Patient 1, a female aged 10 years and 4 months, is the first of two children of a healthy 38-year-old woman and a non-consanguineous 48-year-old man, whose family history was unremarkable. She was conceived naturally. The fetal ultrasound scan at gestational week (gw) 12 was normal, while at gw 21 a choroid plexus cyst and echogenic intracardiac focus were detected, the biparietal diameter was at the 95th centile at gw 21 and >95th centile at gw 33 with normal cerebral morphology. She was born at the 34th gw with a weight of 3080 g (90-97th centile), length of 49 cm (90th centile) and head circumference of 35.6 cm (97th centile). At birth, a diffuse capillary malformation involving the trunk and limbs was observed, associated with cutaneous syndactyly of the 2nd and 3rd toes (). During the first year of life, a plantar epidermal nevus and a small hemangioma, which subsequently disappeared, were observed, together with left hemihyperplasia (detected at the age of 3 months).\nCardiac and abdominal ultrasound scans were repeatedly normal. Brain MRI scans detected increased peritrigonal signal of white matter at the age of 10 months and focal hemimegalencephaly with perisylvian polymicrogyria at the age of 7 years. From the age of 7 years, the girl had episodes of generalized tonic-clonic seizures refractory to antiepileptic therapy. She suffers from mild cognitive impairment and attention deficit disorder, and in the last years had temper tantrums and angry outbursts.\nOn physical examination at the age of 10 years and 4 months, her weight was 35 kg (25th-50th centile), height 138 cm (25th-50th centile) and head circumference 60 cm (+ 5.2 SD). She had left hemihyperplasia, involving face, trunk and limbs (mainly legs) with diffusely soft and thick irregularly marbled skin and prominent capillaries and veins on the trunk, abdomen and limbs. Three small (diameter <0.5 cm) achromic spots were observed on the trunk. Her 3rd right finger was significantly larger than the contralateral one and she had a bilateral proximal 4/5 cutaneous syndactyly of the 2nd and 3rd toes. Besides macrosomia, she had dysmorphic features including malar hypoplasia, hypertelorism (inner canthal distance >97th centile, palpebral length + 1 SD), long philtrum (>97th centile) and high palate, and S-shaped scoliosis.
This 17-year-old boy was the only child born to non-consanguineous parents. His father and grandfather showed diffuse angiomatosis. He was conceived naturally. His fetal ultrasound scan showed IUGR. At birth, a diffuse capillary malformation involving the trunk and limbs was recorded. At age 3 months, he was noted to have left asymmetric overgrowth. During his follow-up visits, cardiac and abdominal ultrasound scans were repeatedly normal. Early developmental milestones were delayed, and at age 7 months, a brain MRI scan revealed focal hemimegalencephaly with right perisylvian polymicrogyria. From age 5 years, he started to manifest episodes of generalized tonic-clonic seizures, which proved to be refractory to antiepileptic therapy. He was severely cognitively impaired and developed an attention deficit disorder. On physical examination, at age 13 years and 8/12 months, his weight was 41.5 kg (10th–25th percentile), height 154.2 cm (10th–25th percentile), and head circumference 50.2 cm (2 SD < 3rd percentile). He had left asymmetric overgrowth, involving the face, trunk, and limbs (mainly the legs) with diffusely soft and thick irregularly marbled skin and prominent capillaries and veins on the trunk, abdomen, and limbs. His 2nd and 3rd left toes were significantly larger than the contralateral and showed proximal cutaneous syndactyly. Besides the increased growth, he had dysmorphic features including malar hypoplasia, long philtrum and high palate, and S-shaped scoliosis. Skin biopsies from the affected (and unaffected contralateral) skin regions were obtained.