Velocardiofacial syndrome

Abstract

Partial tetrasomy of chromosome 22 is a rare multiple congenital anomaly syndrome that is more commonly known as cat-eye syndrome (CES). It is caused by the duplication of a 2-million base region of chromosome 22 (22 pter [right arrow] q 11.2). The phenotype is extremely variable, and its clinical characteristics include a combination of craniofacial, cardiac, renal, gastrointestinal, and genitourinary defects. We describe a rare occurrence of CES in a Brazilian family. Three siblings were effected--monozygotic twin boys and their younger brother. All 3 were born to healthy nonconsanguineous parents. On examination, all 3 were found to have strabismus, primary telecanthus, bilateral coloboma iridis, and low-set ears with posterior rotation of the pinnae. Partial tetrasomy of chromosome 22 was confirmed by fluorescent in situ hybridization. To our knowledge, this" is the first report of such an occurrence in one family. We discuss the genotype and phenotype of CES, with particular reference to inheritance patterns and craniofacial defects.

Introduction

The association among coloboma iridis, auricular deformity, and anal atresia was first described by Haab in 1879. (1) However, it was not until 1965 that Schachenmann et al proposed the term cat-eye syndrome (CES) to describe the phenotype. (2) The estimated incidence of this rare syndrome is 1 in 150,000 live births. (3)

CES is a multiple congenital anomaly syndrome. It is of special interest to otolaryngologists because it consistently manifests as a spectrum of craniofacial defects. The complex genetic pathways that govern craniofacial development are still poorly understood, so analysis of the critical CES regions may provide important clues to unlocking and understanding these pathways. (4)

In 1986, cytogenetic examination of patients with CES revealed that they have an extra G-like chromosome that is smaller than chromosome 21.5 Subsequently, it was shown that the supernumerary CES chromosome is dicentric, the result of the duplication of a 2-million base region of the long arm of chromosome 22 (22 pter [right arrow] q 11.2). (6,7) Diagnosis is confirmed by fluorescent in situ hybridization (FISH) examination with a chromosome 22 library. (8)

The additional chromosome 22 generally arises de novo from one of the parents; transmission is possible by both sexes. (3) When an affected child has been identified, both parents and any siblings should undergo chromosome examination. Any patient with CES and normal fertility has a 50% chance of having an affected child. (1,2,4) No data are available on the risk of CES transmission by unaffected siblings ofa CES patient.

Two types of CES have been described. Depending on the breakpoint on the chromosome, a patient might have small-type CES 1 or large-type CES II. (9) It is interesting that no correlation between the length of the replicated segment and the severity of the clinical features has been demonstrated. (10) The critical CES syndrome region undoubtedly contains one or more genes involved in regulating embryonic development and growth. (3,10) In 2000, Riazi et al reported that they had isolated and characterized a gene--CECR1 (cat-eye syndrome chromosome region, candidate 1)--that maps to this region. It The CECR1 gene is alternately spliced and expressed in numerous tissues, including cranial nerve ganglion VII/VIII, the notochord, the placenta, the lymphoblasts, and the developing heart, lungs, and kidneys. (11) The protein encoded by this gene is similar to previously identified growth factors, and overexpression of CECR1 may be responsible for at least some features of CES. (11)

Case report

A pair of 6-year-old identical twin boys and their 4-year-old brother were referred for assessment to the Department of Paediatric Otolaryngology and the Department of Ophthalmology at the Federal University of Minas Gerais in Belo Horizonte, Brazil. All 3 had been born at the conclusion of uncomplicated full-term pregnancies to healthy, unrelated parents.

Ophthalmologic examination demonstrated that all 3 children had strabismus, primary telecanthus, and bilateral coloboma iridis (figure). Fundoscopy did not detect any other abnormalities. Their external ears were low-set and marked by posterior rotation. Measurements of the external ears, the eyes, and other landmarks were made in accordance with methods established by Hall et al in 1989. (12) The external auditory canals were narrow, and the tympanic membranes were intact and healthy-looking.

