Periventricular heterotopia and white matter abnormalities in a girl with mosaic ring chromosome 6

Clinical description

The patient, a female, is the second child of healthy unrelated parents. Family history,
including her 4-year-old sister, was unremarkable. This patient was born by means
of caesarean delivery because of intrauterine growth retardation at the 39th week
of gestation. Birth weight was 1,785 g (?2SD), length was 43 cm (?2SD) and head
circumference was 29 cm (?2SD). Apgar scores were 8 and 9 at 1 and 5 minutes, respectively.
She was able to sit at 5 months, walk at 14 months. Although at age 3 years she couldn’t
speak in two-word sentences, at age 3 years and 11 months she was able to speak three-word
sentences with postpositions. She had a history of repeated febrile seizures.

At the age of 3 years and 11 months, her weight was 9,300 g (?3SD), length 89.7 cm
(?2.4SD) and head circumference 41.3 cm (?4.4SD). Short stature prompted endocrinological
investigations and karyotyping. Exaggerated growth hormone responses to arginine,
levodopa and clonidine stimulation were within normal range, whereas karyotype analysis
revealed mosaic ring chromosome 6 (Fig. 1). She presented minor dysmorphic features including full lips and epicanthal folds.
Ophthalmological and otological including aural examination were normal, and ultrasound
cardiac examination revealed no anomalies. Kyoto Scale of Psychological Development,
which is a standardized developmental test for Japanese children, was performed at
3 years 10 months, revealing postural-motor skills of 3 years 1 month (subquotient
79), cognitive-adaptive skills of 2 years 6 months (subquotient 64), language-social
skills of 2 years 9 months (subquotient 70), and overall developmental age of 2 years
8 months (developmental quotient 68).

Fig. 1. Chromosome G-banding result from the patient. The total number of cells counted was
hundred. a Ring chromosome (67 %). b Monosomy 6 (25 %). c Dicentric ring chromosome (6 %). d Double ring chromosome (2 %)

Cerebral MRI revealed periventricular heterotopia on the bilateral posterior horn
of the lateral ventricle and white matter abnormalities in the bilateral parietal
and occipital lobe. Neither hydrocephalus nor enlarged lateral ventricles were detected
(Fig. 2). Electroencephalogram (EEG) during induced sleep showed poor normal sleep spindles
and slightly irregular background activity in the bilateral occipital head regions.
The possibility of tuberous sclerosis was also considered with respect to the observed
periventricular nodules. Besides the past episodes of febrile seizure, she never had
an epileptic attack, and anticonvulsant agent was never prescribed, ruling out the
possibility of tuberous sclerosis. This study was approved by institutional review
board (Osaka City University).

Fig. 2. a-f: MRI imaging of the brain of this patient. a and b Axial T1W and T2W image, showing left parietal lobe. c Coronal T2W section showing white matter abnormalities in the bilateral parietal
lobe. d Coronal T2W section showing white matter abnormalities in the bilateral occipital
lobe. e and f Axial and Coronal FLAIR image, showing periventricular heterotopia on the bilateral
posterior horn of the lateral ventricle

Molecular and cytogenomic characterization

This study was conducted following approval by the ethics committee at our institution.
After obtaining the written informed consent from the patient’s family, blood sample
was drawn from the patient. Chromosome analysis was performed on peripheral blood
lymphocyte cultures. Standard G-bands analysis revealed mos 46,XX,r(6)(p25q27)[67]/45,XX,-6[25]/46,XX,dic
r(6:6)(p25q27:p25q27)[6]/47,XX,r(6)(p25q27)?×?2[2]. The microarray-based comparative
genomic hybridization (array-CGH) analysis was performed as described previously 6] and revealed a genomic copy number loss at 6q27 (Fig. 3).

Fig. 3. The result of array-CGH. Vertical and horizontal axes indicate the genomic location
and signal log
₂
ratio, respectively. Dots indicate the location and the signal log
₂
ratio of the microarray probes. a Chromosomal view of the chromosome 6 shows a genomic copy number loss at q27. b Gene view expands the aberration region. The blue rectangle indicates and the blue
bars indicate the aberration region and the locations of the genes. Two genes discussed
in the text are marked by red oblongs. The mean log
₂
ratio of the aberration region is ?0.780567, indicating mosaic deletion