A multilayered approach to the analysis of genetic data from individuals with suspected albinism.

Albinism is a clinically and genetically heterogeneous group of conditions characterised by visual abnormalities and variable degrees of hypopigmentation. Multiple studies have demonstrated the clinical utility of genetic investigations in individuals with suspected albinism. Despite this, the variation in the provision of genetic testing for albinism remains significant. One key issue is the lack of a standardised approach to the analysis of genomic data from affected individuals. For example, there is variation in how different clinical genetic laboratories approach genotypes that involve incompletely penetrant alleles, including the common, 'hypomorphic' TYR c.1205G>A (p.Arg402Gln) [rs1126809] variant. Here, we discuss the value of genetic testing as a frontline diagnostic tool in individuals with features of albinism and propose a practice pattern for the analysis of genomic data from affected families.

Handheld Optical Coherence Tomography in a Young Infant With Albinism and Fovea Plana.

ABSTRACT: We present handheld optical coherence tomography (OCT) diagnosis of Grade 4 foveal hypoplasia (fovea plana) in a 28-day-old infant with albinism. Grade 4 foveal hypoplasia is characterized by the absence of the foveal pit, absence of outer segment lengthening, and absence of outer nuclear layer widening. Binocular visual acuity at 58 months follow-up was 1.2 logarithm of the minimal angle of resolution (logMAR). We describe our handheld OCT acquisition protocol and compare the morphological features with a healthy, age-matched control subject.

Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom.

Overall, approximately one-quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype-phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development.

[Clinical practice guidelines for albinism].

Albinism is an autosomal or X-linked recessive Mendelian trait in man, which mainly manifests as hypopigmentation and related lesions of eye, skin and hair. At least 18 genes have so far been identified as causative genes for albinism. The mutational spectrum is population-specific. Molecular genotyping of albinism is important for genetic and prenatal diagnosis, and is a prerequisite for the practice of precision medicine. Based on long-term study of albinism in Chinese population, a guideline for the clinical management of albinism is provided.

Electroretinograms in idiopathic infantile nystagmus, optic nerve hypoplasia and albinism.

PURPOSE: To study electroretinograms in infantile nystagmus syndrome associated with idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism. METHODS: A total of 30 children with idiopathic infantile nystagmus, 18 with optic nerve hypoplasia, and 18 with albinism were studied. Three electroretinogram protocols were applied according to child's age: 58 (mean: 2.0 years) were recorded with skin electrode to Great Ormond Street Hospital protocol, 11 (mean: 5.3 years) with skin electrode to International Society for Clinical Electrophysiology of Vision protocol, and 7 children (mean: 12.2 years) with HK electrode to International Society for Clinical Electrophysiology of Vision protocol. The electroretinograms were compared to those of age-matched controls. RESULTS: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were comparable to controls in all protocols. Electroretinogram amplitudes in idiopathic infantile nystagmus group showed increased white scotopic and photopic electroretinograms in 26 children (skin electrode to Great Ormond Street Hospital protocol), no difference to the controls in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol), and increased rod electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol). Optic nerve hypoplasia group showed increased white scotopic, photopic, and blue electroretinograms in 15 children (skin electrode to Great Ormond Street Hospital protocol); increased 30-Hz electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol); and reduced combined rod-cone, cone, and 30-Hz electroretinograms in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Albinism group showed increased white scotopic, photopic, and 30-Hz electroretinograms in 17 children (skin electrode to Great Ormond Street Hospital protocol), while it showed reduced cone and 30-Hz electroretinograms in 5 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Implicit times were shorter in albinism. CONCLUSION: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were normal with mostly increased electroretinograms, while reduced electroretinograms did not show a specific pattern as in early-onset retinal dystrophies.

Clinical and genetic variability in children with partial albinism.

Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 - a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.

NGS-based targeted resequencing identified rare subtypes of albinism: Providing accurate molecular diagnosis for Japanese patients with albinism.

Albinism, which is commonly inherited as an autosomal recessive trait, is characterized by a reduction or absence of melanin in the eyes, skin, and hair. To date, more than 20 causal genes for albinism have been identified; thus, the accurate diagnosis of albinism requires next-generation sequencing (NGS). In this study, we analyzed 46 patients who tested negative for oculocutaneous albinism (OCA)1-4 and Hermansky-Pudlak syndrome (HPS)1 based on conventional analysis, in addition to 28 new Japanese patients, using NGS-based targeted resequencing. We identified a genetic background for albinism in 18 of the 46 patients (39%), who were previously tested negative according to the conventional analysis. In addition, we unveiled a genetic predisposition toward albinism in 23 of the 28 new patients (82%). We identified six patients with rare subtypes of albinism, including HPS3, HPS4, and HPS6, and found 12 novel pathological mutations in albinism-related genes. Furthermore, most patients who were not diagnosed with albinism by the NGS analysis showed mild manifestations of albinism without apparent eye symptoms and harbored only one heterozygous mutation, occasionally in combination with skin-color associated gene variants.

