Renal-hepatic-pancreatic dysplasia: a syndrome reconsidered

Five infants, three dying neonatally and two later in the first year of life, had renal, hepatic, and pancreatic dysplasia, a combination of abnormalities first described by Ivemark et al [1959]. The renal malformation consisted of cystic dysplasia, with abnormally differentiated ducts, deficient nephron differentiation, and glomerular cysts. The hepatic abnormality consisted of enlarged portal areas containing numerous elongated biliary "profiles," with a tendency to perilobular fibrosis. Serial liver biopsies in one child with cholestasis from birth showed a progression from bile duct paucity at 1 1/2 wk to typical biliary "dysgenesis" at 7 mo. Four of the five children had intrahepatic ductal dilatation, diagnosed ante mortem in the two older children as Caroli disease. The pancreatic abnormality consisted of fibrosis and cysts, with a diminution of parenchymal tissue. The clinical and functional reflection of these abnormalities in the two children surviving the newborn period included renal insufficiency, chronic jaundice, and insulin-dependent diabetes mellitus. Similar renal, hepatic, and pancreatic abnormalities occur in other syndromes, including trisomy 9, Meckel syndrome, Jeune, Saldino-Noonan, and Elejalde types of chondrodysplasia, and glutaric aciduria II. After exclusion of identifiable syndromes, the remaining cases of renal-hepatic-pancreatic dysplasia do not necessarily constitute a homogeneous group.     

Sensenbrenner syndrome: a new member of the hepatorenal fibrocystic family

Cranioectodermal dysplasia (CED, Sensenbrenner syndrome; OMIM #218330) is an autosomal recessive disorder reported only in 15 cases, which is characterized by dolichocephaly, rhizomelic dwarfism, dental and nail dysplasia, and progressive tubulo-interstitial nephritis (TIN) leading to end-stage renal failure. Herein, we describe a new patient with cranio-ectodermal dysplasia. Unlike previously reported cases, this 4-year-old child presented with tubulo-interstitial nephropathy associated with liver cystic disease and elevated liver enzymes. The liver biopsy demonstrated congenital hepatic fibrosis secondary to ductal plate malformation. The coexistence of a chronic tubulo-interstitial renal disease with lesions associated to malformations of the hepatic ductal plate indicates that CED as a new member of the congenital hepatorenal fibrocystic syndromes.     

Histologic and fine-needle aspiration cytologic features of polycystic disease of the parotid glands: case report and review of the literature

Polycystic disease of the parotid glands is a rare disorder, with only eight examples to our knowledge being reported in the literature. The disease presents as a painless enlargement of one or both parotid glands and does not appear to be associated with other disease processes within the head and neck, or with polycystic disease of the kidney, pancreas, or congenital fibrosis of the liver. The histology has been well described. The overall glandular architecture is preserved but the lobules are markedly distended by cysts whose lining appears to be intercalated duct in differentiation. Characteristic eosinophilic laminated spheroliths lie in many of the cystic spaces. Aspirate smears are characterized by a relatively clean background in which are distributed histiocytes, red blood cells, and small clusters of ductal epithelial cells. Polycystic disease of the parotid glands must be differentiated cytologically from mucous retention reaction, mucoceles, benign lymphoepithelial cysts, and cystic neoplasms, including Warthin's tumor, low-grade mucoepidermoid carcinoma, cystadenoma, and papillary cystadenocarcinoma.     

Renal-hepatic-pancreatic dysplasia: an autosomal recessive malformation.

We report two brothers with a cystic malformation of the kidneys, liver, and pancreas. In both cases the malformation was fatal and the children died shortly after birth. The pathological findings, consisting of multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, dilated pancreatic ducts, and polysplenia, correspond to those reported by Ivemark as renal-hepatic-pancreatic dysplasia. Many polymalformation syndromes include cystic affectation of these three organs, so this syndrome could be an isolated entity or a final common pathway of response of these organs to a variety of developmental disturbances, which could also include splenic abnormalities. We propose an autosomal recessive pattern of inheritance for renal-hepatic-pancreatic dysplasia.     

Unexpected diagnosis of cystic fibrosis at liver biopsy: a report of four pediatric cases

We report here four cases of pediatric patients in whom the diagnosis of cystic fibrosis was made only after the histological examination of a liver specimen obtained by biopsy (three cases) or at autopsy (one case). There were two boys and two girls, aged 13 months to 7.5 years. None had a personal or familial history suggestive of cystic fibrosis. One patient, presenting with myocardial lesion and hepatomegaly, died of heart failure; at autopsy, the liver showed a typical aspect of focal biliary cirrhosis. In the three other cases, liver disease was the only manifestation of cystic fibrosis at the time of diagnosis. Liver biopsy examination showed focal biliary cirrhosis in one case and massive steatosis in two. In all four cases, the diagnosis was confirmed by the existence of known pathogenic mutations in the CFTR gene. The evolution was variable; one patient had progressive liver disease with severe portal hypertension after 7 years; another one had lung complications after 1 year. In conclusion, our experience recalls that the diagnosis of cystic fibrosis must be considered in children presenting with unexplained liver disease; its confirmation by molecular techniques makes it possible to set up an appropriate follow-up.     

