Journal of Pediatric Ophthalmology and Strabismus

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An Italian Family Affected by Autosomal Dominant Microcephaly With Chorioretinal Degeneration

Francesca Simonelli, MD; Francesco Testa, MD; Anna Nesti, MD; Giuseppe de Crecchio, MD; Mario Bifani, MD; Maria Luisa Cavaliere, MD; Ernesto Rinaldi, MD; Maria Michela Rinaldi, MD

Abstract

ABSTRACT

Purpose: We studied an Italian family affected by the autosomal dominant form of microcephaly and Chorioretinal degeneration that was characterized by various degrees of clinical expression.

Methods: An ophthalmologic examination, including visual acuity, visual field testing, an electroretinogram, and fundus photography, and a neurologic examination, including neurodevelopmental status and neuroimaging studies, were performed for all subjects. Skeletal radiography, chromosome studies, and serologie investigations were also performed.

Results: In this family, only two of the six affected members had an association of microcephaly, myopia, and chorioretinal degeneration. The other family members showed microcephaly, slight mental retardation, and short stature, but not chorioretinopathy.

Conclusions: The significant finding in members from this dominant pedigree of microcephaly was the association of short stature and high myopia, heretofore seen only in families with recessive microcephaly. These findings could be useful for genetic counseling in the apparently isolated forms of microcephaly with chorioretinopathy.

J Pediatr Ophthalmol Strabismus 2002;39:288292.

Abstract

ABSTRACT

Purpose: We studied an Italian family affected by the autosomal dominant form of microcephaly and Chorioretinal degeneration that was characterized by various degrees of clinical expression.

Methods: An ophthalmologic examination, including visual acuity, visual field testing, an electroretinogram, and fundus photography, and a neurologic examination, including neurodevelopmental status and neuroimaging studies, were performed for all subjects. Skeletal radiography, chromosome studies, and serologie investigations were also performed.

Results: In this family, only two of the six affected members had an association of microcephaly, myopia, and chorioretinal degeneration. The other family members showed microcephaly, slight mental retardation, and short stature, but not chorioretinopathy.

Conclusions: The significant finding in members from this dominant pedigree of microcephaly was the association of short stature and high myopia, heretofore seen only in families with recessive microcephaly. These findings could be useful for genetic counseling in the apparently isolated forms of microcephaly with chorioretinopathy.

J Pediatr Ophthalmol Strabismus 2002;39:288292.

INTRODUCTION

Microcephaly is a heterogeneous condition that can present either as a single malformation or in association with ocular abnormalities and different degrees of mental retardation.1 The most common ocular alteration is chorioretinal degeneration, which has been reported in both the autosomal recessive and die autosomal dominant forms of microcephaly congenital syndrome.23 The chorioretinopathy of the autosomal dominant form of the syndrome is characterized by focal areas of choro i dal and retinal atrophy that resemble those of gyrate atrophy.4 In contrast, in die autosomal recessive form, there is widespread chorioretinal atrophy, pale optic disc, attenuated retinal vessels, and retinal pigmented clumping, bone spicules, or both as in retinitis pigmentosa.4 Thus far, 12 cases of autosomal recessive2·5"7 and 21 cases of autosomal dominant*·8"11 microcephaly with chorío retí ñopa thy have been reported. No chromosomal location has been associated with this syndrome.

We describe an Italian family with a peculiar association of microcephaly with retinopathy, short stature, and mild mental retardation in six of its members. Inheritance was autosomal dominant.

SUBJECTS AND METHODS

Background

We studied seven members of a family without a history of parental consanguinity from the Campania region of southern Italy (Fig. 1). The research procedures were in accordance with institutional guidelines and the Declaration of Helsinki. Informed consent was obtained from all of the subjects after the nature of the procedures had been fully explained. Neurologic, ophthalmologic, and serologie examinations were performed on all of them. Chromosome studies were also performed.

The subjects were questioned about family history, perinatal history, and exposure to teratogenic agents. The ophthalmologic investigation included refraction, measured with the best-corrected Snellen visual acuity tests; visual field testing, using Goldmann kinetic perimetry with 1-4 and II-4 targets; a physiologic electroretinogram (ERG) performed in accordance with international clinical standards13; a tundus examination with indirect Ophthalmoscopy; and color photography, which served to identify visual retinal abnormalities.

The neurologic examination included neurodevelopmental status, neuroimaging studies, and an electroencephalogram (EEG). Growth parameters (weight, height, and head circumference) were recorded.14 All subjects underwent serologie testing for congenital infection, TORCH (toxoplasmosis, rubella, cyto mégalo virus, and herpes virus), and syphilis. Metabolic screening for plasma ornithine was also performed.15 The subjects' karyotypes were determined by the R-banding technique using peripheral blood lymphocytes.