The color of skin: white diseases of the skin, nails, and mucosa.

White diseases are a heterogenous group characterized by hypopigmentation or depigmentation. Skin and eye color are determined by the number and size of melanosomes present. Melanin is produced by melanosomes in the melanocytes present within the epidermis of the skin, uvea, and retinal pigmented epithelium (RPE). Conditions altering the number of melanocytes or concentration of melanin result in a lack of pigmentation, appearing as "white diseases" ranging from the well-known albinism and vitiligo to more esoteric white hand syndrome and Degos disease.

A 40-Year-Old Man With Albinism and Progressive Dyspnea.

CASE PRESENTATION: A 40-year-old male subject employed as a grocery store manager presented to a pulmonary clinic with a dry cough and progressive dyspnea of 1 year duration. The patient was previously an avid cyclist and first noted his dyspnea when he was unable to bike as far as before. Bilateral interstitial lung infiltrates were recently noted on chest radiography. At the time of presentation, he could no longer cycle due to dyspnea. The patient's medical history was significant for albinism and severe visual impairment. He had no family history of albinism or pulmonary disorders. He had never smoked, drank alcohol only occasionally, and had no significant environmental exposures.

Molecular characterization of a series of 990 index patients with albinism.

Albinism is a clinically and genetically heterogeneous disease characterized by variable degrees of hypopigmentation and by nystagmus, foveal hypoplasia, and chiasmatic misrouting of the optic nerves. The wide phenotypic heterogeneity impedes the establishment of phenotype-genotype correlations. To obtain a precise diagnosis, we screened the 19 known albinism genes in 990 index patients using targeted next-generation sequencing (NGS) and high-resolution comparative genomic hybridization. A molecular diagnosis was obtained in 72.32% of patients. A total of 243 new pathogenic variants were identified. Intragenic rearrangements represented 10.8% of all pathogenic alleles. NGS panel analysis allowed establishing a diagnosis for the rarest forms of the disease, which could not be diagnosed otherwise. Because of the clinical overlap between the different forms of the disease, diagnosis nowadays clearly relies on molecular grounds.

Lower lip squamous cell carcinoma in patients with photosensitive disorders: Analysis of cases treated at the Brazilian National Cancer Institute (INCA) from 1999 to 2012

Background: Lower lip squamous cell carcinoma (LLSCC) is a common malignancy of the head and neck, being mainly a consequence of a chronic exposure to ultraviolet (UV) light solar radiation. Here, we evaluated the clinicopathological profile of patients with photosensitive disorders (xeroderma pigmentosum, lupus erythematosus and albinism) that developed LLSCC. Material and Methods: Data from patients who had a diagnosed LLSCC with a prior xeroderma pigmentosum, lupus erythematosus or albinism diagnosis that were treated at INCA from 1999 to 2012 were collected from patients' medical records (n=16). The control group was composed of 68 patients with LLSCC without a medical history of photosensitivity. The clinicopathological data of this study population were collected and the association between these variables was analyzed by Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method and compared by log-rank test. All statistical analyses were performed using SPSS statistics package. Results: The mean age of patients in the photosensitive and non-photosensitive groups was 42 years and 67 years, respectively (p<0.0001). A previous history of malignant diseases was more common in the photosensitive group (p=0.001). In both groups, most tumors showed a pathological stage I/II disease. Overall and cancer-specific survival were not statistically different. However, disease-free interval showed a significant difference (p=0.01) between the photosensitive and non-photosensitive patients. Conclusions: Photosensitive patients presented LLSCC at earlier age but it usually was not the primary tumor in these patients. Furthermore, a more aggressive pathological behavior was not seen when compared with tumors from non-photosensitive patients. The disease-free interval was lower in photosensitive patients, as expected (AU)

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Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting.

