Cystic fibrosis of the pancreas in a human fetus

Postmortem examination of a 26 week old (postmenstrual) human fetus delivered by Cesarean section revealed meconium ileus and many swollen mucus-secreting cells in the gastro-intestinal mucosa. The pancreas showed extensive fibrosis, acinar destruction and dilatation of ducts containing eosinophilic casts. Mucous glands of the lungs also revealed mucous cells swollen and distended with their secretory products. The patient is believed to have cystic fibrosis of the pancreas, suggesting that the pathologic manifestations of the disease may begin early in fetal life.     

CYSTIC FIBROSIS OF THE PANCREAS IN A HUMAN FETUS

Postmortem examination of a 26 week old (postmenstrual) human fetus delivered by Cesarean section revealed meconium ileus and many swollen mucus-secreting cells in the gastro-intestinal mucosa. The pancreas showed extensive fibrosis, acinar destruction and dilatation of ducts containing eosinophilic casts. Mucous glands of the lungs also revealed mucous cells swollen and distended with their secretary products. The patient is believed to have cystic fibrosis of the pancreas, suggesting that the pathologic manifestations of the disease may begin early in fetal life.     

Prenatal diagnosis of cystic fibrosis by trehalase enzyme assay in amniotic fluid

Amniocentesis and amniotic fluid trehalase enzyme assay were offered to 14 pregnant women at a 1 in 4 risk for a child with cystic fibrosis. Twelve of these pregnancies were screened at the 18th week of gestation; ten proceeded to term, seven following the finding of a normal trehalase activity and three despite the low enzyme level in amniotic fluid. In all ten cases prenatal diagnosis proved to be correct. In two cases with low enzyme activity parents opted for termination at the 19th week, and with PAS-Alcian Blue staining some slight histochemical lesions characteristic of cystic fibrosis were seen in the exocrine glands, including the pancreas and intestinal mucosa, of both fetuses. The total protein content in the meconium of these fetuses was significantly higher than in the controls. Results suggest that trehalase assay in the amniotic fluid is a potential prenatal test for cystic fibrosis and it appears that in fetuses with cystic fibrosis some histochemical and biochemical abnormalities can be observed as early as the 19th week of gestation. The role of ultrasound examination as an additional procedure for the prenatal diagnosis of cystic fibrosis is also discussed.     

Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants.

The development of the exocrine pancreas has been determined quantitatively in 31 infants with cystic fibrosis (CF) both with and without meconium ileus and in 29 control infants. In the normal pancreas, the ratio of acinar to connective tissue volume is 0.5 at 32 weeks postconceptional age (PCA) and increases linearly to 2.0 at 52 weeks PGA. In cystic fibrosis infants, with or without meconium ileus, the ration is 0.5 at 35 weeks PCA anddecreases linearly to 0.3 at 52 weeks PCA. The volume of acinar and duct lumens is greater in CF than control infants but is independent of age or acinar volume. The development of the exocrine pancreas in infants with CF with and without meconium ileus diverges from the normal pattern: There is consistent lack of exocrine tissue before or a full-term birth, which persists throghout the age range of this study. CF infants above 42 weeks PCA can be discriminated from controls on the basis of the quantitative assessment of acinar volume.     

BILATERAL RENAL DYSPLASIA ACCOMPANIED BY PANCREATIC FIBROSIS, MECONIUM ILEUS, AND SITUS INVERSUS TOTALIS

An autopsy case of bilateral renal dysplasia with other congenital malformations is reported. Malformations included severe pancreatic fibrosis with meconium ileus, situs inversus totalis, cardiovascular anomalies, and others. The only syndrome of multiple congenital malformations involving renal dysplasia which is similar to the present case is Ivemark's syndrome, though the present case lacked hepatic lesions. Apart from the pancreatic lesion, there were no abnormalities compatible with cystic fibrosis (mucoviscidosis). It was considered that meconium ileus in the present case was caused by pancreatic achylia secondary to severe pancreatic fibrosis, unrelated to cystic fibrosis, but closely allied to renal dysplasia.     