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Findings on anterior rhinoscopy, oral cavity examination, and flexible fiberoptic nasal endoscopy were normal in all 3 children. The results of audiologic examinations, including speech discrimination testing, were also normal. We determined that all 3 boys were of normal intellect and that their speech and language development was appropriate for their age. Their height, weight, and head circumference were between the 50th and 75th percentiles for their age. No congenital anomalies were detected on subsequent clinical and radiologic investigation of the major systems.

FISH karyotyping with the use of a chromosome 22 library confirmed a diagnosis of CES in all 3 boys. Their parents were offered clinical examination and karyotyping, but both refused; neither exhibited any obvious clinical manifestations of CES.

Discussion

The critical CES region on chromosome 22 undoubtedly contains one or more genes that control the embryonic development of a number of craniofacial structures and other major systems. (5,6,8,11) This region (22 q 11) is known to be susceptible to rearrangements, and it is implicated in other congenital anomaly syndromes such as unbalanced 11/22 translocation, velocardiofacial syndrome, and DiGeorge syndrome. (3)

Some patients with the chromosomal aberration are entirely normal or only marginally affected. Others experience the full pattern of malformation, and some eventually die of their condition. For most patients, however, life expectancy is not significantly shortened and growth retardation is variable. Hyperactivity and behavioral problems have been reported, but most patients have a normal or near-normal intellect. (2,4,6)

A multitude of congenital anomalies associated with CES have been described in the literature. Some of the most consistent findings are abnormalities of the external ear, which are seen in as many as 70% of patients; these abnormalities include preauricular tags or pits, microtia, anotia, and external auditory canal stenosis. (2,3,6) Although malformations of the external ear are common in patients with CES, low implantation and malrotation are rare. Conductive hearing loss may be severe, depending on the degree of malformation and the possibility of additional middle ear defects such as ossicular chain malformations. (3,13) Moderate to severe, nonprogressive sensorineural hearing loss has also been reported. (3,6) Other craniofacial malformations include hypertelorism, flat nasal bridge, choanal atresia, hypoplastic mandible, and clefting of the lip and palate. (14) The most common eye malformation is coloboma iridis, which is present in 50% of CES patients; it can be either unilateral or bilateral. Other findings include inner epicanthic folds, telecanthus, strabismus, corneal clouding, cataracts, and coloboma of the eyelids, choroids, or optic nerve. (4,6,15)

Congenital cardiac malformations occur in approximately 35% of patients; they are characterized by a completely anomalous pulmonary venous return and by the tetralogy of Fallot. (6,16,17) Approximately 50% of patients have renal malformations, most commonly horseshoe kidney, hydronephrosis, or unilateral agenesis. (14,17) Anal atresia, which was originally believed to be a diagnostic criterion, is actually present in fewer than 35% of patients; it always manifests with a fistula into the bladder, vagina, perineum, or urethra. (4,14,17) Abnormalities of the reproductive system include cryptorchidism, hypospadias, hypoplastic uterus, and vaginal atresia. (3,17)

Both parents in our case were asymptomatic and phenotypically normal, and both refused chromosome analysis. However, it is possible that one of them carried the chromosome abnormality. The other possibility is that mosaicism may have occurred in one of the parents, perhaps in the gonads. Had the parents undergone chromosome analysis, the results would have facilitated psychological support and genetic counseling for the family. An accurate diagnosis would have also helped define the risk of recurrence.

As for the patients themselves, it is essential that they be thoroughly assessed soon after birth and that the diagnosis be confirmed by FISH karyotyping. Patients may require surgical correction of the external ear, external auditory canal, choanae, or palate. Of course, early detection and management of hearing loss can prevent any deficits in speech, educational, and social development.

Physicians must be aware of the potential for major abnormalities of the cardiac, renal, and gastrointestinal systems, which may also require surgical correction. Patients must be thoroughly assessed before any surgical or anesthetic procedures are performed. With the appropriate long-term care and support, most patients with CES can live long and productive lives.

