Alagille syndrome associated with a paracentric inversion 20p12.2p13 disrupting the JAG1 gene.

Mutations in the human gene Jagged1 (JAG1) localized in 20p12 have been recently identified as causal for the anomalies found in patients with Alagille syndrome (AGS). This gene encodes a ligand for the Notch1 transmembrane receptor, which plays a key role in cell-to-cell signaling during differentiation and is conserved from C. elegans to human. We report a paracentric inversion (PAI) of chromosome 20p12.2p13 in an individual with AGS who also had alpha-1-antitrypsin deficiency. To our knowledge, this is the first published case of PAI involving the short arm of chromosome 20. Using FISH, fiberFISH, and molecular studies with a approximately 40 kb cosmid clone encompassing the entire 36 kb JAG1 gene, we demonstrate that the gene was disrupted by the inversion breakpoint between exons 5 and 6. An unusual association between two most common causes of chronic liver disease in childhood, AGS and alpha-1-antitrypsin deficiency, as well as their influence on the proband's abnormal phenotype are discussed.

[Magnesium status in children and adolescents with celiac disease]. / Stan odzywienia magnezem u dzieci i mlodziezy z celiakia.

UNLABELLED: Magnesium deficiency has been reported in patients with classical coeliac disease. Classical coeliac disease has been recently very rare, but the frequency of the silent or latent form has increased. The aim of the study was to evaluate the magnesium status in patients with coeliac disease diagnosed according to ESPGAN criteria. 41 GFD(+) patients aged 6-18 years, who were on a gluten-free diet (GFD) for 2.8 to 17.3 years (mean 11 years); with normal villous structure and IgAEmA(-), and 32 GFD(-) patients aged 5-17 years, with villous atrophy and IgAEmA(+): 8--after 7/12-13/12 of gluten challenge, 4--with late onset of coeliac disease, 20--with silent coeliac disease. All of the children did not have any other disorders. Magnesium status was examined by using: an i.v. Mg-loading test (30 mmol/1.73 m2); Mg urinary excretion and Mg concentration in serum, erythrocytes, and in hair. Abnormal values in GFD(+) and GFD(-) patients were found in: Mg i.v. loading test (retention > 40%) in 20 vs 34%, serum Mg (< 0.7 mmol/l) in 7 vs 3%, erythrocytes Mg (< 1.8 mmol/l) in 20 vs 25%. The reversed statistically significant correlation was found between Mg retention and Mg urinary excretion (R = -0.293, p = 0.009). No other statistically significant correlations were found. CONCLUSION: The magnesium deficiency was present in all patients with classical coeliac disease, but only in 1/5 of patients with coeliac disease on a gluten-free diet and in 1/5 of patients with silent coeliac disease.

[Reasons for magnesium deficiency in children with coeliac disease]. / Przyczyny niedoboru magnezu u dzieci i mlodziezy z celiakia.

UNLABELLED: Magnesium (Mg) deficiency is often noted in patients with coeliac disease (CD). The aim of the study was the analysis of the reasons of this deficiency in children with CD, diagnosed according to ESPGAN criteria. MATERIAL: The study was performed on 41 patients aged 6-18 years adhering to strict gluten-free diet GFD(+) for mean 11 years, with normal small intestine mucosa, and IgAEmA(-), and on 32 patients aged 5-17 years on gluten containing diet, with classical CD, silent CD or after gluten challenge--GFD(-). In this group the villous atrophy of the small intestine and IgAEmA(+) were observed. In 18 of these patients Mg deficiency was found using Mg-loading test (30 mmol/1.73 m2). METHODS: The following parameters were analysed: type of the disease, observance of gluten-free diet, sex, and living place. Mg, Ca, Na, protein, fat, and dietary fiber intake was assessed using food frequency questionnaire method, and steatorrhea using faecal fat excretion (g/24 h). RESULTS: The frequency of Mg deficiency was similar in both sexes, occasionally in children from small towns (4.5%), and more often in children from big cities (31.5%), and village (34.4%). Dietary Mg intake below RDA was observed in 23% of children from GFD(+) group, in 19% from GFD(-) one, and in 17.6% in children with Mg deficiency. Insufficient Mg intake was found in 18.2% of children from small towns, in 17.6% from big cities, and in 12.5% from villages; Ca in 36.6%, 58.8%, and 59.3%, and protein in 18.2%, 35.3%, and in 34.4% respectively. In all groups of children high intake of fat and Na was observed. Dietary fiber intake was within the recommended values. All children with classical CD had increased fat excretion (mean 25.9 g/24 h), in other patients it was within normal values [GFD(+) mean 1.95 g/24 h, in GFD(-) without diarrhoea 1.7 g/24 h. CONCLUSIONS: Magnesium deficiency in children with CD depends on the form of the disease, adhering to GFD, diarrhoea with steatorrhea, and/or low Mg intake with the diet.

