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Fryns syndrome in children with congenital diaphragmatic hernia
Fryns Syndrome in Children With Congenital Diaphragmatic Hernia By The Congenital Diaphragmatic Hernia Study Group*
Purpose: Fryns syndrome is characterized by multiple congenital anomalies including Congenital Diaphragmatic Hernia (CDH), and has a reported poor prognosis with a survival rate during the neonatal period of approximately 15%. This report details the management and outcome of patients with Fryns syndrome and CDH.
hours to 14 days). Mortality rate was 83% compared with 33% of patients with unilateral CDH (P ⫽ .01). Ten patients died within the first 24 hours. The parents of 6 patients withdrew support. Of the 4 survivors, 3 have marked developmental delay, whereas the fourth has not yet undergone formal assessment.
Methods: Records of all liveborn patients with CDH between 1995 and 2001 in 83 hospitals were entered into the CDH database. Those with Fryns syndrome were reviewed retrospectively.
Conclusions: The prognosis of infants with Fryns syndrome and congenital diaphragmatic hernia remains grim. Early genetic counseling and recognition of lethal anomalies may assist in determining which patients may survive. J Pediatr Surg 37:1685-1687. Copyright 2002, Elsevier Science (USA). All rights reserved.
Results: A total of 1,833 patients were entered in the database, 23 of these had Fryns (1.3%). All patients experienced early distress requiring intubation. Ten patients (43%) were found to have other major anomalies. Seven patients underwent surgical repair at an average age of 7.5 days (range, 6
F
RYNS SYNDROME was described initially by Fryns, et al, in 1979.1 In this initial description, 2 siblings were stillborn and were each found to have craniofacial anomalies including coarse facies, a flat nasal bridge with a large nose, large mouth, narrow palpebral fissures, low set ears, and cleft palate. In addition, these siblings had hypoplasia of the distal phalanges; a short, webbed neck; and bilateral congenital diaphragmatic hernias.1 Since that time, there have been multiple other case reports of this rare disease.2-10 This syndrome has exhibited a large amount of phenotypic variability; however, the most consistent features are the distal digital hypoplasia, coarse facies, abnormal ears, and congenital diaphragmatic hernia (CDH). CDH is present in approximately 76% to 89% of reported cases.11,12 This syndrome is acquired through an autosomal recessive pattern of inheritance; however, the exact chromosomal abnormality causing this syndrome has not been deciphered.13 Although this syndrome was reported initially as a fatal syndrome, there have been a number of reported survivors outside of the neonatal period. Van Hove et al,12 reported a 14% survival rate in a review of all reported cases to date in 1995. This report details the management and outcome of patients with Fryns syndrome and CDH from a large cohort of patients with CDH. MATERIALS AND METHODS The Congenital Diaphragmatic Study Group was formed in 1995 for the purpose of compiling data of all babies born with CDH to allow
INDEX WORDS: Fryns syndrome, congenital anomaly, congenital diaphragmatic hernia.
assessment of therapies and outcome. Records of all liveborn patients with CDH between 1995 and 2001 in 83 hospitals were entered into the CDH database. Fryns syndrome was diagnosed clinically by the participating hospitals. Those listed in the database as having Fryns syndrome reviewed retrospectively. Patient demographics, birth information, Apgar scores, treatment details, and outcome were recorded. Data from the subset of patients with Fryns syndrome were compared with the registry data to assess differences in demographics, treatment, and outcome. Data were analyzed using the 2 and Student’s t test.
