Table 1.
Patient Deep Phenotyping, Genotyping and Serum Calcium Metabolic Profile
| Patient No. | Sex | Age, years | Genotype | Cutaneous features | Neurological features | Ophthalmological features | Other clinical findings | Age at most recent brain MRI, years | Most recent brain MRI findings | Ionized calcium | PTH |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 3.8 | GNAQ c.548G>A, p.R183Q | CM face (right, including forehead) | Seizures, stroke-like episodes, and headaches. Normal development | Left increased IOP and choroidal hemangioma | - | 3.6 | LA left frontal and temporal lobes associated with cortical calcifications. Underdevelopment of left hemispheric superficial cortical veins, enlargement of left deep medullary veins and osteohypertrophy on the left. Generalized parenchymal volume loss in the left cerebral hemisphere. Prominent left cerebellar vessels | Normal | Normal |
| 2 | M | 3.1 |
GNAQ and GNA11 WT |
No vascular or pigmentary lesions | Seizures, stroke-like episodes, left hemiplegia. Normal development | Normal | - | 2.9 | LA right parietal lobe associated with subjacent parenchymal volume loss and gyriform calcifications. Slight enlargement of the right choroid plexus | Normal | Normal |
| 3 | M | 16.1 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead) and neck | Intellectual disability, autism, and ADHD | Left glaucoma and bilateral choroidal hemangiomas | Joint hypermobility and muscle weakness | 14.8 | LA right parietal, occipital and temporal lobes. Prominent and atypical veins in the right hemisphere and right cerebellum. Progressive volume loss of cerebellar hemispheres | Normal | Low |
| 4 | F | 4.0 | - | CM right forehead | None | Right glaucoma | - | 1.2 | LA right occipital and temporal lobes. Abnormal venous drainage in the DMVs territory. Abnormal vessels on the right sylvian fissure and choroid plexus suggestive of DVA | Normal | Normal |
| 5 | M | 15.9 | - | CM face (bilateral, including forehead), neck, upper trunk, and lower limbs | Seizures, left hemiplegia, severe intellectual disability, autism, and language disorder | Bilateral glaucoma | Left hip subluxation and valgus deformity of left knee (with overlying vascular lesions on the skin) | 13.1 | LA right hemisphere associated with cerebral atrophy and gyriform calcifications. Left cerebellar leptomeningeal angiomatosis | Low | Normal |
| 6 | M | 2.7 | - | CM face (bilateral, including forehead) | None | Left buphthalmos, left glaucoma and cloudy cornea | - | 0.03 | Prominent left cortical and leptomeningeal vessels | Normal | Normal |
| 7 | F | 11.0 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead) and scalp | Seizures, left hemiplegia, headaches, intellectual disability, autism, ADHD and language disorder | Bilateral glaucoma | Scoliosis and leg length discrepancy (with no overlying vascular lesions) | 1.9 | LA right hemisphere with progression of subjacent cerebral atrophy. LA left frontal lobe, insular cortex and mid brain | - | Normal |
| 8 | M | 1.9 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead) right upper limb and right abdomen associated with overgrowth | Seizures, stroke-like episodes and left hemiplegia. Normal development | Normal | Coronal hypospadias and right hydrocele | 1.7 | LA right frontal and parietal lobes associated with calcifications on the frontal lobe. Prominent draining DMVs frontal lobe and left insula | Normal | Normal |
| 9 | F | 11.8 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead), neck and upper trunk | Seizures, right hemiplegia, headaches, intellectual disability, autism, ADHD and language disorder | Left glaucoma | Scoliosis. Cervicothoracic lipoma | 9.6 | LA left hemisphere with subjacent parenchymal volume loss and multiple draining veins. Enhancement of the brainstem. | Low | Normal |