Apolipoprotein E polymorphism in alagille syndrome and progressive familial intrahepatic cholestasis.

The aim of the study was to assess the apolipoprotein E polymorphism (apoE) in two familial cholestatic diseases-Alagille syndrome (AS) and progressive familial intrahepatic cholestasis (PFIC)-and to estimate its association with gallstone formation, cholesterol levels, and response to UDCA treatment. We investigated 16 children with AS age 8.8 +/- 5.7 years (mean +/- SD) and 18 children with PFIC age 6.3 +/- 4.6 years. The frequency of the epsilon-2 allele in AS and PFIC was higher and the frequency of the epsilon-3 allele was lower than in controls. Gallstones were diagnosed in nine children with PFIC and different apoE phenotypes. No association between phenotype and cholesterol levels or response to UDCA therapy was observed in the patients studied. In conclusion, the allele epsilon-2 is overrepresented in AS and PFIC, similar to primary biliary cirrhosis, although this does not seem to contribute to different cholesterol levels, gallstones, and response to UDCA therapy.

[Analysis of liver function in patients with Turner syndrome (TS) and in patients with secondary hypogonadism with estrogen and estrogen- progestagens replacement therapy: a preliminary report]. / Ocena czynnosci watroby u chorych z zespolem Turnera oraz u pacjentek z wtórna niedoczynnoscia gonad leczonych estrogenami i preparatami estro-progestagenowymi--doniesienie wstepne.

OBJECTIVES: Abnormalities of liver function tests were been reported in adults with TS and in patients with oestrogen replacement therapy. DESIGN: The aim of this study was to evaluate the prevalence of liver disease in patients before or with oestrogen therapy. MATERIALS: 79 patients, aged 13(2/12) to 60(4/12), for oestrogen replacement therapy: 13--with secondary hypogonadism (group I), 29--with TS (group II), 19--with menopause (group IV) and 18--with TS, aged 2 to 16(11/12), before oestrogen therapy (group III). METHODS: All patients were tested for liver function tests (ALAT, GGTP, total bilirubin), and patients I-III groups for serum markers of HBV and HCV infection. RESULTS: The frequency of HBV/HCV infection was 38.3% in group I, 13.7%--in group II, 16.7%--in group III. In 13.7% patients of group II and in 16.7% patients of group III the liver disease had been classified as cryptogenic. CONCLUSIONS: The prevalence of HBV/HCV infection in patients with hypogonadism and the prevalence of cryptogenic liver disease in patients with TS, seems to be relatively high. In TS liver function test should be investigated as well before oestrogen therapy and should be turned during the follow up.

[Age at menarche in girls with celiac disease]. / Wiek wystapienia pierwszej miesiaczki u dziewczat chorych na celiakie.

OBJECTIVES: Delayed menarche, amenorrhea, early menopause have been sporadically reported in patients with CD. But control group matched was drawn from healthy individuals. DESIGN: The aim of this study was to investigate the age at menarche in patients with CD and in mothers of patients. MATERIALS: 59 mother/daughter pairs; daughter with coeliac disease: 49--treated with a gluten-free diet [FGD (+)] and 10 with untreated or late onset coeliac disease [FGD (-)]. METHODS: CD was diagnosed on the basis of ESPGAN criteria. All patients and mothers were asked for information on the age at menarche. RESULTS: The mean age of menarche was significantly higher in FGD (-): girls--mean 16.16 years and mother's--mean 15.49 years, than in FGD (+) patients. The mean age of menarche in FGD (+) patients and mother's were: 12.33 and 13.82 years respectively in the country (11 pairs), 13.08 and 13.49 years respectively in the little town (19 pairs), 12.90 and 13.33 years respectively in the town (19 pairs). CONCLUSIONS: The age at menarche in patients with CD and FGD is decreased to age at menarche in mother's, but is higher in the untreated CD patients and mother's. These findings support the hypothesis that the age at menarche in girls with coeliac disease is regulated by gluten-free diet and by other genetic and environmental factors.

Further studies on aminopeptidase-M in blood in children with cholestatic liver diseases and viral hepatitis.

