Behçet's disease and cerebral sinus vein thrombosis in children: a case study and review of the literature.

OBJECTIVES: Central nervous system (CNS) involvement, one of the most severe manifestations of Behçet's disease (BD), is uncommon in children. Because it is rare, the clinical features of this disease in children are not well characterised. Here we describe a teenager with BD which was disclosed following an episode of cerebral sinus vein thrombosis (CSVT) and review the available literature on children with CSVT associated with BD. METHODS: A 12-year-old boy who presented with CSVT is described and the relevant literature, based on a Medline search from 1966 to January 2015 is reviewed. RESULTS: Twenty-three well-documented reports of children with CSVT and BD are described. This manifestation affected mainly males (61%) with a mean age of 12 years (range 4-18). BD was first diagnosed simultaneously or following CSVT in the majority of cases (75%). Multiple sinuses were involved in 30% of the cases. Thrombosis of additional large vessel was identified in 5 of the 23 children. The most common presenting symptom and signs were headache (91%), lasting more than 3 days in most cases (75%), followed by papilledema (43%), seizures (17%), and personality changes (9%). A mixed pattern of CNS involvement including both parenchymal involvement and CSVT, was demonstrated in only two patients (9%). Management of CSVT differed between reports. CONCLUSIONS: CSVT in children is a rarely reported manifestation of BD and has a characteristic clinical picture of a teenage boy presenting with prolonged headache, with no previous diagnosis of BD. A therapeutic approach has not been established yet.

Two novel mutations identified in familial cases with Donohue syndrome.

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype-phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.

A dominant negative heterozygous G87R mutation in the zinc transporter, ZnT-2 (SLC30A2), results in transient neonatal zinc deficiency.

Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation.

Cellular and clinical report of new Griscelli syndrome type III cases.

The RAB27A/Melanophilin/Myosin-5a tripartite protein complex is required for capturing mature melanosomes in the peripheral actin network of melanocytes for subsequent transfer to keratinocytes. Mutations in any one member of this tripartite complex cause three forms of Griscelli syndrome (GS), each with distinct clinical features but with a similar cellular phenotype. To date, only one case of GS type III (GSIII), caused by mutations in the Melanophilin (MLPH) gene, has been reported. Here, we report seven new cases of GSIII in three distinct Arab pedigrees. All affected individuals carried a homozygous missense mutation (c.102C>T; p.R35W), located in the conserved Slp homology domain of MLPH, and had hypomelanosis of the skin and hair. We report the first cellular studies on GSIII melanocytes, which demonstrated that MLPH(R35W) causes perinuclear aggregation of melanosomes in melanocytes, typical for GS. Additionally, co-immunoprecipitation assays showed that MLPH(R35W) lost its interaction with RAB27A, indicating pathogenicity of the R35W mutation.

Idiopathic pancreatitis preceding the diagnosis of inflammatory bowel disease is more frequent in pediatric patients.

BACKGROUND AND OBJECTIVES: Acute pancreatitis (AP) can be a rare extraintestinal manifestation of inflammatory bowel disease (IBD). There are only a few reports of AP presenting before the diagnosis of IBD. We aimed to characterize the demographic, clinical, and laboratory data of patients with IBD in whom AP preceded disease onset and compare the presentation of AP between children and adults. PATIENTS AND METHODS: Pediatric and adult patients presenting with AP as the first symptom of IBD were retrospectively identified (10 years, 7 university hospitals). Demographic and clinical data, IBD type, disease extension, and laboratory data were extracted from the charts. Imaging methods, number of AP episodes, and lag time between onset of first pancreatitis episode and onset of IBD were recorded. RESULTS: AP preceding the diagnosis of IBD was found in 10 in 460 pediatric patients with IBD (2.17%), compared with only 2 in 3500 adults (0.06%). Eight children had colonic disease (4 Crohn disease, 4 ulcerative colitis [3 pancolitis]). Mean amylase level was 1419 and range 100 to 1370. Three children (30%) had mildly elevated transaminases. Median time between onset of first episode of AP in relation to onset of IBD was 24 (range 1-156) weeks. AP most commonly presented with abdominal pain. CONCLUSIONS: IBD presenting as AP was more frequent among the pediatric population with IBD in comparison to adults. It was more common in patients with colitis than in those with ileal disease, suggesting that patients with idiopathic AP should be observed carefully for a possible diagnosis of IBD.