RESULTS
A total of 1,833 patients were entered in the congenital diaphragmatic study group database. Of these patients, 23 had Fryns syndrome, which accounts for 1.3% of all patients with CDH. Two of the patients included in the study group were listed as having either Fryns syndrome or Cornelia de Lange syndrome. In addition, one patient * This manuscript was prepared by the following investigators who assume responsibility for the overall content: Holly L. Neville, Tom Jaksic, Jay M. Wilson, Pamela A. Lally, William D. Hardin, Jr, Ronald B. Hirschl, Max R. Langham, Jr, and Kevin P. Lally. From the Department of Surgery, University of Texas-Houston Medical School, Houston, TX. Presented at the 35th annual meeting of the Pacific Association of Pediatric Surgeons, La Jolla, California May, 12-16, 2002. Supported in part by a grant from the Section on Surgery of the American Academy of Pediatrics. Address reprint requests to Kevin P. Lally, MD, Department of Surgery, University of Texas—Houston, 6431 Fannin, 5.258, Houston, TX 77030. Copyright 2002, Elsevier Science (USA). All rights reserved. 0022-3468/02/3712-0009$35.00/0 doi:10.1053/jpsu.2002.36695
Journal of Pediatric Surgery, Vol 37, No 12 (December), 2002: pp 1685-1687
1685
1686
had an omphalocele, and one patient had a neural tube defect, whereas 8 had cardiac anomalies. The cardiac anomalies included tetralogy of Fallot, atrial septal defect (ASD) with ventricular septal defect (VSD), coarctation of the aorta, ASD, hypoplastic left pulmonary artery, VSD, and total anomalous pulmonary venous return (TAPVR). The hernia defect was present on the left in 15 patients, the right in 3 patients, bilateral in 2 patients and was unspecified in 3 patients. There were 10 boys and 13 girls. The average birth weight was 2.5 kg (range, 1.5 to 2.98 kg). The average gestational age was 36 weeks (range, 31 to 41). The diagnosis of congenital diaphragmatic hernia was made prenatally in 16 patients. Twelve patients were born at the treating institution, whereas the remaining 11 patients were born at an outside facility and transferred to the treating institution after birth. Despite prenatal diagnosis of CDH, 5 patients required transfer to an appropriate treating facility. Twenty-two of the 23 patients had Apgar scores recorded at one and 5 minutes. The median Apgar scores were 2 (range, 1 to 8) and 4.5 (range, 1 to 9), respectively. All patients experienced early distress requiring intubation within an average of 5 minutes (range, 1 to 104 minutes). Five patients required cardiopulmonary resuscitation during the immediate postnatal period. Extracorporeal membrane oxygenation (ECMO) was used in 4 patients. Seven patients underwent surgical repair at an average age of 7.5 days (range, 6 hours to 14 days). One patient underwent repair primarily and 6 patients underwent repaired using a PTFE patch. The surgical approach was abdominal in 4 patients and thoracic in 2 patients. The abdomen was closed primarily in 3 of the patients, whereas the fourth required placement of a silo to allow closure. One operation, performed on ECMO, was complicated by hemorrhage. This patient received aminocaproic acid and eventually survived to be discharged. Of the 7 patients who underwent surgical repair, 4 survived and 3 died. The time to death was 6, 15, and 168 days for the 3 patients. The first of these had care withdrawn after genetic counseling, the second had care withdrawn because of progressive respiratory distress, and the third died of repeated episodes of sepsis. Sixteen patients did not undergo surgical repair of the diaphragmatic defect. All of these patients died with an average age at the time of death of 2.25 days (range, 30 minutes to 11 days). The parents withdrew care in 4 of these 16 patients after genetic counseling was performed. The parents of 2 patients who did not undergo operation also withdrew support. Overall mortality rate was 83% compared with 33% of patients with unilateral CDH (P ⫽ .01). Ten patients died within the first 24 hours. The median time to death was one day (range, 30 minutes to 180 days). Of the survi-
CDH STUDY GROUP
vors, all 4 underwent repair, the average age at extubation was 19 days (range, 13 to 25) and discharge home was 63 days (range, 32 to 129). None went home on oxygen. Two patients required further operations, one to repair an aortic coarctation, and one to perform a silo removal, abdominal closure, and Nissen fundoplication. Three of the 4 survivors have marked developmental delay, whereas the fourth has not yet undergone formal assessment. There was no significant difference in survival rate based on gender, weight, gestational age or use of ECMO. DISCUSSION
