trypsinogen and Syndrome

To evaluate the role of serum enzymes for defining the pancreatic phenotype in Shwachman-Diamond syndrome (SDS), an inherited multisystem condition.. Serum pancreatic trypsinogen and isoamylase were measured in 164 patients known or presumed to have SDS. The diagnosis was confirmed in 90 patients. Among 74 unconfirmed cases, 35 ("probable SDS") had hematologic dysfunction but lacked documented pancreatic dysfunction, whereas 39 patients ("improbable SDS") lacked both documented pancreatic and hematologic dysfunction. Classification and regression tree (CART) analysis was performed in 90 patients with SDS and 134 control patients to establish a rule for defining the pancreatic phenotype of SDS; the rule was then applied to the patients with unconfirmed diagnosis.. In the control patients, serum trypsinogen showed little variation with age, whereas serum isoamylase values rose from birth on, attaining adult values by 3 years. For patients with SDS, serum trypsinogen values were low in young patients and tended to increase with age, whereas serum isoamylase values remained low at all ages. The CART rule combined results from both enzymes and classified the pancreatic phenotype in all but one SDS patient, who was <3 years of age. Excluding patients <3 years of age, CART identified the pancreatic phenotype in 82% and 7% of the "probable SDS" and "improbable SDS" cases, respectively.. Serum pancreatic enzymes are useful for determining the pancreatic phenotype and confirming the diagnosis of SDS.

Topics: Abnormalities, Multiple; Adolescent; Adult; Biomarkers; Child; Child Welfare; Child, Preschool; Chromosome Aberrations; Chromosomes, Human, Pair 7; Clinical Laboratory Techniques; Exocrine Pancreatic Insufficiency; Female; Hematologic Diseases; Humans; Infant; Infant Welfare; Intracranial Hemorrhages; Isoamylase; Male; Pancreas; Phenotype; Retrospective Studies; Syndrome; Trypsinogen

Through early detection, newborn screening (NBS)(1) for cystic fibrosis (CF) offers the opportunity for early intervention and improved outcomes. NBS programs screen for hypertrypsinogenemia, and most also identify mutations in the CF transmembrane conductance regulator (CFTR) gene. Individuals identified by NBS are diagnosed with CF if they have an elevated sweat chloride level or if they have inherited 2 disease-causing mutations in the CFTR gene. Mutations in the CFTR gene can cause CF, but not all CFTR mutations are disease-causing. The term CFTR-related metabolic syndrome (CRMS) is proposed to describe infants identified by hypertrypsinogenemia on NBS who have sweat chloride values <60 mmol/L and up to 2 CFTR mutations, at least 1 of which is not clearly categorized as a "CF-causing mutation," thus they do not meet CF Foundation guidelines for the diagnosis of CF. With what is now near-universal CF NBS in the United States, an increasing number of infants with CRMS are being identified. Given our inadequate knowledge of the natural history of CRMS, standards for diagnosis, monitoring, and treatment are absent. This document aims to help guide the monitoring and care of individuals with CRMS while our knowledge base on appropriate management evolves.

Topics: Adult; Age Factors; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Infant; Infant, Newborn; Metabolic Diseases; Syndrome; Trypsinogen

The aim of this study was to determine whether mutations in SPINK1/PRSS1 genes are associated with benign pancreatic hyperenzymemia (BPH).. Sixty-eight subjects with BPH (including 13 familial cases) were studied. In all, we sequenced germline DNA for all the exons and intro-exon boundaries of PRSS1 and SPINK1.. Nine (13.2%) of the 68 subjects harbored PRSS1 or SPINK1 mutations. As to PRSS1, no hereditary pancreatitis-associated variant was detected, whereas previously undescribed mutations (p.Ala148Val and c.40+1G>A) were respectively found in 2 subjects (2.9%). SPINK1 mutations were detected in 7 subjects (10.3%). Five of them exhibited known mutations (3 p.Asn34Ser, 1 p.Pro55Ser, and 1 c.88-23A>T), whereas 2 had a newly found variant (p.Arg67Gly and c.*32C>T, respectively). Only 2 familial BPH, belonging to 2 different families, were found to carry a mutation (1 with p.Ala148Val for PRSS1 and 1 with p.Asn34Ser for SPINK1).. No known mutations of PRSS1 have been found in BPH, whereas the frequency of known SPINK1 variants is similar to that reported in the general population. No segregation of PRSS1/SPINK1 variants occurs in BPH families. Benign pancreatic hyperenzymemia cannot be explained by mutations in genes whose variants are known to be associated with pancreatitis or by mutations in other PRSS1/SPINK1 genes.

Topics: Adolescent; Adult; Aged; Amylases; Base Sequence; Carrier Proteins; Child; Exons; Female; Genetic Predisposition to Disease; Humans; Introns; Isoamylase; Lipase; Male; Middle Aged; Molecular Sequence Data; Mutation; Pancreas; Pancreatic Diseases; Pancreatitis; Syndrome; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be consistent with the general population. We determined estimates of segregation proportion in a cohort of 84 patients with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All three estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. Although there are no overt signs of disease in adult carriers (parents), the use of serum trypsinogen levels to indicate exocrine pancreatic dysfunction was evaluated as a potential measure for heterozygote expression. No consistent differences were found in levels between parents and a normal control population. Although genetic heterogeneity cannot be excluded, our results indicate that simulation and genetic analyses of Shwachman-Diamond syndrome should consider a recessive model of inheritance.

