Renal Dysplasia, Situs Inversus Totalis, and Multisystem Fibrosis: A New Syndrome

Renal dysplasia was associated with situs inversus totalis and multisystem fibrosis in a severely hydropic stillborn female fetus. The ureters were duplicated and showed fibrous obliteration. The pancreas, thyroid, and uterus were fibrotic, and the lungs had small and large irregular pulmonary lobules bounded by fibrotic septa. An extensive fibrous pericarditis was considered the etiology of hydrops. A similar spectrum of anomalies including bilateral renal dysplasia, situs inversus totalis, and pancreatic and hepatic fibrosis has been described in three separate reports. Our case is similar with additional findings of fibrosis of the thyroid, uterus, pulmonary septa, and pericardial tissues. We believe the presence of situs inversus totalis, renal dysplasia, and multisystem fibrosis constitutes a new syndrome.     

Otocephaly: report of five new cases and a literature review

Otocephaly, characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia, is an extremely rare anomalad, identified in less than 1 in 70,000 births. The malformation spectrum is essentially lethal, because of ventilatory problems, and represents a developmental field defect of blastogenesis primarily affecting the first branchial arch derivatives. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. Polyhydramnios may be the presenting feature, but prenatal diagnosis has been uncommon.

We present five new cases of otocephaly, the largest published series to date, with comprehensive review of the literature and an update of research in the etiopathogenesis of this malformation complex. One of our cases had situs inversus, and two presented with unexplained polyhydramnios. Otocephaly, while quite rare, should be considered in the differential diagnosis of this gestational complication.     

Familial progressive tubulo-interstitial nephropathy and cholestatic liver disease – a newly recognized entity?

We describe two siblings (female and male) with progressive tubulo-interstitial nephropathy and cholestatic liver disease. The main characteristics were progressive renal failure and elevated liver enzymes (AST, ALT and γ-GT). Dialysis was started at the age of 1.9 and 6.5 years, respectively. Renal histology disclosed sclerosed glomeruli and atrophic tubules; the interstitium was fibrotic and infiltrated by lymphocytes. Endoscopic retrograde cholangiopancreatography revealed segmental irregularities and narrowing of the intrahepatic bile ducts, consistent with early primary sclerosing cholangitis. Liver histology showed enlarged portal triads, mild proliferation and inflammation of bile ducts, and fibrosis. At 5.9 years the girl underwent a successful renal transplantation whereas the boy is still on dialysis. Conclusion The association of progressive tubulo-interstitial nephropathy and cholestatic liver disease, consistent with early primary sclerosing cholangitis, constitutes a distinct autosomal recessive entity.     

Hypoglossia, situs inversus and absence of the pituitary in a neonate: teratogenic effect of maternal hyperthermia?]

Hypoglossia is a rare malformation that is not fatal, unlike otocephaly. CASE REPORT: A neonate, born at 39 weeks of GA and dead at 5th day showed hypoglossia, dextrocardia, situs inversus and pituitary aplasia. Maternal hyperthermia was observed at 4 weeks gestation. CONCLUSION: This case is reminiscent of a community of syndrome with agnathia-holoprosencephaly and situs inversus. The responsibility of maternal hyperthermia is raised.     

Cystic Fibrosis Presenting with Neonatal Cholestasis Simulating Biliary Atresia in a Patient with a Novel Mutation

Neonatal cholestasis is a rare presenting feature of cystic fibrosis which usually cannot be differentiated from other types of cholestasis. Herein, the authors report a 63 d-old boy with cystic fibrosis presenting with neonatal cholestasis mimicking biliary atresia. A new mutation in CFTR gene resulting in severe phenotype has been described. The cystic fibrosis patients with c.3871 G?>?T mutation may have acholic gaita mimicking biliary atresia in the absence of insipissated bile with minimal histologic findings in the liver.     

Wiederholtes Vorkommen der Lateralitätssequenz innerhalb einer Familie mit abweichender Expressivität

Background.

