonstrate a paucity of proximal tubules with crowding of glomeruli characteristic of renal tubular dysgenesis (RTD). The degree of dysgenesis was greater in later gestations and associated with more severe growth restriction. Donors in TTTS are at risk for the development of RTD. Several authors suggest ischemia as the underlying cause of “acquired” RTD. However, in this setting there is no evidence of cell death or necrosis, and we suggest that hypoperfusion leading to decreased glomerular filtration is the underlying etiology, with the severity of RTD related to the degree of shunting. Received November 12, 1997; accepted February 12, 1998.     

Familial Renal Tubular Dysgenesis: A Disorder Not Isolated to Proximal Convoluted Tubules

The autopsy findings of a newborn with renal tubular dysgenesis, born to first cousins of Moslim Arob descent, are described. Hypocalvaria and hyperflexible joints were noted in addition to the renal lesion. A microdissection study demonstrated marked shortening of all the nephron segments from the glomeruli to the collecting tubules, rather than an isolated abnormality of the proximal convoluted tubules.     

Fetal Parvovirus B19 Infection and Liver Disease of Antenatal Onset in an Infant with Ebstien's Anomaly

Fetal parvovirus B19 infection has been reported in association with hydrops and fetal demise, myocarditis, and congenital anomalies, as well as with normal outcome of pregnancy. One infant with liver disease of fetal onset associated with parvovirus B19 infection has been described. We have seen another such infant, in whom marked siderosis of the liver suggested accelerated destruction of erythrocytes and portal tract fibrosis with proliferation of bile ducts suggested intrauterine infection. Viral cytopathic effects were not seen. Maternal serum obtained postpartum contained IgM clas antibodies against parvovirus B19, and parvovirus B19 nucleic acid sequences were identified in the infant's liver by polymerase chain reaction studies. We propose that recognition of this combination of siderosis with fibrosis and bile duct proliferation will permit identification of cases of fetal parvovirus B19 infection.     

Autosomal recessive renal tubular dysgenesis: morphologic and genetic study of 2 cases]

Renal tubular dysgenesis (RTD) is a rare and severe nephropathy characterized by persistent fetal anuria leading to oligohydramnios with the Potter sequence, and perinatal death. The diagnosis is based on the histological finding of absence or paucity of proximal tubules. A consanguineous family is described in which 2 siblings, born after pregnancies complicated by oligohydramnios were affected with RTD. Patients were small for gestational age at birth. The first patient died after a few hours, the second after a few days of life, with persistent anuria unresponsive to treatment. Histologically, there was marked reduction in the number of proximal tubule sections and no renin was detected by immunohistochemistry. An homozygous mutation of the gene encoding renin was identified in both patients. This study underlines the interest of the histological examination of the kidney for the diagnostic of RTD in anuric fetuses and newborns, and the possibility of mutation analysis of RAS genes for genetic counselling and early prenatal diagnosis.     

Labeled Lectin Studies of Renal Tubular Dysgenesis and Renal Tubular Atrophy of Postnatal Renal Ischemia and end-Stage Kidney Disease

Renal tubular dysgenesis (RTD), with hypoplasia especially of renal proximal convoluted tubules and clinical neonatal anuria or oliguria, has been reported as a congenital familial (autosomal recessive) disease, variably with features of oligohydramnios, Potter syndrome, or pulmonary hypoplasia. A similar tubular lesion due to antenatal tubular atrophy has been reported for conjoined twins with twin-twin transfusion syndrome or acardia and in infants of mothers given antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors, during pregnancy, and it has been seen as a unilateral lesion in young infants with renal artery stenosis due to arteritis or medial arterial calcinosis. The renal tubular changes in RTD are very like those of the “endocrine kidney” in experimental animals and resemble those of the renal tubular atrophy of end-stage kidney diseases such as glomerulonephritis, tubulointerstitial kidney disease, obstructive uropathy/pyelonephritis, graft rejection of transplanted kidneys, or the renal parenchymal changes seen with protracted dialysis therapy. Labeled lectins that differentially mark proximal convoluted, distal convoluted and connecting, and collecting tubules showed no distinctive differences in stainingpatterns of the hypoplastic renal tubules of infants and children with RTD, postnatal renal artery obstruction, or the various types of end-stage renal disease with the lectins used (PNA, GSL1, UEA, and LTA). The findings suggest that the renal tubular changes in some if not all the conditions studied are the result of renal ischemia. The reported familial RTD with hypernephronic nephromegaly may be a specific disorder, but other forms could reflect renal ischemia acquired in utero or in early or later postnatal life.     

