Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.

Hereditary deafness and retinal dystrophy are each genetically heterogenous and clinically variable. Three small unrelated families segregating the combination of deafness and retinal dystrophy were studied by exome sequencing (ES). The proband of Family 1 was found to be compound heterozygous for NM_004525.3: LRP2: c.5005A > G, p.(Asn1669Asp) and c.149C > G, p.(Thr50Ser). In Family 2, two sisters were found to be compound heterozygous for LRP2 variants, p.(Tyr3933Cys) and an experimentally confirmed c.7715 + 3A > T consensus splice-altering variant. In Family 3, the proband is compound heterozygous for a consensus donor splice site variant LRP2: c.8452_8452 + 1del and p.(Cys3150Tyr). In mouse cochlea, Lrp2 is expressed abundantly in the stria vascularis marginal cells demonstrated by smFISH, single-cell and single-nucleus RNAseq, suggesting that a deficiency of LRP2 may compromise the endocochlear potential, which is required for hearing. LRP2 variants have been associated with Donnai-Barrow syndrome and other multisystem pleiotropic phenotypes different from the phenotypes of the four cases reported herein. Our data expand the phenotypic spectrum associated with pathogenic variants in LRP2 warranting their consideration in individuals with a combination of hereditary hearing loss and retinal dystrophy.

Vestibular phenotype-genotype correlation in a cohort of 90 patients with Usher syndrome.

Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibular evoked myogenic potentials in contradiction to the classical assumption of normal vestibular function. The surprising lack of consistent genotypic to vestibular phenotypic findings as well as no clear vestibular phenotypic patterns among atypical USH cases, indicate that even rigorous vestibular phenotyping data will not reliably differentiate the three USH types.

Inclusion of pregnant and breastfeeding women in research - efforts and initiatives.

Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico-legal challenges that have remained entrenched in the post-diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and -dynamic understanding of medication use in pregnancy.

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the utilization of this information for the development of new drug therapies to improve pregnancy outcome. On March 5-6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given to the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of that workshop. A broad number of topics were covered that ranged from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and noninfectious agents. Research findings in these areas will be critical for the formulation of the development of future treatments and the development of therapies for the prevention of a number of pregnancy disorders of placental origin that include preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented that summarized ongoing clinical efforts in the United States and in Europe that has tested novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy with virally delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by the enhancement of nutrient transport to the fetus by modulation of their placental transporters and the targeting of placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined, especially in the context of the unique pharmacokinetic properties of pregnancy and the hurdles and pitfalls of the translation of research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy with the use of macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community must change their thinking of the pregnant woman and her fetus as a vulnerable patient population for which drug development should be avoided, but rather be thought of as a deprived population in need of more effective therapeutic interventions.

Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage.

OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.

Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.

BACKGROUND: Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth. METHODS AND RESULTS: To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele. CONCLUSIONS: One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.

Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.

Neurofibromatosis type 2.

Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25,000 livebirths and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with the disorder. We review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis type 2.

Ocular and orbital manifestations of the inherited bone marrow failure syndromes: Fanconi anemia and dyskeratosis congenita.

PURPOSE: The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). All 4 syndromes have been associated with various physical abnormalities. As part of a genotype/phenotype/cancer susceptibility study, we determined the prevalence of ophthalmic manifestations in these 4 syndromes. DESIGN: Cross-sectional study of a patient cohort. PARTICIPANTS: Seventy-five patients with an IBMFS and 121 of their first-degree relatives were seen in the National Eye Institute, National Institutes of Health, from 2001 to 2007. The patient group included 22 with FA, 28 with DC, 19 with DBA, and 6 with SDS. METHODS: Every participant underwent a complete ophthalmic evaluation and digital facial photography with an adhesive paper ruler on the patient's forehead for an internal measure of scale. Interpupillary distance (IPD), inner canthal distance (ICD), outer canthal distance (OCD), palpebral fissure length (PFL), and corneal diameter (CD) were measured. Thirteen of the 22 patients with FA underwent axial length (AL) measurements by A-scan ultrasonography. MAIN OUTCOME MEASURES: Type and prevalence of ophthalmic manifestations. RESULTS: Ninety-five percent of patients with FA had at least 1 abnormal parameter, and 25% of patients had at least 4 abnormal parameters. Eighty-two percent of patients had small palpebral fissures, 69% of patients had simple microphthalmia, 64% of patients had small OCD, 55% of patients had microcornea, 28% of patients had ptosis, and 6% of patients had epicanthal folds. In patients with DC, abnormalities of the lacrimal drainage system (29%) were the most prevalent findings, followed by retinal abnormalities (pigmentary changes, retinal neovascularization, retinal detachment, exudative retinopathy) in 21%, cicatricial entropion with trichiasis and blepharitis in 7% each, and sparse eyelashes and congenital cataract in 3.5% each. No significant ophthalmic abnormalities were seen in patients with DBA or SDS. CONCLUSIONS: Syndrome-specific ocular findings are associated with FA and DC and may antedate diagnosis of the specific syndrome. Early recognition of these abnormalities is important for optimal management.

