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Biomedical subjects

D A Piccoli

Publications and source records attributed to D A Piccoli.

At least 37 records · Page 2Linked to original sources
PubMed1998

The Alagille's syndrome and its anaesthetic considerations.

Alagille's syndrome is an inherited disorder affecting multiple organ systems. Most characteristic is the paucity of the interlobular bile ducts with cholestasis. The anaesthetic plan for these patients should be based on careful preoperative preparation and attention to the issues involving hepatobiliary, cardiac, neurodevelopmental, nutritional, haematological, ocular and facial abnormalities. We report the case of a five-and-a-half-year old patient with Alagille's syndrome who sustained a pathological fracture of the femur and was scheduled for closed reduction and application of a hip spica cast. Relevant anaesthetic issues are discussed.

Alagille Syndrome↗
PubMed1998

Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.

Alagille syndrome (AGS) is a dominantly inherited disorder characterized by liver disease in combination with heart, skeletal, ocular, facial, renal, and pancreatic abnormalities. We have recently demonstrated that Jagged1 (JAG1) is the AGS gene. JAG1 encodes a ligand in the Notch intercellular signaling pathway. AGS is the first developmental disorder to be associated with this pathway and the first human disorder caused by a Notch ligand. We have screened 54 AGS probands and family members to determine the frequency of mutations in JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis. Of the 35 identified intragenic mutations, all were unique, with the exceptions of a 5-bp deletion in exon 16, seen in two unrelated patients, and a C insertion at base 1618 in exon 9, also seen in two unrelated patients. The 35 intragenic mutations included 9 nonsense mutations (26%); 2 missense mutations (6%); 11 small deletions (31%), 8 small insertions (23%), and 1 complex rearrangement (3%), all leading to frameshifts; and 4 splice-site mutations (11%). The mutations are spread across the coding sequence of the gene within the evolutionarily conserved motifs of the JAG1 protein. There is no phenotypic difference between patients with deletions of the entire JAG1 gene and those with intragenic mutations, which suggests that one mechanism involved in AGS is haploinsufficiency. The two missense mutations occur at the same amino acid residue. The mechanism by which these missense mutations lead to the disease is not yet understood; however, they suggest that mechanisms other than haploinsufficiency may result in the AGS phenotype.

Alagille Syndrome↗
PubMed1997

Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization.

Alagille syndrome is an autosomal dominant disorder comprising cholestasis (associated with intrahepatic bile duct paucity), characteristic facial appearance, and cardiac, ocular and skeletal defects. Multiple patients have been reported with deletions or translocation involving 20p11.23-p12, providing evidence for the localization of the disease gene to this region. Fifty-six Alagille syndrome patients have been studied by cytogenetic and/or molecular analysis to determine the frequency of detectable abnormalities of 20p12. Two of fifty-six patients studied by cytogenetic analysis had abnormalities: an interstitial deletion in one patient and a translocation in another. Of forty-five patients studied by molecular analysis, three were found to have deletions of 20p, including the two patients identified with cytogenetic abnormalities. Molecular and molecular cytogenetic (FISH) analysis of the translocation (46,XX,t(2;20)(q21.3p12)) demonstrated a deletion at the translocation breakpoint. The deletions identified in the three patients are overlapping, contributing to the delineation of an Alagille syndrome critical region within 20p12. This region lies between markers D20S41 and D20S162. The frequency of detectable cytogenetic abnormalities of 20p12 in this group of Alagille patients is 2/56 (3.6%), and the frequency of molecular deletions is 3/45 (6.7%). This is considerably lower than the frequency of deletions observed in contiguous gene deletion syndromes suggesting that Alagille syndrome may be caused by the alteration of a single gene.

Adolescent↗
PubMed1997

Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.

Byler disease (ByD) is an autosomal recessive disorder in which cholestasis of onset in infancy leads to hepatic fibrosis and death. Children who have a clinically similar disorder, but are not members of the Amish kindred in which ByD was described, are said to have Byler syndrome (ByS). Controversy exists as to whether ByD and ByS (subtypes of progressive familial intrahepatic cholestasis [PFIC]) represent one clinicopathological entity. The gene for ByD has been mapped to a 19-cM region of 18q21-q22. PFIC caused by a lesion in this region, including ByD, can be designated PFIC-1. Examination of haplotypes in siblings with ByS in two unrelated non-Amish families showed that the gene(s) responsible for their disorder(s) did not lie in the PFIC-1 candidate region. On light microscopy and transmission electron microscopy (TEM), liver tissue differed between Amish children with PFIC-1, who had coarsely granular bile and at presentation had bland intracanalicular cholestasis, and the children with ByS in the two non-Amish families, who had amorphous or finely filamentous bile and at presentation had neonatal hepatitis. Bile acid composition of bile also differed: In the Amish children with PFIC-1 and in one ByS family, the proportional concentration of chenodeoxycholic acid (CDCA) in bile was low compared with normal bile; in the other ByS family, it was only slightly reduced. Genetic analysis and light microscopy and TEM of liver may help distinguish PFIC-1 from other forms of ByS.

