Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene.

Cranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support an autosomal-recessive inheritance pattern. Aiming at the elucidation of the genetic basis of CED, we collected 13 patients with CED symptoms from 12 independent families. In one family with consanguineous parents two siblings were affected, permitting linkage analysis and homozygosity mapping. This revealed a single region of homozygosity with a significant LOD score (3.57) on chromosome 3q21-3q24. By sequencing candidate genes from this interval we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with the disease. Examination of IFT122 in our patient cohort revealed one additional homozygous missense change in the patient from a second consanguineous family. In addition, we found compound heterozygosity for a donor splice-site change and a missense change in one sporadic patient. All mutations were absent in 340 control chromosomes. Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls. Furthermore, we transiently knocked down ift122 in zebrafish embryos and observed the typical phenotype found in other models of ciliopathies. Because not all of our patients harbored mutations in IFT122, CED seems to be genetically heterogeneous. Still, by identifying CED as a ciliary disorder, our study suggests that the causative mutations in the unresolved cases most likely affect primary cilia function too.

Comparative study of clinical characteristics of amniotic rupture sequence with and without body wall defect: further evidence for separation.

BACKGROUND: Amniotic rupture sequence (ARS) is a disruption sequence presenting with fibrous bands, possibly emerging as a result of amniotic tear in the first trimester of gestation. Our comparative study aims to assess whether there is a difference in the clinical pattern of congenital limb and internal organ anomalies between ARS with body wall defect (ARS-BWD) and ARS without BWD (ARS-L). METHODS: Among 1,706,639 births recorded between 1998 and 2006, 50 infants with a diagnosis of ARS were reported to the Polish Registry of Congenital Malformations. The information on 3 infants was incomplete, thus only 47 cases were analyzed. These infants were classified into groups of ARS-L (38 infants) and ARS-BWD (9 infants). RESULTS: The ARS-BWD cases were more frequently affected by various congenital defects (overall p < 0.0001), and in particular by urogenital malformations (p = 0.003). In both groups, limb reduction defects occurred in approximately 80% of cases; however, minor and distal limb defects (phalangeal or digital amputation, pseudosyndactyly, constriction rings) predominated in the ARS-L group (p = 0.0008). The ARS-L group also had a higher frequency of hand and upper limb involvement. CONCLUSIONS: This observation suggests that amniotic band adhesion in ARS-L takes place at a later development stage. Although limited by a small sample size, our study contributes to the growing evidence that both ARS entities represent two nosologically distinct conditions.

Parental age as a risk factor for isolated congenital malformations in a Polish population.

Currently available data on the relationship between the prevalence of isolated congenital malformations and parental age are inconsistent and frequently divergent. We utilised the data from the Polish Registry of Congenital Malformations (PRCM) to accurately assess the interplay between maternal and paternal age in the risk of isolated non-syndromic congenital malformations. Out of 902 452 livebirths we studied 8683 children aged 0-2 years registered in the PRCM. Logistic regression was used to simultaneously adjust the risk estimates for maternal and paternal age. Our data indicated that paternal and maternal age were independently associated with several congenital malformations. Based on our data, young maternal and paternal ages were independently associated with gastroschisis. In addition, young maternal age, but not young paternal age, carried a higher risk of neural tube defects. Advanced maternal and paternal ages were both independently associated with congenital heart defects. Moreover, there was a positive association between advanced paternal age and hypospadias, cleft palate, and cleft lip (with or without cleft palate). No significant relationships between parental age and the following congenital malformations were detected: microcephaly, hydrocephaly, oesophageal atresia, atresia or stenosis of small and/or large intestine, ano-rectal atresia or stenosis, renal agenesis or hypoplasia, cystic kidney disease, congenital hydronephrosis, diaphragmatic hernia and omphalocele.

Fecal elastase-1 is superior to fecal chymotrypsin in the assessment of pancreatic involvement in cystic fibrosis.

