13q Deletion Syndrome Involving RB1: Characterization of a New Minimal Critical Region for Psychomotor Delay.

Retinoblastoma (RB) is an ocular tumor of the pediatric age caused by biallelic inactivation of the RB1 gene (13q14). About 10% of cases are due to gross-sized molecular deletions. The deletions can involve the surrounding genes delineating a contiguous gene syndrome characterized by RB, developmental anomalies, and peculiar facial dysmorphisms. Overlapping deletions previously found by traditional and/or molecular cytogenetic analysis allowed to define some critical regions for intellectual disability (ID) and multiple congenital anomalies, with key candidate genes. In the present study, using array-CGH, we characterized seven new patients with interstitial 13q deletion involving RB1. Among these cases, three patients with medium or large 13q deletions did not present psychomotor delay. This allowed defining a minimal critical region for ID that excludes the previously suggested candidate genes (HTR2A, NUFIP1, PCDH8, and PCDH17). The region contains 36 genes including NBEA, which emerged as the candidate gene associated with developmental delay. In addition, MAB21L1, DCLK1, EXOSC8, and SPART haploinsufficiency might contribute to the observed impaired neurodevelopmental phenotype. In conclusion, this study adds important novelties to the 13q deletion syndrome, although further studies are needed to better characterize the contribution of different genes and to understand how the haploinsufficiency of this region can determine ID.

A new clinical and dermoscopic monitoring of infantile hemangiomas treated with oral propranolol.

Oral propranolol (OP) demonstrated high efficacy and safety profile for treatment of critical infantile hemangiomas (IHs). Our aim was to assess the morphologic changes of IHs with standard and high-resolution video dermoscopy (HRVD) from baseline to 18 months either in presence or absence of OP therapy; to investigate if extended anamnestic perinatal data and clinical-dermoscopic characteristics of the IHs can correlate with therapeutic outcome. We enrolled 94 patients (112 IHs): 58 were treated with OP, 35 (42 IHs) for 6 months (group 1), and 23 (25 IHs) for 12-months (group 2); 36 (45 IHs) were followed-up. Clinical-dermoscopic examinations were performed every 3 months during therapy and follow-up. Among 67 treated IHs, superficial and deep IHs with homogenous clinical-dermoscopic aspect developed after the 2 weeks of life achieved the better outcome, stable at 9-month follow-up, independently form treatment duration. Under HRVD, glomerular vessels were prevalent at baseline; corckscrew, comma, and linear-irregular vessels were the prevalent pattern at 1, 3, and 6 months of therapy, respectively. At 12-month follow-up, adequate healing was achieved by 96% of IHs in group 2 and by 78% in group 1, showing dotted vessels. Persistent IHs displayed a reticulated aspect and linear irregular vessels, while arborizing vessels characterized relapsed IHs. A 12-month OP therapy can be considered for newborns presenting with nonhomogenous mixed IHs >3 cm on the perineal area/lower extremities. In conclusion, HRVD allows a real time monitoring of vascular changes in IHs treated with OP and can support physicians in identifying relapses before they become clinically evident.

MRI helps depict clinically undetectable risk factors in advanced stage retinoblastomas.

