Emily Zolfaghari

Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans

Background Several lifestyle and environmental exposures have been suspected as risk factors for oral clefts, although few have been convincingly demonstrated. Studies across global diverse populations could offer additional insight given varying types and levels of exposures. Methods We performed an international case–control study in the Democratic Republic of the Congo (133 cases, 301 controls), Vietnam (75 cases, 158 controls), the Philippines (102 cases, 152 controls), and Honduras (120 cases, 143 controls). Mothers were recruited from hospitals and their exposures were collected from interviewer‐administered questionnaires. We used logistic regression modeling to estimate odds ratios (OR) and 95% confidence intervals (CI). Results Family history of clefts was strongly associated with increased risk (maternal: OR = 4.7; 95% CI, 3.0–7.2; paternal: OR = 10.5; 95% CI, 5.9–18.8; siblings: OR = 5.3; 95% CI, 1.4–19.9). Advanced maternal age (5 year OR = 1.2; 95% CI, 1.0–1.3), pregestational hypertension (OR = 2.6; 95% CI, 1.3–5.1), and gestational seizures (OR = 2.9; 95% CI, 1.1–7.4) were statistically significant risk factors. Lower maternal (secondary school OR = 1.6; 95% CI, 1.2–2.2; primary school OR = 2.4, 95% CI, 1.6–2.8) and paternal education (OR = 1.9; 95% CI, 1.4–2.5; and OR = 1.8; 95% CI, 1.1–2.9, respectively) and paternal tobacco smoking (OR = 1.5, 95% CI, 1.1–1.9) were associated with an increased risk. No other significant associations between maternal and paternal factors were found; some environmental factors including rural residency, indoor cooking with wood, chemicals and water source appeared to be associated with an increased risk in adjusted models. Conclusion Our study represents one of the first international studies investigating risk factors for clefts among multiethnic underserved populations. Our findings suggest a multifactorial etiology including both maternal and paternal factors. Birth Defects Research (Part A) 103:863–879, 2015.

Risk of metastasis and orbital recurrence in advanced retinoblastoma eyes treated with systemic chemoreduction versus primary enucleation

The purpose of this study was to evaluate the risk of metastatic disease and orbital recurrence in advanced retinoblastoma treated with systemic chemoreduction versus primary enucleation.

Long-term outcomes of Group D retinoblastoma eyes during the intravitreal melphalan era

To evaluate outcomes of Group D retinoblastoma (Rb) eyes during the intravitreal melphalan era.

Lack of correlation between age at diagnosis and RB1 mutations for unilateral retinoblastoma: the importance of genetic testing

Retinoblastoma (Rb), an intraocular malignancy of childhood, is most often (98%) caused by a mutation in the RB1 retinoblastoma tumor suppressor gene contained in the long arm of chromosome 13. In 60% of cases, the RB1 mutation exists only in the tumor (i.e., somatic), while in 40% of cases, patients have a germline mutation found in all cells of the body (i.e., germinal) (1). In 1971, Knudson proposed the two hit hypotheses of RB1 stating that patients with the hereditary form of the disease have their first hit (or mutation) in the germline and need one further hit in a somatic cell in the developing retina to cause Rb while the somatic form requires both hits in a single retinal cell to cause Rb (2). This hypothesis was borne from the observation that the bilateral, germline form of the disease presents at approximately 12 months of age, while the somatic form, due to the delay in acquiring the second mutation, presents at approximately 24 months of age(2). While it is true that sporadic cases typically manifest as unilateral, unifocal disease consistent with somatic disease, 15% of unilateral patients without a positive family history may still harbor the hereditary, germline mutation(3). Children with germline mutations have a risk of developing multiple ocular tumors, secondary non-ocular cancers (4,5), an increased risk of secondary cancers when exposed to radiation(6) and an approximate 50% chance of passing this heritable cancer syndrome onto their future progeny. Thus, determining the presence or absence of a germline mutation in RB1 is a critical tool in the management of unilateral Rb. There remains a perception that age at presentation for children with unilateral Rb can help stratify the risk for the presence of a germline mutation and thus identify those children that need genetic testing. However, modern access to molecular testing and more recent publications suggest otherwise (7,8). In this retrospective study, we evaluated a cohort of patients with unilateral disease, without a family history of Rb, for a correlation of age with the presence or absence of a germline RB1 mutation. Our protocol is as follows: we completed retrospective chart review of patients diagnosed with unilateral Rb between January 1990 and April 2017 at Children’s Hospital Los Angeles (CHLA). This protocol was approved by the Institutional Review Board. Inclusion criteria consisted of (1) a clinical diagnosis of unilateral Rb, (2) the absence of family history of Rb, and (3) the results of serum testing for germline RB1 mutations available for review. Data were collected on laterality including the absence of bilateral or multifocal disease, family history, demographics, and tumor group status. Genetic testing was evaluated for a mutation in the RB1, mutation type, and the presence of mosaicism. In order to evaluate the association between age at diagnosis of unilateral Rb and genetic status, we examined differences between those with a normal genetic test result and those who carry an RB1 mutation in terms of age. Statistical analyses were performed in JMP Pro 13. Because age was positively skewed, we used a non-parametric Wilcoxon rank-sum test to compare age between study groups. The tumor groups were compared using a Fisher’s exact test. We identified a total of 182 patients who were diagnosed with unilateral Rb without a family history, received genetic testing which was available for review, and were included in this analysis. Of the 182 patients included in the review, age at diagnosis was between 1 and 130 months. The average age at diagnosis for all patients with unilateral Rb was 23 months with a median age of 19 months. Tumors groups included groups B and C (8%), group D (42%), and group E (49%), with no significant difference in tumor groups between germline RB1 and non-germline patients (p = 0.8753). Forty-seven percent of patients were of Hispanic ethnicity with the next largest groups, Non-Hispanic White and Other as 17% each. Patient demographics and age-related data are presented in Table 1. A positive genetic result with a germline RB1 mutation was found in 32 of 182 patients with unilateral Rb (18%). Of the 32 patients with a germline RB1 mutation, 18 patients (56%) were diagnosed between 1 and 24 months of age and 14 patients (44%) were diagnosed between 25 and 130 months of age. Unilateral patients who tested positive for an RB1 mutation had a mean age at diagnosis of 26 ± 22 months. Unilateral patients who tested negative

