two sisters with toriello-carey syndrome

Brief Clinical Report

Two Sisters With Toriello-Carey Syndrome

Yasutsugu Chinen,1 Takaya Tohma,1 Yoshinori Izumikawa,1 Hirohisa Taketomi,1 Tetsu Iha,1Takao Ohta,1 and Kenji Naritomi2*1Department of Pediatrics, University of the Ryukyus School of Medicine, Okinawa, Japan2Department of Medical Genetics, University of the Ryukyus School of Medicine, Okinawa, Japan

Toriello-Carey syndrome comprises agen-esis of the corpus callosum, telecanthus,short palpebral fissures, small nose with an-teverted nares, Robin sequence, abnormallyshaped ears, cardiac defect, and hypotonia.We describe two Japanese sisters with a To-riello-Carey syndrome whose phenotypeswere as severe as reported male cases. Theyounger sister died suddenly at age 4months. Our patients with a severe pheno-type and possible parental consanguinitysuggest autosomal recessive inheritance ofToriello-Carey syndrome. Am. J. Med.Genet. 87:262–264, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: Toriello-Carey syndrome;telecanthus; agenesis of thecorpus callosum; Robin se-quence; cardiac defect

INTRODUCTION

Toriello and Carey [1988] described three sibs (a girland monozygotic male twins) and one unrelated malewith a hitherto undescribed combination of multiplecongenital anomalies comprising agenesis of corpuscallosum, Robin sequence, telecanthus, short palpebralfissures, small nose with anteverted nares, abnormallyshaped ears, laryngeal anomalies, cardiac defect,brachydactyly, and hypotonia. Because the conditionwas presented in sibs of each sex, they suggested au-tosomal recessive inheritance. Lacombe et al. [1992]described a single case born to nonconsanguineous par-ents and proposed the designation, the Toriello-Careysyndrome. Although Czarnecki et al. [1996] reviewed10 reported cases including two of their own and sug-

gested that an X-linked gene or sex-influenced genemight be involved in Toriello-Carey syndrome, we re-port here on two Japanese sisters supporting an auto-somal recessive mode of inheritance as proposed by theoriginal report.

CLINICAL REPORTPatient 1

The patient was the second child born to a healthyG6P3 22-year-old mother and a healthy 22-year-old fa-ther. This couple was nonconsanguineous. Family his-tory was unremarkable. Pregnancy and delivery at 40weeks of gestation were uneventful. Apgar scores were8 and 9 at 1 and 5 min, respectively. Birth weight was3,136 g (appropriate for gestation), length 47.2 cm(−0.9 SD), and OFC 31.5 cm (−1.2 SD). Severe tetralogyof Fallot consisted of ventricular septal defect, pulmo-nary atresia, dextroposition of the aorta, and right ven-tricular hypertrophy. Blalock-Taussig (B-T) shunt wasplaced at age 2 months and the Rastelli operation atage 4 years, 8 months. She could hold her head up afterage 5 months, crawl after 1 year, and stand with sup-port after 2 years. At 4 2/12 years, she was referred tous for mental retardation and multiple congenitalanomalies. Her weight was 11.5 kg (−2.3 SD), height89.5 cm (−3.1 SD), and OFC 45.2 cm (−2.9 SD). She hadtelecanthus, downward slant of palpebral fissures,arched eyebrows, high and wide nasal bridge with an-teverted nostrils, apparently low-set posteriorly angu-lated ears, short and smooth philtrum, “carp-like” openmouth with drooling, high-arched palate, V-shapeddental arches, cleft uvula, and multiple caries probablycaused by enamel defects with malocclusion (Fig. 1a,b). Other findings included cubitus valgus, mild pal-mature, lax finger joints, bilateral malposition of sec-ond toes, and a small umbilical hernia. A skeletalroentgenogram showed coronal notching of lumbar ver-tebral bodies. Brain magnetic resonance imaging dem-onstrated hypoplastic cerebellar hemisphere, vermis,and corpus callosum (Fig. 1c). She had moderate tosevere mental retardation (average DQ 4 43). Shecould neither walk without help nor speak a word. Atage 6 years she acquired wide-based gait but spoke no

*Correspondence to: Kenji Naritomi, M.D., Department ofMedical Genetics, University of the Ryukyus School of Medicine,207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail:naritomi@med.u-ryukyu.ac.jp

Received 20 May 1999; Accepted 27 July 1999

American Journal of Medical Genetics 87:262–264 (1999)

© 1999 Wiley-Liss, Inc.

meaningful words. Conventional G-banded chromo-somes were normal.

Patient 2

The patient was the younger sister of patient 1. Hermother had had a spontaneous abortion and a normaldelivery between them. She was born after 38 weeks ofgestation when both parents were 28 years old. Birthweight was 2,650 g (−0.9 SD). Pregnancy and deliverywere uneventful. Apgar scores were 7 and 8 at 1 and 5min, respectively. Neonatal cyanosis was caused by se-vere tetralogy of Fallot with patent ductus arteriosus.She was treated with lipo-PGE1. A hypoplastic corpuscallosum was suggested by brain echography. At age 9days, she was transferred to our unit for similar symp-toms to patient 1. Her weight was 2,482 g (−1.6 SD),length 48.5 cm (appropriate for age), and OFC 31.2 cm(−1.5 SD). She had a weak cry and short palpebral fis-sures, telecanthus, puffy upper eyelids, sparse eye-brows, small nose with anteverted nostrils, cleft palate,microretrognathia (Fig. 2 a,b), and dyspnea caused byglossoptosis. Hypoplasia of the left optic disc was sug-gested by an ophthalmologist. Brain magnetic reso-nance imaging showed hypoplastic cerebellar hemi-sphere, aplastic cerebellar vermis, and agenesis of thecorpus callosum (Fig. 2c). At age 3 months, a Blalock-Taussig shunt was performed. She was followed-up athome after discharge, however, she died suddenly atage 4 months.