Case Reports

Case IE-I. A 2-year-old girl was the first child of a normal father and a microcephalic mother. Both the full-term pregnancy and the delivery were uneventful. Her birth weight was 2,700 g (10th percentile) and her body length was 47 cm (10th percentile). At birth, she was noted to be severely microcephalic with an occipite frontal circumference of 30 cm (< -2.8 standard deviation [SD]). There were no signs of congenital infection and no further abnormalities on pediatrie examination.

Figure 1 . Pedigree of an Italian family affected by the auiosomal dominant form of microtephaly and chorioretinal degeneration.

Figure 1 . Pedigree of an Italian family affected by the auiosomal dominant form of microtephaly and chorioretinal degeneration.

At 2 years of age, her motor development was normal and there was no mental retardation (Brunei- Lèzin e test: DQ 104). Results of a neurologic examination, including skeletal radiographs, computed tomography scan, and an EEG, were normal, except for the small head circumference. The eyes were of normal size and a refractive examination by cycloplegia showed 8 D of myopia in both eyes. Results of a slit-lamp examination were normal. Ophthalmoscopy showed a pink optic disc, normal retinal vessels, and, in the m id- periphery, large, round areas of retinal and choroidal atrophy in the lower half of the retina (Fig. 2). At the last ophthalmologic examination, the ocular condition of the 5-year-old subject was unchanged.

Case 11-2. A 25-year-old woman, the mother of case III-l, weighed 50 kg (10th percentile), was 154 cm tall (< 10th percentile), and had an occipitofrontal circumference of 50 cm (< -4.0 SD). There were no signs of congenital infection. Results of a neurologic examination, including skeletal radiographs, a computed tomography scan, and an EEG, were normal, except for the small occipitofrontal circumference and slight mental retardation (IQ measured with the Wechsler Adult Intelligence Scale was 71).

The eyes were of normal size and a refractive examination showed 6 D of myopia with a correctcd visual acuity of 20/20 in both eyes. Results of a slit-lamp examination were normal. Ophthalmoscopy showed a pink optic disc, normal retinal vessels, and, in the mid-periphery, large, multilobed areas of retinai and choroidal atrophy along the major vessels (Fig. 3). Color vision was normal. A Goldmann kinetic visual field examination with mires 1-4 and ?-4 showed shrinkage of the peripheral isopters. On ERG scotopic tracing, the implicit time of the b wave was 70.60 ms and amplitude was 98 uV. In die photopic tracing, the implicit time of the b wave was 50.60 ms and the amplitude was 55.20 µ? The 30-Hz flicker amplitude was 30.90 µ? and the latency was 32.10 ms.

Figure 2. Right eye of case 111-1. Large areas of chorioretina atrophy can be seen.

Figure 2. Right eye of case 111-1. Large areas of chorioretina atrophy can be seen.

Case II-3. A 24-year-old woman, the sister of case II-2, weighed 55 kg (10th percentile), was 150 cm tall (< 3rd percentile), and had an occipitofronta! circumference of 51 cm (< -3.0 SD). There were no signs of congenital infection. Results of a neurologic examination, including a computed tomography scan and an EEG, were normal, except for the small occipitofrontal circumference and slight mental retardation (IQ 68). Her motor development was normal. The eyes were of normal size and a refractive examination showed a visual acuity of 20/20 in both eyes. The results of slit-lamp and fundus examinations were unremarkable. Color vision and the results of visual field testing and an ERG were normal.

Case II-4. A 22-year-old man, the brother of Case 11-2, weighed 62 kg (10th percentile), was 160 cm tall (< 3rd percentile), and had an occipitofrontal circumference of 50 cm (< -4.0 SD). Results of a neurologic examination, including a computed tomography scan and an EEG, were normal, except for the small occipitofronral circumference and slight mental retardation (IQ 65). His motor development was normal. The eyes were of normal size and visual acuity was 20/20 in both eyes. Results of slit-lamp and fundus examinations were unremarkable. Color vision and the results of visual field testing and an ERG were normal.

Figure 3. Right eye of case 11-2. Large areas of chorioretina! atrophy along lhe major vessels can be seen.

Figure 3. Right eye of case 11-2. Large areas of chorioretina! atrophy along lhe major vessels can be seen.

