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.
A 57-year-old Asian woman experienced an abnormal feeling on the left side of her neck and difficulty breathing 90 minutes after eating a Chinese noodle dish containing roasted pork, egg, spinach, seasoned bamboo shoots, laver, and garlic. She was advised to call an ambulance by our triage nurse after telephone consultation and was transported to our hospital by a physician-staffed helicopter due to the long distance from her house to the hospital. She had a history of removal of a left sphenoid ridge meningioma one year earlier. She had experienced limited rigidity of her left neck and limited peripheral cold sensation on her left side in winter since approximately 10 years of age. She had experienced limited peripheral swelling of her left side and limited lower back pain of unknown origin on her left side several times. She had been suffering from oral allergy syndrome since she was young. She sometimes experienced a tingling sensation on her lips and an unpleasant feeling in her throat after eating some types of fruit. Those fruits included mandarins, oranges, kiwis, bananas, and pineapples. She was married but did not have any children.\nOn arrival, 180 minutes after eating the noodles, she had clear consciousness, and her blood pressure was 130/90 mmHg, her heart rate was 80 beats per minute, her percutaneous oxygen saturation was 100% under room air, and her body temperature was 36.9°C. She had left neck and chest swelling without color change. Her breathing difficulty subsided spontaneously.\nThe results of a blood analysis were as follows: white blood cells, 6,000/mm3; hemoglobin, 14.8 g/dL; platelets, 38.3 × 104/mm3; aspartate aminotransferase, 15 IU/L; alanine aminotransferase, 11 IU/L; total bilirubin, 0.5 mg/dL; total protein, 6.7 g/dL; glucose, 118 mg/dL; blood urea nitrogen, 18.9 mg/dL; creatinine, 0.90 mg/dL; amylase, 63 IU/L; creatine phosphokinase, 89 IU/L; sodium, 142 mEq/L; potassium, 4.0 mEq/L; chloride, 106 mEq/L; C-reactive protein, 0.05 mg/dL; prothrombin time, 10.6 (control, 11.9) sec; activated partial thrombin time, 26.4 (control, 26.9) sec; fibrinogen, 310 mg/dL; fibrin degradation products, 0.8 μg/mL; troponin T, 0.06 (0-0.14) ng/mL; and immunoglobulin E (IgE), 429 (0-250) IU/mL. Chest roentgen, an electrocardiogram and cardiac echography findings were all negative. Neck computed tomography (CT) with contrast medium and magnetic resonance imaging (MRI) revealed left-side-limited edema in the subcutaneous area and surrounding esophagus and bronchus (Figures , ).\nThese radiological findings excluded hemorrhaging or pseudoaneurysm formation. She underwent observational admission. After her edema improved, she was discharged on the third hospital day. A follow-up examination one week later showed complete resolution of the neck and chest edema. The results of a blood allergen test analysis (0-1.39) showed an elevated immunoglobulin E (IgE) level as follows: Japanese cedar, 44.30; betula alba, 7.27; orchard grass, 3.42; Japanese cypress, 2.65; dermatophagoides farina, 3.03; house dust, 1.85; and mugwort, 1.70. The remaining allergens were within the normal ranges, as follows (0-1.39): alder 1.35, timothy 0.85, 0.33; cat skin, 0.25; and Candida, 0.22. The results for the following allergens were all zero: ragweed, Alternaria, dog skin, wheat, buckwheat, soybean, rice, tuna, salmon, lobster, crab, milk, beef, chicken, pork, albumen, ovomucoid, peanut, sesame, kiwi, banana and latex. We also obtained blood samples from the bilateral upper extremities at the same time. The examination items that showed ≥5% laterality were as follows: white blood cell count (6,500/mm3 vs. 6,100/mm3), platelets (40.8 × 104/mm3 vs. 38.0 × 104/mm3, aspartate aminotransferase (12 IU/L vs. 11 IU/L), lactate dehydrogenase (184 IU/L vs. 172 IU/L) and creatinine (0.63 mg/dL vs. 0.58 mg/dL). We could not obtain permission from the patient for further a genetic analysis by skin biopsy.