Renal tubular dysgenesis-a case presentation

Renal tubular dysgenesis (RTD) is a lethal, developmental anomaly of the fetal kidney characterized by a defect in differentiation of the proximal and distal convoluted tubules. It is usually associated with oligohydramnios in later pregnancy and Potter's syndrome. A neonate with typical features who presented with mild respiratory distress, dysmorphic appearance and anuria is described. At the age of seven days, peritoneal dialysis was started and was continued until the death of the baby at the age of three months. The diagnosis was made on the bases of clinical and ultrasonographic findings confirmed by renal biopsy. A review of the literature showed that this is the first case of RTD reported in Turkey.     

Disparate clinical presentation of neonatal hemochromatosis in twins

Neonatal hemochromatosis (NH) is a rare disease of gestation that results in fetal liver injury and extrahepatic siderosis. The etiology of NH is not fully understood. However, the rate of recurrence of NH in the pregnancy after an affected one is approximately 80%. A spectrum of liver disease has been recognized, spanning from liver failure in the fetus or neonate to infants that survive with medical therapy. Here we report on 2 sets of fraternal twins, each set with a gross disparity in the severity of presentation: 1 infant with liver failure and the other nearly unaffected. These findings suggest a need to look carefully for subclinical disease in the siblings of patients with NH by using sensitive tests such as those for ferritin and alpha-fetoprotein. They also suggest that affected infants may be missed when using routine clinical testing, which would lead to the apparent rate of recurrence, understating the actual recurrence rate.     

Renal Tubular Dysgenesis in an Hydropic Fetus with Trisomy 21: a Case Report with Literature Review

Renal tubular dysgenesis (RTD) is a rare form of noncystic renal disease characterized by paucity or absence of proximal renal tubules. Always lethal in the perinatal period, it has been associated with Potter sequence and with other congenital malformations. An autosomal recessive inheritance has been suggested. We present a case of renal tubular dysgenesis associated with fetal hydrops and trisomy 21, with a review of relevant literature.     

Inherited renal tubular dysgenesis: the first patients surviving the neonatal period

Renal tubular dysgenesis (RTD) is a clinical disorder either acquired during fetal development or inherited as an autosomal recessive condition. Inherited RTD is caused by mutations in the genes encoding the components of the renin-angiotensin system angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II receptor type 1. Inherited RTD is characterized by early onset oligohydramnios, skull ossification defects, preterm birth and neonatal pulmonary and renal failure. The histological hallmark is the absence or poor development of proximal tubules. So far, all patients died either in utero or shortly after birth. We report the first patients with inherited RTD surviving the neonatal period and still being alive. Genetic and functional analysis of the renin-angiotensin system contributes to the diagnosis of RTD. In conclusion, the clinical diagnosis of inherited RTD is easily missed after birth without renal biopsy or information on affected family members. Genetic and functional analysis of the renin-angiotensin system contributes to correct diagnosis.     

ACE基因突变致遗传性肾小管发育不良1例并文献复习

目的：提高对遗传性RTD的认识和早期诊断水平。方法：报告1例确诊的遗传性RTD患儿的一般情况、肾脏病理、实验室检查和基因测序结果，系统检索文献并复习已报道的类似病例，总结遗传性RTD的遗传和临床特征。结果：患儿女，因“早产后15 min，气促、发绀5 min”入重庆市妇幼保健院，胎龄28+2周，出生体重1 090 g，羊水0 mL，生后Apgar评分1和5 min分别为8和9分。母孕期正规产检，孕23+5及26+1周因“羊水少”行2次羊膜腔穿刺及0.9%生理盐水灌注术。母不良孕产史3次，均因“羊水少”，或早产生后1 d夭折，或孕5月引产。患儿生后反应欠佳，轻度吸气性三凹征，心音有力、律齐，腹软，肝脾肋下未扪及，原始反射均减弱。予呼吸机辅助通气，予2次肺表面活性物质替代治疗，扩容和多巴胺应用下平均血压22~28 mmHg。应用呋塞米后尿量0.14~0.31 ml·kg－1·h－1，患儿日龄44 h时家属放弃抢救治疗后死亡，尸体泌尿系组织病理诊断：肾小管大小不一，近端小管缺乏，部分远端小管及集合管发育不良。患儿为ACE基因复合杂合突变：c.538C>T来源于母亲，c.3073_3074delTC来源于父亲。共检索到11篇文献，报道了36个家系，加上本文共37个家系的64例ACE基因突变胎儿和婴儿，共发现40个ACE基因突变位点。9个家系为近亲结婚。每个家系均有1~4例母孕期羊水少的受累胎儿，羊水少开始于孕中期，早至18周；终止妊娠10例，死胎7例，出生后死亡39例（<3 d死亡33例，~28 d死亡6例；早产儿37例，足月儿2例），存活>1年8例（慢性肾疾病6例，肾移植1例，正常肾功能1例）。新生儿主要以呼吸困难、低血压、无尿为主要表现，部分病例伴有颅骨发育不良、小结肠（结肠直径0.5~0.6 cm）。结论：对于遗传性RTD，完善基因检测对提高产前诊断及RTD早期诊断有重要意义。     