| 10 | M | 11.6 | GNAQ c.548G>A, p.R183Q | CM left forehead | Seizures, right hemiplegia, headaches, intellectual disability, autism, ADHD and language disorder | Normal | Recurrent epistaxis | 7.7 | LA left hemisphere with subjacent parenchymal volume loss. Increased draining veins within the ventricles, cortical signal change and enhancement | Normal | Normal |
| 11 | M | 15.0 | - | Bony prominence left forehead. No vascular or pigmentary lesions on skin | Seizures, headaches, anxiety. Normal development | Right homonymous hemianopia | - | 15.0 | LA left temporal, parietal and occipital lobes with subjacent parenchymal volume loss and gyriform calcifications. Progression of thickening and bone expansion of the diploic spaces of the left frontal bone | Low | Normal |
| 12 | M | 2.4 | - | CM face (left, including forehead) | Seizures, developmental impairment and social communication difficulties | Left glaucoma and left choroidal hemangioma | - | 0.3 | LA left parietal and occipital lobes with subjacent parenchymal volume loss. Choroid plexus asymmetry | - | Normal |
| 13 | F | 9.2 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead), trunk and lower limb | Seizures, cerebral palsy of 4 limbs and intellectual disability | Bilateral glaucoma | Microcephaly | 6.5 | LA both frontal and parietal lobes and left temporal lobe associated with calcifications. Thickening of the skull and prominent deep cerebral DVAs (predominantly on the right) | Normal | Normal |
| 14 | F | 9.4 | GNAQ c.548G>A, p.R183Q | CM left forehead | Seizures, right hemiplegia, intellectual disability, autism, ADHD and language disorder | Left increased IOP | - | 9.4 | LA left frontal, parietal and occipital lobes with subjacent parenchymal volume loss and gyriform calcifications | Low | Normal |
| 15 | M | 11.8 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead), scalp, trunk and limbs associated with overgrowth | Seizures, cerebral palsy of 4 limbs and intellectual disability | Bilateral glaucoma | Scoliosis. Left hip dysplasia and dislocation (with overlying vascular lesions on the skin) | 9.6 | No imaging available | Normal | Normal |
| 16 | M | 1.4 | - | CM forehead (bilateral) and scalp | Seizures, right hemiplegia and developmental impairment | Bilateral increased IOP | 1.6 | LA both parietal lobes and right frontal lobe with calcifications. Prominent deep veins along lateral ventricles, left hippocampus, midbrain and the midline. Bilateral enlargement of choroid plexus | - | - | |
| 17 | F | 4.0 | - | CM face (left, including forehead), scalp and neck | None | Visual field defect | - | 0.4 | LA left occipital lobe. Enlargement of left choroid plexus | Normal | Normal |
| 18 | F | 0.7 | GNAQ c.548G>A, p.R183Q | CM right forehead | Seizures, right hemiplegia and developmental impairment | Normal | - | 0.7 | LA right parietal and temporal lobes associated with subjacent parenchymal volume loss and gyriform calcifications. Enlargement of right choroid plexus | Normal | High |
| 19 | M | 10.9 | GNAQ c.548G>A, p.R183Q | CM face (left, including forehead), trunk and limbs associated with overgrowth | Seizures, stroke-like episodes, intellectual disability, autism, ADHD and language disorder | Left glaucoma | Myasthenia gravis | 10.8 | LA parietal, temporal and occipital lobes. Encephalomalacia related to left hemispheric temporo-parietal-occipital disconnection and anterior temporal lobectomy | Low | Normal |
| 20 | M | 10.8 | - | CM face (bilateral, including forehead), neck and upper trunk. Café-au-lait macule neck | Seizures and headaches. Normal development | Left glaucoma | Obesity, acanthosis nigricans, gynecomastia and isolated adrenarche. Hypomineralis-ed dentition | 7.8 | LA left temporal, parietal and occipital lobes with subjacent parenchymal volume loss and gyriform calcifications. Large transmantle vein on the left extending to enlarged choroid plexus and DVA | Low | Normal |
| 21 | M | 5.5 |
GNAQ and GNA11 WT |