Chediak-Higashi syndrome with early developmental delay resulting from paternal heterodisomy of chromosome 1.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable oculocutaneous albinism, immunodeficiency, mild bleeding diathesis, and an accelerated lymphoproliferative state. Abnormal lysosome-related organelle membrane function leads to the accumulation of large intracellular vesicles in several cell types, including granulocytes, melanocytes, and platelets. This report describes a severe case of CHS resulting from paternal heterodisomy of chromosome 1, causing homozygosity for the most distal nonsense mutation (p.E3668X, exon 50) reported to date in the LYST/CHS1 gene. The mutation is located in the WD40 region of the CHS1 protein. The patient's fibroblasts expressed no detectable CHS1. Besides manifesting the classical CHS findings, the patient exhibited hypotonia and global developmental delays, raising concerns about other effects of heterodisomy. An interstitial 747 kb duplication on 6q14.2-6q14.3 was identified in the propositus and paternal samples by comparative genomic hybridization. SNP genotyping revealed no additional whole chromosome or segmental isodisomic regions or other dosage variations near the crossover breakpoints on chromosome 1. Unmasking of a separate autosomal recessive cause of developmental delay, or an additive effect of the paternal heterodisomy, could underlie the severity of the phenotype in this patient.

Hermansky-Pudlak syndrome type 1 in patients of Indian descent.

Hermansky-Pudlak syndrome (HPS) develops from defects in the biogenesis and/or function of lysosome-related organelles essential to membrane and protein trafficking. Of the eight known human subtypes, only HPS-1 and HPS-4 develop pulmonary fibrosis in addition to the general clinical manifestations of oculocutaneous albinism and bleeding diathesis. We identified HPS-1 in three unrelated patients from different regions of India, who presented with iris transillumination, pale fundi, hypopigmentation, nystagmus, decreased visual acuity, and a bleeding diathesis. Two of these patients carried the homozygous mutation c.398+5G>A (IVS5+5G>A) in HPS1, resulting in skipping of exon 5 in HPS1 mRNA. The third patient carried a novel homozygous c.988-1G>T mutation that resulted in in-frame skipping of HPS1 exon 12 and removes 56 amino acids from the HPS1 protein. Given the discovery of HPS-1 in an ethnic group where oculocutaneous albinism (OCA) is highly prevalent, it is possible that HPS in India is under-diagnosed. We recommend that unconfirmed OCA patients in this ethic group be considered for mutational screening of known HPS genes, in particular c.398+5G>A and c.980-1G>T, to ensure that patients can be monitored and treated for clinical complications unique to HPS.

MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.

OBJECTIVES: To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS). STUDY DESIGN: Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3. RESULTS: These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS. CONCLUSIONS: These findings expand the phenotypes associated with MKS3 mutations. MKS3-related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.

Dyskeratosis congenita: the first NIH clinical research workshop.

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure syndrome, characterized by abnormally short telomeres and mutations in telomere biology genes. The spectrum of telomere biology disorders is growing and the clinical management of these patients is complex. A DC-specific workshop was held at the NIH on September 19, 2008; participants included physicians, patients with DC, their family members, and representatives from other support groups. Data from the UK's DC Registry and the NCI's DC cohort were described. Updates on the function of the known DC genes were presented. Clinical aspects discussed included androgen therapy, stem cell transplant, cancer risk, and cancer screening. Families with DC met for the first time and formed a family support group (http://www.dcoutreach.com/). Ongoing, open collaboration between the clinical, scientific, and family communities is required for continued improvement in our understanding of DC and the clinical consequences of telomeric defects.

Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function.

Recessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafness segregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygous mutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due to a novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. We hypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question we investigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNA expression constructs containing engineered mutations of mouse Myo7a at codons equivalent to pathogenic USH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1B mutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype (DFNB2) than the USH1B-associated alleles because the resulting protein retains some degree of normal function.

Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature.