Albinism is a rare genetic disease, comprising syndromic and non-syndromic forms. We assessed clinical and genetic characteristics in a prospective evaluation of 64 patients (33 children and 31 adults) seen at a specialized day hospital. Causative genetic mutations were found in TYR (23/64, 35.9%), OCA2 (19/64, 29.7%), TYRP1 (1/64, 1.6%), SLC45A2 (12/64, 18.7%), C10orf11 (1/64, 1.6%), HPS1 (3/64, 4.7%), HPS5 (1/64, 1.5%), HPS6 (1/64, 1.6%) and GPR143 (2/64, 3.1%). Causative mutations remained undetermined for one patient (1.6%). Heterogeneity for hair and skin phenotype was noted across and within the different genotypes. Skin and hair hypopigmentation did not correlate with visual impairment. The diagnosis of unrecognized syndromic forms and of cases of ocular albinism in this prospective and comprehensive series of patients with albinism in a European setting is remarkable. Photoprotection was overall good but not optimal.

Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a Caucasian family.

Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes.In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree.From the analysis of the pedigree, we were able to identify a "protective" haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model.

Characterization of Abnormal Optic Nerve Head Morphology in Albinism Using Optical Coherence Tomography.

PURPOSE: To characterize abnormalities in three-dimensional optic nerve head (ONH) morphology in people with albinism (PWA) using spectral-domain optical coherence tomography (SD-OCT) and to determine whether ONH abnormalities relate to other retinal and clinical abnormalities. METHODS: Spectral-domain OCT was used to obtain three-dimensional images from 56 PWA and 60 age- and sex-matched control subjects. B-scans were corrected for nystagmus-associated motion artefacts. Disc, cup, and rim ONH dimensions and peripapillary retinal nerve fiber layer (ppRNFL) thickness were calculated using Copernicus and ImageJ software. RESULTS: Median disc areas were similar in PWA (median = 1.65 mm2) and controls (1.71 mm2, P = 0.128), although discs were significantly elongated horizontally in PWA (P < 0.001). In contrast, median optic cup area in PWA (0.088 mm2) was 23.7% of that in controls (0.373 mm2, P < 0.001), with 39.4% of eyes in PWA not demonstrating a measurable optic cup. This led to significantly smaller cup to disc ratios in PWA (P < 0.001). Median rim volume in PWA (0.273 mm3) was 136.6% of that in controls (0.200 mm3). The ppRNFL was significantly thinner in PWA compared with controls (P < 0.001), especially in the temporal quadrant. In PWA, ppRNFL thickness was correlated to ganglion cell thickness at the central fovea (P = 0.007). Several ONH abnormalities, such as cup to disc ratio, were related to higher refractive errors in PWA. CONCLUSIONS: In PWA, ocular maldevelopment is not just limited to the retina but also involves the ONH. Reduced ppRNFL thickness is consistent with previous reports of reduced ganglion cell numbers in PWA. The thicker rim volumes may be a result of incomplete maturation of the ONH.

Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism.

Hypopigmentation disorders that are associated with immunodeficiency feature both partial albinism of hair, skin and eyes together with leukocyte defects. These disorders include Chediak Higashi (CHS), Griscelli (GS), Hermansky-Pudlak (HPS) and MAPBP-interacting protein deficiency syndromes. These are heterogeneous autosomal recessive conditions in which the causal genes encode proteins with specific roles in the biogenesis, function and trafficking of secretory lysosomes. In certain specialized cells, these organelles serve as a storage compartment. Impaired secretion of specific effector proteins from that intracellular compartment affects biological activities. In particular, these intracellular granules are essential constituents of melanocytes, platelets, granulocytes, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Thus, abnormalities affect pigmentation, primary hemostasis, blood cell counts and lymphocyte cytotoxic activity against microbial pathogens. Among eight genetically distinct types of HPS, only type 2 is characterized by immunodeficiency. Recently, a new subtype, HPS9, was defined in patients presenting with immunodeficiency and oculocutaneous albinism, associated with mutations in the pallidin-encoding gene, PLDN.Hypopigmentation together with recurrent childhood bacterial or viral infections suggests syndromic albinism. T and NK cell cytotoxicity are generally impaired in patients with these disorders. Specific clinical and biochemical phenotypes can allow differential diagnoses among these disorders before molecular testing. Ocular symptoms, including nystagmus, that are usually evident at birth, are common in patients with HPS2 or CHS. Albinism with short stature is unique to MAPBP-interacting protein (MAPBPIP) deficiency, while hemophagocytic lymphohistiocytosis (HLH) mainly suggests a diagnosis of CHS or GS type 2 (GS2). Neurological disease is a long-term complication of CHS, but is uncommon in other syndromic albinism. Chronic neutropenia is a feature of HPS2 and MAPBPIP-deficiency syndrome, whereas it is usually transient in CHS and GS2. In every patient, an accurate diagnosis is required for prompt and appropriate treatment, particularly in patients who develop HLH or in whom bone marrow transplant is required. This review describes the molecular and pathogenetic mechanisms of these diseases, focusing on clinical and biochemical aspects that allow early differential diagnosis.