CM face (left, including forehead), neck and upper trunk | Stroke-like episodes. Social communication difficulties | Normal | - | 3.7 | LA left cerebellar hemisphere associated with a large DVA | Low | Normal |
| 22 | M | 11.2 | GNAQ c.548G>A, p.R183Q | CM right forehead | Seizures, left hemiplegia, intellectual disability, autism and ADHD | Right glaucoma and left homonymous hemianopia | Scoliosis | 6.8 | LA right hemisphere with calcifications. Signs of right functional hemispherectomy with shrinkage of the right cerebral hemisphere and mature cystic leukomalacia. | Low | Normal |
| 23 | M | 13.7 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead) and neck | Seizures, stroke-like episodes, headaches, intellectual disability and language disorder | Right glaucoma | - | 10.5 | LA right frontal lobe with gyriform calcifications | Low | High |
| 24 | F | 10.3 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead), neck, upper trunk and limb associated with overgrowth | Headaches, intellectual disability and language disorder | Left glaucoma | - | 7.1 | LA right temporal lobe, occipital lobes, splenium of corpus callosum, midbrain and pons. Multiple DVAs in supra- and infra-tentorial compartments | Normal | Normal |
| 25 | F | 9.6 | - | CM face (bilateral, including forehead), neck, buttock and lower limb associated with overgrowth | Seizures, left hemiplegia, intellectual disability, autism, language disorder and dyslexia | Normal | - | 6.4 | LA right parietal and occipital lobes with calcifications. Signs of disconnection surgery and likely residual connection medially in the right parietal lobe | Low | Normal |
| 26 | F | 6.00 | GNAQ c.548G>A, p.R183Q | CM face (bilateral, including forehead), neck, trunk and limbs associated with overgrowth | Seizures, left hemiplegia, intellectual disability and autism | Right glaucoma | - | 5.9 | LA right cerebral hemisphere. Enlargement of right choroid plexus | Normal | Normal |
| 27 | F | 2.4 | GNAQ c.548G>A, p.R183Q | CM right forehead | Seizures. Normal development | Normal | - | 2.4 | LA right parietal, temporal, and occipital lobes with calcifications. Enlargement of right choroid plexus | Low | High |
| 28 | F | 15.4 | - | CM face (left, including forehead) and scalp | Seizures, right hemiplegia, headaches, language disorder, intellectual disability | Left glaucoma and left choroidal hemangioma | - | 11.2 | LA left frontal, parietal and temporal lobes with cerebral atrophy and gyriform calcifications. Enlargement of left choroid plexus. Anomalous draining veins on the right cerebral hemisphere | Low | Normal |
| 29 | F | 1.3 | - | CM face (midline, including forehead) | None | Normal | - | 1.2 | LA both frontal, parietal and occipital lobes associated with prominent medullary veins | ||
| 30 | M | 5.9 | GNA11 c.547C>T, p.R183C | CM with naevus anaemicus face (right, including forehead), trunk and limbs associated with undergrowth |
Learning difficulties, Autism | Normal | Leg length discrepancy (with overlying vascular lesions on the skin) | 0.9 | Small ill-defined foci of signal abnormality in the right caudate nucleus and the adjacent internal capsule, with some associated focal ex vacuo dilatation of the right frontal horn | Low | Normal |
| 31 | M | 4.3 | GNAQ c.548G>A, p.R183Q | CM face (right, including forehead) | Seizures, left hemiplegia, stroke-like episodes, intellectual disability and language disorder | Right glaucoma, right choroidal hemangioma | Microcephaly | 2.8 | Bilateral supra- and infratentorial leptomeningeal angiomatosis with right frontal and temporal lobes relatively spared. Enlargement of right choroid plexus. Bilateral gyriform calcifications in the right temporoparietal and left parietal lobes. Anomalous draining veins more prominent | Low | High |
| 321 | F | 10.5 | GNA11 c.547C>T, p.R183C | CM face (bilateral, no forehead involvement), trunk and limbs associated with undergrowth | None | Right iris heterochromia. Right increased IOP | Leg length discrepancy (with overlying vascular lesions on the skin) | 6.7 | Normal brain findings | Normal | Normal |
