Clinical Genetics 1976: 9: 479-482
Natal teeth, patent ductus arteriosus and intestinal pseudo-obstruction: A lethal syndrome in the newborn DAVIDJ . HARRIS, KEITHW. ASHCRAFT, EUGENE C. BEATTY,THOMAS M. HOLDER,AND JOHN C . LEONIDAS The Children’s Mercy Hospital, Kansas City, Missouri, U.S.A. Two male siblings with natal teeth, patent ductus arteriosus and intestinal pseudo-obstruction have been observed. This may be a new X-linked recessive lethal syndrome. Received 16 September, uccepted for publication 14 October 1975
Dilatation of the small bowel without anatomic obstruction occurs occasionally in adults and older children (Maldonado et al. 1970). We have observed two brothers with intestinal dilatation and hypomotility during the neonatal period. Both had mandibular teeth and a patent ductus arteriosus. Xlinked recessive inheritance is suggested. Case Reports Case 1. W. C . (CMH #A90228), was born
at term on October 4, 1972 with a birth weight of 3.1 kg. H e began to vomit bilestained material, and after demonstration of air fluid levels on plain abdominal films, he was referred to this hospital for surgical care. Two teeth were present on the mandible, and a murmur consistent with a patent ductus arteriosus was heard. A radiograph of the chest showed a left diaphragmatic hernia, while a midgut malrotation was demonstrated by barium enema. As shown in Figure 1, the colon is relatively small. At operation, the small bowel was distended, and ‘there was a malrotation without
VOIVUIUS, but no anatomic obstruction was found. The diaphragmatic hernia was repaired and a gastrostomy tube was placed. Postoperatively, gastrointestinal motility did not return, as shown in Figure 2. This film was obtained 3 hours after the administration of a water-soluble contrast medium. Since feeding was impossible, total parenteral nutrition (TPN) was used. At 10 days of age the infant developed symptoms of cardiac failure. Digitalis and diuretic therapy had little effect. A large patent ductus arteriosus (PDA) was the only lesion demonstrated at cardiac catheterization. The PDA was ligated at 42 days. After 2 months, signs of gastrointestinal obstruction persisted. At reoperation no mechanical obstruction could be found. The appendix was removed, the terminal ileum biopsied, and a ventral hernia was repaired. After numerous complications, he finally died of sepsis secondary t o T P N at 5 months of age. Bowel motility had never been effective. Case 2 . P. C . (CMH #B4253), was born at term with a birth weight of 2.8 kg on Jan-
380
HARRIS, ASHCRAFT, BEATTY, HOLDER, AND LEONIDAS
used. A few hours before he died, at 6 weeks of age, both the serum and red cell cholinesterases were found to be low. Further Studies
Fig. 1. Barium enema of Case 1 demonstrating microcolon and malrotation.
uary 13, 1974. Mandibular teeth were present. Bilious vomiting began shortly after birth. He had passed no meconium. Radiographic studies showed delayed emptying of the stomach, dilatation of the duodenum, absent peristalsis and a microcolon. At operation, incomplete rotation of the midgut was observed, as well as a short small bowel, but no anatomic obstruction was demonstrable. A gastrostomy was performed, as well as an appendectomy, and multiple biopsies from the small bowel and colon. Postoperatively, there was no sustained, normal peristaltic activity. A systolic murmur was heard at the left sternal border; the chest radiograph and electrocardiogram were consistent with a patent ductus arteriosus. An attempt was made to feed the infant with the gastrostomy, resulting either in large residual volumes of gastric contents or diarrhea and malabsorption. TPN was not
Pathology Biopsies of the gastrointestinal tract were obtained from both infants. Histologically, all of them were normal, and ganglion cells were present. The following observations were made at the post-mortem examination of the first infant: There were dense intra-abdominal adhesions. The entire small bowel was dilated, and the colon was small. A urachal remnant was present. The ductus arteriosus had been divided. The microscopic examination was unremarkable with the exception of an infiltration of the terminal ileum by chronic inflammatory cells. In the second infant, there was a malrotation of the midgut. The small bowel was dilated and measured 60 cm. The serosa was stripped from the jejunum and the bowel was stimulated with solutions of barium chloride, acetylcholine, pilocarpine, and physostigmine. It responded only to high concentrations of acetylcholine (0.02 mg/ ml). The ductus arteriosus was patent and the foramen ovale was open. The only significant microscopic finding was ulceration of the gastric cardia.