Quantitative evaluation of the development of tracheal submucosal glands in infants with cystic fibrosis and control infants.

The development of the tracheal submucosal glands has been determined quantitatively in 22 infants with cystic fibrosis and in 25 control infants, all under 4 months of age. In cross-sections of normal trachea significant relationships were found between postconceptional age (PCA) and gland area (P less than 0.001), submucosal area (P less than 0.02), tracheal airway diameter (P less than 0.05), and acinar diameter (P less than 0.001). In infants with cystic fibrosis the pattern of development was similar to that of the control infants. No statistically significant differences were found between three subgroups of infants with cystic fibrosis, which included those with meconium ileus with no lung infection, those with meconium ileus with lung infection, and those with lung infection and no history of meconium ileus. The normal pattern of development of tracheal submucosal glands in infants with cystic fibrosis was in contrast to the deficiency of normal maturation seen in the exocrine pancreas of these infants. The lumen fraction, an index of dilatation of acinar lumina, showed no significant relationship with PCA in either the control group or the group with cystic fibrosis. However, statistically significant dilatation of acini was observed in the tracheal submucosal glands of infants with cystic fibrosis (0.14, P less than 0.005).     

Intrauterine aspiration in man in the early fetal period]

A total of 220 futuses obtained as a result of spontaneous and artificial abortions, 9-28 weeks of pregnancy, were investigated. The studies showed that intrauterine aspiration could be performed already beginning with the 11th-12th week of pregnancy. Intrauterine aspiration was determined on the basis of microscopical detection in the bronchi and in alveolar ducts of particles of the amniotic fluid (amnional epithelium and maternal leucocytes from the 11th-12th week, erythrocytes--from the 13th-14th week, horny scales--from the 15th-16th week, meconium--from the 23rd-24th week) and dilatation of the bronchoalveolar lumens. The fetal membranes in inflammation (chorioamnionitis) served as a sourse of aspitating leucocytes. Intrauterine aspiration most often took place in case of harmful effects upon the fetus. The cells of the amnional epithelium and epidermis, being aspirated, produced no harmful effect upon the fetus; the meconium was aspirated in the last hours of the abortion and had no time to produce morphologically identified reaction; aspiration of maternal leucocytes, not infrequently in combination with infection of the lungs, caused a proliferative inflummatory reaction in the fetus in the form of an enlarged number of cells in the stroma of the lungs, rounding of their nuclei, increased number of segmento-nuclear leucocytes and the appearance of round-celled peribronchial infiltrations. A proliferative inflammatory reaction was noted in fetuses beginning with the 13th-14th week of the intrauterine development.     

Variability in the phenotypic expression of fryns syndrome: A report of two sibships

We report on two sibships with four fetuses of 12, 15, 17, and 20 weeks of gestation, respectively, and 1 preterm baby of 31 weeks of gestation affected by a multiple congenital disorder with manifestation suggestive of Fryns syndrome. In addition to the characteristic malformation pattern in Fryns syndrome, they presented with fetal hydrops, cystic hygroma, and multiple pterygias, allowing prenatal ultrasound diagnosis as early as in the 11th week of gestation. The two affected fetuses of family 1 showed severe craniofacial anomalies with bilateral cleft lip and palate, acral hypoplasia, postaxial oligodactyly, persistent truncus arteriosus, and interrupted aortic arch, asplenia sequence, and complex central nervous system midline malformations. In family 2 with three affected sibs, ear anomalies with atresia of the auditory canals, postaxial hexadactyly, intestinal atresias, callosal defects, and eye colobomas were the most outstanding features. On the basis of the present findings and former reports, the inter- and intrafamiliar phenotypic variability in Fryns syndrome, possible pathogenetic mechanisms, and the value of prenatal diagnosis are discussed. In the pathogenetic discussion, a special emphasis is put on the neural crest cell developmental field.     

