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.
The patient was a 3-year-old female born to non-consanguineous parents, a 34-year-old father and a 38-year-old mother (Figure ). She was born at 39 weeks and 4 days gestation by normal vaginal delivery following an uneventful pregnancy. Her birth weight was 2988 g (−0.3 SD), and she measured 50.5 cm (0.4 SD) in height, with an occipitofrontal circumference (OFC) of 32 cm (−0.7 SD). Deformity of the feet was noted at birth. The left second, third, and fourth toes showed cutaneous syndactyly, and the right second and third toes showed syndactyly. An increased volume of subcutaneous adipose tissue in the left chest, the perineum, and the inside of the right thigh was obvious at one week after birth. The entire left leg and the right foot were severely enlarged, and the toes of both feet showed dactylomegaly (Figure and Figure ). Brain magnetic resonance imaging at one month showed normal findings. The patient was diagnosed with bilateral dactylomegaly at 9 months and subcutaneous adipose tissue at the left knee and the distal phalanx of the first, second, and third left toes were surgically removed. At 2 years and 9 months, subcutaneous adipose tissue at the left knee, lower abdomen, perineum, and left lower leg was surgically removed. She showed normal milestones of head control at 3 months, sitting up at 5 months, and walking at 1 year. At 2 years, her weight, height, and OFC were 12.5 kg (0 SD), 85 to 89.5 cm (−1.4 SD∼0 SD, because of different sizes of the legs), and 46.5 cm (−1.1 SD), respectively. It was noted that she had sparse hair and that her skin was thin with a small volume of adipose tissue on parts of the body other than the regions of overgrowth. Intellectual development was normal as per age equivalency and development quotient at 2 years and 4 months was 111. The presented patient was diagnosed with PROS taking into account the following findings: 1) presence of somatic PIK3CA mutation (described below), 2) congenital onset, 3) overgrowth being sporadic and mosaic, 4) overgrowth in adipose and skeletal tissues, 5) isolated macrodactyly, overgrown splayed feet, and overgrown limb, and 6) truncal adipose overgrowth []. According to Martinez-Lopez et al. [], this patient is categorized as CLOVES syndrome of PROS.