Albinismo / Albinism

El albinismo es una enfermedad rara constituida por un grupo de alteraciones genéticas del sistema del pigmento melanina que pueden afectar a la piel, folículos pilosos y ojos. Presentamos un paciente varón de 45 años de edad con antecedentes de consanguinidad que presenta desde su nacimiento síntomas y signos en piel, cabello y ojos propios del albinismo oculocutáneo, con un hermano mayor con el mismo fenotipo. Recientemente se ha confirmado su diagnóstico con el albino-chip. El paciente precisa un seguimiento y controles periódicos por oftalmólogo y dermatólogo, así como seguir unas medidas profilácticas de por vida. Actualmente en España no existe una unidad de referencia para albinismo (AU)

Albinism is a rare disease consisting of a group of genetic alterations in the pigment melanin system which can affect the skin, hair follicles and eyes. We report the case of a 45 year old male patient with a history of consanguinity who has shown from birth symptoms and signs in the skin, hair and eyes, typical in oculocutaneous albinism, with an older brother showing the same phenotype. Diagnosis has been confirmed recently by albinochip. The patient requires regular ophthalmic and dermatological checks and monitoring, as well as following lifelong prophylactic measures (AU)

Prevención de la hemorragia posparto en una gestante afectada de síndrome de Hermansky-Pudlack / Prevention of postpartum hemorrhage in a patient with Hermansky-Pudlak syndrome

El síndrome de Hermansky-Pudlak es una enfermedad multisistémica de herencia autosómica recesiva. Se caracteriza principalmente por albinismo óculo-cutáneo y alteración de la agregación plaquetaria. Se presentan el seguimiento y la finalización de la gestación de una paciente de 30 años afectada de dicho síndrome. Se describen las medidas profilácticas realizadas durante el trabajo de parto con el objetivo de evitar complicaciones hemorrágicas debidas a la disfunción plaquetaria. La finalización de la gestación tuvo lugar a las 38,2 semanas mediante un parto eutócico sin anestesia peridural y con buena evolución materno-fetal(AU)

Hermansky-Pudlak syndrome is a multisystemic disease with autosomal recessive inheritance, mainly characterized by oculo-cutaneous albinism and impaired platelet aggregation. We describe the follow–up and end of pregnancy in a 30-year-old woman with this syndrome, as well as the measures carried out during labor to avoid bleeding complications due to platelet dysfunction. The pregnancy ended at 38.2 weeks through vaginal delivery, without epidural anesthesia and good maternal and fetal outcome(AU)

TYPES OF ALBINISM IN THE BLACK SOUTHERN AFRICA POPULATION.

BACKGROUND: Oculocutaneous albinism (OCA) is the most common inherited disorder in Southern African blacks and several types have been described. Molecular techniques, where available, can be used to confirm a clinical diagnosis and the type of OCA, if necessary, and for prenatal diagnosis. OBJECTIVES: To investigate and classify the different types of albinism commonly found and to determine the clinical implications for each type. DESIGN: A descriptive survey. SETTING: Gauteng province, South Africa, and Lesotho. SUBJECTS: Three groups of subjects with OCA (96 from a genetics clinic, 62 from a dermatology clinic, and 31 from community surveys) from the black African population participated. MAIN OUTCOME MEASURES: Subjects underwent clinical and/or dermatological examinations and were then classified according to type of OCA. RESULTS: Four forms of OCA were identified: most (82%) subjects had OCA2 (a tyrosinase- positive type) with three sub-types: those without large freckles (ephelides) on exposed areas (named OCA 2a in this study), those with such freckles (named OCA 2b), and those with brown albinism (BOCA); the remainder had red/rufous albinism, ROCA (OCA 3). The four forms could be distinguished from each other clinically without using molecular genetic testing. CONCLUSION: The most common types of albinism found in the black population of Southern Africa are OCA2 and OCA3. Given the high prevalence of the disorder, together with the high risk of skin cancer, and the recent persecution of affected individuals in certain East African countries, these findings and their clinical implications have significance in terms of both education and awareness for health professionals and lay people caring for those with albinism.