American Journal of Medical Genetics 36477-479 (1990)

Fkaser Syndrome With Renal Agenesis in Two Consanguineous Turkish Families C. Francannet, P. Lefranqois, P. Dechelotte, E. Robert, G. Malpuech, and J.M. Robert Institut Europden des Genomutations, Lyon (CP., E.R., J.M.R.),Pediatric B et Ge'ne'tique(CP., G.M.) and AnatomoPathologie (P.D.), Hbtel-Dieu, Clermont-Ferrand, and Maternite, Centre Hospitalier, Annecy (P.L.), France

We report on 3 girls and one boy from 2 sibships with F'raser syndrome and renal agenesis. They were born to consanguineous parents, which supports an autosomal recessive mode of inheritance.

KEY WORDS cryptophthalmos, consanguinity, autosomal recessive inheritance

INTRODUCTION In 1988, Boyd et al. reported 11 cases of Fraser syndrome [Fraser, 19621 with detailed postmortem findings. These and some other recently published cases led to descriptions of a severe form of the Fraser syndrome that associates the major manifestations of the syndrome (cryptophthalmos, syndactyly, abnormal genitalia) with renal abnormalities. All the described patients were born to unrelated parents. We report on 4 additional cases with detailed autopsy findings from 2 families with consanguinity. CLINICAL REPORTS The 4 cases were reported t o the French RhBne-Alpes Auvergne birth defects registry [Robert et al., 19881 between 1980 and 1988. The first 3 infants, who were seen and examined by one of us (P.L.), died during the neonatal period. The fourth infant, who was stillborn, was seen and examined by P.D. The pregnancy was selectively aborted following prenatal diagnosis by ultrasound. An autopsy was performed in 3 of the 4 cases. Patient 1 (IV.4, Fig. 1) was the fourth infant of a healthy 31-year-old mother who had no previous history of congenital anomaly or miscarriage. The father was 35 years old and healthy. These parents are Turkish and are first cousins. The infant was born at 40 weeks of gestation after an uncomplicated pregnancy with severe ~

Received for publication May 8,1989; revision received August 9, 1989. InstiAddress reprint requests to Christine Francannet, M.D., tut Europeen des Genomutations, 86, rue Edmond Locard, F-69005 Lyon, France.

0 1990 Wiley-Liss, Inc.

respiratory distress and died after 5 minutes. The birth weight was 3,400 g and the crown-heel length was 52 cm. There was bilateral cryptophthalmos, low-set ears, hooked nose, microstomia, hirsutism, ambiguous genitalia, bilateral syndactyly of fingers and toes with no recognizable digits on either hand or foot, and bilateral talipes equinovarus. Chromosomes were normal (46,XX).The parents refused autopsy. Patient 2 (IV.5, Fig. 11, the fifth infant of the same family, was delivered at 34 weeks and died 5 minutes after birth. Birth weight was 1,900 g and crown-heel length was 44 cm. Postmortem examination showed complete cryptophthalmos on the left side and partial on the right side, small nose and microstomia, low-set ears (Fig. 21, ambiguous genitalia, bilateral syndactyly of fingers and toes (Fig. 3a), left renal agenesis, right renal cystic dysplasia, and single umbilical artery. Chromosomes were normal (46,XX). Patient 3 (IV.8, Fig. 11, a hypotrophic and macerated stillborn at 36 weeks' gestation, was the eighth infant of the same family. Birth weight was 1,600 g and crownheel length was 35 cm. Postmortem examination showed right cryptophthalmos with microphthalmia, low-set ears, small nose with a small cleft, microstomia, bilateral syndactyly of fingers and toes, no recognizable digits on the right hand, syndactyly 3-4 on the left hand, partial syndactyly 2-3 on the left foot, partial syndactyly 2-3-4-5 on the right foot, bilateral renal agenesis, and hypoplastic labia majora. Chromosomes were normal (46,XX). Patient 4 (IV.2, Fig. 4) was the second child of a healthy 23-year-old mother and 28-year-old father, who are Turkish and double first cousins (Fig. 4). There was no previous history of congenital malformation or miscarriage. The pregnancy was complicated by oligohydramnios from the 24th week of gestation. At this stage, ultrasound scan was performed after expanding the volume of the amniotic cavity with physiological saline, and it showed hydrops fetalis and bilateral renal and urinary tract agenesis. The pregnancy was terminated. The fetus weighed 820 g and the crown-heel length was 31 cm. Postmortem examination showed bilateral cryptophthalmos with microphthalmia, typical Potter face (Fig. 5) with compressed and low-set ears; small and flattened nose; high-arched palate; laryngeal stenosis with large lungs filling the chest; agenesis of

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Fig. 1. Family pedigree.

Fig. 2. Patient 2. Note the complete cryptophthalmos on the left side and the partial one on the right side.

the kidneys, ureters, and the urinary bladder; right talipes equinovarus with partial cutaneous syndactyly of the toes; and partial cutaneous syndactyly 1-2 of the right hand (Fig. 3b,c). Chromosomes were normal (46,XY).