| 331 | F | 8.4 | GNA11 c.547C>T, p.R183C | CM and extensive dermal melanocytosis face (including forehead), trunk and limbs associated with overgrowth | Seizures, right hemiplegia, intellectual disability and language disorder | Bilateral glaucoma | 8.7 | LA left hemisphere, right frontal lobe and cerebellar hemisphere. Cortical calcifications left cerebral cortex and right frontal lobe | Normal | Normal | |
| 341 | F | 7.6 | GNAQ c.548G>A, p.R183Q | CM trunk and limbs associated with overgrowth. Dermal melanocytosis lower back and café-au-lait macule lower limb | None | Conjunctival melanosis | - | 3.2 | Normal brain findings | Normal | Normal |
| 351 | F | 14.3 |
GNAQ and GNA11 WT |
CM trunk and limbs. Dermal melanocytosis lower back. Café-au-lait macule, lower limb | None | Normal | Recurrent epistaxis | - | Brain MRI not performed2 | - | High |
| 36 | F | 6.3 | GNA11 c.547C>T, p.R183C | CM with naevus anaemicus face (bilateral, including forehead), trunk and limbs associated with overgrowth. Café-au-lait macular pigmentation, trunk | Language difficulties | Normal | - | 6.0 | Small cortical hyperintensity in right parietal lobe, without diffusion restriction or abnormal enhancement and overlying calvarial thinning. No other intracranial abnormalities | Low | Normal |
| 371 | M | 3.8 | GNA11 c.547C>T, p.R183C | CM with naevus anaemicus face (right, including forehead), upper trunk and limbs. Extensive dermal melanocytosis, trunk and limbs | None | Bilateral glaucoma | - | 0.7 | Suspected calcifications, lateral wall of left lateral ventricle. No focal abnormality or areas of abnormal contrast enhancement | - | Normal |
| 381 | M | 12.6 | GNAQ c.548G>A, p.R183Q | CM face (no forehead involvement), upper trunk and limbs associated with overgrowth. Naevus anaemicus left foot. Extensive dermal melanocytosis, trunk and limbs | ADHD | Normal | - | - | Brain MRI not performed2 | Low | Normal |
| 39 | F | 2.0 | GNAQ c.548G>A, p.R183Q | CM upper trunk and upper limb. Extensive dermal melanocytosis, trunk and limbs | None | Normal | - | - | Brain MRI not performed2 | Normal | Normal |
| 40 | M | 9.8 | GNA11 c.547C>T, p.R183C | CM trunk and limbs associated with naevus anaemicus and undergrowth. Café-au-lait macular pigmentation neck | Intellectual disability, autism and language disorder | Normal | Leg length discrepancy (with overlying vascular lesions on the skin) | 3.1 | Normal brain findings | Normal | High |
| 41 | F | 1.5 | - | CM trunk and lower limbs associated with naevus anaemicus and overgrowth. | None | Normal | - | - | Brain MRI not performed2 | Normal | High |
| 42 | M | 0.2 | - | CM face (bilateral, including forehead), trunk and upper limb | None | Right glaucoma | - | 0.02 | LA right frontoparietal and occipital lobes. Enlargement of right choroid plexus | Normal | Normal |
Abbreviations: ADHD, attention deficit hyperactivity disorder; CM, capillary malformation; DMV, deep medullary vein; DVA, developmental venous anomaly; F, female; IOP, intraocular pressure; LA, leptomeningeal angiomatosis; M, male; MRI, magnetic resonance imaging; PTH, parathyroid hormone; WT, wild-type.
Ionized calcium levels were corrected to pH. Pediatric range references of ionized calcium: 1.15–1.41 mmol/L (<2 years), 1.19–1.37 mmol/L (2–5 years), 1.22–1.31 mmol/L (5–15 years). PTH reference range: 0.7–5.6 pmol/L. Results refer to the first measurements.
According to published guidelines (Waelchli et al, 2014), we currently do not perform MRI/MRA in the absence of vascular lesions on the forehead area unless there are neurological symptoms/signs.
1
indicates a patient previously reported in Polubothu et al. (2020).
2
According to published guidelines (Waelchli et al, 2014), we currently do not perform MRI/MRA in the absence of vascular lesions on the forehead area and neurological symptoms.