Aim of this study was to determine and further characterize the serum aminopeptidase-M in children with liver diseases. Based on our new assay, we have shown two fractions of the enzyme. Activity of the first fraction is expressed in undiluted serum at pH adjusted from 8.5 (pH of storaged serum) to 7.4. Activity of the second fraction (cryptic activity) appears in the serum (pH 7.4) as a result of dilution and/or addition of aniline naphthalene sulfonic acid. In children with Alagille syndrome, extrahepatic biliary duct atresia, Byler's disease, and acute hepatitis due to hepatitis B virus infection, activities of both fractions are highly elevated as compared to healthy children or those with chronic viral hepatitis. Moreover, serum aminopeptidase-M seems to reflect other aspects of the pathological process than those reflected by the alanine aminotransferase and gamma-glutamyltranspeptidase. Due to increased activity and broad substrate specificity, the enzyme seems to be also a cofactor of cholestasis and hepatitis.

Clinical, biochemical and histological analysis of seven patients with cholesteryl ester storage disease.

Lysosomal acid lipase (LAL) deficiency leads to two phenotypically different diseases: cholesteryl ester storage disease (CESD) and Wolman's disease. Lysosomal acid lipase hydrolyzes cholesteryl esters and triglycerides. Deficiency of LAL results in intralysosomal storage of cholesteryl esters and triglycerides. CESD has a chronic and benign course and is characterized by hepatomegaly and mild hypercholesterolemia. It leads to fibrosis (cirrhosis) and early atherosclerosis. This report presents the clinical, biochemical and microscopic data of seven patients with CESD followed up over 10 years. The physical development of all the study children remained within the normal range; 7 patients had hepatomegaly and 6 also had splenomegaly. Three patients had normal cholesterol, triglycerides and transaminases values; the other four had slightly elevated levels for these parameters. The activity of LAL in all patients was reduced to below 30% of the lower normal value. Histologically, cholesteryl crystals and lipid storage vacuoles in Kupffer cells were present in all examined patients except one. Accumulation of cholesteryl esters was visible on thin-layer chromatography of lipid extracts obtained from liver biopsies.

Serum and salivary antigliadin antibodies and serum IgA anti-endomysium antibodies as a screening test for coeliac disease.

Serum and salivary IgA and IgG antigliadin antibodies were determined by an enzyme-linked immunosorbent assay in 18 children with villous atrophy and 30 children on a gluten-free diet for coeliac disease in whom normal intestinal mucosa was found. Serum IgA anti-endomysium antibodies were also determined by an immunofluorescence method in these children. Serum IgG antigliadin and IgA anti-endomysium antibodies had the highest sensitivity (100 and 94.4%, respectively), followed by serum IgA antibodies to gliadin (72.2%), salivary IgA antigliadin (61.2%) and IgG antigliadin (50%) antibodies. The highest specificity was found for serum IgA anti-endomysium (100%) and IgA antigliadin (96.6%) antibodies and salivary IgA and IgG antigliadin antibodies (93.3%), while serum IgG antigliadin antibodies were found to be least specific (63.3%).

Alpha-1-antitrypsin subtypes in Polish newborns.

Alpha-1-antitrypsin phenotypes of umbilical cord serum from 741 Polish newborns were studied by isoelectric focusing. The frequencies of the PI alleles were: PI*M1 = 0.7199, PI*M2 = 0.1613, PI*M3 = 0.0965, PI*S = 0.0094, PI*Z = 0.0067, and PI*Var(F,I,L) = 0.0060. The data obtained for Poland were compared to those for other European populations.

[Polymorphism locus Pi (alpha1-antitrypsin) of residents in the Poznan province]. / Polimorfizm locus Pi (alpha 1-antytrypsyny) u mieszkanców województwa poznanskiego.

Locus Pi (Pi-protease inhibitor) polymorphism in the Polish population was determined with isoelectrofocusing human blood proteins in super-thin agarose gel. There were 13 phenotypes of alpha 1-antitrypsin in the tested 631 sera collected from blood donors and inhabitants of both Poznan city and Poznan province. An incidence of locus Pi alleles in the Polish population was determined: PiM1 = 0.7464; PiM2 = 0.1656; PiM3 = 0.0570; PiS = 0.0142; PiZ = 0.015; PiVar = 0.0016. Out of rare Pi variants PiI = 0.0008 and PiR = 0.0008 were identified. The obtained results were compared with those for the European populations.

De novo mutation within the intron-exon junction in the PiZ allele of the alpha-1-antitrypsin gene.