DISCUSSION According to the diagnostic criteria suggested by Thomas et al. [1986], these 4 patients have Fraser syndrome. Patients 1,2, and 3 had the 4 major criteria of this syndrome: cryptophthalmos, syndactyly, abnormal genitalia, and a sibship with cryptophthalmos syndrome. They also had 2 or 3 of the minor criteria: malformation of the nose, malformation of the ears, malformation of the larynx, cleft lip and/or palate, skeletal defects, umbilical hernia, renal agenesis, and mental retardation. Our fourth case seems to fulfill the criteria, since cryptophthalmos and syndactyly were associated

Fig. 3. a: Patient 2. Note the syndactyly of feet. b, c: Right foot and right hand of patient 4. Note the partial cutaneous syndactyly of the toes and the partial syndactyly of the right thumb and right index finger.

with 4 minor criteria (malformation of the nose, malformation of the ears, malformation of the larynx, and renal agenesis). Several families with a severe form of F'raser syndrome have been described [Barry and Shortland-Webb, 1980; Bieber et al., 1982; Boyd et al., 1988; Burn and Marwood, 1982; Chemke, 1981;Codere et al., 1981;Emberger et al., 1976; Koenig and Spranger, 1986; Lurie and Cherstvoy, 1984; Mashimoto et al., 1987; Mortimer et al., 1985; Thomas et al., 19861. Some ofthese families included sib pairs, suggesting an autosomal recessive disorder. Both families described here are Turkish. As consanguineous marriage rates in Turkish populations (21.21%) are high compared to Western countries [Basaran et al., 19881, one needs to be aware that the parental consanguinity may be coincidental. Nevertheless, we believe that these 2 families lend support to the hypothesis of autosomal recessive inheritance.

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Fig. 4. Family pedigree.

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Fig. 5. Patient 4. Note the Potter face with bilateral cryptophthalmos.

ACKNOWLEDGMENTS The authors are to Jean-C1aude GUY Ragonnaud, and Marc Fort for their tribution in setting up the figures.

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REFERENCES

Barry DR, Shortland-Webb WR (1980): A case of the cryptophthalmos syndrome. Ophthalmologica 180:234-240. Basaran N, Sayli BS, Basaran A, Solak M, Artan S, Stevenson J D (1988):Consanguineous marriages in the Turkish population. Clin Genet 34:339-341. Bieber FR, Page DV, Holmes LB (1982): Variation in expression of the cryptophthalmia syndrome. Am J Med Genet 34:81A. Boyd PA, Keeling JW, Lindenbaum RH (1988):Fraser syndrome (cryptophthalmos-syndactyly syndrome): A review of eleven cases with postmortem findings. Am J Med Genet 31:159-168. Burn J , Marwood RP (1982): Fraser syndrome presenting as bilateral renal agenesis in three sibs. J Med Genet 19:360-361. Chemke J (1981): Absent eyelids, genital abnormalities, congenital heart defect, absent kidney and limb abnormalities. Synd Ident 7:18-19. Codere F, Brownstein S,Chen MF (1981): Cryptophthalmos syndrome with bilateral renal agenesis. Am J Ophthalmol 91:737-742. Emberger JM, Pinceman D, Taib J , Caderas de Kerleau J (1976):Etude anatomique d u n e observation de cryptophtalmie bilaterale. J Genet Hum 24 (Suppl):23-29. Fraser GR (1962): Our genetic load: A review of some aspects of genetical variation. Ann Hum Genet 25387-415. Koenig R, Spranger J (1986): Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clin Genet 29:413-416. Lurie LW, Cherstvoy ED (1984):Renal agenesis as a diagnostic feature of the cryptophthalmos-syndactyly syndrome. Clin Genet 25:528-532. Mashimoto H, Ikeda T, Matsuo H, Maeda H, Shimokawa I, Fujishita H (1987): Cryptophthalmia syndrome with laryngeal atresia and bilateral renal agenesis: A case report and a review of the literature. Cong Anom 27:l-10. Mortimer G, McEwan HP, Yates JRW (1985):Fraser syndromepresenting as monozygotic twins with bilateral renal agenesis. J Med Genet 22:76-78. Robert E, Francannet C, Robert J M (1988): Le registre de malformations de la region RhBne-AlpeslAuvergne. J Gynecol Obstet Biol Reprod 17:601-607. Thomas IT, Frias JL, Felix V, Sanchez de Leon L, Hernandez RA, Jones MC (1986): Isolated and syndromic cryptophthalmos. Am J Med Genet 25:85-98.

Fraser syndrome with renal agenesis in two consanguineous Turkish families.

We report on 3 girls and one boy from 2 sibships with Fraser syndrome and renal agenesis. They were born to consanguineous parents, which supports an ...
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