Genetics The parents are not consanguineous and come from large families. The father was 22 years old at the time the first child was born and has been in good health. The mother was 21 years old when the first child was born and developed cholecystitis several weeks after the delivery. She underwent a cholecystectomy. A Meckel's diverticulum was also removed. She developed intestinal obstruction after the death of the second infant and was found t o have peritoneal ad-
A LETHAL SYNDROME I N THE NEWBORN
483
Flg. 2. 3-hour film from gastrointestinal series on Case 1. No peristalsis was
seen.
hesions which were divided, but there was nothing to suggest a disorder similar to that of the two infants. There is one normal sibling, a girl aged 3 years. The maternal grandmother was from a sibship of seven with only one male surviving infancy. The mother was one of five with no surviving males, as shown in Figure 3. The probability of a particular distribution of sexes in a sibship of a given size can be calculated from the binomial distribution. In performing this calculation it is assumed
that the probability of having a male is equal to that of having a female, or 0.5 (Stern 1973). In this case the probability of observing the grandmother’s sibship in all families of seven is 0.055, while the probability of observing a sibship of five females like the mother’s is 0.031. If the mother of each sibship is a carrier of an X-linked lethal, half of the conceived males would die, so that the probability of a male birth is 0.33. The probability for the grandmother’s sibship, making the assumption of
482
HARRIS, ASHCRAFT, BEATTY, HOLDER, AND LEONIDAS
m
m
m
XE" Ltl.tlW
m
W . u d sponl.".o".
.)arts
Fig. 3. Partial pedigree of kindred with triad of Intestinal pseudo-obstruction, patent ductus arteriosus and natal teeth.
an X-linked lethal becomes 0.209, while the probability of the mother's sibship is 0.135. The fit to the X-linked lethal hypothesis is better.
The occurrence of a similar complex of malformations in siblings suggests a heritable syndrome. Individuals of both sexes have been observed in one family with the isolated pseudo-obstruction observed later in life (Maldonado et aI. 1970). This may represent an autosomal recessive form. The occurrence of three anomalies in two male siblings and the observed sex distribution in the mother's ascendants point towards an X-linked recessive gene determination. Acknowledgment
This study was supported in part by the Carrie J. Loose Trust, the Victor Speas Trust, and funds from the Children's Mercy Hospital, Kansas City, Missouri.
Comment
As reviewed by Maldonado et al. (1970), the physiology of intestinal pseudo-obstruction, other than the demonstration of hypomotility, is not well understood. Attempts to elucidate the mechanism in the second infant were not rewarding. Cholinesterases may have been abnormal because of malnutrition (Barclay 1973). The poor response to pharmacological agents applied to the muscle post mortem may have been the result of chronic dilatation and stretching of the muscle fibers. Perhaps study of other patients with similar disorders at operation early in the course of the disorder may disclose a pharmacological approach to this problem.
References
Barclay, G. P. T. (1973). Pseudocholinesterase activity as a guide to progress in malnutrition. Amer. J . clin. Path. 59, 712-716. Maldonado, J. E., J. A. Gregg, P. A. Green & A. L. Brown (1970). Chronic intestinal pseudo-obstruction. A m e r . J . M e d . 49, 203212.
Stern, C. (1973). Principles of Human Genetics. W. H. Freeman. San Francisco, pp. 195-220. Address: David J . Harris, M . D . Genetic Counseling Center The Children's Mercy Hospital 24th at Gillham Road Kansas City, Missouri 64108 U.S.A.
