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Editor—Case 1, a male, was born at 38 weeks' gestation by normal delivery to unrelated parents. Mild bilateral renal pelvis dilatation was noted on prenatal scans as was a slight increase in liquor volume. An amniocentesis, which was performed for maternal age, showed a 46,XY karyotype. His birth weight was 2593 g (9th centile), length 47.5 cm (50th centile), and OFC 32.7 cm (50th centile). Features noted at birth included neck oedema, a large anterior fontanelle (6 cm × 7 cm), a short penis with a large scrotum, and an anteriorly placed anus. Echocardiography showed a patent ductus arteriosus with mild septal and right ventricular wall hypertrophy. His cranial ultrasound was reported to show partial agenesis of the corpus callosum. Postnatal renal ultrasound showed mild dilatation of the left pelvicalyceal system. At 7 months his growth parameters were weight 6.37 kg (0.4th centile), length 64.5 cm (2nd centile), and OFC 44 cm (25th centile).
Bilateral inguinal herniae were present from 3 months and repaired at 4 months of age. Ophthalmological examination showed a hypoplastic left disc and a small coloboma of the right disc. He also has hypermetropic astigmatism and bilateral entropion which required surgery. During his first year he developed eczema and persistent diarrhoea. He sat at 7 months, crawled at 1 year, and walked independently at 2 years. His linear growth progressed close to the 3rd centile and his OFC followed the 90th centile. The facial features of note are his wide mouth, long, smooth philtrum, and small posteriorly angulated ears (fig 1). His hair grows well but is brittle and coarse. He has one extra tooth in the mandible and all his teeth are irregular and pointed. He was due to attend mainstream school. He had required speech therapy for delayed language. Urinary mucopolysaccharides, oligosaccharides, and white cell enzymes were normal. The triglycerides were at the upper range of normal at 1.4 mmol/l (range 0.5-1.8 mmol/1) and the cholesterol was at the lower range of normal (2.8 mmol/l, normal range approximately 1.7-5.2 mmol). A 7-dehydrocholesterol result was not available as the child left the country before this test became available. In addition, there were no records of the parental cholesterol levels. Thyroid function at 10 months showed T4 107 μmol/l and TSH 5.7 IU/l. Blood chromosomal analysis showed a normal 46,XY karyotype. Skeletal survey was normal.
(A, B) Front and side view of case 1 showing hypertelorism, a wide mouth, and posteriorly rotated ears.
Case 2, a male, was born at 32 weeks' gestation, weighing 2000 g, to unrelated parents, following spontaneous onset of labour and a normal delivery. There was a history of polyhydramnios during the pregnancy. He has one normal female sib. He was admitted to the special care baby unit for five weeks because of his prematurity. Dysmorphic features noted at birth included hypertelorism, a persistent large posterior fontanelle, a large anterior fontanelle, a narrow, high arched palate with midline cleft of the upper alveolar margin, two neonatal teeth, and a right inguinal hernia (fig 2).
(A, B, C) Front and side view of case 2 aged 7 months and 5 years showing hypertelorism, a wide mouth, and posteriorly rotated ears.
Motor development was noted to be delayed; he sat at 10 months and walked at 18 months. He has had both inguinal and umbilical hernia repairs. He has required speech therapy and requires special help at school. At the age of 8 years, he is hyperactive and is said to have an attention deficit disorder. Ophthalmological assessment showed hypermetropic astigmatism. He was also noted to have tortuosity of the fundal vessels. On examination aged 8 years, his weight (24.3 kg) and head circumference (51 cm) were on the 25th centile and his height was <25th centile (118.5 cm). He had coarse hair with two crowns. In addition, he was noted to have abnormally shaped, slender teeth. An orthopantomogram showed abnormalities of several of the teeth in the position of the incisors and canines. Many were slender and canine-like. In addition, some deciduous teeth were absent. At the age of 8, none of his adult teeth have erupted. The possibility of an ectodermal dysplasia was raised, although following consultation with a dermatologist this was excluded.
Urinary amino and organic acids (including glycosaminoglycans), performed on two separate occasions, excluded a mucopolysaccharide disorder. Cholesterol and triglyceride levels, measured on two occasions, were normal. A 7-dehydrocholesterol level was also normal. A skeletal survey was normal. Chromosomal analysis showed a normal 46,XY karyotype.
In case 1, a CT scan was reported to show diffuse low density areas in the cerebral white matter bilaterally. The corpus callosum was hypoplastic. MRI scan aged 18 months showed multiple cystic areas within the white matter radiating out at right angles from the ventricles into all lobes, but especially the parietal, occipital, and temporal lobes (fig 3) Their signal intensity paralleled that of CSF. The basal ganglia and brain stem were spared with very little involvement of the corpus callosum. A repeat MRI scan aged 4 years showed an increase in the number and size of the spaces suggesting a progressive process. The ventricles were mildly dilated suggesting some atrophic change.
Case 1, aged 4 years. MRI of the head/sagittal T1W + coronal/axial T2W, showing multiple, well defined areas of CSF signal intensity throughout both cerebral hemispheres, especially in the periventricular white matter. They are of varying sizes, being seen as linear streaks in the cortex but oval or rounded areas in the white matter. All tend to be orientated at right angles to the lateral ventricles.