妊娠同族免疫性肝病-新生儿血色病1例报告并文献复习

目的提高对妊娠同族免疫性肝病-新生儿血色病（GALD-NH）临床特点的认识。方法对广州市妇女儿童医疗中心诊断的1例GALD-NH患儿的临床表现及尸检病理诊断过程进行回顾性分析,文献复习总结该类患儿的临床特征。结果男,生后第2 d发病,肝功能和凝血功能异常,少尿,全身水肿（大量胸腔积液、腹水）,血小板减少为主要表现,积极对症治疗无效,生后43 d死亡。尸体解剖病理诊断为急性肝功能衰竭,肝外组织（胰腺、甲状腺）铁染色阳性,肝组织膜复合攻击物C5b-9免疫组化阳性,确诊GALD-NH。系统检索中国知网、维普、万方数据库、PubMed和Web of Science数据库,检索时间均从建库至2018年12月20日,12篇英文文献。报道的89例与本文病例合并后共90例NH,表现为胎儿水肿（17例）、羊水少（21例）、宫内发育迟缓（33例）,生后出现铁代谢异常（65例）、肝功能衰竭（62例）、凝血机制异常(58例);肝外铁沉着阳性(48例),肝组织C5b-9免疫组化阳性14例;铁螯合剂+抗氧化治疗36 例,单纯IVIG治疗4例,单纯换血治疗 9 例,IVIG+换血治疗20 例,肝移植13例;死亡 55 例,存活35 例,随访28例,均预后良好。结论GALD-NH罕见,生后早期发病,以铁代谢异常、肝功能衰竭和凝血机制异常为主要表现,肝外组织铁沉着及肝活检为确诊依据,早期换血+IVIG治疗为病因治疗,病死率高,存活者预后良好。     

Neonatal hemochromatosis: a case report with unique presentation

Acute liver failure (ALF) is a relatively rare condition in neonates, and early diagnosis and treatment are crucial for the treatable conditions. Neonatal hemochromatosis (NH) is a rare clinical condition that is clinically defined as severe neonatal liver disease associated with hepatic and extrahepatic iron deposition in a distribution similar to that seen in hereditary hemochromatosis. Although a few cases have been reported with spontaneous remission, early and aggressive medical treatment is essential for improving the outcome. Despite aggressive treatment, some patients may require liver transplantation. We report a five-day-old male infant with NH and associated Duarte variant galactosemia, renal tubulopathy and hypertyrosinemia, who was successfully treated with combination medical treatment. Combination therapy may reduce the need for liver transplantation in infants with NH. Early diagnosis and aggressive treatment are important as in galactosemia or tyrosinemia for the outcome. Thus, NH may be listed as a treatable cause of ALF in neonates.     

