Metabolic alkalosis and secondary hyperaldosteronism in cystic fibrosis (author's transl)]

The prolonged use of a salt restricted infant formula (1.9 mEq Na/kg/day and 1,4 mEq C1/kg/day) in a child with undiagnosed cystic fibrosis led to a life threatening metabolic disturbance. The main features were hypochloraemic alkalosis due to massive loss of electrolytes in the sweat. Urinary electrolyte excretion, however, had been lowered to a minimum due to aldosteron induced reabsorption. Plasma aldosterone levels were initially high, but returned to normal after addition of salt to the feeds. Prior to admission a sweat test had been negative. The patient clearly demonstrates the unique metabolic feature of cystic fibrosis of the ability to retain electrolytes in the tubulus and at the same time the inability of the sweat glands to reabsorb sodium and chloride. Contrary to present experience severe prolonged salt restriction is believed to be able to diminish sweat electrolytes to subpathological values.     

A fetal case of transient abnormal myelopoiesis with severe liver failure in Down syndrome: prognostic value of serum markers

The authors recently encountered a lethal case of Down syndrome with transient abnormal myelopoiesis (TAM). Although the peripheral white blood cell count and blast cells had improved without specific treatment, the patient died of severe coagulopathy due to liver fibrosis when he was 5 years old. The prognosis of TAM with liver fibrosis was poor. The patient had high levels of N-terminal peptide of III procollagen, type IV collagen, and hyaluronic acid. These serum makers are noninvasive indicators of liver fibrosis and may be useful as prognostic indicators of TAM in Down syndrome.     

Extremely short small bowel induces focal tubulointerstitial fibrosis.

BACKGROUND: Arginine becomes an essential amino acid after massive resection of the small bowel as a result of decreased biosynthesis of citrulline in the remaining small bowel. It is also reported that nitric oxide (NO) is synthesized from l-arginine by NO synthase (NOS), and NO is involved in the regulation of blood flow in the kidney. The authors observed a patient with an extremely short small bowel, showing focal tubulointerstitial fibrosis. The experiment was designed to clarify whether massive small bowel resection (SBR) produces focal tubulointerstitial fibrosis in the kidney. METHODS: An experimental study was performed using 4-week-old rats with 90% proximal SBR either with or without arginine supplementation for 6 weeks after surgery. RESULTS: In rats without arginine supplementation, low plasma levels of citrulline and arginine increased urinary excretion of orotate, and focal tubulointerstitial fibrosis was observed 6 weeks after 90% SBR. The data from plasma amino acid chromatography and increased excretion of urinary orotate suggested the presence of arginine deficiency. The kidney pathology was similar to that of our patient. Rats with arginine supplementation after 90% SBR and pair-fed control rats without 90% SBR showed almost normal glomeruli and tubulointerstitium. CONCLUSIONS: Experimental study strongly suggests that arginine deficiency causes focal tubulointerstitial fibrosis in the kidney after massive SBR.     

Mitochondrial myopathy with lactic acidaemia,Fanconi-De Toni-Debré syndrome and a disturbed succinate: cytochrome c oxidoreductase activity

A patient with severe muscular hypotonia, failure to thrive, a metabolic acidosis and a renal tubular dysfunction is presented. The disease followed a fatal course. Blood lactate and pyruvate levels as well as lactate/pyruvate ratios were strongly elevated. There were a massive excretion of lactate in urine, a generalized hyperaminoaciduria, a proteinuria and a mellituria. The carnitine concentration was diminished in blood and muscle tissue. Biochemical investigations of skeletal muscle and liver tissue revealed a defect in the respiratory chain at the level of succinate: cytochrome c oxidoreductase. The defect could not be demonstrated in cultured fibroblasts.     

Xeroderma pigmentosum group G with severe neurological involvement and features of Cockayne syndrome in infancy

We describe a premature, small for gestational age infant girl with micropthalmia, bilateral congenital cataracts, hearing impairment, progressive somatic and neurodevelopmental arrest, and infantile spasms. She presented a massive photosensitive reaction with erythema and blistering after minimal sun exposure, which slowly gave place to small skin cancers. Her skin fibroblasts were 10-fold more sensitive than normal to UV exposure due to a severe deficiency in nucleotide excision repair. By complementation analysis, the patient XPCS4RO was assigned to the very rare xeroderma pigmentosum (XP) group G (XP-G). One allele of her XPG gene contained a 526C-->T transition that changed Gln-176 to a premature UAG stop codon. Only a minor fraction of XPG mRNA was encoded by this allele. The second, more significantly expressed XPG allele contained a 215C-->A transversion. This changed the highly conserved Pro-72 to a histidine, a substitution that would be expected to seriously impair the 3' endonuclease function of XPG in nucleotide excision repair. In cases suspected of having XP and/or early-onset Cockayne syndrome, extensive DNA repair studies should be performed to reach a correct diagnosis, thereby allowing reliable genetic counseling and prenatal diagnosis.     