Laterality sequences are abnormalities in the development of normal body asymmetry. In addition to reversal of sides with partial or complete situs inversus, bilateral left-sidedness or right-sidedness can occur. In the case of bilateral left-sidedness called situs ambiguus it is usually associated with polysplenia. Bilateral right-sidedness mostly presents with asplenia. The asplenic form is characterized of complex severe cardiac anomalies. The Ivemark syndrome, or polyasplenia syndrome is the association of situs ambiguus and cardiac malformations.

Case report.

We describe two siblings with laterality sequences of different phenotypic expressivity. The elder brother has had a situs inversus totalis. His younger brother, who died at the age of eleven days was diagnosed with Ivemark-syndrome and polysplenia. The occurence of these two forms of laterality sequences in one family is rare.

Intrauterine diagnosis.

Intrauterine diagnosis based on molecular genetic methods is not yet available in this syndrome. The fetal echocardiography at 18.-20. weeks of gestation is an effective method of early prenatal detection.     

Double-Inlet and Double-Outlet Left Ventricle in Situs Inversus

Double-outlet left ventricle is a rare congenital cardiac malformation that has been traditionally difficult to diagnose accurately. We report a unique case of situs inversus totalis, L-loop, double-inlet left ventricle and double-outlet left ventricle with pulmonary stenosis, diagnosed mainly by transesophageal echocardiography and magnetic resonance imaging.     

Abernethy malformation complicated by hepatopulmonary syndrome and a liver mass successfully treated by liver transplantation

Osorio MJ, Bonow A, Bond GJ, Rivera MR, Vaughan KG, Shah A, Shneider BL. Abernethy malformation complicated by hepatopulmonary syndrome and a liver mass successfully treated by liver transplantation.
Pediatr Transplantation 2011: 15: E149–E151. © 2010 John Wiley & Sons A/S. Abstract: A seven‐yr‐old boy presented with persistent oxygen requirement following a respiratory infection. Physical exam was remarkable for orthodeoxia and digital clubbing. Laboratory evaluation showed elevated A‐a oxygen gradient of 48 mmHg and mildly elevated transaminases. Sonography showed a 13 cm multilobulated liver mass and a biopsy revealed histological findings consistent with focal nodular hyperplasia. MAA scan revealed 23% right to left shunting. Abdominal CTA and MRV demonstrated the absence of the intrahepatic portal vein with an extrahepatic portocaval shunt. Abernethy malformation is a rare anomalous intra‐ or extrahepatic communication between portal blood flow and systemic venous return. In rare cases, Abernethy malformation results in HPS. Ours is the sixth case report to describe the co‐existence of these two entities. Surgical correction of anomalous hepatic vasculature or liver transplant is imperative to restoration of lung function and also to prevent progression of possible malignant liver tumors. We describe the second patient with Abernethy and HPS who underwent liver transplant with complete resolution of HPS.     

“Mirror,Mirror on the Wall”… Pediatric liver transplantation in the case of situs inversus totalis with a disrupted inferior vena cava

We present the unique case of a 15‐month‐old male born with biliary atresia and situs inversus totalis and disrupted inferior vena cava who underwent a successful liver transplantation. The patient had previously undergone a failed Kasai procedure and presented with persistent hyperbilirubinemia. The patient was transplanted with a left lateral segment donor having standard arterial anatomy. Technical considerations included identifying completely replaced arterial anatomy in the recipient from the superior mesenteric artery and creating a branch patch between the gastroduodenal artery and HA, anastomosing the donor left hepatic vein to confluences of the donor left, middle, and right hepatic veins, using a “lazy‐S” configuration of portal vein anastomosis, and suspending the allograft to the abdominal wall. Post‐operatively, his liver function tests and total bilirubin normalized and he progressed to tolerating an oral diet with tube‐feed supplementation.     

Successful liver transplantation in a child with Caroli's disease

Abstract:  CD is a rare autosomal recessive disease, characterized by multifocal cystic dilatation of intrahepatic bile ducts. The course of the disease is characterized by intrahepatic cholelithiasis, recurrent episodes of cholangitis, because of cholelithiasis, hepatic abscesses often ending in death caused by uncontrolled infection. Other conditions such as choledochal cyst and renal cystic disease are frequently associated, and patients have a higher risk for the development of cholangiocarcinoma. Endoscopic drainage of the bile duct is palliative and ineffective. OLT appears to be the treatment of choice. In monolobar cases partial liver resection has been shown to be a curative therapeutic option. We report on the course of disease in a Turkish girl who was diagnosed with CD in the neonatal period. At the age of 8.2 yr, she received OLT and is in good health 57 months post-transplantation.     

