American Journal of Medical Genetics 22:357-360 (1985)

Brief Clinical Report: Autosomal Recessive Syndrome of Sacral and Conotruncal Developmental Field Defects (Kousseff Syndrome)

Helga V. Toriello, Joan K. Sharda, and Edgar J. Beaumont

Blodgett Memorial Medical Center (H. V. T ) and Butterworth Hospital (J. K. S., E.J.B.), Grand Rapids, Michigan and Department of PediatricsMuman Development, Michigan State Univiersity, East Lansing (H. V. 1)

Kousseff [ 19841 reported on three sibs with an autosomal recessive syndrome of sacral meningocele, conotruncal heart defects, and minor anomalies of head and neck. We report on a fourth case and discuss the findings from a developmental field perspective and the ramifications for genetic counseling.

Key words: spina bifda, myelomeningocele, congenital heart defect, neural crest cell, multiple congenital anomalies, autosomal recessive inheritance

INTRODUCTION

Kousseff [1984] reported on 3 sibs with a syndrome of sacral meningocele, conotruncal cardiac defects, unilateral renal agenesis (in one of the sibs), apparently lowset posteriorly angulated ears, retrognathia, and short neck with low posterior hairline. Inheritance was thought to be autosomal recessive. We report on a fourth case with virtually identical clinical findings and suggest that this represents a recognizable condition-the Kousseff syndrome.

CLINICAL REPORT

This male infant was born at term by repeat Cesarean section to a 26-year-old (3.5, P2, Ab2 Hispanic mother. The father of the child is Afro-American and unrelated to the mother. During her pregnancy the mother had a mild “kidney infection,” which was treated with antibiotics. Birth weight was 2,780 gm, length was 50.5 cm, occipito-frontal circumfrence (OFC) was 33.0 cm, and Apgar scores were 8 and 9 at 1 and 5 min, resepectively. A midline, round sacral mass was noted at birth.

Received for publication January 28, 1985; revision received March 14, 1985.

Address reprint requests to Dr. Helga V. Toriello, GenetidBirth Defects/Neurology Clinic, Blodgett Memorial Medical Center, 1840 Wealthy St., Grand Rapids, MI 45906.

0 1985 Alan R. Liss, Inc.

358 Toriello, Sharda, and Beaumont

Subsequent examination showed a normal cranium, normal anterior fontanelle measuring 1.5 x 2.0 cm, depressed nasal tip, retrognathia, small (( 3 cm), apparently lowset posteriorly angulated ears, long fingers, and wide space between the first and second toes (Figs. 1,2). Although the nipples appeared wideset, measurements showed that the chest was small; at age 1 month, chest circumference was 31.0 cm (( 3rd centile); internipple distance was 8.0 cm (25th centile). Fingerprint patterns and palmar creases were unremarkable.

The sacral mass was 3.5 cm in diameter, was pedunculated and cystic, and was fully epithelialized without cerebrospinal fluid leak; it transilluminated well. The infant had good tone in all limbs and an anal wink upon pinprick. When the mass was removed it was found to be a sacral myelomeningocele containing cauda equina neural elements. Cerebral ventricles and kidneys were normal on ultrasonagraphy . A soft systolic murmur was first audible on the fifth day of life and was associated with a slight increase in precordial activity. Chest films and ECG demonstrated, respec- tively, marked cardiomegaly with mildly increased pulmonary markings and right axis deviation and right ventricular hypertrophy. When the murmur became continu- ous an echocardiogram showed a large interventricular septa1 defect, overriding aorta, and possible poulmonary atresia. Aortic dimensions and left atrial diameter were markedly increased. Cardiac catheterization demonstrated a truncus arteriosus type I, with some restriction at the truncal valve. At 1 month, hydrocephalus was suspected, but CT scan was normal. Chromosomes were also normal (46,XY).

DISCUSSION

Both spina bifida cystica (SBC) and conotruncal congenital heart defects are causally heterogeneous malformations. Most of these defects occur in families in a

Fig. 1. Propositus at 1 month. Note depressed nasal tip and small chest.

Fig. 2 . Side view of propositus. Note retrognathia, small and apparently lowset ear, and short neck.

Kousseff Syndrome 359

pattern consistent with the multifactorial model, although, in rare cases, each defect can also be caused by a single autosomal or X-linked gene [Zuckerman et al, 1962; Toriello et al, 19801. Each of these malformations can also occur as part of several associations and syndromes [Noonan, 1978; Optiz and Gilbert, 19821.

