Familial Diaphragmatic Agenesis: An Autosomal-Recessive Syndrome With a Poor Prognosis

By David L. Gibbs, Henry E. Rice, Jody A. Farrell, N. Scott Adzick, and Michael R. Harrison San Francisco, California

0 Diaphragmatic agenesis is a severe form of congenital diaphragmatic hernia for which an autosomal recessive form of inheritance has been proposed. The authors report six families with 13 pregnancies with diaphragmatic agenesis in which inheritance followed an autosomal recessive pattern, including the first reported case of bilateral diaphragmatic agenesis in twins. None of the thirteen affected fetuses survived. Familial diaphragmatic agenesis appears to be a distinct clinical entity with a worse prognosis than postero- lateral diaphragmatic hernia. Copyrigbto 1997 by W.5. Saunders Company Family 2

were performed. Autopsy results showed an absent left hemidiaphragm and hypoplastic lungs. In 1986, the woman had a healthy girl fathered by a different man. In 1992, the woman had another pregnancy with the original father. Thts male fetus was found to have a CDH, and was referred to our institution. Chromosome studies of the fetus, mother, and father were normal. Ultrasound studies showed a large left diaphrag- matic defect with liver herniated and Incarcerated into the left chest. The fetus died m utero at 26 weeks’ gestation, and no autopsy was performed.

INDEX WORDS: Familial diaphragmatic agenesis, autosomal- recessive inheritance, congenital diaphragmatic hernia.

D IAPHRAGMATIC AGENESIS (DA) is a particu- larly severe form of congenital diaphragmatic

hernia (CDH), which some authors believe is appropri- ately viewed as a distinct clinical entity separate from the more common posterolateral (Bochdalek) diaphragmatic defect.ie3 With improved antenatal diagnosis and perina- tal care, increasing numbers of cases of DA are being diagnosed and evaluated for treatment. An autosomal recessive mode of inheritance has been proposed, but is not agreed on universally.3,4 An accurate diagnosis of DA and an understanding of possible modes of inheritance have important implications in the care and counseling of patients and families with diaphragmatic agenesis.

Our large referral base for prenatally diagnosed CDH includes 202 cases from 1990 through 1995. During this time we evaluated six families with multiple occurrences of diaphragmatic agenesis. We report six families with 13 cases of prenatally diagnosed DA that provide insight into patterns of inheritance and underscore the devastat- ing nature of this anomaly (Fig 1).

In 1984. a 23-year-old woman had a baby girl born with lung hypoplasia. transposition of the great vessels, and atria1 septal defect who died 1 hour after birth. Two prior pregnancies had resulted in healthy baby girls. In 1993 she was referred to UCSF when a routine ultrasound scan showed a fetus with liver incarcerated in the left chest. Fetal chromosomes were normal. This female fetus was delivered at term and underwent surgical repair of her CDH with extracorporeal membrane oxygenation (ECMO) support, but died at 19 days of life from refractory pulmonary hypertension. Surgical and subsequent autopsy findings were remarkable for left diaphragmatic agenesis and hypoplasttc left lung.

The mother was again referred in 1994 for her fifth pregnancy, when she was again noted by ultrasound to have a female fetus with a left CDH and holoprosencephaly. Chromosome studies of the fetus. mother, and father were all normal. The fetus delivered at term at another institution and dted 1 hour later. Autopsy findings showed an absent left hemidiaphragm, holoprosencephaly, and a unicomuate uterus.

Family 3

In 1992 a 3 1 year-old-woman had a boy born with a large left CDH who died 24 hours later. No autopsy was performed. Prior pregnancies included two healthy girls and a miscarriage. A subsequent pregnancy in 1993 resulted in a healthy boy. In 1995 she was referred to us with a female fetus with a left CDH. Thts fetus delivered at another instttution but died 2 hours later of severe bilateral lung hypoplasia. Autopsy results showed bilateral diaphragmatic aplasia with only a S-mm to 1.5.cm antenor rim of diaphragm on each side. The lungs were markedly hypoplastic.

