History:

A term Caucasian girl is the second child born to parents who have no known medical problems. The pregnancy was uncomplicated and the delivery was uneventful, with Apgar scores of 8 at 1 minute and 10 and 5 minutes. The baby was sent home with mother a day after delivery. Within two days, the mother brought the baby back to clinic because the child had seemed irritable and was feeding poorly, with vomiting. When asked about bowel movements, the mother recalled not changing diapers frequently and not noticing any stool in them.

The case in image 5.1 represents meconium ileus. The abnormal pancreatic secretions with cystic fibrosis lead to inspissation of the meconium, which distends the ileum. Rupture with meconium peritonitis is a potential complication.

The colon of another neonate in image 5.2 shows a dilated segment of colon above an aganglionic segment. This baby had Hirschsprung's disease.

Later in life, the child with cystic fibrosis develops widespread pulmonary bronchiectasis from recurrent pneumonias as a consequence of abnormal pulmonary secretions. The lung is filled with areas of bronchopneumonia and abscess formation. Eventually, the parenchyma of the pancreas is replaced by fibrofatty tissue. Few islets of Langerhans remain.

Questions:

1. What are the differential diagnostic possibilites in this case when the mother brings in the baby?

Causes for gastrointestinal tract obstruction in the neonate include pyloric stenosis (1 in 500 live births), which should be most common in male infants of 2 to 6 weeks age. Congenital atresias (esophagus, small intestine) are usually not isolated, but are associated with other anomalies, often visible. Hirschsprung's disease (1 in 5000 to 8000 live births) results from an aganglionic segment of colon may lead to abdominal distension, enterocolitis, and possible perforation. Meconium ileus with cystic fibrosis, as in this case, is another possibility.

2. What inherited disorder could account for these findings? What is its frequency and inheritance pattern?

The findings could be explained by cystic fibrosis, which results from mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which regulates epithelial chloride ion transport. The mutations result in abnormal viscid secretions that damage the respiratory tract, genitourinary tract, and certain exocrine glands such as the pancreas.

The carrier frequency is about 1 in 25 Caucasians in the U.S. so that the frequency of births is about 1 in 2500. It is autosomal recessive. The deltaF508 mutation on chromosome 7 accounts for about 2/3 of cases, and about a dozen other mutations account for 90% of the rest, but there are hundreds of mutations known. Thus, there is no single, simple genetic screening test for all of them.

3. What additional laboratory test could you do, for initial diagnosis of his disease?

A sweat chloride test by iontophoresis would reveal an elevated sweat chloride with cystic fibrosis.

4. Discuss recurrence risks for genetic disorders. What is the risk for having a baby with any significant anomaly? How do you know if an anomaly is related to an environmental factor or a genetic factor?

Autosomal recessive = 1 in 4, autosomal dominant = 1 in 2 (assuming complete penetrance).

Risk for recurrence with multifactorial inheritance (by two or more defective genes) is higher than for the standard recurrence risk in any pregnancy of about 3%. Not all anomalies are genetic--some may be environmental (infection, uterine anomaly, teratogen). The pattern of findings can be used to determine if the anomalies fit with a particular etiology, but in many cases it can be hard to tell. Even if the pattern of anomalies points to a specific syndrome, the cause of the syndrome and its exact inheritance pattern may not be known. As time goes on, more genes are discovered to explain anomalies, both sporadic and inherited, but this just makes potential screening or confirmation more complex.