Microcephaly is defined as head circumference more than three standard deviations below the mean for age and sex. This anomaly has been reported both as isolated and as associated with various syndromes in which there are other evident ocular anomalies.
We examine three different types of pigmentary chorioretinal changes found in three (two boys and one girl) out of five siblings. Four of the five children, including the three with pigmentary changes, had autosomal recessive non-sex-linked microcephaly. Intelligence was normal in all cases.
Autosomal recessive inherited microcephaly with average normal intelligence in different segregates of first cousin intermarriage was diagnosed by both measurement of head circumference and x-ray. Four of the siblings were examined at the ophthalmic clinic at the School Health Department. The fifth and eldest, a boy, died at the age of 2 years and 41 days, diagnosed as having acute leukemia. No further history of this child could be obtained. Family history disclosed that the fathers sister, who is married to a cousin, has a boy with microcephaly who could not be brought for examination because he was living abroad. There was no family history of polyposis. Both parents were normal and had no detectable ophthalmic anomalies.
All siblings were born after a full- term, normal pregnancy. Delivery was normal. All were breast fed and had no problems during early infancy and childhood. The four living siblings were healthy with normal intelligence, as noticed from their school achievements.
Examination showed these four siblings had wellheads. There was no pigmentary cutaneous anomaly. Neurologic examination revealed absence of any neurologic anomaly, including hyperreflexia, clonus, or any psychoneurologic problem. None of the siblings had anemia or rectal bleeding. Colon x-rays were normal with no filling defects or undulations of the colon margins. Calvarium and mandible x-rays were normal with no detectable osteomas. There was no associated soft tissue anomaly.
FIGURE 1: Fundus photograph of Case 7 showing a background of fine granular pigmentary variations with interspersed hyperpigmentary spots and pale whitish spots.
FIGURE 2 : Fundus photograph of case 2 showing a diffuse area of chorioretinal pigment atrophy with normal choroidal vasculature and interspersed spots of hyperpigmentation.
CASE 1. The third sibling in the family is a 13-yearold boy who had been to the school health department referred because of his inability to see clearly at a distance. His head circumference was 44 cm.
Visual acuity was 20/100 in both eyes, corrected to 20/25 with - 1.50 in both eyes. Color vision was normal, as was convergence and divergence. There was no nystagmus or detectable exophthalmos. Pupils were equal and both reactive to direct and consensual light and accomodation (PERLA). Lacrimal apparatus was normal. The conjunctiva, cornea, anterior chamber, lens, and vitreous as examined by slit lamp were normal. The iris showed no transillumination defect, and the intraocular pressure (IOP) was 12 mm Hg in both eyes, as measured by applanation tonometry. Fundus examination revealed a background of fine granular pigmentary changes with interspersed hyperpigmented spots in the mid-peripheral and peripheral regions. In addition, the peripheral fundus showed scattered depigmented atropic areas revealing the sclera. There were also scattered pale whitish spots masking the retinal vessels in some areas (Figure 1). None of these changes seemed related to the blood vessels. Both the disc and retinal vessels were normal. The visual field was normal. The child was asked to bring the other members of the family for examination.
CASE 2. The second sibling of the family is a 14-yearold girl. She had a head circumference of 42 cm. She had no problems with visual acuity, and there was no history of night blindness.
Visual acuity was 20/20 and refraction was +0.25 in both eyes. Color vision and ocular muscle balance were normal, and there was no detectable squint. Convergence and divergence were normal, pupils PERLA, and there was no detectable exophthalmos or nystagmus. Lacrimal apparatus was normal. The lids, conjunctiva, cornea, anterior chamber, lens, and vitreous were all normal in both eyes by slit lamp examination. The iris was normal and there was no transillumination defect. IOP, as measured by applanation tonometry, was 14 mm Hg in both eyes. Fundus examination showed a diffuse area of chorioretinal pigment atrophy with normal choroidal vasculature (Figure 2). There were interspersed spots of hyperpigmentation in the mid-peripheral and peripheral fundus as seen in Case i . Both the disc and retinal vessels were normal. There was no detectable visual field defect.
CASE 3. The fourth sibling of the family is a 12-yearold boy. His head circumference was 43 cm.
Visual acuity was 20/25 and refraction piano in both eyes. Ocular muscle movements, convergence, and divergence were normal. There was no detectable squint, nystagmus, nor exophthalmos; pupils were PERLA. Lacrimal apparatus was normal. The conjunctiva, cornea, anterior chamber, lens, and vitreous were all normal by slit lamp examination. The iris showed no transillumination defect. IOP was 12 mm Hg as measured by applanation tonometry. Fundus examination showed a background of fine granular variations in pigment interspersed with hyperpigmentary spots in the mid-peripheral and peripheral fundus, together with peripheral depigmented atrophic areas and pale whitish spots masking the retinal vessels (Figure 3), as seen in Case 1 . There were also a few patches of chorioretinal atrophy about 0.5 to 1 disc in diameter. These patches were roughly round or oval and sharply demarcated by pigmentary edge. The retinal vessels crossed in front of them and the large choroidal and scleral vessels showed through them. Both the optic disc and retinal vessels were normal. There was no detectable visual field defect.