羊水甲胎蛋白浓度与胎儿畸形的关系

目的了解羊水甲胎蛋白（AFP）浓度与胎儿畸形的关系。方法对2007年1月至2012年5月在本院进行羊膜腔穿刺的孕17～23w孕妇5262例,运用酶联免疫吸附法对羊水进行AFP检测,根据其2．5倍中位数倍数（MoM）值进行分组,观察孕妇的妊娠结局,分析羊水AFP升高与胎儿畸形的关系。结果1．各孕周羊水AFP的2．5MoM值分别为：孕17w 41150ng／ml,18w38395ng／ml,19w 34995ng／ml,20w 31700ng／ml,21w 29655ng／ml,22w 26940ng／ml,23w 21800ng／ml。2．羊水AFP≥2．5MoM时发生率明显升高的胎儿畸形为：神经管缺陷,颈部淋巴管瘤,死胎。结论羊水AFP≥2．5MoM时,临床诊断除考虑神经管缺陷,还应警惕是否有颈部淋巴管瘤或死胎可能。羊水AFP≥2．5MoM对于诊断神经管缺陷的特异度及阴性预测价值较高,但灵敏度及阳性预测价值一般,需结合系统彩超排除相关畸形。     

Cystic fibrosis in Ontario

The incidence of cystic fibrosis in Ontario, Canada has been determined from clinical data, from the cystic fibrosis database of the Hospital for Sick Children, Toronto, and from population statistics in the Province of Ontario. The survey included 420 confirmed cases of cystic fibrosis born during the period 1966–1980. The mean incidence during this period was one in 2,927. In the last 5-year period, a decline was noted in incidence that may have reflected in part the effectiveness of early diagnosis and genetic counseling in affected families. During the period of the survey, over 60% of cases were diagnosed within the first year of life, 74% by age 2 years, and 90% by age 5 years. Clinical diagnosis in the first year of life was more common in males (65%) than in females (54%), a consistent finding during the period of the survey. The incidence of meconium ileus was 15.7% of ascertained cases of cystic fibrosis, with similar incidences in males (16.4%) and females (14.4%). Although survival has not been the subject of this survey, mortality in the neonatal period was significantly higher in males than in females with cystic fibrosis.     

Serum CA 19–9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests

Abstract. Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19–9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19–9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19–9 levels. Serum CA 19–9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (F508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb CT, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19–9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19–9 levels was significantly different between the three groups (p<0.01); high CA 19–9 levels were found in 60% (30/50) of group Apatients and in 46.6% (6/13) of group B patients, but in only 5.2% (2/38) of the controls. CA 19–9 levels were inversely related to forced expiratory volume in 1 s, while no association was found with the other clinical parameters examined. Our findings suggest that the serum CA 19–9 in cystic fibrosis patients originates in the respiratory system, and has a useful ancillary role, particularly when diagnostic uncertainty exists. Hence, the diagnosis of cystic fibrosis should be considered in patients with borderline sweat tests and high CA 19–9 levels, but normal levels do not exclude cystic fibrosis.     

Cystic fibrosis in Ontario

The incidence of cystic fibrosis in Ontario, Canada has been determined from clinical data, from the cystic fibrosis database of the Hospital for Sick Children, Toronto, and from population statistics in the Province of Ontario. The survey included 420 confirmed cases of cystic fibrosis born during the period 1966-1980. The mean incidence during this period was one in 2,927. In the last 5-year period, a decline was noted in incidence that may have reflected in part the effectiveness of early diagnosis and genetic counseling in affected families. During the period of the survey, over 60% of cases were diagnosed within the first year of life, 74% by age 2 years, and 90% by age 5 years. Clinical diagnosis in the first year of life was more common in males (65%) than in females (54%), a consistent finding during the period of the survey. The incidence of meconium ileus was 15.7% of ascertained cases of cystic fibrosis, with similar incidences in males (16.4%) and females (14.4%). Although survival has not been the subject of this survey, mortality in the neonatal period was significantly higher in males than in females with cystic fibrosis.     