Prolidase deficiency: it looks like systemic lupus erythematosus but it is not.

Three siblings with recalcitrant leg ulceration, splenomegaly, photosensitive rash, and autoantibodies were suspected of having prolidase deficiency. Urine was checked for iminodipeptiduria, fibroblasts were cultured and analyzed for prolidase activity, and DNA was extracted for identifying the causative mutation. Glycyl proline was found as the dominant dipeptide in the urine. The activity of proline dipeptidase in fibroblasts was 2.5% of control fibroblasts. Sequence analysis of the PEPD gene revealed a homozygous nonsense C-->G transition at nucleotide 768. In conclusion, prolidase deficiency was diagnosed in siblings with skin ulceration autoantibodies and a lupus-like disease. A novel nonsense mutation was found, associated with the severe outcome of our patients.

Cystic fibrosis transmembrane conductance regulator ion channel function testing in recurrent acute pancreatitis.

GOALS: To understand the relationship between acute recurrent pancreatitis and cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. BACKGROUND: An emerging number of patients present with a nonclassic phenotype of cystic fibrosis (CF) with partial features or single-organ disease only. The association between the phenotype of recurrent pancreatitis CFTR dysfunction is unclear. METHODS: Patients with idiopathic recurrent pancreatitis were referred for electrophysiologic investigation. RESULTS: Thirty-three patients (18 males) aged 20+/-12 years with recurrent pancreatitis were studied. Three patients had mild asthma and 1 patient had mild ulcerative colitis. There was no family history of CF. All patients had normal imaging of the pancreatic duct by endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. No patient was pancreatic insufficient. Mean sweat chloride values were 41+/-14 meq/L (range: 18 to 64). Nasal potential difference (NPD) measurement was pathologic in 7 patients. Mean basal potential difference in these 7 patients was -33+/-13 mV and there was an abnormal response to chloride-free and isoproterenol solutions. There was no difference in sweat chloride concentration between the 2 groups. Mutation analysis revealed W1282X/5T, D1152H/5T, and W1282X/- in 3 patients with abnormal NPD and 1 W1282X allele was found in 1 patient with normal NPD. CONCLUSIONS: In this series, 21% of patients with recurrent pancreatitis have abnormalities of CFTR function. Patients presenting with recurrent, "idiopathic" pancreatitis require CFTR function testing.

Peritoneal adhesions and intestinal obstructions in patients with familial Mediterranean fever--are they more frequent?

OBJECTIVE: Familial Mediterranean fever (FMF) is characterized by recurrent episodes of peritonitis. A controversy exists as to whether intestinal obstruction due to peritoneal adhesions is more common among FMF patients compared with healthy controls. The aim of the study was to estimate the rate of spontaneous or postsurgical small-bowel obstruction (SBO) in FMF patients. METHODS: We reviewed the charts of 560 FMF patients followed in our clinic for the occurrence of spontaneous SBO. We also assessed the occurrence of postappendectomy intestinal obstruction among 89 FMF patients compared with 417 individuals without FMF who underwent an appendectomy without other abdominal surgery in the same medical center. RESULTS: Ten of 471 FMF patients (2.1%) developed spontaneous SBO, 8 of whom required laparotomy and adhesiolysis. Six of 89 FMF patients (6.7%) who underwent appendectomy developed SBO. None of the non-FMF patients developed SBO. CONCLUSIONS: Our retrospective study showed that FMF patients are at a higher risk than healthy individuals for developing SBO either spontaneously or as a postsurgical complication. Physicians should be alert to this possible complication when FMF patients arrive at the emergency room.

Investigation of unexplained infant deaths in Jerusalem, Israel 1996-2003.