DISCUSSION

We described two sisters with apparent Toriello-Carey syndrome and the cardinal findings of telecan-thus, cleft palate, high-arched palate, cardiac defect(severe tetralogy of Fallot), agenesis of the corpus cal-losum, and cerebellar hypoplasia. The younger sisterwas more severely affected and died in early infancy

with Robin sequence, short palpebral fissures, and hy-poplastic left optic disc. Although the parents deniedconsanguinity, a distant relationship is plausible, be-cause they are habitants in a small remote islandwhere a higher consanguinity rate had been suggested.The occurrence in sisters with phenotypic severityequal to that of males and possible consanguinitystrongly suggest autosomal recessive inheritance.

As pointed out by Jespers et al. [1993], most majoranomalies found in Toriello-Carey syndrome are mid-line field defects, e.g., telecanthus/hypertelorism,broad nasal bridge, cleft palate, laryngeal and pharyn-geal hypoplasia, cardiac defect, omphalocele, corpuscallosum hypoplasia, and vermis hypoplasia. A similarcombination of anomalies is seen in the Opitz syn-drome (MIM #145410 and #300000). Although cerebel-lar hypoplasia has not been reported in Opitz syn-drome, Guion-Almeida and Richieri-Costa [1992] re-ported central nervous system midline anomalies (e.g.,Dandy-Walker anomaly, enlarged cisterna magna, en-larged fourth ventricle, and callosal aplasia or hypopla-sia) in the Opitz syndrome. However, apparent autoso-mal recessive inheritance in our case determined thediagnosis of Toriello-Carey syndrome.

To our knowledge, 11 patients with Toriello-Careysyndrome have been described in six reports [Torielloand Carey, 1988; Lacombe et al., 1992; Jespers et al.,1993; Camera et al., 1993; Czarnecki et al., 1996; Till etal., 1997]. Major findings in 13 cases, including our twocases, are telecanthus/hypertelorism (13/13), micro-gnathia (12/13), cardiac defects (12/13), blepharophi-mosis (11/13), cleft palate (11/13), small nose (10/13),hypotonia (9/13), agenesis of corpus callosum (9/13),

Fig. 1. Patient 1: facial appearance (a), high-arched palate and V-shaped dental arches with multiple caries (b), and hypoplastic corpus cal-losum and cerebellum (magnetic resonance imaging) (c).

Fig. 2. Patient 2: frontal (a) and lateral (b) facial appearance and agen-esis of the corpus callosum and cerebellar hypoplasia (magnetic resonanceimaging) (c).

Toriello-Carey Syndrome 263

and anteverted nares (9/13). Czarnecki et al. [1996]provided a review of 10 cases and pointed out the pre-dominance of affected males (8 of 10 cases) and moreserious clinical course in males. They found no earlydeath in two females in contrast to six males of eightpatients. This suggested that an X-linked gene or sex-influenced gene might be involved in Toriello-Careysyndrome. However, we report here on two sisters withtypical severe phenotype of Toriello-Carey syndromeincluding one early infancy death. Our cases supportautosomal recessive inheritance as proposed originallyby Toriello and Carey [1988]. In addition, because dif-ferential diagnosis between Toriello-Carey syndromeand Opitz syndrome may be difficult, reported malepredominance in Toriello-Carey syndrome might becaused by diagnostic confusion with X-linked recessiveform of Opitz syndrome especially in sporadic casesand in male sib cases.

REFERENCES

Camera G, Righi E, Romagnoli G. 1993. Toriello-Carey syndrome: report ofa new case. Clin Dysmorphol 2:260–263.

Czarnecki P, Lacombe D, Weiss L. 1996. Toriello-Carey syndrome: evi-dence for X-linked inheritance. Am J Med Genet 65:291–294.

Guion-Almeida ML, Richieri-Costa A. 1992. CNS midline anomalies in theOpitz G/BBB syndrome: report on 12 Brazilian patients. Am J MedGenet 43:918–928.

Jespers A, Buntinx I, Melis K, Vaerenberg M, Janssens G. 1993. Twosiblings with midline defects and Hirschsprung disease: variable ex-pression of Toriello-Carey or new syndrome? Am J Med Genet 47:299–302.

Lacombe D, Creusot G, Battin J. 1992. New case of Toriello-Carey syn-drome. Am J Med Genet 42:374–376.

Till M, Bourgeois J, Plauchu H. 1997. Toriello-Carey syndrome. Am J MedGenet 70:332.

Toriello HV, Carey JC. 1988. Corpus callosum agenesis, facial anomalies,Robin sequence, and other anomalies: a new autosomal recessive syn-drome? Am J Med Genet 31:17–23.

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