Family I

CASE REPORTS Family 4

In 1984, a 24-year-old woman had a boy born with a CDH who dted shortly after delivery at another institution. No chromosome studies

From the Diviston of Pedratrrc Surgery and the Fetal Treatment Center; Department of Surger), Universtty of Californra, San Francisco. CA.

Presented at the 27th Annual Meeting of the Amerrcan Pediatric Surgical Association, San Diego, Callfornta, May 20-23. 1996.

Address reprint requests to Michael R. Harrtson. MD. Fetal Treat- ment Center, 513 Pamassus Ave, Room I601-HSW San Franctsco. CA 94143-0570.

A 38-year-old woman with a history of two prior elective termma- tions was referred with twins with left CDH diagnosed by routine ultrasound scan. The parents opted to terminate the pregnancy at 20 weeks’ gestation. Postmortem findings were remarkable for monochori- onic, diamniotic twins, both of whom had complete bilateral agenesis of the diaphragm. A subsequent pregnancy resulted in a healthy baby girl.

Family 5

Copyrighr 0 1997 by W.B. Saunders Cornpan!: 0022-3468/97/3202-0044$03.00/O

A 3 l-year-old woman had four pregnancies with four different men that resulted in three normal boys and a girl who was born wtth a large left CDH who died at 19 days after surgtcal repair. No autopsy was performed. She then had four pregnancies with another man, resulting in a normal boy and girl, a boy with a large left CDH who died at 7 days of life after surgtcal repair, and a female fetus who was diagnosed in

366 Journal of Pedtatric Surgery, Vol32, No 2 (February), 1997: pp 366-368

FAMILIAL DIAPHRAGMATIC AGENESIS 367

Fig 1. Pedigree of seven families with multiple episodes of diaphragmatic agenesis. (Circle indicates girl; square indicates boy; triangle represents miscarriage or termination of fetus with no known diagnosis; solid filled shape represents fetus with DA/CDH; shape filled with vertical lines indicates significant diagnosis other than DAKDH; diagonal line indicates decreased; and arborlike junction-represents twin.)

utero to have a left CDH with hermated hver. Chromosome studies of

the fetus, mother, and father were all normal The baby delivered at term

at another inntltution. but died the first day of llte m the operating room

durmg attempted repair of her dlaphragmatlc defect Postmortem

findmgn were remarkable for a hypoplastlc left lung and left dlaphrag-

matlc agenesis.

Family 6

In 1987 a 22.year-old woman had a boy born v+lth a large left CDH

who died shortly after birth. In 1992 she underwent removal of an

ectoplc pregnancy. In 1995 she was referred to us at 33 weeks’ gestation

with a male fetus with I large left CDH The baby was delIvered at term

at our mstitutlon, placed on ECMO at 5 houra of age and subsequently

underwent repan of his dlaphragmatlc defect. Surgical tindmga in-

cluded the presence of only a thm anterior nm of dlaphragmatlc tissue

ECMO was contmued for 10 day5 postoperatlvely. One week later.

inhaled mtrlc oxide therapy was required for I4 days for refractory

pulmonary hypertension The infant died at 4 months of age of

pulmonary msufficlency Postmortem findmgs Included hypoplastic

lungs, left dlaphragmattc agenesIs. and bilateral mgumal hermns.

DISCUSSION

The developing diaphragm normally forms during the third through eighth weeks of gestation from the fusion of the pleuroperitoneal membrane, septum transversum, dorsal esophageal mesentery, and marginal ingrowths of body wall musculature.‘.z True agenesis or aplasia of the diaphragm is thought to result from failure of develop- ment of three of the four diaphragmatic anlagen (pleuro- peritoneal membrane. septum transversum, and dorsal esophageal mesentery).s Although a distinction from a large posterolateral hernia has not always been made in the literature. true diaphragmatic agenesis results in the

368 GIBBS ET AL

presence of only a thin rim of muscular tissue anteriorly derived from the remaining anlage-body wall muscula- ture.

