PMC4068070_01
Patient's images. A) Patient at of 7.5 years showing facial characteristics including right palpebral ptosis, low set ears, and small mouth with thin upper lip. B) Patient's hands showing brachymetaphalangism.
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F1
He presented a characteristic phenotype including slight trigonocephaly, right palpebral ptosis, low set ears, small mouth with a thin upper lip and micrognathia (Figure  1A), with small hands and feet with fleshy fingertips, brachymetaphalangism (Figure  1B), bilateral single palmar creases, short neck and scoliosis.
Brain MRI of the patient at 4.8 years. A) Unenhanced midline sagittal T1-weighted image shows hyperintensity corresponding to ectopic posterior pituitary lobe at the median eminence (arrowhead). The pituitary gland and sella turcica are small, and the pituitary stalk is not visible (white arrow). B) Axial FLAIR image reveals a small nonspecific hyperintense lesion in the right globus pallidus (black arrow).
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F2
A brain MRI was performed with sagittal and coronal 3 mm-thick T1- and T2-weighted images for the hypothalamic-pituitary region, revealing pituitary hypoplasia, pituitary stalk interruption and an ectopic posterior pituitary lobe (Figure  2A). Additionally, a small focal nonspecific T2 hyperintensity was noted in the right globus pallidus that was unchanged at a 6-month brain MRI follow-up (Figure  2B).
Patient's growth chart. In the figure height measurements from birth to 7.5 years are reported.
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F3
Substitutive GH therapy was started and led to a significant growth velocity increase as shown in Figure  3.
Karyotype, array-CGH analysis, FISH analysis. A) Cut-out of chromosomes 2 from two metaphases. The der(2) are highlighted by the arrows. B) Array-CGH profile of patient's chromosome 2 showing the 2p distal duplication (upper panel in the enlargement) and the concurrent 2q distal deletion (lower panel in the enlargement). The experiment was performed by using a 180 K platform (180 K SurePrint G3 Human Kit, Agilent Technologies, Santa Clara, CA) as reported elsewhere
. C) FISH analysis with subtelomeric chromosome 2 specific probes (VIJyRM2052 in green, 2p; D2S447, in red, 2q; (Vysis TelVysion, Abbott Molecular, Abbott Park, IL) shows green signals at both extremities of the rearranged chromosome 2 (yellow arrow), flanked by its normal homolog. D) The protein-coding genes included in the duplication (upper panel) and the deletion (lower panel) are reported, according to UCSC Genome Browser (http://genome-euro.ucsc.edu/).
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F4
Since the prenatal karyotype resulted to be normal, a high-resolution banding karyotype was requested, and an abnormality at the distal long arm of one chromosome 2 was observed (Figure  4A). This analysis showed a complex genomic imbalance consisting of a 2p25 distal duplication of about 9.6 Mb and a 2q37 distal deletion of about 7.3 Mb, containing 26 and 61 protein coding genes respectively: arr[hg19] 2p25.3p25.1(30,341-9,588,369)x3,2q37.2q37.3(235,744,424-243,041,305)x1 (Figure  4B-D). Situ Hybridization (FISH) analysis, performed with subtelomeric chromosome 2 specific probes (VIJyRM2052 for 2p; D2S447 for 2q, both from Vysis TelVysion, Abbott Molecular, Abbott Park, IL) confirmed the presence of the two imbalances and showed that the duplicated 2p region was located distally at 2 q (Figure  4C). Since the rearrangement was detectably by high-resolution banding, the same karyotype analysis was performed on parental blood samples showing that the rearrangement was de novo.