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Editor,—We describe a family with chorioretinal dysplasia, microcephaly, mental retardation, and lymphoedema.
The proband presented with a severe multiple malformation syndrome, with anomalies of the brain, heart, and eyes. Ocular anomalies included microphthalmia and chorioretinopathy. Pedal lymphoedema was obvious at birth. These features overlap with three previously distinguished conditions (microcephaly with chorioretinopathy (MIM 156590), microcephaly with microphthalmia and retinal folds (MIM180060), and microcephaly and lymphoedema (MIM152950), and this suggests that they can be the variable expression of a single entity. In all children with microcephaly, a history of pedal oedema and detailed eye examination are essential.
The index patient, a male, was born as the second child, to unrelated parents. He was born at a gestational age of 37 weeks by elective caesarean section for unexplained intrauterine growth retardation. He was severely microcephalic and had marked lymphoedema of the dorsum of both feet. Facial features were peculiar with, in addition to the microcephaly, low set ears and retrognathia. There was a transverse palmar groove on the left side, a right sided hydrocele and cardiac examination revealed the presence of an atrial septal defect, a small ventricle septal defect, and a right aortic arch. Neurological examination revealed axial hypertonia and severe developmental delay. Axial T1 weighted MR image at 4 months showed microcephaly and microlissencephaly. Asymmetry of the eyes was noted and the right eye had an abnormal leucocoric appearance. Corneal diameters were 11.5 mm on the right and 9 mm on the left. There was an iris bombans on the cataractous right eye with pressure of 30 mm Hg. Ultrasound showed the characteristics of a persistent hyperplastic primary vitreous (PHPV). After a surgical procedure with iridectomy the pressure normalised. On funduscopy of the left eye a dystrophic retina with punched out lesions was seen (Fig 1). The second patient is the 3 year old brother of the index patient. He was microcephalic and showed marked lymphoedema of both feet at birth. Development was moderately retarded. Ophthalmological examination revealed bilateral chorioretinal dysplasia with the punched out lesions being localised in the periphery and midperiphery. Optic discs had a waxy pale aspect, macular reflex was dull (Fig 2). A fERG performed under sedation using contact lens electrodes showed a severely attenuated cone and rod response. The third patient is the 27 year old father of both patients. He was mildly mentally retarded. Physical examination revealed microcephaly and dilated veins on the dorsal side of his feet. On funduscopy subtle atrophic pigment epithelial changes could be noted temporally from the optic disc on the right eye; on the left eye atrophic changes were prominent. A fERG was performed and showed a normal rod and cone response.
In all three patients high resolution chromosomal analysis on a peripheral blood lymphocyte culture revealed a 46,XY normal male karyotype after G-banding.
In literature, three distinct conditions have been delineated—microcephaly with chorioretinopathy (MIM 156590)) microcephaly with microphthalmia and retinal folds (MIM180060), and microcephaly and lymphoedema (MIM152950). The features in the present family overlap with these three disorders. This suggests that, in at least some instances, they can be the variable expression of a single genetic condition.
In the syndrome with microcephaly with chorioretinopathy variable expressivity and the presence of mental retardation as an associated feature have repeatedly been reported.1 Male to male transmission of microcephaly, chorioretinal dysplasia, and mental retardation has also been described.23 Microcephaly with microphthalmia and retinal folds (MIM180060) has been reported as an apparently separate condition. However, microcephaly and microphthalmia were also present in the youngest child in the present family, but not in his father and brother, suggesting that both conditions might belong to the same spectrum of a single genetic disorder. Microcephaly and lymphoedema (MIM152950) was first described by Leung in 1985 in five individuals in a four generation family.4 There was no mental retardation. Congenital lymphoedema has also been described in three other isolated cases of microcephaly-chorioretinopathy.5-7 In the present family, the microcephaly and lymphoedema of the feet in patients 1 and 2 was associated with mental retardation as well as chorioretinopathy. This suggests that the three disorders previously distinguished could be the variable expression of a single genetic condition.
Ophthalmological findings reported in the autosomal dominant syndrome of microcephaly-chorioretinal dysplasia syndrome (MIM156590) include chorioretinal dysplasia, myopic astigmatism, and retinal dystrophy. Chorioretinal dysplasia represents the most common ocular abnormality seen in all patients of this report. Microphthalmia as seen in the proband has been reported before.58 Closed angle glaucoma secondary to a persistent primary hyperplastic vitreous (PHPV) has not been described. The spectrum of eye anomalies seen in the three patients of a single family clearly indicate the wide variety of eye anomalies that can be associated with a single genetic entity.
Feingold and Bartoshesky and Limwongse et alsuggested before that the three entities might represent the variable expression of a single entity.37 The clinical variability in the expression of this syndrome is remarkable. The proband of the present family had a severe multiple malformation syndrome, with anomalies of the brain, heart, and eyes. The presence of marked lymphoedema of the feet suggested the diagnosis which was confirmed upon examination of his brother and father, who had milder manifestations with microcephaly and developmental delay. Interestingly, the eye anomalies had not been diagnosed in either of them, and in addition the pedal oedema had disappeared. This suggests that in all children with microcephaly, a careful eye examination is warranted.
Counselling in microcephaly is difficult, and in the absence of a specific aetiological diagnosis, an empirical recurrence risk of 15–20% is often cited.910 Chorioretinal dysplasia-microcephaly-mental retardation syndrome (CDMMS) with autosomal recessive inheritance was described by McKusicket al.10
In a sporadic patient with microcephaly, chorioretinal dysplasia, and mental retardation the clinical distinction between and autosomal dominant and recessive inheritance is not possible.8However, the association with pedal lymphoedema could indicate probable autosomal dominant inheritance, since this has not been described in the autosomal recessive families.
Koen Devriendt is a senior clinical investigator of the Fund for Scientific Research-Flanders (Belgium) (FWO).
This paper was presented at the EPOG meeting Cambridge in September 2000 by I Casteels