To the best of our knowledge, the occurrence of CES in 3 siblings, including a pair of monozygotic twins, and the auricular abnormality we observed have not been described before.

Acknowledgment

Dr. Keogh would like to acknowledge The Royal College of Surgeons in Ireland for bestowing a Surgical Traveling Fellowship in 2001.

References

(1.) Haab O. Albrecht v Graefes. Arch Ophthalmol 1879;24:257.

(2.) Schachenmann G, Schmid W, Fraccaro M, et al. Chromosomes in coloboma and anal atresia. Lancet 1965;19:290.

(3.) Cat eye syndrome. Online Mendelian Inheritance in Man. #115470, www.ncbi.nlm.nih.gov (accessed Aug. 19, 2004).

(4.) Guanti G. The aetiology of the cat eye syndrome reconsidered. J Med Genet 1981;18:108-18.

(5.) Mears AJ, Duncan AM, Budarf ML, et al. Molecular characterization of the marker chromosome associated with cat eye syndrome. Am J Hum Genet 1994;55:134-42.

(6.) Schinzel A, Schmid W, Fraccaro M, et al. The "cat eye syndrome": Dicentric small marker chromosome probably derived from a no. 22 (tetrasomy 22pter to q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 1981;57:148-58.

(7.) Hoo JJ, Robertson A, Fowlow SB, et al. Inverted duplication of 22pter-q11.21 in cat-eye syndrome. Am J Med Genet 1986;24: 543-5.

(8.) Liehr T, Pfeiffer RA, Trautmann U. Typical and partial cat eye syndrome: Identification of the marker chromosome by FISH. Clin Genet 1992;42:91-6.

(9.) Magcnis RE, Sheehy RR, Brown MG, et al. Parental origin of the extra chromosome in the cat eye syndrome: Evidence from heteromorphism and in situ hybridization analysis. Am J Med Genet 1988;29:9-19.

(10.) McTaggart KE, Budarf ML, Driscoll DA, et al. Cat eye syndrome chromosome breakpoint clustering: Identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenet Cell Genet 1998;81:222-8.

(11.) Riazi MA, Brinkman-Mills P, Nguyen T, et al. The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome. Genomics 2000;64:277-85.

(12.) Hall JG, Froster-Iskenius UG, Allanson JE. Handbook of Normal Physical Measurements. Oxford: Oxford University Press, 1989.

(13.) McDermid HE, Duncan AM, Brasch KR, et al. Characterization of the supernumerary chromosome in cat eye syndrome. Science 1986;232:646-8.

(14.) Carmi R, Abeliovich D, Bar-Ziv J, et al. Malformation syndrome associated with small extra chromosome. Am J Med Genet 1980;5: 101-7.

(15.) Cory CC, Jamison DL. The cat eye syndrome. Arch Ophthalmol 1974;92:259-62.

(16.) Mears AJ, el-Shanti H, Murray JC, et al. Minute supernumerary ring chromosome 22 associated with cat eye syndrome: Further delineation of the critical region. Am J Hum Genet 1995;57:667-73.

(17.) Gerald PS, Davis C, Say B, Wilkins J. Syndromal association of imperforate anus: The cat eye syndrome. Birth Defects Orig Art Ser 1972;VIII 2:79-84.

From the Hospital of the Federal University of Minas Gerais, Belo Horizonte, Brazil (Dr. Godinho, Dr. Morales, Dr. Calixto, and Dr. Goncalves), and the Royal College of Surgeons, Dublin, Ireland (Dr. Keogh).

Reprint requests: Ivan J. Keogh, MD, 24 Tyrrelstown Blvd., The Bellgree, Tyrrelstown, Dublin 15, Ireland. Phone: 353-87-234-4399; fax: 353-1-809-3384; e-mail: ivankeogh@oceanfree.net

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