Natal teeth, patent ductus arteriosus and intestinal pseudo-obstruction: A lethal syndrome in the newborn DAVIDJ . HARRIS, KEITHW. ASHCRAFT, EUGENE C. BEATTY,THOMAS M. HOLDER,AND JOHN C . LEONIDAS The Children’s Mercy Hospital, Kansas City, Missouri, U.S.A. Two male siblings with natal teeth, patent ductus arteriosus and intestinal pseudo-obstruction have been observed. This may be a new X-linked recessive lethal syndrome. Received 16 September, uccepted for publication 14 October 1975
Dilatation of the small bowel without anatomic obstruction occurs occasionally in adults and older children (Maldonado et al. 1970). We have observed two brothers with intestinal dilatation and hypomotility during the neonatal period. Both had mandibular teeth and a patent ductus arteriosus. Xlinked recessive inheritance is suggested. Case Reports Case 1. W. C . (CMH #A90228), was born
at term on October 4, 1972 with a birth weight of 3.1 kg. H e began to vomit bilestained material, and after demonstration of air fluid levels on plain abdominal films, he was referred to this hospital for surgical care. Two teeth were present on the mandible, and a murmur consistent with a patent ductus arteriosus was heard. A radiograph of the chest showed a left diaphragmatic hernia, while a midgut malrotation was demonstrated by barium enema. As shown in Figure 1, the colon is relatively small. At operation, the small bowel was distended, and ‘there was a malrotation without
VOIVUIUS, but no anatomic obstruction was found. The diaphragmatic hernia was repaired and a gastrostomy tube was placed. Postoperatively, gastrointestinal motility did not return, as shown in Figure 2. This film was obtained 3 hours after the administration of a water-soluble contrast medium. Since feeding was impossible, total parenteral nutrition (TPN) was used. At 10 days of age the infant developed symptoms of cardiac failure. Digitalis and diuretic therapy had little effect. A large patent ductus arteriosus (PDA) was the only lesion demonstrated at cardiac catheterization. The PDA was ligated at 42 days. After 2 months, signs of gastrointestinal obstruction persisted. At reoperation no mechanical obstruction could be found. The appendix was removed, the terminal ileum biopsied, and a ventral hernia was repaired. After numerous complications, he finally died of sepsis secondary t o T P N at 5 months of age. Bowel motility had never been effective. Case 2 . P. C . (CMH #B4253), was born at term with a birth weight of 2.8 kg on Jan-
380
HARRIS, ASHCRAFT, BEATTY, HOLDER, AND LEONIDAS
used. A few hours before he died, at 6 weeks of age, both the serum and red cell cholinesterases were found to be low. Further Studies
Fig. 1. Barium enema of Case 1 demonstrating microcolon and malrotation.
uary 13, 1974. Mandibular teeth were present. Bilious vomiting began shortly after birth. He had passed no meconium. Radiographic studies showed delayed emptying of the stomach, dilatation of the duodenum, absent peristalsis and a microcolon. At operation, incomplete rotation of the midgut was observed, as well as a short small bowel, but no anatomic obstruction was demonstrable. A gastrostomy was performed, as well as an appendectomy, and multiple biopsies from the small bowel and colon. Postoperatively, there was no sustained, normal peristaltic activity. A systolic murmur was heard at the left sternal border; the chest radiograph and electrocardiogram were consistent with a patent ductus arteriosus. An attempt was made to feed the infant with the gastrostomy, resulting either in large residual volumes of gastric contents or diarrhea and malabsorption. TPN was not
Pathology Biopsies of the gastrointestinal tract were obtained from both infants. Histologically, all of them were normal, and ganglion cells were present. The following observations were made at the post-mortem examination of the first infant: There were dense intra-abdominal adhesions. The entire small bowel was dilated, and the colon was small. A urachal remnant was present. The ductus arteriosus had been divided. The microscopic examination was unremarkable with the exception of an infiltration of the terminal ileum by chronic inflammatory cells. In the second infant, there was a malrotation of the midgut. The small bowel was dilated and measured 60 cm. The serosa was stripped from the jejunum and the bowel was stimulated with solutions of barium chloride, acetylcholine, pilocarpine, and physostigmine. It responded only to high concentrations of acetylcholine (0.02 mg/ ml). The ductus arteriosus was patent and the foramen ovale was open. The only significant microscopic finding was ulceration of the gastric cardia.
