Address correspondence to: Dr. Robert Roger Lebel, Genetics Services, 360 West Butterfield Road, Suite 245, Elmhurst, IL 60126. Tel: 708-832-4363. Fax: 708-832-9580. (all authors) Hinsdale Hospital, Hinsdale, IL and High Tech Medical Park, Palos Heights, IL

Synonyms: VATER, VACTEL, VACTERL, twinning.

Definition: Multiple-malformation association.

Prevalence: Approximately 300 reported cases.

Etiology: Multifactorial.

Pathogenesis: Uncertain.

Associated anomalies: Vertebral, rib, gastrointestinal, pulmonic, cardiac, limb, renal.

Differential diagnosis: None.

Prognosis: Highly variable: from mild to lethal.

Recurrence risk: From 1%, up to 50%.

Management: Depending on actual malformations.

MESH Vater BDE 0987 ICD9 759.8 (other anomalies) 753.0 (renal agenesis) CDC 753.000

Introduction

Monozygous twins, thought prenatally to be normal, were discordant for multiple malformations (VACTERL association) at birth. The affected twin had total renal agenesis, but normal lungs because the co-twin produced amniotic fluid. Death of the affected twin occurred due to respiratory distress associated with tracheo-esophageal fistula.

Case report

A 19-year-old primigravida was known to be carrying twins. Date of last menstruation was uncertain. She was given an expected date of confinement based on community-hospital ultrasound examining the second trimester. No abnormalities were appreciated in either fetus. She was not diabetic, and had no documented potentially teratogenic exposures. Spontaneous rupture of membranes occurred at 32 weeks of gestation. Emergency Cesarean section was performed, indicated by breech presentations.

The first-born, an apparently normal female, had Apgar scores of 8 at 1 minute and 9 at 5 minutes. Weight was 1163g (<10th percentile for 32 weeks). Respiratory distress developed, and the child was transferred to a nearby university medical center where she did well. She was lost to follow-up, and we do not have a karyotype, but she was anatomically normal.

The second twin, considered in the delivery room to be a male, had Apgar scores of 2 at 1 minute and 2 at 5 minutes. Weight was also 1163g. Cyanosis, failure to move or to cry, and bradycardia (maximum rate of 98 beats per minute) were apparent; neither a neonatologist nor an anesthesiologist could achieve endotracheal intubation. Cardiac arrest occurred 103 minutes after delivery. No external malformations were noted by those in attendance.

At autopsy, external malformations were: 1) maldefinition of genitalia (small phallus, no apparent urethral meatus; abnormal labia, appearing somewhat like a bifid scrotum), and 2) imperforate anus. The total length of the body was 374 mm (50th percentile for 30 weeks, below 5th for 32); crown-rump length was 258 mm (50th percentile for 30 weeks).

Radiographs revealed L4-5 vertebral fusion, and asymmetry of lumbar arches. Introduction of contrast material under fluoroscopic observation revealed an H-type tracheo-esophageal fistula near the carina. This was judged to have obstructed the intubation.

The internal examination was notable for tracheo-esophageal fistula, stenosis of right mainstem bronchus, blind esophagus above the diaphragm, hypoplastic right heart and pulmonic arteries, accessory spleen at the tail of the pancreas, absent kidneys, ureters and bladder (total agenesis), hypoplastic uterus and normal lungs.

The umbilical cord from this child had only one artery; that from the normal sister was trivascular. There was a narrow urethral lumen. An in-situ neuroblastoma was found in the left adrenal. The ovaries and ducts had a normal appearance but the uterus was hypoplastic. The membranes were diamniotic-monochorionic, (monozygous). Fibroblasts revealed a genotype of 46,XX (normal for a female).

Discussion

Total renal agenesis is usually associated with intrauterine or perinatal fetal demise, due to the effects of severe oligohydramnios: compression of the fetus with resultant heart failure, and/or severe pulmonary insufficiency after prolonged inability to expand and mature the alveolar tree. In renal agenesis in one of a pair of monoamniotic twins, the fetus with normal renal function has the opportunity to provide fluid volume for the affected fetus, changing the natural history of the condition. We are aware of only two previous reports of such events.