Growth hormone deficiency,situs inversus,hypertrichosis and brachydactyly

A 6 year-old female showed growth hormone deficiency, situs inversus totalis, short stature, blue sclerae, facial dismorphism, brachydactyly, developmental delay and hypertrichosis. The described phenotype represents a new syndromic situs inversus with a characteristic phenotype. Here, we present the first patient with this association in the literature.     

Syndromatic paucity of interlobular bile ducts: hepatic histopathology of the early and endstage liver

Morphologic findings of the liver in syndromatic paucity of intrahepatic bile ducts (SPIHBD) during infancy include paucity of interlobular bile ducts, features of "giant cell hepatitis," dilated lymphatics and veins in the portal tract, perisinusoidal fibrosis, and bile duct epithelial changes with a concentric layering of mesenchymal cells around bile ducts reminiscent of renal dysplasia. The latter change is characteristic of SPIHBD. Although the disease is characterized by paucity of bile ducts, morphometric studies show paucity of interlobular bile ducts in less than half of the patients during infancy. Reduced numbers of portal tracts and increased percentage of portal tracts devoid of bile ducts are more constant findings. It was impossible to predict from the early biopsy which patients would develop more severe portal fibrosis. Later in the disease portal fibrosis is variable and unevenly distributed, being more severe near the hilum regardless of the prior performance of a Kasai-type operation or the state of patency of the extrahepatic bile ducts. Hypoplasia of the extrahepatic bile ducts is the usual finding in SPIHBD, but if atresia of extrahepatic bile ducts is associated with intrahepatic paucity of bile ducts, the hepatic histopathology is that of PIHBD. Recognition of PIHBD would avoid unwarranted surgical procedures.     

Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single approximately 440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease.     

Clinical characteristics and mutation analysis of three Chinese children with autosomal recessive polycystic kidney disease

Background

There are few studies on the genotypes and phenotypes of autosomal recessive polycystic kidney disease in Chinese patients.

Methods

PKHD1 mutations in three children were detected with PCR and direct sequencing, and their clinical data were retrospectively reviewed.

Results

All of the children had bilateral enlarged polycystic kidneys, congenital hepatic fibrosis and intrahepatic bile duct dilatation. One of three children had classical multiple small cysts throughout the kidneys, and the other two children had bilateral multiple renal cysts of various sizes. Two children had abnormally shaped livers, portal hypertension and splenomegaly. Two heterozygous mutations (p.T36M, and p.P137S) were detected in Patient 1 and two were detected in Patient 2 (p.L2658X and p.V836A). One heterozygous mutation (p.L1425R) was detected in Patient 3.

Conclusions

The study shows that renal and liver phenotypes of the Chinese children varied. Five mutations were identified in the three children, three of which were novel mutations.     

胆道闭锁与上皮间质转化机制的研究进展

胆道闭锁是危及婴幼儿生命的肝胆系统疾病,以肝内外胆管进行性炎症和纤维化为特征,导致胆汁淤积以及进行性肝纤维化和肝硬化,最终进展为肝功能衰竭,是婴幼儿时期肝移植的主要指征.Kasai手术的广泛开展,使胆道闭锁患儿获得更多的生存机会,但术后60％的患儿1年内需行肝移植,只有25％的患儿自体肝存活至10岁.证据表明上皮间质转化在胆管纤维化中扮演着非常重要的角色,并且TGF-β1表达增强与胆道闭锁发生具有一定的相关性;而肝细胞生长因子(HGF)可明显抑制纤维化促进因子TGF-β1的表达,从而抑制组织纤维化.本文就胆道闭锁可能的发病机制、上皮间质转化在组织纤维化中的作用、针对上皮间质转化的抗纤维化治疗以及胆道闭锁治疗方法的展望作一综述.     

Liver disease in autosomal recessive polycystic kidney disease

Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD.     