This study compared high-resolution MRI with histology in advanced stage retinoblastomas in which ophthalmoscopy and ultrasonography did not give an exhaustive depiction of the tumour and/or its extension. MRI of orbits and head in 28 retinoblastoma patients (28 eyes) treated with primary enucleation were evaluated. Iris neoangiogenesis, infiltrations of optic nerve, choroid, anterior segment and sclera suspected at MR and histology were compared. Abnormal anterior segment enhancement (AASE) was also correlated with histologically proven infiltrations. Brain images were also evaluated. Significant values were obtained for: prelaminar optic nerve (ON) sensitivity (0.88), positive predictive value (PPV) (0.75) and negative predictive value (NPV) (0.71); post-laminar ON sensitivity (0.50), specificity (0.83), PPV (0.50) and NPV (0.83); overall choroid sensitivity (0.82), and massive choroid NPV (0.69); scleral specificity (1), and NPV (1). AASE correlated with iris neoangiogenesis in 14 out of 19 eyes, and showed significant values for: overall ON PPV (0.65), prelaminar ON sensitivity (0.65), and PPV (0.61), post-laminar ON NPV (0.64); overall choroid sensitivity (0.77), PPV (0.59) and NPV (0.73); scleral NPV (0.83); anterior segment sensitivity (1), and NPV (1). Odds ratios (OR) and accuracy were significant in scleral and prelaminar optic nerve infiltration. Brain examination was unremarkable in all cases. High-resolution MRI may add important findings to clinical evaluation of advanced stage retinoblastomas.

Successful treatment of macular retinoblastoma with superselective ophthalmic artery infusion of melphalan.

PURPOSE: To report our experience with superselective ophthalmic artery infusion of melphalan (SOAIM) for macular retinoblastoma to obtain tumor control while preserving as much useful vision as possible. METHODS: Five patients with newly diagnosed unilateral retinoblastoma involving the macula were selected within a group of patients eligible for SOAIM as the primary treatment. RESULTS: The mean tumor basal dimension and thickness in this group of five patients with macular retinoblastoma were 11.6 and 12.3 mm, respectively. The stage at diagnosis ranged from II to VB (Reese-Ellsworth) or B to D (International Classification System). Tumor regression with SOAIM was achieved in all cases with regression patterns type I in four cases and III in one case. CONCLUSIONS: SOAIM can be of value in the treatment of macular retinoblastoma. It may allow the salvage of the residual eyesight with a low rate of complications due to the local and systemic toxicity related to chemotherapy.

Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments.

PURPOSE: To report our experience in superselective ophthalmic artery infusion of melphalan (SOAIM) for intraocular retinoblastoma. METHODS: From June 2008 to October 2010, 38 patients (18 women, 20 men; age range at first treatment, 7 months to 22 years) with 41 eyes with retinoblastoma were scheduled for SOAIM, for 17 newly diagnosed retinoblastomas Tumour, Node and Metastasis (TNM) 7th Edition 1a (n = 1), 1b (n = 1), 2a (n = 7), 2b (n = 4) and 3a (n = 4) and 24 retinoblastomas with partial remission/relapse TNM 7th Edition 1b (n = 13), 2a (n = 1) and 2b (n = 10). Eight patients (ten eyes) have been treated by SOAIM alone. Follow-up was 6-27 months in 28 patients (30 eyes). RESULTS: Ophthalmic artery cannulation failed in two patients. Thirty-six patients underwent 140 treatments by internal (n = 112) or external (n = 28) carotid arteries. No major procedural complications occurred. Two patients have been lost to follow-up. Remaining 34 patients (37 eyes) had no metastatic disease. Four patients suffered permanent ocular complications: chorioretinal dystrophy (n = 2), ptosis (n = 1) and strabismus/exotropia (n = 1). Eight (22%) eyes in eight (24%) patients underwent enucleation: 7/16 (43%) newly diagnosed retinoblastomas and 1/22 (4.5%) retinoblastomas undergoing partial remission/relapse. For all treated eyes, Kaplan-Meier eye enucleation-free rates (K-M) were 85.4% (95% CI, 73.3-97.5%), 74.4% (95% CI, 57-91.8%) and still stable at 6, 12 months and 2 years, respectively. For eyes with partial remission/relapse, and eyes at presentation, K-M at 2 years were 95.5% (95% CI, 86.9-100%) and 45.6% (95% CI, 16.6-74.6%), respectively. CONCLUSION: Superselective ophthalmic artery infusion of melphalan was safe and powerful, especially following other therapies. Superselective ophthalmic artery infusion of melphalan should be added to focal therapies spectrum. In selected cases, melphalan should be combined with other chemotherapeutic agents.