The VACTERL association is a malformation complex which may occur as a sporadic event (increased risk to infants of diabetic mothers), or may be hereditary (probable autosomal dominant pattern - MIM 192350)2. The name is an acronym for the syndrome, but the condition may be diagnosed with as few as 3 components present (especially in the event of a familial recurrence):

The VACTERL association has been diagnosed prenatally³. When abnormalities are severe, this may be possible quite early, if a sufficiently detailed ultrasound examination is performed. In the present case, the opportunity to appreciate total renal agenesis and/or other abnormal features of the fetus appears to have been missed due to the examination having been relatively cursory.

Complete or unilateral renal agenesis may occur as an isolated malformation, which can be inherited as a dominant trait (MIM 191830, renal dysplasia,^3,4), or may be associated with other abnormalities in syndromes.

Combined urogenital malformations, such as in this child with ambiguous genitalia as well as total renal agenesis, may be an extreme manifestation of renal dysplasia, but association of tracheo-esophageal fistula, imperforate anus, vertebral malformations and cardiac abnormalities, with normal karyotype, make this clearly an instance of VACTERL.

Since this child was a monozygous twin, her malformation syndrome may be considered a sporadic developmental field defect, perhaps a manifestation of the twinning process. Single umbilical artery is associated with urogenital.

The presence of in-situ neuroblastoma is of interest because the lesion has not, to our knowledge, been reported in association with VACTERL. It has, however, been reported with various malformations including mitral atresia, abnormal great vessels, cleft palate with hydrocephaly and microphthalmia, hydronephrosis due to bilateral uretero-pelvic obstruction, hypoplastic right ventricle, Arnold-Chiari malformation with imperforate anus and heart defects, and Tetralogy of Fallot⁵.

In situ neuroblastoma lesions have been considered to be histologically (and presumably pathologically) identical to neuroblastomas, found as microscopic incidental findings at autopsy. Beckwith and Perrin5 disputed this theory, noting discreteness of lesions, lack of invasiveness, and higher than expected incidence in their series of patients. They accepted the hypothesis that some of these lesions progress to more highly differentiated neoplasms.

This autopsy is of special interest because it illustrates the fact that much of the phenotype often referred to as Potter syndrome is largely dependent on the prolonged severe oligohydramnios which ordinarily occurs in total renal agenesis. The co-twin with kidneys produced a normal volume of amniotic fluid, which we suppose must have been available to the anephric twin via disruption of the separating membrane. Thus, lungs of the anephric child were normally developed, there were no contractures of the large joints or signs of congestive heart failure (despite major cardiac malformation), and there was no deformation of the skull and face.

This case differs from the previously reported cases known to us. The infants seen by Mauer et al.6 were normal except for for their renal dysgenesis; the anephric male died of uremia at 11 days of life. It was only as his health deteriorated that the lethal abnormality was noted. The surviving boy was then studied, and found to have unilateral renal agenesis; he did well.

DiLorenzo et al^.7, reported ultrasound at 19 weeks of gestation suggestive of caudal regression in one twin. At birth, the child had sirenomelia but normal lung and no other signs usually seen in Potter syndrome or singleton sirens. The autopsy revealed total renal agenesis but normal lungs. It is of interest that sirenomelia is also reported as a sporadic event with increased risk in certain circumstances (e.g. maternal diabetes and monozygous twinning).

References

1. Potter, EL: Pathology of the Fetus. Chicago: Year Book Medical Publications, 1961.

2. McKusick VA: Mendelian Inheritance in Man. Tenth Edition. Baltimore: Johns Hopkins University Press, 1992.

3. Weaver DD: Catalog of Prenatally Diagnosed Conditions. Second Edition. Baltimore. Johns Hopkins University Press, 1992.

4. Buchta RM, Viseskul C, Gilbert EF, Sarto GE, Opitz JM: Familial bilateral renal agenesis and hereditary renal adysplasia. Z Kinderheilk 115:111-129, 1973.

5. Beckwith JB, Perrin EV: In situ neuroblastomas: a contribution to the natural history of neural crest tumors. Am J Pathol 43:1089-1104, 1963.

6. Mauer SM, Dobrin RS, Vernier RL: Unilateral and bilateral renal agenesis in monoamniotic twins. J Pediatr 84:236-238, 1974.

7. DiLorenzo M, Brandt ML, Veilleux A: Sireno¬melia in an identical twin: a case report. J Pediatr Surg 26:1334-1336, 1991.