In case 2, CT brain scan showed multiple cystic spaces (fig 4). MRI scan at the age of 6 years confirmed the presence of these cystic spaces. These were noted to be more confluent in the occipital region (fig 5). The ventricles were of normal size. The findings were similar to case 1.
(A, B) Case 2 aged 6 years 9 months. CT of the head showing multiple areas of low density within the cerebral white matter bilaterally, most prominent posteriorly.
(A, B) MRI of the head (sagittal/coronal T1W and axial T2W) showing a similar appearance to that shown in fig 3. The CSF density areas in the cerebral white matter are most prominent in the parieto-occipital regions where there is associated localised ventricular dilatation. Some involvement of the corpus callosum is also noted. The brain is otherwise normal.
Frontonasal dysplasia is a developmental field defect of midfacial development. Clinical features include a broad nose, hypertelorism, low anterior hairline, and sometimes bony defects of the forehead. It is usually a sporadic malformation and is known to occur with a high frequency in twins. There are reports of this malformation occurring with CNS anomalies, in particular frontal encephaloceles and agenesis of the corpus callosum. Dobyns et al 1 have reported the association of frontonasal dysplasia with bilateral periventricular nodular heterotopia. Additional features including mental retardation and epilepsy were present in their cases. However, the CNS findings in our cases are distinct with no evidence of nodular heterotopia.
Virchow-Robin spaces are invaginations of the subarachnoid space containing cerebrospinal fluid that accompanies small arteries and arterioles as they perforate the surface of the brain. The distribution of the abnormalities seen on the MRI scans of these two cases mirrored the perivascular distribution of the Virchow-Robin spaces. Dilatation of Virchow-Robin spaces have been described in a number of conditions including old age dementia, HIV encephalopathy, and multiple sclerosis (MS).2 In children, similar MRI findings are seen with mucopolysaccharidosis.3 Neither of our cases had any other clinical features of a mucopolysaccharide disorder and screening of urinary amino acids was negative. In addition, the basal ganglia and corpus callosum are frequently involved in the mucopolysaccharide disorders. In our cases, only case 1 had some involvement of the corpus callosum and the basal ganglia were spared in both cases. The pathogenesis of large Virchow-Robin spaces remains unknown. Increased CSF pulsations, vascular ectasia, or an abnormality of arterial wall permeability have all been postulated as possible mechanisms.2 These spaces may also have an important immunological role in reactions to foreign antigens that gain access to them.2 It is felt that this immunological role may have implications for the understanding of the pathogenesis of a number of neuropathological conditions including encephalitis, MS, and HIV encephalopathy. Both HIV encephalopathy and MS are progressive in nature. The fact that case 1 had features suggesting a progressive process may indicate that the abnormality seen in our cases has a metabolic or autoimmune basis.
Rollins et al 4 described the prevalence of dilated Virchow-Robin spaces in 1250 children having consecutive MRI scans. Thirty seven children (3%) were shown to have such abnormalities on MRI scanning. Five of these children were said to have coarse or dysmorphic features and the remainder were referred with headaches, seizures, or developmental delay. All of the children with dysmorphic features had a negative urinary amino and organic acid screen. Four of the 37 were said to be hyperactive, although none of these had dysmorphic features. In their study, the size and number of the dilated Virchow-Robin spaces appeared to be static in contrast to case 1. Unfortunately, the authors did not describe the dysmorphic features of the five cases in detail, nor were there any clinical photographs so it is not possible to determine whether their cases had similar clinical features to our own. A number of other case reports have described similar MRI findings but without a dysmorphic phenotype.5-8
It is difficult to establish the significance of the low normal cholesterol level in association with high normal triglyceride level in case 1. Cholesterol has a role in myelination of the brain in early fetal life. The child has left the country and is therefore no longer available for further testing. The fact that case 2 had consistently normal levels suggests that the association may be coincidental.
Blepharocheilodontic syndrome shares some of the ectodermal characteristics in common with our cases, but the degree of hypertelorism is milder and cleft lip/palate is a common finding in BCD.9 In contrast, Sener10 described a female child with similar dysmorphic features and identical MRI findings to our own cases. This child was said to have normal development up to the age of 5 years. Subsequently she developed mild developmental delay and had to leave normal school aged 13 years. She was noted to have dental anomalies with hypodontia, dental occlusions, and several buccal frenulae. She was also noted to have thin hair and nail abnormalities. The author suggested that her features were consistent with ectodermal dysplasia and that her condition was slowly progressive in nature. No karyotype was reported for this patient. Slaney et al 11 reported a boy with dysmorphic features similar to the case reported by Sener.10 However, this child, a boy, had different abnormalities on MRI scan with evidence of periventricular grey matter heterotopia. All three cases (that of Sener10 and our two) have occurred sporadically with no parental consanguinity. Both males and females have been affected. The genetic basis remains unknown although the similarities on scan to the mucopolysaccharide storage disorders and the suggestion of a progressive nature raises the possibility of autosomal recessive inheritance.