Comparison of folic acid coenzyme distribution patterns in patients with methylenetetrahydrofolate reductase and methionine synthetase deficiencies

Folic acid coenzyme distribution patterns were examined in the liver and kidney of two patients with homocystinuria due to different inborn errors of metabolism affecting the remethylation of homocysteine to methionine. One patient, with severe mental retardation (and death at 3 1/2 yr), had greatly reduced levels of methylenetetrahydrofolic acid (THF) reductase in fibroblasts as well as in liver and kidney. Chromatographic separation of folate coenzymes in liver showed an abnormal pattern with THF as the main component and almost no methyl-THF but total folate was normal. The other patient, who was dystrophic, microcephalic, and had megaloblastic anemia died at age 4 months. He had reduced levels of methionine synthetase in liver and kidney due to a defect of intracellular cobalamin metabolism. Chromatographic analysis of his tissues showed methyl-THF to be the principal folate form and a markedly reduced total folate. These results support the "methyl-THF trap" hypothesis and offer information with respect to the possible therapy of these two disorders.     

Life‐threatening acute gastric dilatation with aorta compression in a 3‐year‐old child

We report a fatal case of acute gastric dilatation in a 3‐year old boy who presented with severe abdominal pain and massive gastric distension in the emergency room. On physical examination the patient was in shock due to acute abdomen and lower limb ischemia. Initial laboratory findings showed multi‐organ failure with acute renal failure and pancreatitis. Abdominal computed tomography (CT) showed marked dilatation of the stomach resulting in compression of the abdominal aorta. The left kidney, spleen and pancreas were not visible on CT due to the necrotic changes. The patient was quickly stabilized by initial volume resuscitation, but suddenly deteriorated immediately after gastric decompression via nasogastric tube, and died from multi‐organ failure 3 h after initial presentation.     

Analysis of the pathomorphology of the intra- and extrahepatic biliary system in biliary atresia

OBJECTIVE: Aim of the study was to investigate the pathomorphological changes in the liver and triangular cord of the porta hepatis in biliary atresia and assess the relationship between the degree of differentiation of fibroblasts in the triangular cord of the porta hepatis and the liver fibrosis scores. METHODS: From September 2005 to May 2006, 21 patients with biliary atresia (66+/-20 days old) underwent a Kasai procedure. The liver biopsy and the remnant of the porta hepatis were conserved. Five cases with cholestasis syndrome and 10 cases with choledochal cyst were used as a control group. Liver biopsies were performed in the control group. The micro- and ultrastructure of the liver and the remnant of the porta hepatis were assessed in the biliary atresia and the control group. Ultrastructural features were examined by transmission electron microscopy. The semiquantitative differences in liver fibrosis grading between the biliary atresia and the control group was evaluated with a 3-grade staging system. The degree of differentiation of fibroblasts (FB) in the triangular cord of the porta hepatis was assessed as follows: 1) juvenile type: above 50 % FBs were juvenile, 2) senior type: above 50% FBs were senior, 3) median type: between the former 2 types. The differentiation scores of FB in the porta hepatis were assessed in relation to the liver fibrosis score. RESULTS: 1) The pathological changes with BA are characterized by inflammation and fibrosis in the hepatic portal area. The fibrosis scores in the biliary atresia group (I: 2 cases, II: 12 cases, III: 7 cases) were significantly higher than in the control group (I: 8 cases, II: 5 cases, III: 2 cases; p=0.01. 2) In the biliary atresia group, the extrahepatic biliary system of all cases showed a triangular cord in the porta hepatis. The triangular cord of porta hepatis was characterized by hyperplasia of canaliculi, atresia or stenosis of the bile ducts, inflammation infiltration, cholestasis, and interstitial fibrosis. 3) The ultrastructural features of BA showed active fibroblasts, a loss of microvilli, dense deposits in the hepatocytes and liver sinusoid, and dilatation of canaliculi. 4) The differentiation scores of FB in the porta hepatis were positively related to the liver fibrosis score (p=0.04). CONCLUSION: The main pathological changes of biliary atresia are inflammation and fibrosis in the hepatic portal area. The ultrastructural features of biliary atresia suggested that the differentiation scores of FB in the triangular cord of the porta hepatis were positively related to the liver fibrosis score.     

Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation

Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene (INSR) causing either defects in insulin binding or receptor autophosphorylation and tyrosine kinase activity. We report a patient with pronounced clinical picture of leprechaunism who developed severe progressive hypertrophic obstructive cardiomyopathy (HOCM) and renal tubular dysfunction which improved on continuous subcutaneous infusion of recombinant human insulin-like growth factor-1 (rhIGF-I). INSR gene molecular analysis and insulin receptor (IR) autophosphorylation on cultured fibroblasts were performed. A novel homozygous missense mutation p.Leu795Pro was found, located in the extracellular portion of the β subunit of the insulin receptor. The post-binding defect of the insulin receptor signaling in cultured fibroblasts demonstrated decreased insulin receptor autophosphorylation. Conclusion: Treatment with rhIGF-I partially reversed severe progressive HOCM and renal tubular dysfunction in a patient with Donohue syndrome associated with a novel p.Leu795Pro INSR gene mutation causing a severe decrease in IR autophosphorylation.     

Severe neonatal mitochondrial cytopathy caused by isolated COX defect

We report a neonate with isolated cytochrome c oxidase (COX) defect and severe multisystemic involvement. The patient had severe encephalopathy, predominant since birth, and died due to hypoxic-ischemic myocardiopathy. He was the second son of non-consanguineous, healthy parents who also had a daughter with chronic encephalopathy. The neonate presented dysmorphic phenotype, hepatic and muscular involvement, and possibly tubular involvement. Metabolic studies revealed markedly increased lactic/pyruvic concentrations. Diagnosis was based on muscular enzymatic studies and ultrastructural mitochondrial anomalies, while the mitochondrial DNA and results of the COX technique were normal. Histological examination revealed a massive subendocardial infarction. Aspects of this entity with relevance for genetic counseling are discussed.     

Atypical varicella zoster infection associated with hemophagocytic lymphohistiocytosis

Two adolescents, on immunosuppressive therapy for graft‐versus‐host disease, developed hemophagocytic lymphohistiocytosis (HLH) after varicella zoster virus (VZV) reactivation. In the absence of dermatome restricted characteristic skin lesions, VZV reactivation was not immediately recognized and treatment with acyclovir was delayed. The first patient developed optical neuritis and died 2 months after the VZV episode due to massive intracranial hemorrhage. The second patient presented with severe abdominal pain and pancreatitis, followed by atypical skin eruptions, which prompted a faster diagnosis. Both patients recovered from their HLH, the first patient being successfully treated with immunosuppressive agents and the second with VZV treatment only. These two cases demonstrate the difficulties in recognizing VZV reactivation, and in order to start adequate and timely treatment, the need to consider VZV as a possible cause of HLH in severely immunocompromised patients. Pediatr Blood Cancer 2009;53:226–228. © 2009 Wiley‐Liss, Inc.     

Severe gastric variceal bleeding successfully treated by emergency splenic artery embolization

Bleeding from gastric varices due to splenic vein obstruction is extremely rare in children, but it can be catastrophic. Reported herein is the case of a teenager with splenic vein thrombosis and chronic decompensated liver disease from autoimmune hepatitis who presented with massive gastric variceal bleeding. Standard medical management did not control the bleeding. Due to decompensated liver disease and continuous active bleeding, emergency partial splenic artery embolization was preferred over splenectomy or a shunt procedure. Bleeding was successfully controlled by partial splenic artery embolization by decreasing the inflow of blood into the portal system. It is concluded that emergency partial splenic artery embolization is a safer alternative life‐saving procedure to manage severe gastric variceal bleeding due to splenic vein obstruction in a patient with high surgical risk. To our knowledge, only one other patient with similar management has been reported in the pediatric age group.     

Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II

The carbohydrate deficient glycoprotein (CDG) syndromes are a family of genetic multisystemic disorders with severe nervous system involvement. This report is on a child with a CDG syndrome that differs from the classical picture but is very similar to a patient reported in 1991. Both these patients are therefore designated CDG syndrome type II. Compared with type I patients they have a more severe psychomotor retardation but no peripheral neuropathy nor cerebellar hypoplasia. The serum transferrin isoform pattern obtained by isoelectric focusing showed disialotransferrin as the major fraction. The serum disialotransferrin, studied in the present patient, contained two moles of truncated monoantennary Sialyl-Gal-GlcNAc-Man(alpha 1-->3)[Man(alpha 1-->6)]Man(beta 1-->4)GlcNAc (beta 1-->4)GlcNAc-Asn per mole of transferrin. A profoundly deficient activity of the Golgi enzyme N-acetylglucosaminyltransferase II (EC 2.4.1.143) was demonstrated in fibroblasts.     