Fryns syndrome is an uncommon genetic condition that frequently involves diaphragmatic herniation. Prior reports had estimated that neonates with Fryns syndrome represented approximately 4% to 10% of all patients with CDH.14,15 The review of the Congenital Diaphragmatic Study Group database showed only a 1.3% incidence of Fryns syndrome over the past 6 years. This difference may be owing to several reasons. First, because information regarding the diagnosis of Fryns syndrome was not specifically requested in the database, presence of the syndrome may be underreported. Second, differences in diagnostic criteria used for Fryns syndrome and the difficulties in which practitioners may have in distinguishing Fryns syndrome from the Pallister Killian or Cornelia de Lange syndromes may have resulted in fewer cases being reported. Last, there may be a difference because of improvements in prenatal diagnosis resulting in termination of pregnancies or the recognition of lethal components of this syndrome at an outside facility resulting in the decision to forego transport to a treating center. Management of the congenital diaphragmatic hernia in patients with Fryns syndrome should not dictate care. Initial resuscitation should be performed to allow identification of associated anomalies and determine prognosis. Lethal anomalies may include severe cardiac or cerebral abnormalities. Once genetic counseling has been performed, the decision to proceed with surgical therapy for the diaphragmatic hernia can be made. Although once thought to be a lethal complex of anomalies, there is significant phenotypic variability, and survival rate has been reported to be approximately 15%.12 The anomalies associated with Fryns syndrome in those patients who do survive appear to have a significant negative impact on the patient’s quality of life. In our series, 3 of the 4 survivors showed significant developmental delay and the fourth is expected to have developmental delay, however, has yet to undergo formal evaluation. One patient, who also had an omphalocele, requires oxygen and home tube feedings. Overall survival rate in this study group
FRYNS SYNDROME AND CDH
1687
was 17% including the infants in whom care was withdrawn, which is similar to the reported survival rate of all patients with Fryns syndrome. Early genetic
counseling should be stressed to allow identification of lethal anomalies to assist in determining which patients are most likely to survive.
REFERENCES 1. Fryns JP, Moerman F, Goddeeris F, et al: A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum Genet 50:65-70, 1979 2. Langer JC, Wintrop AL, Whelan D: Fryns syndrome: A rare familial cause of congenital diaphragmatric hernia. J Pediatr Surg 29:1266-1267, 1994 3. Ayme S, Julian C, Gambarelli D, et al: Fryns syndrome: Report on 8 new cases. Clin Genet 35:191-201, 1989 4. Vargas JE, Cox GF, Korf BR: Discordant phenotype in monozygotic twins with Fryns syndrome. Am J Med Genet 94:42-45, 2000 5. Samueloff A, Navot D, Birkenfeld A, et al: Fryns syndrome: A predictable, lethal pattern of multiple congenital anomalies. Am J Obstet Gynecol. 156:86-88, 1987 6. Lubinsky M, Severn C, Rapoport JM: Fryns syndrome: A new variable multiple congenital anomaly (MCA) syndrome. Am J Med Genet. 14:461-466, 1983 7. Schwyzer U, Briner J, Schinzel A: Fryns syndrome in a girl born to consanguineous parents. Acta Paediatr Scand 76:167-171, 1987 8. Goddeeris P, Fryns JP, Vandenberghe K: Diaphragmatic defects, craniofacial dysmorphism, cleft palate and distal limb deformities: A new lethal syndrome. J Genet Hum 28:57-60, 1980 9. Young ID, Simpson K, Winter RM: A case of Fryns syndrome. J Med Genet 23:82-88, 1986
10. Moerman P, Fryns JP, Vandenberghe K, et al: The syndrome of diaphragmatic hernia, abnormal face and distal limb anomalies (Fryns syndrome): Report of two sibs with further delineation of the multiple congenital anomaly (MCA) syndrome. Am J Med Genet 31:805-814, 1988 11. Cunniff C, Jones KL, Saal HM, et al: Fryns syndrome: An autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia. Pediatrics 85:499504, 1990 12. Van Hove JLK, Spiridigliozzi GA, Heinz R, et al: Fryns syndrome survivors and neurologic outcome. Am J Med Genet 59:334340, 1995 13. Meinecke P, Fryns JP: The Fryns syndrome: Diaphragmatic defects, craniofacial dysmorphism, and distal digital hypoplasia. Further evidence for autosomal recessive inheritance. Clin Genet 28:516520, 1985 14. Phillip N, Fambarelli, Guys JM, et al: Epidemiological study of congenital diaphragmatic defects with special references to aetiology. Eur J Pediatr 150:726-729, 1991 15. Dillon E, Renwick M: Antenatal detection of congenital diaphragmatic hernias: the northern experience. Clin Radiol 48:264-267, 1993
Purpose: Fryns syndrome is characterized by multiple congenital anomalies including Congenital Diaphragmatic Hernia (CDH), and has a reported poor prognosis with a survival rate during the neonatal period of approximately 15%. This report details the management and outcome of patients with Fryns syndrome and CDH.