Bile↗
PubMed1997

Vertebral compression fractures in pediatric patients with Crohn's disease.

Osteoporosis is known to be a significant complication of Crohn's disease in adult patients. The association of osteoporosis and the development of vertebral compression fractures is well delineated. This case report describes 5 pediatric patients with Crohn's disease in whom vertebral compression fractures associated with a marked reduction in bone density developed. As in adults, the association of osteoporosis and Crohn's disease in pediatric patients is multifactorial, including corticosteroid use, calcium and vitamin D homeostasis, malnutrition, alteration in sex hormones, and site of disease. At the time of diagnosis of the vertebral fractures, the patients' ages ranged from 10.6 to 16.8 years, they had persistent and severe back pain, and 3 of 5 patients had a decrease in height. They were taking 13.7-41.6 mg/day of corticosteroid, and all 5 patients had terminal ileal involvement. Bone mineral density measured by dual-energy x-ray absorptiometry was well below 2SD from the mean in all patients (z-score, -2.31 to -5.11). Because of the high morbidity and mortality associated with fractures that result from low bone mineral density, medical care of all pediatric patients with Crohn's disease should include an evaluation of bone mineral density.

Adolescent↗
PubMed1997

Chronic intestinal pseudoobstruction associated with fetal alcohol syndrome.

Alcohol acts as a teratogen in the fetus, resulting in prenatal or postnatal growth failure, characteristic facial dysmorphic features, and central nervous system dysfunction. The toxic effects of alcohol on the developing brain are well recognized, but gastrointestinal neuropathy has not been described in fetal alcohol syndrome (FAS). Five children with FAS presented in infancy with signs and symptoms suggestive of chronic intestinal pseudoobstruction. They were not able to sustain adequate caloric intake by mouth, and all required prolonged special methods of alimentation. We performed antroduodenal manometry in these children to determine whether their symptoms were associated with a gastrointestinal motility disorder. All patients had abnormally propagating phase III-like episodes during fasting (retrograde in four, simultaneous in two). Persistent clusters of stationary contractions were a prominent feature in two patients. In utero neurotoxicity of alcohol may not be limited to the central nervous system, but may also cause an enteric neuropathy presenting in infancy as chronic intestinal pseudoobstruction.

Child↗
PubMed1997

Mutations in the human Jagged1 gene are responsible for Alagille syndrome.

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae, as well as a characteristic facial appearance. Identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene of 20p12. We have generated a cloned contig of the critical region and used fluorescent in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region we identified JAG1, the human homologue of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frame-shift mutations, two splice donor mutations and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.

Alagille Syndrome↗
PubMed1997

Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.

Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates. We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome. All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype.

Alagille Syndrome↗
PubMed1997

Alagille syndrome.

Alagille syndrome (OMIM 118450) is an autosomal dominant disorder associated with abnormalities of the liver, heart, eye, skeleton, and a characteristic facial appearance. Also referred to as the Alagille-Watson syndrome, syndromic bile duct paucity, and arteriohepatic dysplasia, it is a significant cause of neonatal jaundice and cholestasis in older children. In the fully expressed syndrome, affected subjects have intrahepatic bile duct paucity and cholestasis, in conjunction with cardiac malformations (most frequently peripheral pulmonary stenosis), ophthalmological abnormalities (typically of the anterior chamber with posterior embryotoxon being the most common), skeletal anomalies (most commonly butterfly vertebrae), and characteristic facial appearance. Inheritance is autosomal dominant, but expressivity is highly variable. Sibs and parents of probands are often found to have mild expression of the presumptive disease gene, with abnormalities of only one or two systems. The frequency of new mutations appears relatively high, estimated at between 15 and 50%. The disease gene has been mapped to chromosome 20 band p12 based on multiple patients described with cytogenetic or molecular rearrangements of this region. However, the frequency of detectable deletions of 20p12 is low (less than 7%). Progress has been made in the molecular definition of an Alagille syndrome critical region within the short arm of chromosome 20. We will review the clinical, genetic, cytogenetic, and molecular findings in this syndrome.

Alagille Syndrome↗
PubMed1997

A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy.

We describe a childhood mitochondrial disorder in which the clinical symptoms began and remained confined to the gastrointestinal (GI) system during the first 4 y. Seizures heralded the onset of progressive encephalopathy at age 7. Peripheral neuropathy, retinitis pigmentosa, and neural deafness developed subsequently. Laboratory investigations disclosed elevated levels of plasma lactate, and a muscle biopsy revealed ragged red fibers lacking cytochrome c oxidase activity and diminished levels of respiratory chain enzyme complexes. Molecular genetic tests failed to show any of the previously reported pathogenic mitochondrial DNA (mtDNA) mutations. We therefore screened the whole mitochondrial genome by coupling restriction digestions with single-strand conformational polymorphism (SSCP) patterns. We identified a unique SSCP in the segment that encompassed the tRNA(Lys) gene, and direct sequencing of this segment revealed a G-->A transition at an evolutionarily conserved nucleotide at mtDNA position 8313. This G8313A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in the white blood cells and platelets from his maternal relatives. This report illustrates how GI symptoms can be the initial manifestation in a mitochondrial disorder and suggests that mitochondrial dysfunction should be considered in differentials of unexplained chronic GI symptoms, especially when lactic acidosis or other unrelated clinical signs or symptoms are present.