Study of the Malformation of Ductal Plate of the Liver in Meckel Syndrome and Review of Other Syndromes Presenting with This Anomaly

Meckel syndrome (MIM 249.000) is an autosomal recessive disorder with a variable spectrum of anomalies. Since the first reports of this syndrome, very broad diagnostic criteria have been proposed, but the process of defining them continues. It is probable that at least two of three manifestations, including cystic kidney dysplasia, occipital encephalocele or other anomaly of the central nervous system, and postaxial polydactyly occur in most cases. Arrest of the development of intrahepatic bile ducts at the stage of the bilaminar plate formation or ductal plate malformation is considered of high diagnostic value in Meckel syndrome, but there is no complete agreement in the literature about its occurrence. The aims of this investigation were to study the prevalence and morphologic patterns of ductal plate malformation of the liver in Meckel syndrome by evaluating the dilatation of primitive biliary structures and the increase in connective tissue of the portal tract. Archival data files from four German centers (Berlin, Freiburg, Heidelberg, Mainz) were reviewed. Liver sections of 30 well-studied fetuses with Meckel syndrome were immunostained with antibodies against cytokeratins (intermediate filaments of the cytoskeleton) and factor VIII (an endothelial cell marker) and were evaluated both qualitatively and quantitatively. Cystic kidney dysplasia, occipital encephalocele, and postaxial polydactyly were found in 100%, 90%, and 83.3% of the fetuses, respectively. Ductal plate malformation of the liver was a constant anomaly in Meckel syndrome, seen as frequently as renal lesions. We observed essentially two kinds of hepatic lesions: 23 cases showed mainly a cystic dilatation of primitive biliary structures with little portal fibrosis, while 7 cases showed mainly rings of interrupted curved lumina around a central fibrovascular axis and pronounced portal fibrosis. In these seven cases an abnormal pattern of the portal vein, with many small and closely spaced branches of the portal vein (the so-called pollard willow pattern), was also seen. With respect to other fetal developmental anomalies, no difference between the two types of lesions was found. We also provide a potentially useful comprehensive review of other genetic syndromes in which ductal plate malformations may occur. Received May 14, 1999; accepted October 11, 1999.     

Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis (CHF) is an uncommon autosomal recessive malformation. It may be associated with extrahepatic manifestations such as polycystic kidney disease. The main consequence is portal hypertension and bleeding from varices. Despite liver transplantation as a therapeutic option for this patient, long-term impact of liver transplantation on renal functions of patients with autosomal recessive polycystic kidney disease with associated liver disease is not well known. In this study, we aimed to analyze the patient's renal function after liver transplantation by creatinine clearance, glomerular filtration rate, and renal resistive indexes. Between March 1997 and September 2002, three of 50 orthotopic liver transplantation (OLT) were performed because of CHF associated with ARPKD at Ege University Organ Transplantation and Research Center. Baseline immunosuppression consisted of prednisone and cyclosporine A (CSA). The mean follow-up of the patients was 2.1 yr. Blood urea and creatinine levels were decreased after operation in all patients and remained within the normal range at the sixth and 12th month, whereas the level of the third patient were increased at the 18th month. RRI values of patients were not found different at the sixth month whereas, RRI values of patients were decreased at the 12th month and remained unchanged at the 18th month of follow-up. During the study period hypertension developed in one patient at the 16th month and resolved with antihypertensive treatment and decreasing dosage of CSA. Kidney function has remained satisfactory in all of the patients despite the use of cyclosporine. OLT can provide good survival in patients with CHF associated with ARPKD.     

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.     

Neonatal diagnosis of primary ciliary dyskinesia: report of one case]

Primary ciliary dyskinesia is a rare, genetic disorder resulting of an abnormal ultrastructural morphology of cilia. Such disease is rarely recognized in neonatal period. We report on a newborn who exhibited unexplained respiratory distress. The diagnosis of primary ciliary dyskinesia was suggested by the association of bilateral and multiple atelectasis and situs inversus. Diagnosis was confirmed by three months of age by ultrastructural study of cilia. Primary ciliary dyskinesia is a rare disease. Diagnosis should be considered in unexplained cases of neonatal respiratory distress, especially when situs inversus totalis and multiple atelectasis are present. Diagnosis requires ciliary studies that can be performed in newborn infants.