Atypical Retinal Pigment Epithelial Hyperplasia and Glial Proliferation Masquerading as Progressive Recurrent Retinoblastoma: A Case Report Review and Clinicopathologic Correlation

Background: Recurrences of retinoblastoma tumors, particularly scar recurrences, are a common phenomenon in the management of this cancer. Consolidative treatment with laser and cryotherapy are required for local control of disease. It is known that consolidative therapy can induce retinal pigment epithelium (RPE) hyperplasia and gliosis. Herein we report extensive RPE hyperplasia and gliosis during laser therapy for a focal scar recurrence, which presented as a progressive retinal opacification mimicking active retinoblastoma. Method: This is a retrospective case review. Results: A 2-month-old premature male was diagnosed with sporadic bilateral retinoblastoma (International Intraocular Retinoblastoma Classification [IIRC] group B in the right eye and IIRC group A in the left eye). The patient underwent laser therapy for a focal recurrence which demonstrated a white lesion during therapy and was subsequently enucleated. While there was a focal recurrence and infiltration of the retina (seen both on optical coherence tomography and histopathologic section), the majority of the white, progressive lesion was from extensive RPE hyperplasia and gliosis secondary to laser therapy. Conclusion: Clinicopathologic correlation of the active recurrence and adjacent gliosis is demonstrated.

Iris Hypoplasia as the Presenting Sign of Retinoblastoma in a Child With a 13q Deletion

Germline partial chromosomal deletions of the entire RB1 gene (13q deletions), account for 6% of the RB1 mutational spectrum. The authors report the rare case of one patient with suspected bilateral iris heterochromia who actually had iris hypoplasia (often masquerading as heterochromia) and bilateral retinoblastoma, due to 13q deletion syndrome. [J Pediatr Ophthalmol. 2018;55:e10-e13.].

Optic Nerve Obscuration in Retinoblastoma: A Risk Factor for Optic Nerve Invasion?

Background: The objective of this study is to evaluate the risk of optic nerve invasion associated with optic nerve obscuration at diagnosis or persisting during treatment. Methods: Retrospective review from 2011-2016 of patients with advanced retinoblastoma (Group D/E) with complete obscuration of the nerve at diagnosis and a second group of patients with persistent, complete obscuration throughout treatment. Results: Advanced retinoblastoma was diagnosed in 102 eyes of 86 patients. The optic nerve was obscured in 69 eyes (68%) at diagnosis. Of these, 30 (43%) underwent salvage therapy and 39 (57%) primary enucleation. Histopathologic analysis of primarily enucleated eyes showed 41% prelaminar and 15% postlaminar invasion. Four eyes in the salvage group demonstrated persistent nerve obscuration; 2 were subsequently enucleated without evidence of nerve invasion. Average follow-up was 23.5 months (range 1-62 months). Conclusions and Relevance: Optic nerve obscuration at diagnosis may be associated with postlaminar optic nerve invasion. While persistent, complete obscuration of the optic nerve by retinoblastoma during treatment is a poor prognostic sign for both globe salvage and vision, it does not appear, in this small cohort, to increase the risk of optic nerve invasion. With appropriate control of the intraocular tumor, these eyes can be salvaged.