Diaphragmatic hernia of all types occurs between one in 800 and one in 5,000 births.’ True agenesis or aplasia of the diaphragm has been reported to be responsible for anywhere from 1% to 30.9% of all cases of diaphrag- matic hernia.‘.3 This range in incidence is likely a reflection of improved early prenatal diagnosis and the concentration of perinatal care in specialized centers.

fetuses were affected suggesting that an X-linked mode of inheritance is unlikely. Greater than 25% of all fetuses in this study were affected, but a selection bias may exist because only families with more than one case of DA were considered.

In 1968 Passarge et al suggested that unilateral DA may have an autosomal recessive mode of inheritance.6 In a case report and review of the literature, Hitch et al” subsequently identified 40 families with multiple epi- sodes of CDH, and suggested an autosomal recessive mode of inheritance. However, no distinction was made between posterolateral (Bochdalek) hernias and true diaphragmatic agenesis. In 1995 Tsang et al’ reported their experience with 17 neonates with DA, but did not find any familial association in their series. Long-term survival in this group of patients was 29.48, compared with 64.5% of infants with posterolateral defects.

Three fetuses had complete agenesis of both hemidia- phragms, an extremely rare finding. Only seven cases have been reported in the literature, and bilateral diaphrag- matic agenesis has never been reported in twins. Jasnosz et al5 reported that in three of seven cases of complete bilateral diaphragmatic agenesis, affected fetuses had siblings with unilateral diaphragmatic hernia or agenesis. An autosomal recessive mode of inheritance for bilateral diaphragmatic agenesis is also supported by our findings.

The diagnosis of diaphragmatic agenesis in our series of families with CDH was based on pathological informa- tion from surgical and autopsy reports. and was made if only a thin muscular rim of anterior diaphragm was present. For several of the affected siblings in our series, no definitive pathological information was available, and diagnosis was based on prenatal ultrasound scan. In each case for which definitive information was available, true agenesis of the diaphragm on one or both sides was present. A diagnosis of diaphragmatic agenesis was suggested in each remaining case by the presence of a large hernia with sonographic evidence of liver hernia- tion into the chest.

Familial DA was also associated with a dismal progno- sis in our series. Among 13 fetuses with presumed or pathologically proven DA identified, there were no survivors. Although all families were referred to our center for possible in utero treatment, no patient under- went fetal intervention, and only two received postnatal care at our center. Although all the fetuses diagnosed prenatally had access to optimal postnatal care including ECMO, the babies born previously to each family died before or shortly after birth, and did not always have access to definitive surgery or support with ECMO. It is also noteworthy that relatively few other congenital anomalies were found in either affected infants or their siblings. One fetus of 13 had a significant anomaly other than DA (holoprosencephaly), and only one sibling without DA had significant anomalies (multiple cardiac defects).

Results shown in our series suggest an autosomal recessive mode of inheritance in fetuses with familial DA. Fetuses were born to healthy parents, ruling out an autosomal dominant condition. Both male and female

We present six families with multiple episodes of diaphragmatic agenesis for which an autosomal recessive mode of inheritance seems likely. The prognosis for these fetuses is poor. These findings should influence the counseling and perinatal treatment of families with history of diaphragmatic agenesis or multiple episodes of congenital diaphragmatic hernia.

REFERENCES

1. Pollack LD, Hall JG: Posterolateral (Bochdalek’s) diaphragmatic hernia in sisters. Am J Dis Child 133: I I86- 1188. 1979

2. Srlpathl V, Beasley SW: Familial occwrence of complete agenesis of the diaphragm. J Paediatr Child Health 28: 190-19 1, 1992

3. Tsang TM, Tam PK. Dudley NE, et al: Diaphragmatic agenesis as a distinct chmcal entity. J Pediatr Surg 30: 16-18. 1995

4. Hitch DC. Carson JA, Smith EI. et al: Famlhal congenital

dlaphragmatlc hernia is an autosomal recessive vanant. J Pediatr Surg 24:860-864, 1989

5. Jasnosz KM, Hermansen MC, Smder C. et al: Congenital com- plete absence (bilateral agenesis) of the diaphragm: A rare variant of congenital diaphragmatlc hernia Am J Perinatol 11:340-343. 1994

6. Passarge E. Halsey H. German J: Unilateral agenesls of the diaphragm. Humangenetik 5:226-230, 1968