This 6-year-old girl is the third child of a healthy 42-year-old woman and a non-consanguineous 52-year-old healthy man, whose family history was unremarkable. She was conceived naturally. She was born at term after a normal pregnancy: her fetal ultrasound scans were normal. Birth weight was 3.800 g (75th centile), length 51 cm (75th centile), and head circumference 36 cm (75th centile). At birth, macrodactyly of the I and II toe of the left foot with partial syndactyly between the 2nd and 3rd toes was recorded. Based on these clinical data, she was suspected to have Proteus syndrome. At the age of 1 month, a subcutaneous mass in her left abdominal region was observed. General physical examination at age 2 months showed that her weight was 5600 g (90th percentile), length 56 cm (50th percentile), and head circumference 38.5 cm (50th percentile). She presented macrodactyly of the I and II toes of the left foot with increased growth of the left leg and a subcutaneous mass in the left abdominal region; magnetic resonance imaging (MRI) of the abdomen revealed that the mass was compatible with a subcutaneous lipoma, which was later confirmed by histological examination of a sample of biopsied tissue. The girl was first referred to one of our institutions at age 4 months and followed up at age 9 months, 3 years and 10/12 months, and 5 years; she is still under follow-up at our institutions. Cognitive development is normal. During her last diagnostic work-up and follow-up controls, she underwent surgery for reduction of the abdominal mass and for removal of the first toe and transposition of the second toe to replace the first toe. Skin biopsies from the affected (and unaffected contralateral) regions were obtained during these procedures (Fig. a).
It is a 13-year-old boy born as only child from healthy non-consanguineous parents. He was born at 38 weeks of gestational age. Maternal preeclampsia was detected in the last month. Growth parameters at birth were: weight 3,880 g (+2.5 Standard deviation (SD)), length 54 cm (+3 SD), and Occipital frontal circumference 38.5 cm (+4.5 SD). No facial dysmorphisms were evident at birth. He showed mild respiratory distress, treated with oxygen support in incubator for few hours, transient hypoglycemia, requiring early oral feeding, and jaundice, treated with phototherapy.\nNormal acquisition of milestones was reported with exception of mild delay in independent walking. The patient hold up the head at 4 months, he sat unsupported at 7 months, and began walking independently at age 18 months. He started speech therapy at the age 3 years due to language delay. The first formal neuropsychological test was assessed at 11 years (WISC IV), showing a total IQ of 55, with language subitem being the worst skill. He attended the secondary school with support. He has fluent language, can read and write well. He is quiet and sociable, no behavioral problems and Autism spectrum disorder were reported. He never had seizures. As a child, at age 2 years, he suffered from viral infection with myocarditis and transient hepatosplenomegaly that spontaneously resolved after 6 months. Periodic ultrasound examination of heart, kidneys, and thyroid gave normal results. Endocrine evaluations, including Follicle-stimulating hormone, Luteinizing hormone, Thyroid-stimulating hormone, FT4-FT3, testosterone, and IGF1, gave normal results. Kidney and liver function were normal. Growth profile in term of weight and height was always harmonic and above normal ranges for Centers for Disease Control and Prevention's growth charts (respectively, weight at +3.5 SD and height at 4 SD), whereas Occipital frontal circumference measure progressively increased till +8 SD at the age of 10 years. A bone age study was performed at 7 years of age, showing mild advanced bone age (8 years). At age 12 years, weight was 80 kg (+3.6 SD), height 180 cm (+4 SD), Occipital frontal circumference 66.5 cm (+8 SD).\nHe was presented with trunk hypotonia and minor facial anomalies (Figure ). Pectus excavatum, mild joint hyperlaxity (Beighton score 3/9), and moderate scoliosis treated with corset, were also present. He underwent dermatological examination and dermoscopy because of multiple small acquired nevi. The only atypical lesion was surgically excised, and diagnosed as dysplastic Clark nevus. A small hyperkeratotic lesion on the foreskin of about 3 mm in diameter was present from birth. Brain CT scan performed at age 2 years, due to macrocephaly, showed hypodensity of the bilateral posterior periventricular white matter, and mild asymmetric lateral ventricle enlargement. Brain MRI at 12 years showed a Chiari malformation type I with right cerebellar tonsillar ectopia 12 mm below mcRae's line and mild lateral ventricular asymmetry without hydrocephalus. Symmetric megalencephaly without polymicrogyria was diagnosed.