Genetic heterogeneity between two clinical forms of cystic fibrosis evidenced by familial analysis and linked DNA probes

CF heterogeneity has been evidenced from both clinical and genetic observations. At least two clinical forms of CF are easily distinguishable: CF with meconium ileus and CF without meconium ileus. The results of prenatal diagnosis have shown that the recurrence rates of CF are different in these two clinical forms. Molecular analysis of Restriction Fragment Length Polymorphisms (RFLPs) tightly linked to the cystic fibrosis (CF) gene defined several types of CF and normal chromosomes in a French sample of 64 families with CF. The CF mutation is tightly linked to one XV-2C and KM19 RF l Ps haplotype but is differently linked to J3.11 RFLP alleles, depending on whether or not the clinical form of CF is associated with ileus. A distortion of the segregation ratio observed between normal and CF haplotypes in the families with ileus could explain the high recurrence rate of CF in such families.     

Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis,genetic counseling,and mutation-specific therapy

PurposeNewborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France in 2002. It involves a four-tiered procedure: immunoreactive trypsin (IRT)/DNA/IRT/sweat test was implemented throughout France in 2002. The aim of this study was to assess the performance of molecular CFTR gene analysis from the French NBS cohort, to evaluate CF incidence, mutation detection rate, and allelic heterogeneity.MethodsDuring the 8-year period, 5,947,148 newborns were screened for cystic fibrosis. The data were collected by the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant. The mutations identified were classified into four groups based on their potential for causing disease, and a diagnostic algorithm was proposed.ResultsCombining the genetic and sweat test results, 1,160 neonates were diagnosed as having cystic fibrosis. The corresponding incidence, including both the meconium ileus (MI) and false-negative cases, was calculated at 1 in 4,726 live births. The CF30 kit, completed with a comprehensive CFTR gene analysis, provides an excellent detection rate of 99.77% for the mutated alleles, enabling the identification of a complete genotype in 99.55% of affected neonates. With more than 200 different mutations characterized, we confirmed the French allelic heterogeneity.ConclusionThe very good sensitivity, specificity, and positive predictive value obtained suggest that the four-tiered IRT/DNA/IRT/sweat test procedure may provide an effective strategy for newborn screening for cystic fibrosis.     

Three autopsied cases of cystic fibrosis in Japan

The incidence of cystic fibrosis (CF) is very rare in Japanese, while it is frequent in Caucasians. Here we report on three Japanese cases of CF. One of the patients had consanguineous parents. All three patients initially developed meconium ileus, and hepatobiliary and pancreatic changes became more severe as age increased. The DeltaF508 mutation, the most frequent mutation associated with CF in Caucasians, was not found in these patients. To evaluate the relationship between the severity of hepatic lesions and a history of meconium ileus, we examined hepatic lesions in the present three cases, and we reviewed 22 Japanese autopsied cases of CF in the literature. No correlation was found between the incidence of biliary cirrhosis and a history of meconium ileus, because the cases with meconium ileus showed a high mortality during the neonatal period, before biliary cirrhosis developed. The high incidence of meconium ileus in Japanese CF patients may relate to a clinically severe phenotype and reflect a different genetic background between Caucasians and Japanese.     

β-glucuronidase deficiency as a cause of fetal hydrops

Mucopolysaccharidosis type VII (MPS VII) was diagnosed in a case of severe fetal hydrops. β-glucuronidase deficiency was demonstrated in the amniotic fluid, which was obtanined at 25 weeks of gestation, and in the fibroblasts of the child, which were cultured atter fetal death in the 26th week of gestation. In the amniotic fluid the two-dimensional eletrophoresis pattern of glycosaminoglycans was in agreement with MPS VII. Based on these results, prenatal diagnosis could be offered to the couple for the next pregnancy.     