A proband homozygous for the PiZ allele of the alpha-1-antitrypsin gene was found to be a heterozygous carrier of the additional nucleotide substitution (C-T) within the intron IV-exon V junction (position 9955 in intron IV, 3 bp upstream of its 3'-splice site). This mutation was not found in DNA from either the PiZ heterozygous parents or the PiZ homozygous brother of proband.

Procollagen type III peptide in the assessment of liver fibrosis in children with congenital alpha-1-antitrypsin deficiency.

In 31 children with congenital alpha 1-antitrypsin deficiency the concentration of procollagen type III peptide was determined in a trial establishing liver fibrosis degree and monitoring of fibrosis progression. No correlation was found between the degree liver fibrosis determined by histological examination and the serum concentration of procollagen type III peptide. The concentration of procollagen type III peptide was higher with coexistent cholestasis and in case of inflammatory processes outside the liver (pneumonia). In progressing cirrhosis with inflammatory reaction the concentration was higher than in advanced cirrhosis and non-inflammatory liver fibrosis.

[Leigh disease in a 17-year-old boy]. / Choroba Leigha u 1,5-rocznego chlopca.

A boy aged 1.5 year with deficient weight and height, retardation of motor development, decreased muscle tonus, finger tremor and periodic tachypnoea without detectable respiratory system changes is presented. Gasometry demonstrated metabolic acidosis with respiratory alkalosis, high concentration of lactic acid in serum and cerebrospinal fluid, increasing metabolic acidosis after glucose load, and lack of hyperglycaemic response after alanine load, and cortical atrophy in CT. On the basis of these changes Leigh's disease was diagnosed.

[Delayed puberty in an 18-year-old female patient with late diagnosis of celiac disease]. / Opóznienie dojrzewania u 18-letniej chorej z pózno rozpoznana celiakia.

A case of a 18-year female patient is presented. The patient suffered from certain symptoms of malabsorption syndrome. She was also retarded sexually. Celiac disease was diagnosed according to ESPGAN criteria. Gluten -free diet produced body weight increase, pain relief, improved well-being and normal menstruation.

[Herpetiform dermatitis and atopic dermatitis]. / Dermatitis herpetiformis a Dermatitis atopica.

History data and clinical pattern were analysed in 33 children with herpetiform dermatitis (DH) and in 34 children with atopic dermatitis (DA). The differences are stressed between DH and DA as which it is frequently misdiagnosed, which is the cause of delayed treatment in DH (in the studied group 2.8 years on the average). The development of skin changes with accompanying itching in a child at preschool age should suggest the supposition of DH.

[Alpha 1-antitrypsin phenotypes and their role in the development of early and late cirrhosis of the liver]. / Fenotypy alpha 1-antytrypsyny i ich rola w rozwoju wczesnej i póznej marskosci watroby.

On the basis of cooperation with the Children's Health Centre the role was analysed of certain phenotypes of alpha 1-antitrypsin (alpha 1-AT), mainly Pi Z and Pi MZ phenotypes in the development of infantile cirrhosis. A significant participation was demonstrated of the latter phenotype in patients developing infantile cirrhosis. The preliminary analysis of the incidence of pathological alpha 1-AT phenotypes in the group of patients with cirrhosis manifested at the adult age seems to indicate the higher incidence of the Pi MZ phenotype as compared with the general population. The genetically determined low serum alpha 1-AT activity is probably one out of many factors determining the development of this disease. Further studies will be aimed at explaining whether the combination of action of two factors: alpha 1-AT deficiency and exposure to hepatotoxic agents is not accelerating the appearance of the disease and is not potentiating its clinical intensity.

["Munchausen syndrome by proxy" as an example of diagnostic error]. / Zespól "Munchausen by proxy" jako szczególny przyklad bledu diagnostycznego.

A case of the girl who underwent multiple hospitalizations is presented. Gastrointestinal disorders were seen in the infancy together with skin rash of allergic type, hypoglycaemia without any clear reason in the fourth year of age, and polyuria with hyponatremia and hypokalemia since the sixth year of age. Mother's lack of concern was unexplainable in view of the deteriorating child's health. Samples of the urine and faeces supplied by the mother have shown the laboratory findings suggesting that potassium chloride was added to the faeces and natrium hydrocarbonate--to the urine. Urine collected during polyuria contained large quantities of furosemide. Long-term follow-up, numerous examinations and performed tests have led to the diagnosis of the particular form of the ill-treated child syndrome, so-called "Munchausenn by proxy" syndrome.