Journal of Pediatric Ophthalmology and Strabismus

Colobomatous Microphthalmia, Heart Disease, Hearing Loss, and Mental Retardation-A Syndrome

Helen Mintz Hittner, MD, FACS; Norma J Hirsch, MD, FAAP; Gustave M Kreh, MD; Arnold J Rudolph, MD

Abstract

The primary causations of typical colobomatous syndromes appear to have their origins before fertilization and not during intrauterine development. The defective closure of the optic cleft which occurs at about the sixth week of intrauterine life is known to be under genetic influence and can be caused by a single gene defect (dominant, recessive, or sex-linked) or by abnormal chromosomes. Additionally, phenotypes of colobomatous syndromes can be caused by environmental agents including congenital viral infections.

The grouping of congenital malformations into recognizable patterns may be of great val ue to the clinician. When a phenotype is recognized, it is useful in determining prognosis and in detecting malformations which may be amenable to therapy.

The present paper describes ten patients with colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing loss, and mental retardation as their primary clinical manifestations. Multiple other patients have been seen with two or three of these clinical manifestations, however, these patients are not included in this report.

MATERIALS AND METHODS

All patients were evaluated at Texas Children's Hospital, Houston, Texas. The younger patients included were primarily ascertained by referral to Texas Children's Hospital for evaluation and treatment of congenital heart disease and multiple congenital anomalies. The older patients included were identified as ophthalmologic patients noted to have multiple systemic abnormalities. Each patient had complete cardiac and ophthalmologic evaluation. Formal mental testing and audiograms were performed where possible. There was a complete examination for evidence of other congenital anomalies. All patients had chromosome analysis (patients born since 1974 had banded chromosome studies) and all were found to have normal karyotypes. In addition, patients evaluated in infancy had IgM and TORCH (toxoplasmosis, rubella, cytomegalic inclusion disease, herpes) titers performed. Maternal TORCH titers were also obtained where appropriate. No evidence of congenital viral illness was detected in any of the patients described. In each case, the pregnancy history was negative with regard to environmental agents which might produce this phenotype.

CASE REPORTS

Ten patients were identified who had colobomatous microphthalmia, heart disease, abnormalities of the external ears with associated hearing loss, and mental retardation. The systemic manifestations excluding the ocular findings are summarized in Table I. The ocular findings are summarized in Table II. Examples of the variation of ocular malformations are shown in Figure 1. Examples of the variation of external ear abnormalities are shown in Figure 2.

All of the patients had abnormal appearing external ears, ranging in severity from minor variations in shape to severe defects with absence of an external auditory canal opening (Fig. 2). Hearing loss was present in all and tended to be severe, Careful examination of the pinna may be a simple way to detect an underlying potentially surgically correctable hearing loss.19 An abnormal pinna is more often associated with a middleear anomaly than with any other congenital malformation including a urinary tract anomaly.20

Mental retardation was present in all and in most cases was severe. In two patients cerebral dysgenesis was suspected. In one autopsied patient, cerebellar hypoplasia was present.

In addition to the four major manifestations of the syndrome, other anomalies were present in some of the patients. Of those, the most frequent was a Vllth nerve paralysis in six of the ten patients. Three were on the right side and three were on the left side. In each case, the Vllth nerve paralysis occurred on the same side as the more malformed external ear. Anomalies of the vertebrae and/or ribs occurred in three patients. Two patients had major anomalies of the genitourinary system. Two patients had marked gastrointestinal abnormalities consisting of pharyngeal incoordination or paralysis requiring…

The primary causations of typical colobomatous syndromes appear to have their origins before fertilization and not during intrauterine development. The defective closure of the optic cleft which occurs at about the sixth week of intrauterine life is known to be under genetic influence and can be caused by a single gene defect (dominant, recessive, or sex-linked) or by abnormal chromosomes. Additionally, phenotypes of colobomatous syndromes can be caused by environmental agents including congenital viral infections.