胎儿水囊状淋巴管瘤的产前诊断及预后分析

目的探讨胎儿囊性淋巴瘤（cystic hygroma，CH）的产前诊断及妊娠期的处置。方法回顾性分析2006年1月～2008年4月间我院35例胎儿CH产前超声声像、介入性羊膜腔穿刺查胎儿染色体及TORCH感染情况、胎儿病理。结果发生在颈背部者33例，腋窝2例。足月分娩6例并存活，引产29例（包括死胎2例）。染色体核型分析异常者共19例，占58%，其中Turner′s综合征最常见，共11例，占33%；Down′s综合征5例，占15%；Trisomy182例，占6%；Tri-somy131例，占3%。结论超声及介入性羊膜腔穿刺查胎儿染色体在早期诊断及处置胎儿CH起决定性作用，胎儿CH与Turner综合征等染色体异常相关。     

beta-Glucuronidase deficiency as a cause of fetal hydrops.

Mucopolysaccharidosis type VII (MPS VII) was diagnosed in a case of severe fetal hydrops. beta-glucuronidase deficiency was demonstrated in the amniotic fluid, which was obtained at 25 weeks of gestation, and in the fibroblasts of the child, which were cultured after fetal death in the 26th week of gestation. In the amniotic fluid the two-dimensional electrophoresis pattern of glycosaminoglycans was in agreement with MPS VII. Based on these results, prenatal diagnosis could be offered to the couple for the next pregnancy.     

Fetal varicella syndrome: disruption of neural development and persistent inflammation of non-neural tissues

Primary varicella zoster virus (VZV) infection during pregnancy is rare. If it occurs between the 8th and 20th week of gestation, fetal varicella syndrome results in 1–2% of the fetuses. We report about a varicella infection that affected a pregnant mother in the 12th week of gestation. At 33 weeks, a premature girl was born with destruction of neurons in spinal cord, spinal ganglia and plexus myentericus, and secondary developmental disturbance including mummification of one arm and segmental intestinal atresia. The brain did not show any abnormalities. However, VZV DNA could be detected by PCR in tissues from the brain and spinal ganglia. Chronic necrotizing inflammation was found in the placenta, fetal membranes, and one ovary. These locations showed nuclear inclusions which by in-situ-hybridization were proven to be VZV derived. This case demonstrates that in the fetal age, ’neurotropism’ of VZV signifies severe destruction but not necessarily persistent inflammation of neural tissue. However, due to the inefficient fetal immune system, inflammation can go on for weeks, preferentially in non-neural tissues. Received: 19 October 1999 / Accepted: 31 March 2000     

Prenatal diagnosis of Walker-Warburg syndrome in three sibs

Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterized by diffuse neurodysplasia, resulting in brain and eye abnormalities. We report on 3 prenatally diagnosed cases of this syndrome born to a consanguineous couple. An ultrasonographic examination showed hydrocephalus at the 27th week of the first pregnancy. Amniocentesis documented a normal male karyotype. The couple opted for termination of the pregnancy but declined an autopsy. Seven months later, hydrocephalus was observed at 20 weeks of the second pregnancy. Termination of pregnancy was performed at the 22nd week. Autopsy of this male fetus showed dilated ventricles, thin cortex, and type II lissencephaly with microscopic evidence of chaotic architecture. Eye examination showed retinal dysplasia. Notwithstanding the lack of demonstrable muscle change, the diagnosis of Walker-Warburg syndrome was made. Ten months later, hydrocephalus was discovered in the third fetus, a female, at 13 weeks of gestation. Termination of pregnancy was performed at 20 weeks. At autopsy, brain, eye, and muscular findings were similar to those of the previous case. In addition, cystic changes and a stenosis of the pyelo-ureteral junction were found in the right kidney. Type II lissencephaly and retinal dysplasia are characteristic of WWS. Muscular dystrophy has been pointed out as an additional abnormality in postnatal cases. By contrast, the lack of demonstrable muscle changes in the fetal period must be emphasized. Those cases illustrate practical problems in the ultrasound and pathologic diagnosis of WWS in the fetal period. Am. J. Med. Genet. 76:107–110, 1998. © 1998 Wiley-Liss, Inc.