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.
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.