hours to 14 days). Mortality rate was 83% compared with 33% of patients with unilateral CDH (P ⫽ .01). Ten patients died within the first 24 hours. The parents of 6 patients withdrew support. Of the 4 survivors, 3 have marked developmental delay, whereas the fourth has not yet undergone formal assessment.
Methods: Records of all liveborn patients with CDH between 1995 and 2001 in 83 hospitals were entered into the CDH database. Those with Fryns syndrome were reviewed retrospectively.
Conclusions: The prognosis of infants with Fryns syndrome and congenital diaphragmatic hernia remains grim. Early genetic counseling and recognition of lethal anomalies may assist in determining which patients may survive. J Pediatr Surg 37:1685-1687. Copyright 2002, Elsevier Science (USA). All rights reserved.
Results: A total of 1,833 patients were entered in the database, 23 of these had Fryns (1.3%). All patients experienced early distress requiring intubation. Ten patients (43%) were found to have other major anomalies. Seven patients underwent surgical repair at an average age of 7.5 days (range, 6
F
RYNS SYNDROME was described initially by Fryns, et al, in 1979.1 In this initial description, 2 siblings were stillborn and were each found to have craniofacial anomalies including coarse facies, a flat nasal bridge with a large nose, large mouth, narrow palpebral fissures, low set ears, and cleft palate. In addition, these siblings had hypoplasia of the distal phalanges; a short, webbed neck; and bilateral congenital diaphragmatic hernias.1 Since that time, there have been multiple other case reports of this rare disease.2-10 This syndrome has exhibited a large amount of phenotypic variability; however, the most consistent features are the distal digital hypoplasia, coarse facies, abnormal ears, and congenital diaphragmatic hernia (CDH). CDH is present in approximately 76% to 89% of reported cases.11,12 This syndrome is acquired through an autosomal recessive pattern of inheritance; however, the exact chromosomal abnormality causing this syndrome has not been deciphered.13 Although this syndrome was reported initially as a fatal syndrome, there have been a number of reported survivors outside of the neonatal period. Van Hove et al,12 reported a 14% survival rate in a review of all reported cases to date in 1995. This report details the management and outcome of patients with Fryns syndrome and CDH from a large cohort of patients with CDH. MATERIALS AND METHODS The Congenital Diaphragmatic Study Group was formed in 1995 for the purpose of compiling data of all babies born with CDH to allow
INDEX WORDS: Fryns syndrome, congenital anomaly, congenital diaphragmatic hernia.
assessment of therapies and outcome. Records of all liveborn patients with CDH between 1995 and 2001 in 83 hospitals were entered into the CDH database. Fryns syndrome was diagnosed clinically by the participating hospitals. Those listed in the database as having Fryns syndrome reviewed retrospectively. Patient demographics, birth information, Apgar scores, treatment details, and outcome were recorded. Data from the subset of patients with Fryns syndrome were compared with the registry data to assess differences in demographics, treatment, and outcome. Data were analyzed using the 2 and Student’s t test.