Genetics The parents are not consanguineous and come from large families. The father was 22 years old at the time the first child was born and has been in good health. The mother was 21 years old when the first child was born and developed cholecystitis several weeks after the delivery. She underwent a cholecystectomy. A Meckel's diverticulum was also removed. She developed intestinal obstruction after the death of the second infant and was found t o have peritoneal ad-
A LETHAL SYNDROME I N THE NEWBORN
483
Flg. 2. 3-hour film from gastrointestinal series on Case 1. No peristalsis was
seen.
hesions which were divided, but there was nothing to suggest a disorder similar to that of the two infants. There is one normal sibling, a girl aged 3 years. The maternal grandmother was from a sibship of seven with only one male surviving infancy. The mother was one of five with no surviving males, as shown in Figure 3. The probability of a particular distribution of sexes in a sibship of a given size can be calculated from the binomial distribution. In performing this calculation it is assumed
that the probability of having a male is equal to that of having a female, or 0.5 (Stern 1973). In this case the probability of observing the grandmother’s sibship in all families of seven is 0.055, while the probability of observing a sibship of five females like the mother’s is 0.031. If the mother of each sibship is a carrier of an X-linked lethal, half of the conceived males would die, so that the probability of a male birth is 0.33. The probability for the grandmother’s sibship, making the assumption of
482
HARRIS, ASHCRAFT, BEATTY, HOLDER, AND LEONIDAS
m
m
m
XE" Ltl.tlW
m
W . u d sponl.".o".
.)arts
Fig. 3. Partial pedigree of kindred with triad of Intestinal pseudo-obstruction, patent ductus arteriosus and natal teeth.
an X-linked lethal becomes 0.209, while the probability of the mother's sibship is 0.135. The fit to the X-linked lethal hypothesis is better.
The occurrence of a similar complex of malformations in siblings suggests a heritable syndrome. Individuals of both sexes have been observed in one family with the isolated pseudo-obstruction observed later in life (Maldonado et aI. 1970). This may represent an autosomal recessive form. The occurrence of three anomalies in two male siblings and the observed sex distribution in the mother's ascendants point towards an X-linked recessive gene determination. Acknowledgment
This study was supported in part by the Carrie J. Loose Trust, the Victor Speas Trust, and funds from the Children's Mercy Hospital, Kansas City, Missouri.
Comment
As reviewed by Maldonado et al. (1970), the physiology of intestinal pseudo-obstruction, other than the demonstration of hypomotility, is not well understood. Attempts to elucidate the mechanism in the second infant were not rewarding. Cholinesterases may have been abnormal because of malnutrition (Barclay 1973). The poor response to pharmacological agents applied to the muscle post mortem may have been the result of chronic dilatation and stretching of the muscle fibers. Perhaps study of other patients with similar disorders at operation early in the course of the disorder may disclose a pharmacological approach to this problem.
References
Barclay, G. P. T. (1973). Pseudocholinesterase activity as a guide to progress in malnutrition. Amer. J . clin. Path. 59, 712-716. Maldonado, J. E., J. A. Gregg, P. A. Green & A. L. Brown (1970). Chronic intestinal pseudo-obstruction. A m e r . J . M e d . 49, 203212.
Stern, C. (1973). Principles of Human Genetics. W. H. Freeman. San Francisco, pp. 195-220. Address: David J . Harris, M . D . Genetic Counseling Center The Children's Mercy Hospital 24th at Gillham Road Kansas City, Missouri 64108 U.S.A.