Familial Occurrence of Ivemark Syndrome with Splenic Hypoplasia and Asplenia in Sibs

Two sibs with Ivemark syndrome are described. This is the fourth observation of familial Ivemark syndrome, while over 200 cases reported in the literature have been sporadic.

One of the affected sibs reported here had total absence of the spleen, while a hypoplastic spleen was found in the other sib. The occurrence of splenic aplasia and splenic hypoplasia in the same family would be in support of the unitary concept of Ivemark syndrome. Contrary to previous concepts, Ivemark syndrome with splenic hypoplasia and Ivemark syndrome with splenic aplasia represent variants of one and the same disease entity.

     

Joubert syndrome with congenital hepatic fibrosis: An entity in the spectrum of oculo-encephalo-hepato-renal disorders

Joubert syndrome is an autosomal recessive inherited condition characterized by agenesis or hypoplasia of the cerebellar vermis, retinal dystrophy, chorioretinal colobomata, oculomotor abnormalities, episodic hyperpnea, ataxia, and mental retardation. Congenital hepatic fibrosis has not previously been described in Joubert syndrome. We report two unrelated children with Joubert syndrome and hepatosplenomegaly. On histopathological examination, both had congenital hepatic fibrosis. Both were also found to have congenital medullary cystic disease of the kidneys. Joubert syndrome appears to be one of a spectrum of congenital malformation syndromes involving the central nervous system, eye, liver and kidneys. © 1994 Wiley-Liss, Inc.     

The role of the F508C mutation in congenital bilateral absence of the vas deferens

PurposeCongenital bilateral absence of the vas deferens is a pathologic condition associated with normal spermatogenesis, azoospermia, and lack of both vasa deferentia. A significant association between mutations in the cystic fibrosis transmembrane conductance regulator gene among men with congenital bilateral absence of the vas deferens has been established. The objective of this study was to determine whether the F508C variant in the cystic fibrosis transmembrane conductance regulator gene has a significant effect on congenital bilateral absence of the vas deferens prevalence, when present in conjunction with a second cystic fibrosis transmembrane conductance regulator disease causing mutation.Methods and ResultsWe compared the frequency of F508C in male subjects submitted for diagnostic testing on suspicion of cystic fibrosis or during cystic fibrosis carrier screening, to men with a clinical diagnosis of congenital bilateral absence of the vas deferens. Although frequencies of F508C did not vary significantly between 850 individuals undergoing cystic fibrosis carrier screening and those submitted for diagnostic testing on suspicion of cystic fibrosis, the frequency of F508C in the congenital bilateral absence of the vas deferens population was significantly higher than expected (χ² = 6.95, corrected P = 0.0486).ConclusionWe conclude that the F508C variant in cystic fibrosis transmembrane conductance regulator may represent a pathogenic defect and lead to congenital bilateral absence of the vas deferens when combined with a second cystic fibrosis transmembrane conductance regulator mutation.     

Neonatal diabetes mellitus,congenital hypothyroidism,hepatic fibrosis,polycystic kidneys,and congenital glaucoma: a new autosomal recessive syndrome?

We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function. The phenotype observed in the two sibs was identical. Although a combination of liver, kidney, and pancreatic involvement has been described in Ivemark syndrome (hepato-renal-pancreatic syndrome), the coexistence of NDM, CH, and glaucoma in both sibs suggests the possibility that this combination of manifestations describes a new autosomal recessive syndrome. Mutation analysis for several candidate genes is warranted.     

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p

We report on two sibs, both males, one born at 37 the other at 24 weeks of gestation, both with a syndrome similar to that seen in three sets of sibs by Gillessen-Kaesbach et al. [1993: Am J Med Genet 45:511-518]. Both propositi had polycystic kidneys and hepatic fibrosis indistinguishable from that seen in autosomal recessive polycystic kidney disease (ARPKD), and skeletal and facial anomalies. Skeletal abnormalities included "butterfly" vertebrae, square shape of pelvis, and brachymelia. The facial anomalies included hypertelorism, epicanthic folds, and anteverted nares. Additional external findings were apparently low-set ears and a short neck. Histopathological examination of the kidneys showed radial orientation and cystic dilatation of the cortical and medullar tubules. The liver showed "congenital hepatic fibrosis." The hepatic findings in the second infant were less severe. Renal abnormalities were limited to focal tubular cystic changes. Linkage analysis with polymorphic markers of the region 6p21.1-p12, flanking the gene locus of ARPKD, showed different haplotypes in the sibs, thus excluding the ARPKD gene locus in this family and indicating genetic heterogeneity.     

