Taking the family history in genetic disease: a guide for ophthalmologists.

PURPOSE OF REVIEW: The family pedigree is an important tool in the field of ophthalmology. Recent advances in genetic testing for ophthalmic conditions underlie the need to offer genetic testing to patients when appropriate. Future availability of gene therapy for some ocular diseases further illustrates the importance of gene testing for patients seen in the ophthalmology clinic. RECENT FINDINGS: The pedigree is the first step in the genetic screening process and can guide the clinician in determining the likely genetic cause of a given disorder. Although not every patient warrants generating a pedigree, for patients whose condition may have a heritable basis, it is worthwhile to document the family history for several reasons. The pedigree gives us information about the mode of inheritance and can give clues toward a diagnosis. We can also determine whether family members are at risk for developing disease and calculate the recurrence risk for future offspring. The pedigree can help differentiate between a syndrome and an isolated ocular disease and may indicate the need for a specialist referral if there is risk of other systemic abnormalities. The pedigree gives us important information that may guide us in deciding which genes to test for and allows us to counsel the family appropriately. SUMMARY: The purpose of this review is to inform ophthalmologists on how to take a detailed family history relevant to possible genetic disorders, outline the information that can be obtained from the family history, and describe how this information can be used to optimize patient care.

Macular cysts in retinal dystrophy.

PURPOSE OF REVIEW: To describe the entity of macular cysts in retinal dystrophy, differentiate it from cystoid macular edema (CME), and review the role of carbonic anhydrase inhibitors in management. RECENT FINDINGS: Macular cysts in retinal dystrophy are seen in retinopathies caused by mutations in the NR2E3 gene, juvenile X-linked retinoschisis (XLRS), and some other retinal dystrophies. These must be distinguished from CME. Optical coherence tomography can clearly demonstrate intraretinal cysts which may not be clinically detectable. Intravenous fluorescein angiography (IVFA) does not show macular hyperfluorescence (i.e. leakage). Molecular genetic testing aids in the diagnosis and elucidation of pathophysiology. Carbonic anhydrase inhibitors may promote resolution of the cysts resulting in visual improvement. SUMMARY: Non-CME macular cysts in retinal dystrophies can be differentiated from CME by a combination of clinical examination, IVFA, and molecular genetic testing to identify causative phenotype. Carbonic anhydrase inhibitors may be effective in promoting resolution.

Macular cystoid spaces in patients with retinal dystrophy.

BACKGROUND: Non leaking macular cystoid spaces (MCS) are seen in some retinal dystrophies. Carbonic anhydrase inhibitor (CAI) treatment may reduce the size of MSC and improve vision. METHODS: A retrospective study of patients with retinal dystrophy with MCS seen between 2009 and 2013 at two sites. Patients had ophthalmic examination, optical coherence tomography (OCT) and genetic testing. Patients with vision worse than 20/30 were treated with CAI. Post treatment visual acuity (VA), central foveal zone (CFZ) thickness, and qualitative estimation of MCS size were assessed. RESULTS: Eighteen patients, 6-47 years old, were included. IVFA was performed in 15 (83%) patients. Of the 26 eyes in 13 patients who were treated and followed, VA improved in 15 eyes (58%) of 10 patients. Ten of these 15 eyes had decreased CFZ thickness and 9/10 showed qualitative MCS improvement. Regression analysis showed that change in CFZ thickness was not significantly predictive of change in final visual acuity (p = 0.405). Five of 15 eyes with improved VA had paradoxically increased CFZ thickness and 2/5 had enlarged MCS. Three of the treated eyes (11%) in two patients had decreased VA with decreased CFZ thickness and improved MCS in 2/3 eyes. Eight eyes (31%) in six patients showed no change in VA with decreased CFZ thickness in 6/8 eyes with improved MCS. Genetic testing showed mutations of NR2E3, XLRS, CRB1, GPR98 and CNGB1. CONCLUSION: Non-leaking MCS occur in a variety of retinal dystrophies. Therapy with topical or systemic CAI has variable efficacy and may result in VA improvement with or without qualitative improvement in MCS and CFZ thickness.

PITX2 and FOXC1 spectrum of mutations in ocular syndromes.

Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.

Albinism for the busy clinician.

Albinism is a group of disorders characterized principally by its ophthalmic features with or without systemic manifestations. Persons with albinism manifest a wide variety of phenotypes and limited number of genotypes. Modern molecular genetics has encouraged a new classification and understanding of the subtypes of these disorders. In addition to the ocular and systemic manifestations, ophthalmologists must be familiar with the specific visual needs and psychological challenges of these individuals as well as those of their families.