American Journal of Medical Genetics 49:261-262 (1994)

Autosomal Recessive Colobomatous Microphthalmia Joel Zlotogora, Cyril Legum, Judith Raz, Saul Merin, and David BenEzra Departments of Human Genetics (J.Z.) and Ophthalmology (J.R., S.M., D.B.), Hadassah Hebrew University Medical Center, Jerusalem, and the Department of Human Genetics (C.L.), Ichilov Hospital, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Colobomatous microphthalmia was studied in multiple relatives of 5 families. In these fam- ilies, the disorder was an autosomal recessive trait as opposed to the usual autosomal domi- nant form of the disorder. A relatively high incidence of this recessive allele is found in the Iranian Jewish community. 0 1994 Wiley-Liss, Inc.

KEY WORDS: autosomal recessive inheri- tance, coloboma, Jewish dis- orders, microphthalmia

INTRODUCTION Anophthalmia and microphthalmia may be due to

many different causes. The classification of the heredi- tary forms of anophthalmia or microphthalmia is usu- ally made according to the presence or absence of addi- tional malformations. True anophthalmia is due to a developmental failure of the optic pit and is usually an autosomal recessive trait. Microphthalmia is generally associated with high hyperopia and with colobomatous malformations or malformations other than colobomas. In addition, anophthalmia or microphthalmia may also be part of a syndrome or a multisystem disorder [Sorsby, 1970; Warburg, 19911.

Microphthalmidanophthalmia with other colobo- matous malformations are pathogenetically caused by the faulty closure of the embryonic fissure and are con- sidered an autosomal dominant trait with incomplete penetrance [McKusick, 1990; Pagan, 19811. We report on 5 families in which the disorder is inherited as an autosomal recessive trait.

THE FAMILIES All members of the families 1-4 including the parents

of the affected children had a complete ophthalmological examination by one of the authors. The abnormal find- ings are reported. Physical examination of the probands

Received for publication March 27, 1992; revision received Au-

Address reprint requests to Joel Zlotogora, M.D., Hadassah Hos- gust 26, 1992.

pital, P.O. Box 12000, Jerusalem, il 91120 Israel.

0 1994 Wiley-Liss, Inc.

and, if necessary, of the parents was performed in the genetic clinic. No nonophthalmological manifestations were found in any of the individuals in these families. The intelligence of all the affected members was normal. In families 1,3,4,5 high resolution chromosomes were examined in a t least one affected individual and were normal.

Family 1 The parents, Moslem Arabs, are distantly related but

do not know their exact relation. They have had 5 chil- dren (3 boys and 2 girls) and one stillbirth. Two of their children, a boy and a girl, have a bilateral micro- phthalmia, microcornea, and coloboma of the iris, cho- roid, and optic discs. The boy’s chromosomes are normal.

Family 2 The parents are healthy Jews from Iran related as

first cousins. Four of their 6 children have eye malforma- tions. Microphthalmia and coloboma of choroid are pres- ent in 3 children, bilateral in one and unilateral in the other 2. The youngest child has choroid and optic nerve coloboma.

Family 3 The parents are second cousins, healthy Jews from

Iran. Among their 5 children, 3 have eye malformations. One girl has a left microphthalmia and a coloboma of the optic disc in both eyes; the other girl has a left micro- phthalmia and coloboma of the optic disc of the right eye. The affected boy has bilateral anophthalmia; his chro- mosomes are normal. His twin sister is unaffected.

Family 4 The parents are related as third cousins; they are

Jews originating from Syria. Among their 4 children, 2 girls have eye malformations. Both girls have bilateral microphthalmia with bilateral colobomas. The chromo- somes of the eldest child are normal.

Family 5 (Fig. 1) The proposita’s parents are healthy Jews from Iran,

distantly related. The proposita is of normal intel- ligence; she is married and has 4 normal children. She was born with left microphtalmia and bilateral col- oboma of optic nerve. Physical examination was other- wise normal. Her chromosomes are normal. In her

262 Zlotogora et al.

I

Fig. 1. Pedigree of family 5. Affected individuals are represented by solid symbols. Only the proposita was examined by us.

family, there are 4 additional individuals with mi- crophthalmia; they were not examined by us and the data were obtained only from the proposita. Among the affected, there are 2 brothers; one of them died in in- fancy and was reported to have bilateral micro- phthalmia. The 3 other patients have unilateral micro- phthalmia but no further clinical details were available. One of the 4 affected relatives of the propositus is mar- ried and has 6 normal children. The parents of all af- fected individuals in the family are normal and in each case are consanguineous.

DISCUSSION Familial colobomatous microphthalmidanophthal-

mia has been reported as an autosomal dominant trait with incomplete penetrance [McKusick, 1990; Sorsby, 19701. The disorder is variable in its expressivity. Differ- ent combinations of malformations ranging from bilat- eral anophthalmia to a partial unilateral coloboma may be seen in affected individuals even within the same family [Warburg, 19821. Affected children born to nor- mal parents have been reported, and therefore autoso- ma1 recessive inheritance was proposed in some cases [McMillan, 1921; Pagon et al., 19811. However, in most reports, this observation could also be explained by in- complete penetrance of a dominant gene. In the families reported here, more than one affected child was born to unaffected parents and no other affected persons were known in the previous generations. The parents of the affected children were related in all the families; both males and females were affected (10 females and 6 males) and they had 25 normal sibs. These observations strongly support the existence of an autosomal recessive gene in those families. It should be noted that 3 of the families, including the large kindred of 4 families with

affected individuals, are Jews originating from Iran. It is probable that, in this population, the recessive form of colobomatous microphthalmia is frequent. Iranian Jews represent a community of approximately 150,000 indi- viduals in Israel [Statistical Abstracts, 19911. In this community, the rate of consanguinity is high even nowa- days, and various recessive diseases have been found with a high incidence [Goodman, 19791.

The existence of an autosomal recessive form of col- obomatous microphthalmia is important for genetic counseling. In families with an affected child in which both parents had a detailed normal ophthalmologic ex- amination, the possibility of a recessive inheritance of colobomatous microphthalmia should be raised. Signifi- cant phenotypic variability exists in the autosomal re- cessive form, similar to the variability in the autosomal dominant form.

REFERENCES Goodman RM (1979): “Genetic Disorders Among the Jewish People.”

Baltimore: The Johns Hopkins University Press. McKusick VA (1990): “Mendelian Inheritance in Man. Catalogs of

Autosomal Dominant, Recessive, and X-linked Phenotypes.” 9th ed. Baltimore: The Johns Hopkins University Press.

McMillan L (1921): Anophthalmia and maldevelopment of the eyes: Four cases in the same family. Brit J Ophthal 5:121-122.

Pagon RA (1981): Ocular coloboma. Survey Ophthal 25233-235. Pagon RA, Kalina RE, Lechner DJ (1981): Possible autosomal-reces-

Sorsby A (1970): “Ophthalmic Genetics.” 2nd ed. London: Butterworth,

Statistical Abstracts of Israel (1991). Warburg M (1982): Diagnostic precision in microphthalmos and col-

oboma of heterogeneous origin. Birth Defect Original Series 18: 31-51.

Warburg M (1991): An update on microphthalmos and coloboma. A brief survey of genetic disorders with microphthalmos and col- oboma. Ophthal Paediatr Genet 12:57-63.

sive ocular coloboma. Amer J Med Genet 9:189-193.

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