The grouping of congenital malformations into recognizable patterns may be of great val ue to the clinician. When a phenotype is recognized, it is useful in determining prognosis and in detecting malformations which may be amenable to therapy.

The present paper describes ten patients with colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing loss, and mental retardation as their primary clinical manifestations. Multiple other patients have been seen with two or three of these clinical manifestations, however, these patients are not included in this report.

MATERIALS AND METHODS

All patients were evaluated at Texas Children's Hospital, Houston, Texas. The younger patients included were primarily ascertained by referral to Texas Children's Hospital for evaluation and treatment of congenital heart disease and multiple congenital anomalies. The older patients included were identified as ophthalmologic patients noted to have multiple systemic abnormalities. Each patient had complete cardiac and ophthalmologic evaluation. Formal mental testing and audiograms were performed where possible. There was a complete examination for evidence of other congenital anomalies. All patients had chromosome analysis (patients born since 1974 had banded chromosome studies) and all were found to have normal karyotypes. In addition, patients evaluated in infancy had IgM and TORCH (toxoplasmosis, rubella, cytomegalic inclusion disease, herpes) titers performed. Maternal TORCH titers were also obtained where appropriate. No evidence of congenital viral illness was detected in any of the patients described. In each case, the pregnancy history was negative with regard to environmental agents which might produce this phenotype.

CASE REPORTS

Ten patients were identified who had colobomatous microphthalmia, heart disease, abnormalities of the external ears with associated hearing loss, and mental retardation. The systemic manifestations excluding the ocular findings are summarized in Table I. The ocular findings are summarized in Table II. Examples of the variation of ocular malformations are shown in Figure 1. Examples of the variation of external ear abnormalities are shown in Figure 2.

Fig. 1. (a) Right eye of LR (Patient No. 5i- coloboma of optic nerve and large coloboma of choroid and retina, (b) Left eye of JJ I Patient No. 6)- coloboma of optic nerve and moderate coloboma of choroid and retina, (c) Right eye of FR iPatient No. 9)- normal optic nerve and small coloboma of choroid and retina. The inferior position is "typical. " (d) Right eye of EW (Patient No. 1 ) - mild coloboma of optic nerve and linear coloboma of choroid and retina. A superior field loss was present which correlated with the inferior position of the coloboma.

Fig. 1. (a) Right eye of LR (Patient No. 5i- coloboma of optic nerve and large coloboma of choroid and retina, (b) Left eye of JJ I Patient No. 6)- coloboma of optic nerve and moderate coloboma of choroid and retina, (c) Right eye of FR iPatient No. 9)- normal optic nerve and small coloboma of choroid and retina. The inferior position is "typical. " (d) Right eye of EW (Patient No. 1 ) - mild coloboma of optic nerve and linear coloboma of choroid and retina. A superior field loss was present which correlated with the inferior position of the coloboma.

Fig. 2. (a) Left ear of JJ (Patient No. 6)- mildly abnormal configuration on left pinna. Audiogram revealed no response to air or bone conducted stimuli, (b) Left ear of FR (Patient No. 9}- moderately abnormal configuration of left pinna. Audiogram was not performed but clinically the patient was unresponsive to sound, (c) Left ear of LR (Patient No. 5)moderately abnormal configuration of left pinna. Audiogram revealed no response to air or bone conducted stimuli, (d) Left Ear of PS (Patient No. 7)severely malformed left pinna. Audiogram was not performed but clinically the patient was unresponsive to sound.

Fig. 2. (a) Left ear of JJ (Patient No. 6)- mildly abnormal configuration on left pinna. Audiogram revealed no response to air or bone conducted stimuli, (b) Left ear of FR (Patient No. 9}- moderately abnormal configuration of left pinna. Audiogram was not performed but clinically the patient was unresponsive to sound, (c) Left ear of LR (Patient No. 5)moderately abnormal configuration of left pinna. Audiogram revealed no response to air or bone conducted stimuli, (d) Left Ear of PS (Patient No. 7)severely malformed left pinna. Audiogram was not performed but clinically the patient was unresponsive to sound.