BACKGROUND: Sudden infant death syndrome (SIDS) is a diagnosis of exclusion that may be assigned only after investigations including a forensic autopsy are performed to exclude possible organic and environmental causes of death. Israeli society is influenced by the Jewish and Islamic faiths, which permit autopsy only under selected circumstances. Against this background, we carried out a study to determine what examinations are performed to investigate unexplained infant deaths in Jerusalem, Israel. METHODS: We examined hospital, Ministry of Health and Ministry of Interior records of unexplained infant deaths in the Jerusalem district from the years 1996-2003. RESULTS: Ninety six cases were identified from all sources. Forty nine (51%) infants were brought to a hospital at or near the time of death. Studies to determine the cause of death were performed in 54% of cases for which medical records were available for review. These studies included bacterial cultures (44%), skeletal surveys (12%), computerised tomography (3%) and metabolic studies (3%). Only one forensic autopsy was performed, and in no instance was the death site examined by medical personnel. There was a high rate of retrospective review by district health physicians. The most frequently assigned cause of death was SIDS. CONCLUSIONS: : The capacity of public health officials and forensic pathologists to investigate unexplained infant deaths is strongly affected by the legal, religious and political milieu in which they work. Efforts should be made to develop socially acceptable methods of improving the quality of infant death investigations in Jerusalem.

Changes in reducing power profile of gastric juice in patients with active duodenal ulcer.

Reactive oxygen species have been postulated to play a role in the pathogenesis of mucosal GI injury and in peptic ulcer disease (PUD). The low molecular weight antioxidants (LMWA) group plays an important role in the defense mechanism of the GI tract against oxidative damage, and is a major component of the reducing capacity of biological tissues and fluids. We hypothesized that altered gastric LMWA anti oxidative status might play a role in the pathogenesis of upper GI disorders such as PUD and could be evaluated by measuring gastric juice reducing power. The aim of the present study was to determine, by cyclic voltammetry, changes in the overall antioxidant activity of the gastric juice in active duodenal ulcer (DU) obtained during upper endoscopy from patients as compared with normal subjects. The results show that in 28/37 (76%) of the control subjects, gastric juice demonstrated a reducing power of at least two anodic waves indicating at least two different LMWA groups. Three or more anodic waves were recorded in 12 normal subject (32%). In contrast, 16/25 (64%) of gastric juice samples obtained from active DU patients exhibited only one anodic wave usually at a high potential (>900 mV). These results imply that gastric juice normally possesses a reducing power profile that can be determined by cyclic voltammetry. This profile is significantly changed in untreated DU disease. These changes in active DU may indicate decreased gastric antioxidant activity reflecting reduced mucosal protection that leading to increased susceptibility of the gastro-duodenum to injury.

Atrial natriuretic peptide in children with pneumonia.

Atrial natriuretic peptide (ANP) has known natriuretic, diuretic, and vasodilatatory effects. It is synthesized and stored in the atrial cells. Stretching of the atrial muscle fibers during an increase in venous return sets a response of ANP release into the blood stream. High levels of ANP were measured in a number of lung diseases. Pneumonia in children is frequently accompanied by the hyponatremia of the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH). High levels of ANP were found among patients with SIADH. Our objective was to determine if ANP plasma levels are altered in children with pneumonia, and to evaluate a possible correlation between severity of pneumonia and ANP levels. Blood samples from 28 children diagnosed with pneumonia were collected. Plasma ANP levels were determined by radioimmunoassay and compared to levels in 25 children without pneumonia. ANP levels in the pneumonia group (mean +/- SD, 16.02 +/- 11.69 pg/ml) increased significantly (P < 0.01) compared to levels in the control group (mean +/- SD, 7.44 +/- 9.29 pg/ml). Children in the pneumonia group also exhibited low levels of plasma sodium (mean +/- SD, 134.88 +/- 2.5 mmol/l) compared to levels in children without pneumonia (mean +/- SD, 139.77 +/- 4.15 mmol/l) (P < 0.01). There was no correlation between ANP plasma levels and severity of pneumonia. In conclusion, ANP levels in children with pneumonia, as in other lung diseases, are increased. High ANP levels may play a role in maintaining water and electrolyte equilibrium during a state of inappropriate ADH secretion accompanying pneumonia.

Sludge ball, pseudolithiasis, cholelithiasis and choledocholithiasis from intrauterine life to 2 years: a 13-year follow-up.