BILATERAL RENAL DYSPLASIA ACCOMPANIED BY PANCREATIC FIBROSIS, MECONIUM ILEUS, AND SITUS INVERSUS TOTALIS

An autopsy case of bilateral renal dysplasia with other congenital malformations is reported. Malformations included severe pancreatic fibrosis with meconium ileus, situs inversus totalis, cardiovascular anomalies, and others. The only syndrome of multiple congenital malformations involving renal dysplasia which is similar to the present case is Ivemark's syndrome, though the present case lacked hepatic lesions. Apart from the pancreatic lesion, there were no abnormalities compatible with cystic fibrosis (mucoviscidosis). It was considered that meconium ileus in the present case was caused by pancreatic achylia secondary to severe pancreatic fibrosis, unrelated to cystic fibrosis, but closely allied to renal dysplasia.     

Factors Influencing Family Participation in a Longitutdinal Study: Comparison of Pediatric and Healthy Samples

Compared participation levels in a longitudinal study of parent-childrelationships from infancy to 4 years in families of childrenwith cystic fibrosis, congenital heart disese, and with no chronicillnes. Demographic (parent's age, education) and child, parentand family variables (medical status, family environment) wereinvestigated for their predictive value of families' participation.34% of families (71/209) were lost to the study at a later date.Families of children with cystic fibrosis were the least likelyto be lost. Parents' age and /or education predicted participationin all groups. Families in both pediatric samples participatedless when parental well-being was less optimal, and the levelof mother-infant attachment organization was lower. Unlike demographicfactors, family factors have diferential impact on participationin families in pediatric and nonpediatric samples.     

Detection of the cystic fibrosis delta-F508 mutation at autopsy by site-directed mutagenesis

In Causasian populations cystic fibrosis (CF) is the most common autosomal recessive disorder. CF was previously considered rare in Mexico; however, the reported frequency is about 1% in autopsies. This discrepancy appears to be due to the inability to diagnose the illness during life. It is now known that in developing countries a great number of affected children die without the benefit of CF diagnosis and appropriate treatment. In this study we have used the PCR-mediated sitedirected mutagenesis technique for the detection of the delta-F508 mutation in a 6-month old Mexican boy who died without definitive diagnosis. The tissue available from the child was a formaldehyde fixed paraffin-embedded liver. We identified the delta-F508 mutation in homozygous form in the propositus and in a heterozygous form in his parents. This represents the first report of CF molecular diagnosis in Mexico. © 1993 Wiley-Liss, Inc.     

The influence of genetic counselling in the era of DNA testing on knowledge, reproductive intentions and psychological wellbeing

Subjects of reproductive age at risk of having an affected child with a severe single gene disorder such as Duchenne muscular dystrophy (DMD) or cystic fibrosis (CF) were surveyed to ascertain: their views on genetic counselling and antenatal testing; their knowledge of their risk of having an affected child; and their psychological wellbeing. Questionnaires were posted to 209 individuals at 130 addresses; a 65% response rate was achieved. The majority of those surveyed were under 40 years of age (91%), half of them had received genetic counselling only once and for 47% the first encounter was after the diagnosis of their affected child. Most patients expressed their intention to use prenatal testing. However, less than 50% of those counselled knew their risk of having an affected child. Knowledge of risk was associated with the type of disease in the family (p<0.001) (inheritance of DMD was poorly understood by relevant subjects) and was positively associated with the participant's level of education (p<0.05). We did not detect a significant association between the number of intended children and the risk of having an affected child. In terms of family relations, genetic counselling appears to be beneficial for the nuclear family, the couple and their children, but some counsellees reported a detericration in relations with other relatives. The results indicate that couples at risk of having a child with a severe genetic disorder value the counselling provided, but many of them do not remember important facts in relation to their risk status.     

Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development

Sterility due to bilateral destruction in utero or in early infancy resulting in congenital absence of the vas deferens is the rule in male patients with cystic fibrosis. To understand the developmental pattern of this anomaly, the microscopic morphology of the male excretory system was analyzed during development and the expression of the cystic fibrosis transmembrane conductance regulator protein was explored by immunohistochemistry. We observed that cystic fibrosis fetuses had no excretory ducts agenesis or obstruction until 22 weeks of gestation. However, a focal inflammatory pattern and mucinous plugs in the oldest cystic fibrosis case suggested a disruptive mechanism. Immunolabeling of cytoplasmic epithelial cystic fibrosis transmembrane conductance regulator protein was demonstrated in all cystic fibrosis and control cases with a similar pattern of expression of the protein between age-matched controls and cystic fibrosis cases. At midgestation, an apical intensification appeared in both cystic fibrosis and control cases and was stable during the remainder of fetal life. No gradient of intensity could be detected between the different segments of the excretory tract. These findings are different from those reported in adults. The absence of any morphologic anomaly until 22 weeks of gestation, the focal destruction of the epithelial structures during the second trimester, and the chronological pattern of expression of cystic fibrosis transmembrane conductance regulator are of interest for a better understanding of the pathophysiology of this disease.     

