The patient was a 9-year-old male referred at the age of six for orthopedic assessment because of right leg pain and gait disturbance. He was the eldest child of non-consanguineous parents. Maternal family history was unremarkable except for a second degree uncle with pes cavus. The parents were both healthy and the father reported that he was macrosomic at birth. Pregnancy was full term and delivery was uneventful. The patient's birth weight was 4270 g (>90th percentile), length 53 cm (>90th percentile). The patient's medical history revealed a mild delay in motor milestones, he started walking at 18 months. Speech acquisition was also delayed. At the age of 8 years, neurological examination confirmed motor awkwardness, psychomotor delay, and gait disorder (walking on toes and pes cavus). Cerebro-spinal MRI revealed swelling at D8-L1, hyperintense on T2-weighted images with irregular enhancement, ascribable to expansive intramedullary lesion without CNS dissemination. Bilateral dysgenesis of the lateral semicircular canal of the inner ear was also associated. Abnormalities of gyration and abnormal foliation of some sectors of both cerebellar hemispheres were also observed. The patient underwent to biopsy. Histological examination identified a pilocytic astrocytoma (WHO grade I). At physical examination, mild facial dysmorphisms was observed. The child presented low and flat forehead, very arched eyebrows, small nose with large filter, small mouth, downslanting and curled ears, short neck. Additionally, the child had small hands with flared distal phalanges, "drumstick-like"), and cafe-au-lait spots on the back. Auxological examination revealed mild obesity. The parents gave written informed consent for genetic studies.
Array-CGH analysis, performed on the proband, revealed the presence of two deletions of chromosome 22 and a duplication of chromosome 15. The extent of the deletion at 22q11.21 band (large deletion) was 1.417 Mb (chr22:18,894,835-20,311,763) (Fig. 4, A-B) while the second deletion at band 22q11.23 (short deletion) (chr22:25,664,618-25,911,651) spanned 247 Kb (Fig. 4, C). Furthermore, the patient carried a duplication spanning 484.3 Kb (chr15:100,051,182-100,996,155) at q26.3 band of a chromosome 15 (Fig. 4, D). The short deletion of chromosome 22 and the duplication of chromosome 15 were inherited from his apparently normal father, while his phenotypically normal sister inherited only the short deletion. His mother had no abnormalities (Fig. 3, B). The large deletion of chromosome 22 was described as proximally nested 1.5 Mb deletion harboring TBX1 and is present in 7-14% of DiGeorge/Velo-cardio-facial patients (DGS/VCFS). FISH experiments confirmed the presence of the short deletion on the metaphases of the father and showed that the large and short deletions were both on the same chromosome 22 on the metaphases of the son (Fig. 2, C).