Case ÍI-5. A 19-year-old woman, the sister of case II-2, weighed 46 kg (10th percentile), was 145 cm tall (< 3rd percentile), and had an occipitofrontal circumference of 48 cm (< -4.2 SD). Results of a neurologic examination, including skeletal radiographs, a computed tomography scan, and an EEG, were normal, except for the small occipitofrontal circumference and slight mental retardation (IQ 79). Her motor development was normal. The eyes were of normal size and a refractive examination showed a visual acuity of 20/20 in both eyes. Results of slit-lamp and fundus examinations were normal. Color vision and the results of visual field testing and an ERG were normal

Case 1-1. A 52-year-old man, the grandfather of case IH-I, weighed 62 kg (10th percentile) and was 158 cm tali (< 3rd percentile). He had microcephaly with an occipitofrontal circumference of 51 cm (< -3.0 SD). His motor development was normal. Results of a neurologic examination, including a computed tomography scan and an EEG, were normal, except for the small occipitofrontal circumference and slight mental retardation (IQ 63). The eyes were of normal size and a refractive examination showed a visual acuity of 20/20 in both eyes. A slit-lamp examination revealed nothing of note. Color vision and the results of funduscopy, visual field testing, and an ERG were normal.

Case 1-2. A 48-year-old woman, the grandmother of case III-l, had a normal height and head circumference. Results of physical and neurologic examinations were normal. The eyes were of normal size and a refractive examination showed a visual acuity of 20/20 in both eyes. Slitlamp and fundus examinations revealed nothing of note.

RESULTS

The features found in all of our subjects, except cases 1-2, II-2, and III-l, were microcephaly, short stature, and mental retardation. Chorioretinal dystrophy and myopia were found only in the proband, case III-l, and her mother, case II-2. In both cases, large, round areas of cho rio ret i nal atrophy were localized in the lower half of the retina. Case 11-2 showed aberrant scotopic and photopìc ERG responses and a peripheral defect of the visual field. An ERG was not performed on case III-l because of her poor collaboration. Only cases II-2 and III-l had the fully expressed chorioretinal dysplasia microcephaly syndrome; a mild degree of mental retardation and height less than the 10th percentile were additional features in the mother (case 11-2).

None of the subjects examined had any relevant dysmorphic features. Results of the skeletal radiographs were normal except for the skull films, which showed a small cranial size. Serologie assessments for TORCH and syphilis and metabolic screening for hyperornithinemia had negative results. The results of cytometric hemochrome analysis and urinalysis were within the normal range. A chromosome examination showed a 46,XX karyotype. This family was affected by the autosomal dominant form of microcephaly with chorioretinal degeneration with various degrees of expression.

DISCUSSION

In the families with autosomal dominant microcephaly and chorioretinal degeneration described so far, locomotor problems have been infrequent, there have been no abnormalities on EEG, and only one individual has had short stature.3·8"12 Ocular findings have been characterized by choroidal and retinal atrophy localized in the lower retina, which is rarely associated with nystagmus, substantial refractive alteration, microcornea- microphthalmia, or optic atrophy.'6

In this family, in which transmission was autosomal dominant, only two members (cases II-2 and III-l) had an association of microcephaly, myopia, and chorioretinal degeneration. The other family members showed microcephaly, slight mental retardation, and short stature, but not cho rio reti nopathy. Moreover, only those members with high myopia had chorioretinal atrophy. There is probably a causal relationship, because pathologic myopia of the retina can result in areas of focal chorioretinopathy and abnormal findings on ERG. Unlike the other autosomal dominant families described so far, this family had short stature and myopia highest in case III-l), which hitherto have been reported as features of autosomal recessive families."'·17 None of our subjects was affected by microcornea- microphthalmia. Although microcephaly and slight mental retardation were present in all subjects but one and short stature was present in four of six affected subjects, the ocular alterations were present in only two subjects. Also, in earlier reports of autosomal dominant families, microcephaly and chorioretinopathy did not invariably occur in association in the same individual,8·10'1 irl<i which clearly demonstrates that this syndrome has a variable clinical expression.

Given the apparent lack of metabolic dysfunction, it is not feasible to hypothesize the pathogenetic mechanism underlying the alterations described in our subjects.

On the basis of this report, clinicians should be alert to the possibility that ram il i es with autosomal dominant microcephaly and the classic focal areas of choroidal and retinal atrophy may also show high myopia, relevant ERG abnormalities, and short stature hitherto described only in the recessive form. These findings could be useful for genetic counseling in the apparently isolated forms of microcephaly or retinopathy. In such cases, the possibility of a syndromic association must be considered and the family must be exhaustively screened.

REFERENCES

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10.3928/0191-3913-20020901-09

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