Liver disease and common-bile-duct stenosis in cystic fibrosis

To determine the incidence of common-bile-duct lesions and their relation to liver disease in cystic fibrosis, we performed hepatobiliary scanning in 50 of 61 patients with cystic fibrosis who had hepatomegaly, abnormal liver function, or both and in 31 of 92 patients with cystic fibrosis who did not have hepatomegaly or abnormal liver function. Ninety-six percent of the patients with liver disease had evidence of biliary tract obstruction, which was defined cholangiographically as a stricture of the distal common bile duct in the majority of cases. All the patients without liver disease had normal intrahepatic and common-duct excretion of tracer. Abdominal pain was significantly more common in patients with common-duct obstruction (P less than 0.001), and enlarged gallbladders occurred only in such patients. Since fasting levels of serum bile acids were elevated in nearly half these patients, irrespective of the severity of their liver disease, serum bile acids may be markers of the severity of the common-duct lesion. We conclude that strictures of the distal common bile duct are common in patients with cystic fibrosis and liver disease. This association requires further study, since surgical relief of common-duct obstruction may prevent or ameliorate the hepatic complications of cystic fibrosis.     

Family stress with chronic childhood illness: cystic fibrosis, neuromuscular disease, and renal disease

Parents of children with neuromuscular disease (N = 16), cystic fibrosis (N = 16), and renal disease (N = 11) were compared with parents of control subjects matched by age to the clinical cases; the instrument used was the Questionnaire on Resources and Stress (QRS). The three clinical groups exhibited different patterns of stressful response, consistent with the nature of their illnesses and the requirements for care imposed on the families. Parents of children with neuromuscular disease reported a wide spectrum of problems, both qualitatively and quantitatively different from those experienced in the other two clinical samples. Parents of children with cystic fibrosis also experienced extensive stress, but less than anticipated. Parents of children with renal disease reported stress in only a few areas, in keeping with the nature of the disease. The relationship between severity of functional impairment from cystic fibrosis and QRS scales was examined and found to be equivocal. The 285-item and 66-item versions of the QRS were compared and judged to be appropriate for different situations (research vs. clinical screening).     

New syndrome?: Three sibs diagnosed prenatally with situs inversus totalis, renal and pancreatic dysplasia, and cysts

Recently we described a previously apparently undescribed autosomal recessive syndrome in two sib fetuses with situs inversus totalis, cystic dysplastic kidneys and pancreas, bowing of the lower limbs and clavicles, severe intrauterine growth retardation, and oligohydramnios. This syndrome differs from that of Ivemark and related syndromes due to lack of liver involvement. After these two sibs, this consanguineous family had a third child and an early prenatal diagnosis of pancreatic and dysplastic renal cysts was made in the 19.5-week-old fetus. The last case supports the genetic hypothesis.     

Children with cystic fibrosis benefit from massage therapy.

OBJECTIVE: To measure the effects of parents giving massage therapy to their children with cystic fibrosis to reduce anxiety in parents and their children and to improve the children's mood and peak air flow readings. METHODS: Twenty children (5-12 years old) with cystic fibrosis and their parents were randomly assigned to a massage therapy or a reading control group. Parents in the treatment group were instructed and asked to conduct a 20-minute child massage every night at bedtime for one month. Parents in the reading control group were instructed to read for 20 minutes a night with their child for one month. On days 1 and 30, parents and children answered questions relating to present anxiety levels and children answered questions relating to mood, and their peak air flow was measured. RESULTS: Following the first and last massage session, children and parents reported reduced anxiety. Mood and peak air flow readings also improved for children in the massage therapy group. CONCLUSIONS: These findings suggest that parents may reduce anxiety levels by massaging their children with cystic fibrosis and their children may benefit from receiving massage by having less anxiety and improved mood, which in turn may facilitate breathing.     

Hardikar syndrome: long term outcome of a rare genetic disorder

Hardikar syndrome is a rare disorder of unknown etiology. Features of the syndrome are manifold with a predominance of liver and renal involvement. The syndrome is clearly distinct from other previously described syndromes such as Alagille syndrome, congenital hepatic fibrosis, Caroli disease, and Kabuki make-up syndrome. To date, only four cases of Hardikar syndrome have been published worldwide. We report here on the long term outcome of these patients.