DISCUSSION

The present paper describes a constellation of clinical manifestations which has four major components which include colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing loss, and mental retardation.

The ten patients in the current report all had normal chromosomes. No evidence of congenital viral syndrome or exposure to environmental teratogens was found. It is important that many laboratory tests and a good pregnancy history be obtained to eliminate other causes of multisystem anomalies. Patient AW was the daughter of EW, indicating that the syndrome may be heritable. No other family members were affected so a definite genetic pattern could not be established.

This syndrome has no apparent restriction of race, hence, five white, two black, two MexicanAmerican, and one Oriental were the patients identified. There is no sex predilection with five males and five females among the patients.

Colobomatous microphthalmia was present in all patients in different degrees. The colobomata of the iris, retina, choroid, and optic nerve varied in severity (Fig. 1). Four patients had unilateral iris colobomata. Seven patients had bilateral and two patients had unilateral colobomata of the choroid and retina. Five patients had bilateral and four patients had unilateral colobomata of the optic nerve. Microphthalmia and/or colobomata have been associated with extra ocular defects similar to those in this report several times.1-7

Many of the patients were initially referred for cardiac evaluation. Cardiac malformations ranged from relatively mild to severe, including: ventricular septal defect (3); atrial septal defect 1);patentductusarteriosus(5);patentforamen ovale (2); endocardial cushion defect (1); total anomalous pulmonary venous return (1 ); Tetralogy of Fallot (1); and bicuspid aortic valve (1). Extracardiac anomalies in infants with congenital heart disease vary from 13 to 37% in autopsy series and from 9 to 42% in clinical series.9-18

Table

TABLE ISUMMARY OF NONOCULAR FINDINGS IN THE PATIENTS

TABLE I

SUMMARY OF NONOCULAR FINDINGS IN THE PATIENTS

Table

TABLE ISUMMARY OF NONOCULAR FINDINGS IN THE PATIENTS

TABLE I

SUMMARY OF NONOCULAR FINDINGS IN THE PATIENTS

Table

TABLE IISUMMARY OF OCULAR FINDINGS IN THE PATIENTS

TABLE II

SUMMARY OF OCULAR FINDINGS IN THE PATIENTS

All of the patients had abnormal appearing external ears, ranging in severity from minor variations in shape to severe defects with absence of an external auditory canal opening (Fig. 2). Hearing loss was present in all and tended to be severe, Careful examination of the pinna may be a simple way to detect an underlying potentially surgically correctable hearing loss.19 An abnormal pinna is more often associated with a middleear anomaly than with any other congenital malformation including a urinary tract anomaly.20

Mental retardation was present in all and in most cases was severe. In two patients cerebral dysgenesis was suspected. In one autopsied patient, cerebellar hypoplasia was present.

In addition to the four major manifestations of the syndrome, other anomalies were present in some of the patients. Of those, the most frequent was a Vllth nerve paralysis in six of the ten patients. Three were on the right side and three were on the left side. In each case, the Vllth nerve paralysis occurred on the same side as the more malformed external ear. Anomalies of the vertebrae and/or ribs occurred in three patients. Two patients had major anomalies of the genitourinary system. Two patients had marked gastrointestinal abnormalities consisting of pharyngeal incoordination or paralysis requiring gastrostomy. Two patients had musculoskeletal abnormalities consisting of abnormal tongue and proximal musculature. The multiplicity of other systemic anomalies is indicative of etiologic differences of this phenotype. Other patients have been evaluated in our center who presented with three or less of the four major manifestations of the syndrome. Therefore, it is postulated that less severe forms of the syndrome may also occur.

The identification of a patient with two or more of the manifestations of the phenotype described in this report should alert the clinician to undertake a multisystem approach to the evaluation of the patient. In this way, the patient's clinical status can be more completely defined and his prognosis delineated.