OBJECTIVE: Evaluation and follow-up of infants with cholelithiasis and pseudolithiasis in a pediatric ward. PATIENTS & METHODS: Prospective study from April 1990 to October 2003 identified hospitalized infants younger than 2 years with ultrasonographic findings of cholelithiasis, choledocholithiasis or pseudolithiasis. Associated abnormalities or contributory factors were recorded and patients were followed for from 6 months to 13 years (mean, 4 years). RESULTS: Thirty-four patients were diagnosed between the age of 3 weeks and 24 months. Thirteen (38%) had been treated with third-generation cephalosporins. Other associated factors were dehydration in 10 (29%), urinary tract infection in two (6%) and one each for cholestatic liver disease, total parenteral nutrition, immunoglobulin A deficiency and prematurity. Six infants (17%) had no known risk factor. Six additional patients were diagnosed by antenatal ultrasound. CONCLUSIONS: Cholelithiasis in infants hospitalized for a variety of common pediatric conditions is not rare. Dehydration and treatment with third-generation cephalosporins are important associated factors. The classic risk factors of hemolysis and previous gastrointestinal surgery, were not found in our group. The overall prognosis was good. Pseudolithiasis disappeared in all infants. Of the 21 infants with cholelithiasis, only two developed cholecystitis. In nine infants, spontaneous resolution occurred. In the absence of other clinical or imaging evidence of biliary tract disease, conservative management is advised.

Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

Intestinal protein loss and hypoalbuminemia in children with pneumonia.

BACKGROUND: Intestinal protein loss has been reported mainly in diseases affecting the gastrointestinal tract. Intestinal protein loss during pneumonia with effusion has not been reported to date. The authors attempted to assess the associations between pneumonia with effusion and intestinal protein loss and hypoalbuminemia in children. METHODS: This was a prospective consecutive case series study of in children hospitalized with pneumonia and effusion during a period of 4(1/2) years. Serum albumin, C-reactive protein (CRP), and fecal alpha-1 antitrypsin (alpha-1-AT) were measured in the first 72 hours of hospitalization. Two control groups were studied: one consisted of 50 febrile children hospitalized because of viral or mild bacterial infections, and the other consisted of 20 afebrile children hospitalized because of convulsive disorders. RESULTS: Sixty-seven children ages 4 months to 14 years hospitalized with pneumonia and effusion were enrolled in the study. Fifty-nine percent (40 children) were found to have elevated fecal alpha-1-AT excretion (range, 2-10 mg/g) compared with none in the two control groups (P < 0.000).Fifty-two percent (35 children) of the children with pneumonia and effusion had mild to moderate hypoalbuminemia (range, 22-34 g/L). Only one child (2%) in the febrile control group had a low albumin of 34 g/L; none were found in the afebrile control group. The level of fecal alpha-1-AT was inversely correlated with serum albumin level. CONCLUSIONS: Pneumonia with effusion in children is often associated with an intestinal protein loss that can be monitored by measuring gastrointestinal loss of protein, namely fecal alpha-1-AT. In most cases the development of hypoalbuminemia correlates with the development of intestinal protein loss.

Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A.

Griscelli syndrome (GS), a rare autosomal recessive disorder, is characterized by partial albinism, along with immunologic abnormalities or severe neurological impairment or both. Mutations in one of two different genes on chromosome 15q can cause the different subtypes of GS. Most patients with GS display the hemophagocytic syndrome and have mutations in RAB27A, which codes for a small GTPase. Two patients with neurological involvement have mutations in MYO5A, which codes for an actin-based molecular motor. The RAB27A and MYO5A gene products interact with each other and function in vesicle trafficking. We report the molecular basis of GS in a Muslim Arab kindred whose members have extremely variable neurological involvement, along with the hemophagocytic syndrome and immunologic abnormalities. The patients have normal MYO5A genes but exhibit a homozygous 67.5-kb deletion that eliminates RAB27A mRNA and immunocytofluorescence-detectable protein. We also describe the molecular organization of RAB27A and a multiplex polymerase chain reaction assay for the founder deletion in this kindred. Finally, we propose that all patients with GS have RAB27A mutations and immunologic abnormalities that sometimes result in secondary neurological involvement. The two patients described elsewhere who have MYO5A mutations and neurological complications but no immunologic defects may not have GS but instead may have Elejalde syndrome, a condition characterized by mild hypopigmentation and severe, primary neurological abnormalities.