RESULTS
A total of 1,833 patients were entered in the congenital diaphragmatic study group database. Of these patients, 23 had Fryns syndrome, which accounts for 1.3% of all patients with CDH. Two of the patients included in the study group were listed as having either Fryns syndrome or Cornelia de Lange syndrome. In addition, one patient * This manuscript was prepared by the following investigators who assume responsibility for the overall content: Holly L. Neville, Tom Jaksic, Jay M. Wilson, Pamela A. Lally, William D. Hardin, Jr, Ronald B. Hirschl, Max R. Langham, Jr, and Kevin P. Lally. From the Department of Surgery, University of Texas-Houston Medical School, Houston, TX. Presented at the 35th annual meeting of the Pacific Association of Pediatric Surgeons, La Jolla, California May, 12-16, 2002. Supported in part by a grant from the Section on Surgery of the American Academy of Pediatrics. Address reprint requests to Kevin P. Lally, MD, Department of Surgery, University of Texas—Houston, 6431 Fannin, 5.258, Houston, TX 77030. Copyright 2002, Elsevier Science (USA). All rights reserved. 0022-3468/02/3712-0009$35.00/0 doi:10.1053/jpsu.2002.36695
Journal of Pediatric Surgery, Vol 37, No 12 (December), 2002: pp 1685-1687
1685
1686
had an omphalocele, and one patient had a neural tube defect, whereas 8 had cardiac anomalies. The cardiac anomalies included tetralogy of Fallot, atrial septal defect (ASD) with ventricular septal defect (VSD), coarctation of the aorta, ASD, hypoplastic left pulmonary artery, VSD, and total anomalous pulmonary venous return (TAPVR). The hernia defect was present on the left in 15 patients, the right in 3 patients, bilateral in 2 patients and was unspecified in 3 patients. There were 10 boys and 13 girls. The average birth weight was 2.5 kg (range, 1.5 to 2.98 kg). The average gestational age was 36 weeks (range, 31 to 41). The diagnosis of congenital diaphragmatic hernia was made prenatally in 16 patients. Twelve patients were born at the treating institution, whereas the remaining 11 patients were born at an outside facility and transferred to the treating institution after birth. Despite prenatal diagnosis of CDH, 5 patients required transfer to an appropriate treating facility. Twenty-two of the 23 patients had Apgar scores recorded at one and 5 minutes. The median Apgar scores were 2 (range, 1 to 8) and 4.5 (range, 1 to 9), respectively. All patients experienced early distress requiring intubation within an average of 5 minutes (range, 1 to 104 minutes). Five patients required cardiopulmonary resuscitation during the immediate postnatal period. Extracorporeal membrane oxygenation (ECMO) was used in 4 patients. Seven patients underwent surgical repair at an average age of 7.5 days (range, 6 hours to 14 days). One patient underwent repair primarily and 6 patients underwent repaired using a PTFE patch. The surgical approach was abdominal in 4 patients and thoracic in 2 patients. The abdomen was closed primarily in 3 of the patients, whereas the fourth required placement of a silo to allow closure. One operation, performed on ECMO, was complicated by hemorrhage. This patient received aminocaproic acid and eventually survived to be discharged. Of the 7 patients who underwent surgical repair, 4 survived and 3 died. The time to death was 6, 15, and 168 days for the 3 patients. The first of these had care withdrawn after genetic counseling, the second had care withdrawn because of progressive respiratory distress, and the third died of repeated episodes of sepsis. Sixteen patients did not undergo surgical repair of the diaphragmatic defect. All of these patients died with an average age at the time of death of 2.25 days (range, 30 minutes to 11 days). The parents withdrew care in 4 of these 16 patients after genetic counseling was performed. The parents of 2 patients who did not undergo operation also withdrew support. Overall mortality rate was 83% compared with 33% of patients with unilateral CDH (P ⫽ .01). Ten patients died within the first 24 hours. The median time to death was one day (range, 30 minutes to 180 days). Of the survi-
CDH STUDY GROUP
vors, all 4 underwent repair, the average age at extubation was 19 days (range, 13 to 25) and discharge home was 63 days (range, 32 to 129). None went home on oxygen. Two patients required further operations, one to repair an aortic coarctation, and one to perform a silo removal, abdominal closure, and Nissen fundoplication. Three of the 4 survivors have marked developmental delay, whereas the fourth has not yet undergone formal assessment. There was no significant difference in survival rate based on gender, weight, gestational age or use of ECMO. DISCUSSION