Although Opitz and Gilbert [1982] have suggested that midline defects tend to occur together more often than by chance (schisis-association), they have also sug- gested that “several pleitropic mutations tend to exert their effect predominantly on the midline.” The occurrence of several of these malformations in one child could be construed as an example of schisis-association; however, the occurrence in sibs and the phenotypic consistency in all cases with respect to major malformations and minor anomalies suggest that this is more likely an example of the latter case, ie, a monogenic syndrome that affects several midline structures (spinal cord, heart, and kidneys). However, it must be noted that in this syndrome midline structures are affected in a specific way: To date the SBC has always been a sacral defect, and the cardiac anomaly has always been a conotruncal defect. This syndrome provides evidence for the hypothesis that at least two developmental field defects can cause SBC, with sacral and some lumbosacral defects being pathogenetically distinct from higher level defects, such as encephaloceles [Toriello and Higgins, 19851. Conotrun- cal heart defects are also likely to be a developmental field defect, and pathogeneti- cally distinct from blood flow defects [Ardinger et al, 1984; Graham and Merill, 19841. Furthermore, Bockman and Kirby 119841 have shown that cephalic neural crest contributes not only to head and neck structures but also to the formation of the aorticopulmonary septum. Therefore, a developmental field defect of this region could lead to both conotruncal cardiac defects and minor facial anomalies, such as micrognathia, anomalous ears, and short neck.

Holmes et a1 119761, and more recently Khoury et a1 119821 and Martin et a1 [1983], have suggested that isolated neural tube defects (NTD) have a recurrence of 2-3 % ; however, NTD with other malformations has a recurrence risk of essentially 0%. Clearly, the latter figure must be viewed with caution; it is likely that in some instances NTD’s with other malformations are attributable to monogenic syndromes with high recurrence risks. In the present case, as in the Meckel syndrome, that risk is 25%.

The Kousseff syndrome might not be a rare condition. Among 470 infants with conotruncal defects, three had associated myelomeningocele [Wallgren et al, 19781 ; and among 434 children with myelomeningocele four had conotruncal heart defects [Brown, 19751. Therefore, this syndrome could account for as many as one per hundred SBC cases.

In summary, we describe sacral SBC, conotruncal cardiac defect , and minor facial anomalies in an infant. The same findings were reported in three sibs by Kousseff [ 19841 ; autosomal recessive inheritance is likely. We suggest the eponym Koussefs syndrome.

REFERENCES

Ardinger HH, Clarke EB, Hanson JW (1984): Cardiovascular anomalies in craniofacial disorders: Pathogenetic and epidemiologic implications. Paper presented at the David W. Smith Workshop on Malformations and Morphogenesis, Boca Raton, FL.

Bockman DE, Kirby ML (1984): Dependence of thymus development on derivatives of the neural crest. Science 223:498-500.

360 Toriello, Sharda, and Beaumont

Brown SF (1975): Congenital malformations associated with myelomeningocele. J Iowa Med Soc 65: 101-104.

Graham JM Jr, Merill E (1984): Cardiac features of the “CHARGE” association: Support for involve- ment of the neural crest. Paper presented at the David W. Smith Workshop on Malformatins and Morphogenesis, Boca Raton, FL.

Holmes LB, Driscoll SG, Atkins LA (1976): Etiologic heterogeneity of neural tube defects. N Engl J Med 294:365-369.

Khoury MJ, Erickson JD, James LM (1982): Etiologic heterogeneity of neural tube defects. I1 Clues from family studies. Am J Hum Genet 34:980-987.

Kousseff BG (1984): Sacral meningocele with conotruncal heart defects: A possible autosomal recessive trait. Pediatrics 74:395-398.

Martin RA, Fineman RM, Jorde LB (1983): Phenotypic heterogeneity in neural tube defects: A clue to causal heterogeneity. Am J Med Genet 16:519-525.

Noonan JA (1978): Association of congenital heart disease with syndromes or other defects. Pediatr Clin North Am 25:797-816.

Opitz JM, Gilbert EF (1982): Editorial comment: CNS anomalies and the midline as a “developmental field.” Am J Med Genet 12:443-455.

Toriello HV, Higgins JV (1985): Possible causal heterogeneity in spina bifida cystica. Am J Med Genet 21:13-20.

Toriello HV, Warren ST, Lindstrom JA (1980): Brief communication: Possible X-linked anencephaly and spina bifida-Report of a kindred. Am J Med Genet 6: 119-121.

Wallgren EI, Landtman B, Rapola J (1978): Extracardiac malformations associated with congenital heart disease. Eur J Cardiol 7:15-24.

Zuckerman HS, Zuckerman GH, Mammen RE, Wassermil M (1962): Atrial septa1 defect. Familial occurrence in four generations of one family. Am J Cardiol 9:5 15-520.

Edited by John M. Opitz and James F. Reynolds