Adolescent↗
PubMed1996

Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease.

The classic clinical presentation for type IV glycogen storage disease (branching enzyme deficiency, GSD IV) is hepatosplenomegaly with failure to thrive occurring in the first 18 months of life, followed by progressive liver failure and death by age 5 years. Although there have been two patients without apparent liver progression previously reported, no long-term follow-up clinical data have been available. We present here the clinical spectrum of the non-progressive liver form of GSD IV in four patients, and long-term follow-up of the oldest identified patients (ages 13 and 20 years). None has developed progressive liver cirrhosis, skeletal muscle, cardiac or neurological involvement, and none has been transplanted. Branching enzyme activity was also measured in cultured skin fibroblasts from patients with the classic liver progressive, the early neonatal fatal, and the non-progressive hepatic presentations of GSD IV. The residual branching enzyme activity in the patients without progression was not distinguishable from the other forms and could not be used to predict the clinical course. Our data indicate that GSD IV does not always necessitate hepatic transplantation and that caution should be used when counselling patients regarding the prognosis of GSD IV. Patients should be carefully monitored for evidence of progression before recommending liver transplantation.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1996

Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis.

We report the successful treatment of two patients with chronic, intractable Clostridium difficile infection using whole-bowel irrigation with a polyethylene glycol solution (Golytely) as adjunctive therapy. Before this treatment, both patients had recurrent symptoms of diarrhea, weight loss, abdominal pain, and documented C. difficile toxin-positive stools despite multiple pharmacologic treatments. Each child was prescribed myriad drug therapies, including vancomycin, metronidazole, bacitracin, and rifampin. Cholestyramine and lactobacillus were also tried alone and in combination with antibiotics. In each case, symptoms recurred shortly after cessation of therapy. Whole-bowel irrigation was subsequently administered until profuse, clear liquid stools were produced. This treatment was followed by a 3-week course of oral vancomycin and lactobacillus. In both cases, the patient became asymptomatic within 3 days of therapy; they have remained symptom-free for 36 and 48 months, respectively. We suggest that whole-bowel irrigation clears active C. difficile organisms, toxins, and spores from the intestine and is effective as an adjunct to routine therapy for chronic, relapsing C. difficile infections.

Anti-Bacterial Agents↗
PubMed1995

Intravenous sedation in pediatric upper gastrointestinal endoscopy.

To assess the safety and efficacy of intravenous sedation in pediatric upper endoscopy, all elective outpatient procedures performed during a 2-year period (January 1, 1991 through December 31, 1992) were retrospectively reviewed. Of 614 children, 553 received intravenous meperidine and midazolam; 61 received fentanyl and midazolam. The mean dose of meperidine was 1.5 +/- 0.7 mg/kg and of fentanyl 0.0031 +/- 0.0014 mg/kg. Less midazolam was needed for children receiving fentanyl than for those receiving meperidine (0.05 +/- 0.03 mg/kg versus 0.08 +/- 0.05 mg/kg, p < 002). Recovery time (minutes) was shorter for those receiving fentanyl (74.7 +/- 22.8 versus 95.1 +/- 23.0, p < .003). Side effects occurred in 117 patients (19.1%), of which the majority were mild (83%); all were transient with no residual sequelae. Inability to complete the procedure occurred in fewer than 1%. We conclude that both combinations of medication are safe and effective for children of all ages. The use of fentanyl/midazolam results in a shorter recovery time and a lower dose of midazolam.

Adjuvants, Anesthesia↗
PubMed1995

Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12.

Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome.

Alagille Syndrome↗
PubMed1994

Inflammatory bowel disease in children.

IBD is one of the most significant chronic diseases afflicting children and adolescents. As in adults, UC and CD constitute the two major disease entities, with many of the characteristics of these two diseases being similar in adults and children. With technical advances, a complete endoscopic examination of the colon and terminal ileum can be performed in most children without difficulty. There are, however, a number of aspects of the presentation, course, and management of these diseases that are unique to the pediatric population. Because the impact of inadequate nutrition is much greater in the growing child than in adults, growth failure is a common, serious complication of malnutrition in this population. The psychological impact of a chronic illness on both the developing child and the family can also be significant. The management of this population is further complicated by the lack of adequate studies that assess not only the effect of a medical or surgical therapy on disease activity, but also address the issues of growth and pubertal development. It has been a challenge to extrapolate data from adult studies to the pediatric population. The management of children and adolescents requires a critical understanding of the differences between pediatric and adult patients to maximize growth potential and minimize longterm sequelae of treatment. After a long period of limited controlled studies, however, collaborative efforts are underway to investigate most aspects of pediatric IBD, and we look forward to exciting advances toward the optimal management of children and adolescents with IBD.

Child↗