Fryns syndrome is an uncommon genetic condition that frequently involves diaphragmatic herniation. Prior reports had estimated that neonates with Fryns syndrome represented approximately 4% to 10% of all patients with CDH.14,15 The review of the Congenital Diaphragmatic Study Group database showed only a 1.3% incidence of Fryns syndrome over the past 6 years. This difference may be owing to several reasons. First, because information regarding the diagnosis of Fryns syndrome was not specifically requested in the database, presence of the syndrome may be underreported. Second, differences in diagnostic criteria used for Fryns syndrome and the difficulties in which practitioners may have in distinguishing Fryns syndrome from the Pallister Killian or Cornelia de Lange syndromes may have resulted in fewer cases being reported. Last, there may be a difference because of improvements in prenatal diagnosis resulting in termination of pregnancies or the recognition of lethal components of this syndrome at an outside facility resulting in the decision to forego transport to a treating center. Management of the congenital diaphragmatic hernia in patients with Fryns syndrome should not dictate care. Initial resuscitation should be performed to allow identification of associated anomalies and determine prognosis. Lethal anomalies may include severe cardiac or cerebral abnormalities. Once genetic counseling has been performed, the decision to proceed with surgical therapy for the diaphragmatic hernia can be made. Although once thought to be a lethal complex of anomalies, there is significant phenotypic variability, and survival rate has been reported to be approximately 15%.12 The anomalies associated with Fryns syndrome in those patients who do survive appear to have a significant negative impact on the patient’s quality of life. In our series, 3 of the 4 survivors showed significant developmental delay and the fourth is expected to have developmental delay, however, has yet to undergo formal evaluation. One patient, who also had an omphalocele, requires oxygen and home tube feedings. Overall survival rate in this study group
FRYNS SYNDROME AND CDH
1687
was 17% including the infants in whom care was withdrawn, which is similar to the reported survival rate of all patients with Fryns syndrome. Early genetic
counseling should be stressed to allow identification of lethal anomalies to assist in determining which patients are most likely to survive.
REFERENCES 1. Fryns JP, Moerman F, Goddeeris F, et al: A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum Genet 50:65-70, 1979 2. Langer JC, Wintrop AL, Whelan D: Fryns syndrome: A rare familial cause of congenital diaphragmatric hernia. J Pediatr Surg 29:1266-1267, 1994 3. Ayme S, Julian C, Gambarelli D, et al: Fryns syndrome: Report on 8 new cases. Clin Genet 35:191-201, 1989 4. Vargas JE, Cox GF, Korf BR: Discordant phenotype in monozygotic twins with Fryns syndrome. Am J Med Genet 94:42-45, 2000 5. Samueloff A, Navot D, Birkenfeld A, et al: Fryns syndrome: A predictable, lethal pattern of multiple congenital anomalies. Am J Obstet Gynecol. 156:86-88, 1987 6. Lubinsky M, Severn C, Rapoport JM: Fryns syndrome: A new variable multiple congenital anomaly (MCA) syndrome. Am J Med Genet. 14:461-466, 1983 7. Schwyzer U, Briner J, Schinzel A: Fryns syndrome in a girl born to consanguineous parents. Acta Paediatr Scand 76:167-171, 1987 8. Goddeeris P, Fryns JP, Vandenberghe K: Diaphragmatic defects, craniofacial dysmorphism, cleft palate and distal limb deformities: A new lethal syndrome. J Genet Hum 28:57-60, 1980 9. Young ID, Simpson K, Winter RM: A case of Fryns syndrome. J Med Genet 23:82-88, 1986
10. Moerman P, Fryns JP, Vandenberghe K, et al: The syndrome of diaphragmatic hernia, abnormal face and distal limb anomalies (Fryns syndrome): Report of two sibs with further delineation of the multiple congenital anomaly (MCA) syndrome. Am J Med Genet 31:805-814, 1988 11. Cunniff C, Jones KL, Saal HM, et al: Fryns syndrome: An autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia. Pediatrics 85:499504, 1990 12. Van Hove JLK, Spiridigliozzi GA, Heinz R, et al: Fryns syndrome survivors and neurologic outcome. Am J Med Genet 59:334340, 1995 13. Meinecke P, Fryns JP: The Fryns syndrome: Diaphragmatic defects, craniofacial dysmorphism, and distal digital hypoplasia. Further evidence for autosomal recessive inheritance. Clin Genet 28:516520, 1985 14. Phillip N, Fambarelli, Guys JM, et al: Epidemiological study of congenital diaphragmatic defects with special references to aetiology. Eur J Pediatr 150:726-729, 1991 15. Dillon E, Renwick M: Antenatal detection of congenital diaphragmatic hernias: the northern experience. Clin Radiol 48:264-267, 1993