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).
A seven-and-a-half-year-old male child was sent to our Pediatric Endocrinology Centre for macrocephaly and right lateralized overgrowth, reported from birth. Parents were not related and no noteworthy diseases were reported in his family history. The pregnancy was characterized by spontaneous abortion of the dizygotic twin at 16 gestational weeks. Fetal ultrasounds were normal. He was born at 35 weeks of gestational age by an emergency caesarean section for acute fetal suffering. Birth weight was 3010 g (1.65 standard deviations [SD]), birth length was 51 cm (2.45 SD) and birth occipito-frontal circumference (OFC) was 36 cm (2.93 SD).\nThe perinatal period was characterized by hospitalization because of the mild prematurity, neonatal jaundice treated with phototherapy and the findings of hypotonia. In his first months of life he presented a progressive increase of the OFC and was submitted to brain Magnetic Resonance Imaging (MRI) and to neurosurgical evaluation, which permitted an initial diagnosis of isolated benign macrocephaly. The MRI was repeated at the age of 2, revealing ventriculomegaly, Chiari Malformation type I and an arachnoid left temporo-polar cyst. At neurological evaluation, he presented a developmental delay characterized by an acquisition of sitting position at 30 months of life and autonomous walking at 3 years of life and a speech delay with first production of words after 2 years of age. Since he was 3 years old he has been suffering from pain episodes at right lower limb unrelated to physical activity or other specific events, usually characterized by prolonged duration, good response to paracetamol and associated to limb failure and fall to the ground.\nAt our first physical examination his weight was 24.9 kg (0.54 SD), height 118.3 cm (− 1.42 SD) and OFC 60.5 cm (> 3 SD). He had several capillary malformations on medial axis. His face presented two frontonasal hemangiomas, a hyperpigmented brownish stain on the forehead with telangiectasia, and two on flat hemangiomas the trunk; furthermore, the patient had low-set ears, teeth with serrated edges, diffuse muscular hypotonia, joint hypermobility, and a fine and gross motor dyspraxia associated to a mild intellectual disability. His right lateralized overgrowth involved face, trunk and limbs (mainly legs). In particular, he showed a mild asymmetry of the face and of the facial mime with the right side more represented, different length and diameter of the legs (the right were 66 cm and 40 cm respectively and the left one 63 cm and 36 cm) and of the forearms, measured from elbow to the end of the middle finger (the right were 29 cm and 14 cm respectively, the left one 26 cm and 12 cm).\nX-ray, ultrasounds and MRI of lower limbs were performed confirming the asymmetry in length of the legs and showing a musculature and a panniculus adiposus of the right side more represented than the contralateral. Echocardiogram and abdominal ultrasound were normal.\nBrain MRI was repeated confirming previous findings of ventriculomegaly, arachnoid left temporo-polar cyst, cerebellar tonsillar ectopia. Furthermore, it revealed a markedly thick corpus callosum (mega-CC), abnormalities of white matter, an area of polymicrogyria, and a pituitary gland with a mild reduction in volume for age (Fig. ). The electroencephalography showed sporadic and isolated paroxysmal abnormalities. The functional evaluation permitted a diagnosis of mild intellectual disability, attention-deficit, hyperactivity disorder and emotional disturbance (Wechsler Intelligence Scale for Children-IV: Total Intelligence Quotient 51).\nOn the basis of these clinical signs and symptoms we hypothesized an OS and sent the patient to geneticists for specific evaluation. Pediatric geneticists of the Pediatric Department of MBBM Fundation, Monza, Italy, confirmed our diagnostic suspicion and diagnosed a segmental OS. Consequently, the child was submitted to the molecular analysis of 21 selected genes involved in the PI3K/AKT/mTOR pathway (PIK3R1, PIK3R2, PIK3CA, PTEN, PDK1, PDK2, KRAS, AKT1, AKT2, AKT3, RICTOR, MAPKAP1, MLST8, MTOR, IRS1, GAB1, GAB2, THEM4, MAPK8IP1, PTPN11, RPTOR). To identify causative mosaic somatic mutation on these genes the genomic DeoxyriboNucleic Acid (DNA) was extracted from cutaneous biopsy of affected tissue and Targeted Next generation sequencing (NGS) was performed. The pathogenic point mutation c.2740G > A (pGly914Arg) in PIK3CA exon 18 was isolated in the genomic DNA of our patient. It was identified in heterozygosity and was presented as somatic mosaic with a frequency of 31.2%. The identified variant was verified by Sanger sequencing.