Neonatal hemochromatosis. A cause of liver failure in utero. Report of two cases and review of the literature

Neonatal hemochromatosis is a rare clinical pathologic entity, defined by severe neonatal liver failure of intrauterine onset associated with intra-and extra- hepatic siderosis that spares reticuloendothelial system. It is the most frequently recognized cause of liver failure in neonates. The cause is unknown but it may develop secondary to abnormal fetoplacental iron handling or perinatal liver disease or be familial or as a consequence of gestational alloimmune disease. It's a syndrome with a common feature rather than a single pathologic entity, with maternal transmission and a high recurrence in the sibship. Death from multisystem organ failure usually occurs in the first few days or weeks of life. We report two newborn with neonatal hemochromatosis. The first died for multiorgan failure, despite aggressive support. The second underwent to liver transplantation. Since 1993, an antioxidant-chelator cocktail has been used in addition to standard supportive care, but this remains controversial. By 2002, a preliminary report suggested that treatment with weekly intravenous immunoglobulin during the later half of pregnancy, for woman whose most recent gestation was affected with proven NH. The diagnosis is suspected in the presence of severely impaired hepatic synthetic function accompanied by high serum ferritin levels, but is confirmed only by demonstration of increased hepatic iron stores, and extra-hepatic siderosis shown by autopsy or in vivo, which can be achieved by biopsy of the minor salivary glands or magnetic resonance imaging. Neonatal hemochromatosis is the most common specific indication for liver transplantation in the first three months of life and appears to be the treatment of choice, and must as well be considered as soon as it becomes apparent that medical support, which should include chelation-antioxidant treatment, is ineffective, before irreversible neurological complications appear.     

Pathology teach and tell: neonatal hemochromatosis with massive hepatic necrosis

Neonatal hemochromatosis (NH) is an uncommon disorder clinicopathologically defined by severe liver disease of intrauterine onset associated with extrahepatic siderosis that spares reticuloendothelial elements. NH phenotypically is a similar disorder to hereditary hemochromatosis. However, its extremely early onset of liver failure makes it notably unique. Massive liver necrosis in the newborn is a rare occurrence, but whenever present hemochromatosis should be considered in the differential diagnosis. Herein, we report a case of neonatal hemochromatosis that had massive hepatic necrosis with sparing only little parenchyma. The outcome was fatal within the first month of life.     

Renal Proximal Tubular Dysgenesis Associated with Severe Neonatal Hemosiderotic Liver Disease

We report the necropsy findings for three infants with the unusual combination of proximal renal tubular dysgenesis and severe congenital liver disease with excessive iron in several organs resembling neonatal hemochromatosis. Two of the infants were caucasian siblings and one was an Australian aborigine. One died in utero at 35 weeks of gestation and two died at 7 days. The liveborn infants presented with anuria and liver failure. The livers all showed marked loss of hepatocytes and replacement by pseudotubules in the collapsed lobules. The liveborn infants also showed giant cell transformation ofhepatocytes, small regenerative nodules, cholestasis, and normal bile ducts. Absence of proximal renal convolutions was confirmed by epithelial membrane antigen positivity in nearly all tubules. In each family there was another sibling with congenital liver disease, fatal in one case, but no renal tubular dysgenesis. No infection or metabolic disease was uncovered in any of our patients, and the cause of the hepatocyte destruction was not determined. The combination in three infants of two rare congenital diseases could be genetic or acquired in utero from the same etiological agent. Alternatively, the absence of proximal convolutions could be secondary to hypoperfusion, perhaps because of shock due to extensive necrosis of hepatocytes.     

PATHOLOGY TEACH AND TELL: NEONATAL HEMOCHROMATOSIS WITH MASSIVE HEPATIC NECROSIS

Neonatal hemochromatosis (NH) is an uncommon disorder clinicopathologically defined by severe liver disease of intrauterine onset associated with extrahepatic siderosis that spares reticuloendothelial elements. NH phenotypically is a similar disorder to hereditary hemochromatosis. However, its extremely early onset of liver failure makes it notably unique. Massive liver necrosis in the newborn is a rare occurrence, but whenever present hemochromatosis should be considered in the differential diagnosis. Herein, we report a case of neonatal hemochromatosis that had massive hepatic necrosis with sparing only little parenchyma. The outcome was fatal within the first month of life.     

Extensive hepatic necrosis in a premature infant.

A fatal case of fulminant hepatic failure that occurred in the neonatal period is reported in a premature infant born after 27 4/7-weeks' gestation. Immediately after birth the infant had severe hypoxia and hypotension resulting from birth asphyxia, hypovolemic shock, and septicemia. At autopsy, histological appearance of the liver showed virtually total hepatocellular necrosis without features of fibrosis. Although the exact cause of hepatocellular injury cannot be fully ascertained, it is assumed that hypoxia and hypotension must have been the predominant factors leading to massive hepatic necrosis.