3-Methylglutaconic and 3-methylglutaric aciduria in a patient with suspected 3-methylglutaconyl-CoA hydratase deficiency

A girl suffering from marked muscular hypotonia, severe statomotor and mental retardation, bilateral optic atrophy with chorioretinal degeneration, convulsions and a moderate compensated metabolic acidosis is described. Screening for metabolic disorders revealed massive 3-methylglutaconic with 3-methylglutaric aciduria leading to the tentative diagnosis of 3-methylglutaconyl-CoA hydratase deficiency. Metabolite excretion was correlated with variation of leucine intake. 3-methyl-3-hydroxyglutaryl-CoA lyase activity in cultured fibroblasts was normal. The suspected metabolic defect was not demonstrable in cultured skin fibroblasts, however.Abbreviation MSUD Maple syrup urine disease     

Partial 3-methylcrotonyl-CoA carboxylase deficiency in an infant with fatal outcome due to progressive respiratory failure

Isolated partial 3-methylcrotonyl-CoA carboxylase (MCC) deficiency has been described to be the cause for a distinct relatively mild clinical picture in a single patient. We describe another patient with isolated partial MCC deficiency who suffered from failure to thrive, muscular hypotonia and progressive respiratory insufficiency with fatal outcome at the age of 6.5 months. MCC deficiency was suspected at 3 months of age on the basis of mildly elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine and confirmed by enzyme analysis in lymphocyte and fibroblast homogenates. Residual MCC activity in lymphocytes was 25% of the mean normal value. Residual activity in fibroblasts was lower than in lymphocytes (3.8% of mean normal) and not significantly different from that in patients with complete MCC deficiency. However, the residual incorporation of ¹⁴C-isovalerate into macromolecules in intact fibroblasts, was clearly higher (28% of mean normal) than in fibroblasts with complete MCC deficiency (<4%). In both patients with partial deficiency the residual MCC activity was higher in lymphocytes than in fibroblasts. Clinical symptoms and signs in our patient attributable to MCC deficiency include muscular hypotonia, failure to thrive (already present at birth), progressive respiratory failure due to diaphragmatic paresis and a moderate brain atrophy. The clinical presentation was more severe than in many patients with complete MCC deficiency. Dietary therapy was biochemically effective as shown by normalization of organic acid excretion, however, had no effect on the CNS symptoms. Conclusion We speculate that the severity of the disease could be related primarily to deficiency of MCC activity in the brain. Variable MCC activity among various organs may explain the peculiar clinical picture in this patient. Received: 14 April 1997 and in revised form: 16 June 1997 / Accepted: 22 August 1997     

Absence of a serum factor in patients with cystic fibrosis.

A serum factor was demonstrated in normal individuals which (1) enhances the incorporation of L-[3H]fucose into cultured human skin fibroblasts, (2) is nondialyzable, (3) is heat labile at 50 degrees, (4) is present in the noneuglobulin fraction, and (5) appears to be deficient in serum from patients with cystic fibrosis. The specific activity of L-[3H]fucose incorporated into skin fibroblasts from normal individuals in the presence of serum from 12 control subjects was 3,337 +/- 168 cpm/mg protein in contrast to 2,294 +/- 172, the activity obtained either in the presence of serum from 10 age-matched patients with cystic fibrosis or in the absence of serum. These differences were significant at P less than 0.001. In comparison, no significant difference was detected in the amount of L-[3H]fucose incorporated into skin fibroblasts derived from normal individuals and patients with cystic fibrosis. The plasma membrane of cultured skin fibroblasts derived from patients with cystic fibrosis appears to be grossly unaltered in its protein and L-fucose labeling pattern.     

Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II.

The carbohydrate deficient glycoprotein (CDG) syndromes are a family of genetic multisystemic disorders with severe nervous system involvement. This report is on a child with a CDG syndrome that differs from the classical picture but is very similar to a patient reported in 1991. Both these patients are therefore designated CDG syndrome type II. Compared with type I patients they have a more severe psychomotor retardation but no peripheral neuropathy nor cerebellar hypoplasia. The serum transferrin isoform pattern obtained by isoelectric focusing showed disialotransferrin as the major fraction. The serum disialotransferrin, studied in the present patient, contained two moles of truncated monoantennary Sialyl-Gal-GlcNAc-Man(alpha 1-->3)[Man(alpha 1-->6)]Man(beta 1-->4)GlcNAc (beta 1-->4)GlcNAc-Asn per mole of transferrin. A profoundly deficient activity of the Golgi enzyme N-acetylglucosaminyltransferase II (EC 2.4.1.143) was demonstrated in fibroblasts.     