The fifth sibling of the family was an 11-year-old boy, with a head circumference of 42 cm. His visual acuity was 20/20 in both eyes and he had no detectable ophthalmic anomaly.
Twenty-four-hour urine levels of epinephrine and norepinephrine, urine and serum amino-acid levels, and electroencephalograms were all normal. Toxoplasma direct and indirect HA tests were normal. TPHA and Wasserman tests were normal. Skull radiographs confirmed the small size of the cranial vaults. Radiographic examinations of the chest, optic foramina, and skeleton; renal sonograms, cranial and orbital CT scans were all normal.
True microcephaly has been shown to be autosomal recessive.' Various anomalies have been associated with it, including microphthalmia, microcornea, corectopia, aniridia, corneal opacities, cataracts, macular coloboma, and retinal dystrophy.2 Most of these anomalies have been reported in cases of isolated microcephaly without proof of inherited disorder. McKusick et al reported autosomal recessive microcephaly associated with microphthalmia, small discs, patchy degeneration of the retinal pigment epithelium up to 1.5 disc diameters, and choroidal atrophy.3 Blair et al described association of hypertrophy of retinal pigment epithelium with Gardners syndrome.4,5 Parke et al described two brothers with microcephaly, normal intelligence, and multiple fine depigmented spots in the retinal pigment epithelium with patches of hypertrophy, together with coincidental autosomal dominant hyperreflexia.6
The three siblings described above are of true microcephaly without mental retardation associated with hypertrophy of the retinal pigment epithelium, similar to that described in Gardners syndrome.4 In addition to these conditions, there were associated generalized fine granular pigmentary variations together with superimposed pale whitish superficially placed white spots in front of the retinal vessels in the two boys. In addition, the younger boy (case 3) had discrete patches of chorioretinal atrophy. On the other hand, the girl (case 2) showed a diffuse area of chorioretinal pigment atrophy in addition to the areas of hyperpigmentation. None of these conditions was accompanied by visual field defects or other systemic anomalies.
To our knowledge the combinations of the retinal, chorioretinal, and preretinal changes in association with autosomal recessive inherited microcephaly have not been described before. The combinations of conditions we report differ from apparently similar cases in that the gross structure and function of the eyes were normal, including absence of strabismus, nystagmus, or microphthalmia, and absence of high refractive error. There was no vitreous anomaly or inflammation. There was no neuro-epithelial, retinal, vascular, or optic disc dysplasia. There was no reactive hyperplasia or migration of the retinal pigment epithelium.
FIGURE 3 : Fundus photograph of case 3 showing hyperpigmentary spots, pale whitish spots, and patch of chorioretinal atrophy.
The above-mentioned conditions primarily resulted from the same genetic defect. Although any conclusions at this point would be premature, it seems that although current literature suggests that the lesions of congenital hypertrophy of the retinal pigment epithelium may be specific for Gardners syndrome,4,5,7 these anomalies also may be associated with other inherited problems.
1. Book JA, Schut JW, Reed SG: A clinical and genetical study of microcephaly. Am J Ment Defic 1953; 57:637.
2. Brandon MWG, Kirman BH, Williams CE: Microcephaly. Journal of Mental Science 1959; 105:721-747.
3. McKusick VA, Stauffer M, Knox DL, et al: Chorioretinopathy with hereditary microcephaly. Arch Ophthalmol 1966; 75:597-600.
4. Blair NP Trempe CL: Hypertrophy of the retinal pigment epithelium associated with Gardners syndrome. AmJ Ophthalmol 1980; 90:661-667.
5. Llopis MD, Menezo JL: Congenital hypertrophy of the retinal pigment epithelium and familial polyposis of the colon (letter to the Editor). Am J Ophthalmol 1987; 103:235-236.
6. Parke JT, Riccardi VM, Lewis RA, et al: A syndrome of microcephaly and retinal pigmentary abnormalities without mental retardation in a family with coincidental autosomal dominant hyperreflexia. Am J Med Genet 1984; 17:585-594.
7. Traboulsi EI, Krush A, Maumenee IH: Pigmented ocular fundus lesions in hereditary diseases with gastrointestinal polyposis. Presented at the American Academy of Ophthalmology Annual Meeting, Dallas, November 11, 1987.