Topics: Abnormalities, Multiple; Adolescent; Adult; Algorithms; Child; Child, Preschool; Cohort Studies; Computer Simulation; Exocrine Pancreatic Insufficiency; Family Health; Female; Genes, Recessive; Genetic Heterogeneity; Hematologic Diseases; Heterozygote; Humans; Infant; Male; Models, Genetic; Paternal Age; Phenotype; Syndrome; Trypsinogen

With the use of clinical data from a large international cohort, we evaluated and compared affected siblings and isolated cases.. Data from 116 families were collected, and patients conforming to our predetermined diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings and singletons were compared with the use of t tests, Wilcoxon scores, and chi2 analysis.. Eighty-eight patients (33 female, 55 male; median age 5.20 years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63 patients were isolated cases, and 25 affected siblings were from 12 multiplex families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed a low serum trypsinogen concentration. Patients older than 4 years more often had pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were reported in 7 patients. Short stature with normal nutritional status was a prominent feature.. Clinical features among patients with Shwachman syndrome varied between patients and with age. Similarities in phenotype between isolated cases and affected sibling sets support the hypothesis that Shwachman syndrome is a single disease entity.

Topics: Bacterial Infections; Bone Diseases, Developmental; Celiac Disease; Child; Child, Preschool; Cohort Studies; Exocrine Pancreatic Insufficiency; Female; Growth Disorders; Hematologic Diseases; Hepatomegaly; Humans; Infant; Infant, Newborn; Male; Neutropenia; Nuclear Family; Phenotype; Statistics, Nonparametric; Syndrome; Trypsinogen

We compared pancreatic acinar and ductal secretion in two patients with Johanson-Blizzard syndrome, age-matched control subjects, and patients with other primary pancreatic diseases. Patients with Johanson-Blizzard syndrome had preservation of ductular output of fluid and electrolytes, as in patients with Shwachman syndrome but differing from those with cystic fibrosis, who have a primary ductular defect. They also had decreased acinar secretion of trypsin, colipase and total lipase, and low serum immunoreactive trypsinogen levels, consistent with a primary acinar cell defect.

Topics: Case-Control Studies; Colipases; Consanguinity; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Female; Humans; Infant; Infant, Newborn; Lipase; Malabsorption Syndromes; Male; Pancreas; Pancreatic Diseases; Pancreatic Ducts; Syndrome; Trypsin; Trypsinogen

Topics: Chromosomes, Human, Pair 13; Cystic Fibrosis; False Positive Reactions; Genetic Testing; Humans; Male; Syndrome; Trisomy; Trypsinogen

Plasma immunoreactive cationic trypsin(ogen) levels were determined in 32 control subjects and 43 patients with varying degrees of pancreatic insufficiency including 35 with cystic fibrosis (CF) and eight with Shwachman's syndrome. In six CF infants less than 2 years of age, plasma trypsin(ogen) levels were significantly elevated (97.3 +/- 62.2 ng/ml) above the normal range for nine controls (7.0 +/- 5.9 ng/ml; P less than 0.025). Four of these infants had steatorrhea, three of whom had undetectable duodenal trypsin activity after stimulation with secretin-cholecystokinin. In two CF infants, molecular size fractionation by gel filtration of plasma followed by radioimmunoassay of the column fractions demonstrated that trypsinogen was the only immunoreactive species in the circulation. In contrast, in older CF patients with steatorrhea (mean age, 15.3 +/- 4.6 years), plasma cationic trypsin(ogen) levels were undetectable or low (1.1 +/- 1.7 ng/ml). This finding clearly distinguished them from older CF patients without steatorrhea (mean age, 14.3 +/- 3.9 years) in whom cationic trypsin(ogen) levels were significantly higher (23.3 +/- 17.6 ng/ml; P less than 0.01). The mean trypsin(ogen) concentration in the older CF patients without steatorrhea did not differ from the mean value for 23 normal subjects of similar age. Plasma cationic trypsin(ogen) levels in two Schwachman's patients with steatorrhea (0.19 and 0.86 ng/ml) were significantly lower than the values found in six Shwachman's patients without steatorrhea (5.9 +/- 2.3 ng/ml; P less than 0.025). Furthermore, in nine older CF patients and eight Schwachman's patients, circulating trypsin(ogen) levels were highly correlated with duodenal trypsin output after secretin-cholecystokinin stimulation (r = 0.946, P less than 0.01; r = 0.899, P less than 0.01, respectively). These results suggest that in CF infants high levels of circulating trypsin(ogen) persist even in those with Shwachman's syndrome, however, circulating trypsin(ogen) accurately reflects residual pancreatic function.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Female; Humans; Infant; Male; Radioimmunoassay; Syndrome; Trypsin; Trypsinogen

Topics: Amylases; Child; Cystic Fibrosis; Enteropeptidase; Humans; Infant; Methods; Neutropenia; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Peptide Hydrolases; Syndrome; Trypsinogen