Combined heterotopic liver–pancreas transplantation as a curative treatment for liver cirrhosis and diabetes mellitus in cystic fibrosis

Cystic fibrosis (CF) is an inherited disease with a defect in epithelial chloride transport that results in a multisystem disease. Although pulmonary disease remains the primary cause of morbidity and mortality, focal biliary cirrhosis and portal hypertension may develop in up to 8% of these patients. Liver transplantation (TX) is an accepted therapy and shows good results. We report on a patient with cystic fibrosis homozygous for the most common CFTR mutation delta F 508 who received a combined heterotopic liver and pancreas transplantation at the age of 18 yr. He suffered from CFRD, which untypically required high doses of insulin. In addition, the patient had pulmonary complications, was chronically colonized with multiresistant Pseudomonas aeruginosa (MBL) and had an allergic bronchopulmonary aspergillosis (ABPA). The patient remained in stable health for 54 months post‐TX and was able to live a nearly normal life. With a follow‐up of five yr, the function of the liver and pancreas allografts was excellent. However, and sadly, his pulmonary function continued to deteriorate from progression of his CF, and he died of respiratory failure due to a severe pneumonia and septicemia at the age of 23 yr and five months.     

Pancreatic agenesis as cause for neonatal diabetes mellitus

BACKGROUND: Pancreatic agenesis is a rare cause of neonatal diabetes mellitus and the knowledge about the clinical features is sparse. A patient with pancreatic agenesis and double outlet right ventricle is reported. This association has not previously been reported. In addition a synopsis of the patients (n = 14) with pancreatic agenesis who have hitherto been described is given. METHOD: We studied one patient and obtained information on 13 additional patients with pancreatic agenesis by reviewing literature. RESULTS: Literature review: In one patient the pregnancy was terminated at 19 weeks. 31 % (4/13) of the infants died in the first week and 69 % (9/13) in the first six weeks of live, 17 % (2/12) were born preterm and 83 % (10/12) at term, 93 % (13/14) had severe intrauterine growth restriction, onset of diabetes was in 6 out of 10 infants during the first two days of live, ketonuria is rare and has been reported only once. 64 % (9/14) of the infants with pancreatic agenesis had additional malformations mainly of the biliary system (50 %) and/or the heart (36 %). 31 % (4/13) of the infants survived the neonatal period and developed normally. Failure to thrive was compensated by catch-up growth after replacement of pancreatic enzymes and surgical correction of the cardiac malformation. CONCLUSIONS: Pancreatic agenesis is a clinical entity characterized by severe intrauterine growth retardation, early onset of permanent neonatal diabetes mellitus without ketoacidosis, failure to thrive due to pancreatic exocrine dysfunction and associated malformations mainly of the biliary system or of the heart. Because of the high neonatal mortality, awareness of pancreatic agenesis as a possible cause of severe intrauterine growth restriction is important for the optimal treatment of diabetes mellitus, exocrine pancreatic insufficiency and the associated malformations.     

Familial hemophagocytic lymphohistiocytosis (case report)

This is the report of a female infant ten weeks of age, who was admitted to our hospital with hyperpyrexia, hemolytic anemia and disseminated intravascular coagulation. The further course of the disease was characterized by: continuing hemolysis resulting in severe normochromic, normocytic anemia, unrelenting disseminated intravascular coagulation, increasing hepato-splenomegaly with hyperbilirubinemia and ascites. No causative infectious organism could be identified. The infant died at the age of 14 weeks from respiratory insufficiency. Autopsy revealed massive hepato-splenomegaly, ascites and bilateral pneumonia. Histologic evaluation demonstrated lymphohistiocytic infiltrates of the periportal areas of the liver, the spleen and lymphnodes. Meninges were infiltered by macrophages with ingested erythrocytes. Differential diagnosis includes an infection with leptospira icterohemorrhagica (Weils disease) and erythrophagocytosis observed after various viral infections. Also histiocytosis X or malignant histiocytosis has to be taken into consideration. The most probable diagnosis in our patient is that of familiar hemophagocytic reticulosis although the familiarity in our patient was lacking. Intra vitam diagnosis can only be established by liver biopsy which could not be performed in our patient due to the severe coagulation disturbance.