OBJECTIVE: Exocrine pancreatic function in patients with cystic fibrosis (CF) can be evaluated by direct and indirect tests. In pediatric patients, indirect tests are preferred because of their less invasive character, especially in CF patients with respiratory disease. Fecal tests are noninvasive and have been shown to have a high sensitivity and specificity. However, there is no comparative study in CF patients. Therefore, the aim of the present study was to compare the sensitivity and the specificity of the fecal elastase-1 (E1) test with the fecal chymotrypsin (ChT) test in a large cohort of CF patients and healthy subjects (HS). DESIGN: One hundred twenty-three CF patients and 105 HS were evaluated. In all subjects, E1 concentration and ChT activity were measured. In the CF group, fecal fat excretion was also determined. The sensitivity and specificity of the fecal E1 test and ChT test were compared. RESULTS: With a cutoff level of 3 U/g, ChT specificity in HS was similar to that of E1, but E1 sensitivity in CF patients was significantly higher (90.2% vs 81.3%). With a cutoff level of 6 U/g, ChT and E1 sensitivity in CF patients was identical, but E1 specificity in HS was again significantly higher (98.1% vs 90.5%). In all CF patients with severe steatorrhea (>15 g/d), E1 concentrations were abnormal and ChT activity was lower than 3 U/g. In contrast, in pancreatic-sufficient patients and patients with mild steatorrhea (< or =15 g/d), the E1 sensitivity was significantly higher compared with ChT (69.2% vs 41.0%). CONCLUSIONS: The fecal E1 test is superior to fecal ChT determination in the assessment of CF pancreatic involvement in pancreatic-sufficient patients and those patients with mild steatorrhea.

[Comparison of faecal lipase test and faecal elastase-1 test in the assessment of exocrine pancreatic function in cystic fibrosis]. / Porównanie przydatnosci oznaczania elastazy-1 i lipazy w stolcu w ocenie funkcji zewnatrzwydzielniczej trzustki u chorych na muskowiscydoze.

OBJECTIVE: In pediatric patients, indirect tests are preferred because of their less invasive character. Among those, faecal elastase-1 test has so far been shown been shown to have the highest sensitivity and specificity. However, the role of the faecal lipase test in the diagnostic work up for pancreatic insufficiency in cystic fibrosis (CF) patients has not been defined. Therefore, the aim of the present study was to compare the sensitivity and the specificity of faecal lipase test to the faecal elastase-1 test in the assessment of exocrine pancreatic function. MATERIAL AND METHODS: 63 CF patients and 95 healthy subjects (HS) were evaluated. In all subjects, faecal elastase-1 concentration (ELISA) and lipase activity (ELISA) were measured. In 50 HS, sample-to-sample (n=3) variation from the same stool and day-to-day variation from three consecutive stools were determined twice. The presence of pancreatic insufficiency patients was documented in 55 pancreatic insufficient CF patients by the determination of faecal fat excretion and in 12 pancreatic sufficient patients by the direct test. The sensitivity and specificity of the faecal elastase-1 test and faecal lipase test were compared. RESULTS: The sample-to-sample variation (mean + SEM: 13.2+1.2% vs. 23.4+2.2%) and day-to-day variation (mean + SEM: 16.3+1.2% vs. 32.5+2.6%) were significantly lower (p<0.0001) for elastase-1 determinations than for lipase measurements. With the cut-off levels giving the same specificity for both tests (95.8%), the sensitivity of faecal elastase-1 test (87.3%) was significantly higher (p<0.04) than that of faecal lipase test (77.8%). IN CONCLUSION: Faecal lipase test is less useful in the assessment of exocrine pancreatic function sensitive than faecal elastase-1 test.

Serum lipase after secretin stimulation detects mild pancreatic involvement in cystic fibrosis.

BACKGROUND: The assessment of severe pancreatic insufficiency in cystic fibrosis (CF) is not a diagnostic problem. However, identification of mild cases remains a challenge. The aim of this study was to assess the ability of serum lipase after secretin stimulation to identify mild pancreatic insufficiency in patients with CF. MATERIAL AND METHODS: Thirty patients with CF and pancreatic insufficiency (CF-PI) and 30 patients with CF and pancreatic sufficiency (CF-PS) were studied. Thirty healthy subjects with no known gastrointestinal disease served as controls. In all subjects, fecal fat excretion, fecal elastase-1 (E1) concentration and basal and secretin-stimulated serum lipase concentration were measured. RESULTS: All patients with CF-PI and 3 with CF-PS had abnormally low fecal E1 concentrations. The remaining 27 CF-PS patients and all controls had normal values. Basal and post-stimulation lipase levels were extremely low in patients with CF-PI. Mean basal and poststimulation serum lipase concentrations were significantly higher in CF-PS who had normal fecal E1 concentrations but were still below those of controls (P < 0.001). Among the 27 CF-PS patients with normal fecal elastase, high basal and poststimulation lipase values were found in 6 and 17 patients respectively. CONCLUSION: In patients with CF-PS who have normal fecal elastase-1 concentration, the measurement of basal or secretin-stimulated lipase levels might be helpful in identifying the progression of the destructive process in the pancreas.