SUMMARY

A syndrome consisting of colobomatous microphthalmia, heart disease, abnormalities of theexternal ear with associated hearing loss, and mental retardation is described. Nine children and one adult were evaluated. There is no race or sex predilection. The syndrome can be heritable, as shown by a mother and daughter who were among the patients. In addition to the four major components enumerated, multiple other anomalies may be associated. In some cases, the syndrome may occur incompletely. Whenever two or more of the four components are recognized, the other systems usually affected should be investigated.

ACKNOWLEDGMENT

The authors are grateful to the Cardiology Section of the Department of Pediatrics of Baylor College of Medicine which referred some of the patients and assisted in the evaluation of all of the patients in this report.

REFERENCES

1. Goldberg M, McKusick V: X-linked colobomatous microphthalmos and other congenital anomalies. Am J Ophthalmol 71:1128, 1971.

2. Ho CK, Kaufman RL, Podos SM: Ocular colobomata, cardiac defect, and other anomalies: A study of seven cases including two sibs. J Med Genet 12:289, 1975.

3. James PML, Karseras AG, Wybar KC: Systemic associates of uveal coloboma. Br J Ophthalmol 58:917, 1974.

4. Zeiter HJ: Congenital microphthalmos, a pedigree of four affected siblings and an additional report of forty-four sporadic cases. Am J Ophthalmol 55:910, 1963.

5. Lenz W: Rezessiv-geschlechtsgebundene Mikrophthalmie mit Multiplen Missbildunge. Z Kinderheilk 77:384, 1955.

6. Hoefnagel D, Kennan ME, Allen FJ: Heredofamilial bilateral anophthalmia. Arch Ophthalmol 69:120, 1963.

7. Hermann J, Optiz JM: The Lenz microphthalmia Syndrome. In The First Conference on the Clinical Delineation of Birth Defects 5(2):138, 1969.

8. Greenwood RD, Rosenthal A, Paris') L, et al: Extracardiac abnormalities in infants with congenital heart disease. Pediatr 55:485, 1975.

9. R owe DR, Mehrizi A: The Neonate with Congenital Heart Disease. Philadelphia, WB Saunders Co. 1968.

10. Boesen I, Melchior JC, Tersley E, et al: Extracardiac congenital malformations in children with congenital heart disease. Acta Paediatr 146:28, 1963.

11. Wiland OK: Extracardiac anomalies in association with congenital heart disease. Lab Invest 5:380, 1956.

12. Abbot ME: In Nelson's Loose-Leaf Living Medicine, vol 4. New York, Nelson, 1927.

13. Gibson S, Clifton W: Congenital heart disease. Am J Dis Child 5:761. 1938.

14. Okada R, Johnson D, Lev M: Extracardial malformations associated with congenital heart disease. Arch Pathol 85:649, 1968.

15. Campbell M: Causes of malformations of the heart. Br Med J 2:895, 1965.

16. MacMahon B, McKeown T. Record RG: The incidence and life expectation of children with congenital heart disease. Br Heart J 15:121, 1953.

17. Lamy M, DeGrouchy J, Schweisguth O: Genetic and nongenetic factors in the etiology of congenital heart disease. A study of 1,188 cases. Am J Human Genet 9:17, 1957.

18. Emerit I, Vernant P, Corone P, et al: Malformations extracardiaques associées a des cardiopathies congenitales (etude statistique portant sur 1 ,000 cas). Acta Genet Med GemeUol 1 6:27, 1967.

19. Jaffe BF: Pinna anomalies associated with congenital conductive hearing loss. Pediatr 57:332, 1976.

20. Hilson D: Malformation of ears as sign of malformation of genitourinary tract. Br Med J 2:785. 1957.

TABLE I

SUMMARY OF NONOCULAR FINDINGS IN THE PATIENTS

TABLE I

SUMMARY OF NONOCULAR FINDINGS IN THE PATIENTS

TABLE II

SUMMARY OF OCULAR FINDINGS IN THE PATIENTS

10.3928/0191-3913-19790301-10

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