Cystinosis is a rare autosomal recessive metabolic disorder characterized by the intracellular accumulation of cystine, the disulfide of the amino acid cysteine, in many organs and tissues. Infantile nephropathic cystinosis is the most severe phenotype. Corneal crystal accumulation and pigmentary retinopathy were originally the most commonly described ophthalmic manifestations, but successful kidney transplantation significantly changed the natural history of the disease. As cystinosis patients now live longer, long-term complications in extrarenal tissues, including the eye, have become apparent. A case of an adult patient with infantile nephropathic cystinosis is reported. He presented with many long-term ocular complications of cystinosis. After 4 years of follow-up, the patient died from sepsis. Pathology of the phthisical eyes demonstrated numerous electron-transparent polygonal spaces, bounded by single membrane, in corneal cells, retinal pigment epithelial cells, and even choroidal endothelial cells. The ophthalmic manifestations and pathology of infantile nephropathic cystinosis are discussed and reviewed in light of the current report and other cases in the literature.

Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy.

PURPOSE: Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities. DESIGN: Cross-sectional study of a series of patients. PARTICIPANTS: Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004. METHODS: All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible. MAIN OUTCOME MEASURES: Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings. RESULTS: Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy. CONCLUSIONS: Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients.

Rieger's anomaly and other ocular abnormalities in association with osteogenesis imperfecta and a COL1A1 mutation.

A patient with osteogenesis imperfecta (OI) and some features of Ehlers-Danlos syndrome had Rieger's anomaly and other associated ocular abnormalities. He carried a COL1A1 mutation (c.3313delA) that has only rarely been seen in OI. The association of ocular anterior chamber abnormalities with OI has not been reported previously, while OI with Ehlers-Danlos syndrome features has only been described in some kindreds. The patient had serious complications as a result of his ocular anomalies. We speculate that the course of his disease and, perhaps, its co-existence with OI could be exacerbated by his collagen type-I defect, although no causality can be established by this report of a single case.

Eye movement abnormalities in hermansky-pudlak syndrome.

BACKGROUND: Hermansky-Pudlak Syndrome (HPS) is a type of oculocutaneous albinism associated with a bleeding diathesis and pulmonary fibrosis. Although it is known that patients with HPS exhibit nystagmus, the nature of these abnormal eye movements has not been studied. METHODS: Twenty-seven patients with HPS, diagnosed by platelet morphology and genetic analysis, underwent a systemic evaluation and complete eye examination. Twenty-five had eye movement recordings using magnetic search coil, infrared, or video oculography. RESULTS: All patients had iris transillumination, foveal hypoplasia, and variable hypopigmentation in skin and eyes. All had bleeding tendencies, and 2 reported excessive bleeding during strabismus surgery. Nine patients had pulmonary fibrosis. Visual acuities ranged from 20/20- to 20/320. Twenty patients had strabismus despite 6 having strabismus surgery previously. Ocular oscillations consistent with congenital nystagmus (CN) were clinically evident in 24 of 27 patients, and half showed periodic alternating nystagmus. In 3 patients without CN, eye movement recordings revealed minimal end-gaze nystagmus, square-wave jerks, drift during fixation and saccades, and low-gain pursuit. These patients had melanin in the posterior pole and better visual acuities than the others (P = 0.002). CONCLUSIONS: Most patients with HPS have CN, and many have periodic alternating nystagmus. Some have subtle eye movement abnormalities without clinically evident nystagmus, which can obscure the diagnosis, especially if hypopigmentation is mild. Absence of clinical nystagmus in a child with HPS suggests good vision. Patients with albinism, especially before surgery, should be evaluated for HPS to prevent life-threatening complications.

Retinal visualization in an eye with corneal crystals using indocyanine green videoangiography.

PURPOSE: To report a patient in whom clear imaging of the retina, impossible with conventional methods, was obtained using indocyanine green (ICG) videoangiography. DESIGN: Interventional case report. METHODS: A 31-year-old patient with nephropathic cystinosis and complaints of decreased vision in the left eye underwent a complete ophthalmologic evaluation, including conventional photography, fluorescein angiography, and ICG videoangiography. RESULTS: With conventional methods (direct and indirect ophthalmoscopy, photography, and fluorescein angiography), the view of the left retina was obscured by densely packed corneal cystine crystals. During ICG angiography, clear imaging of the retina was obtained with near-infrared illumination. CONCLUSION: Indocyanine green videoangiography can be a useful tool in cases with cystinosis and other corneal opacities, where visualization and imaging of the retina are important but impossible with conventional methods.

Bilateral late posterior chamber intraocular lens dislocation with the capsular bag in a patient with gyrate atrophy.

A pseudophakic patient with gyrate atrophy of the choroid and retina presented with bilateral intraocular lens (IOL) dislocation with the capsular bag several years after uneventful cataract surgery. The patient had not performed strenuous physical activity. One IOL was initially repositioned by nonsurgical manipulations, while the other required surgical repositioning. Eventually, IOL exchange was performed successfully in both eyes.