Pigmentary Anomalies Research Articles

Pigmentation anomalies and lesions in bats from Oaxaca, Mexico

Pigmentation anomalies and lesions in bats from Oaxaca, Mexico

FIRST RECORD OF ALBINISM AND PIEBALDISM IN Atelognathus patagonicus GALLARDO, 1962 (ANURA: BATRACHYLIDAE), LAGUNA BLANCA NATIONAL PARK, ARGENTINIAN PATAGONIA

Among the different types of pigmentary anomalies, albinism is the most common in amphibians. The Critically Endangered Patagonia frog (Atelognathus patagonicus) is endemic to the northwest Argentinian Patagonia, and inhabits small temporary lagoons isolated from each other. During the monitoring of two sub-populations of the species, we found 32 individuals (4.5%; N = 714) with pigmentary anomalies in Antiñir lagoon, inside Laguna Blanca National Park. Among them, 31 were albinos (five tadpoles, two metamorphs and 24 juveniles) recognized for having transparent skin and red eyes. One individual was found with piebaldism, presenting patches without pigmentation and eyes of normal color. This is the first record of pigmentary anomalies for Atelognathus patagonicus, which may have ecological and conservation implications for the species.

Concepts of multi-level dynamical modelling: understanding mechanisms of squamous cell carcinoma development in Fanconi anemia.

Fanconi anemia (FA) is a rare disease (incidence of 1:300,000) primarily based on the inheritance of pathogenic variants in genes of the FA/BRCA (breast cancer) pathway. These variants ultimately reduce the functionality of different proteins involved in the repair of DNA interstrand crosslinks and DNA double-strand breaks. At birth, individuals with FA might present with typical malformations, particularly radial axis and renal malformations, as well as other physical abnormalities like skin pigmentation anomalies. During the first decade of life, FA mostly causes bone marrow failure due to reduced capacity and loss of the hematopoietic stem and progenitor cells. This often makes hematopoietic stem cell transplantation necessary, but this therapy increases the already intrinsic risk of developing squamous cell carcinoma (SCC) in early adult age. Due to the underlying genetic defect in FA, classical chemo-radiation-based treatment protocols cannot be applied. Therefore, detecting and treating the multi-step tumorigenesis process of SCC in an early stage, or even its progenitors, is the best option for prolonging the life of adult FA individuals. However, the small number of FA individuals makes classical evidence-based medicine approaches based on results from randomized clinical trials impossible. As an alternative, we introduce here the concept of multi-level dynamical modelling using large, longitudinally collected genome, proteome- and transcriptome-wide data sets from a small number of FA individuals. This mechanistic modelling approach is based on the "hallmarks of cancer in FA", which we derive from our unique database of the clinical history of over 750 FA individuals. Multi-omic data from healthy and diseased tissue samples of FA individuals are to be used for training constituent models of a multi-level tumorigenesis model, which will then be used to make experimentally testable predictions. In this way, mechanistic models facilitate not only a descriptive but also a functional understanding of SCC in FA. This approach will provide the basis for detecting signatures of SCCs at early stages and their precursors so they can be efficiently treated or even prevented, leading to a better prognosis and quality of life for the FA individual.

Retyping and molecular pathology diagnosis of dyschromatosis universalis hereditaria.

Dyschromatosis universalis hereditaria (DUH) is characterized by diffuse symmetrically distributed hypopigmented macules mixed with hyperpigmentation. DUH is divided into three types by Online Mendelian inheritance in man (OMIM) that is, DUH1 (OMIM 127500), DUH2 (OMIM 612715) and DUH3 (OMIM 615402) according to the different linkage regions. Although each condition possesses corresponding phenotypic characteristics and the prognosis for each is somewhat different, these disorders are highly overlapped and difficult to differentiate in the clinical setting. Our latest study reveals a novel DUH subtype that presents a mild phenotype of pigmentation anomalies and is named PER3rs772027021 SNP related DUH or DUH4 by us, which make the DUH subtype can be further retyped. Heterozygous distribution or mosaic-like distribution of melanin is a newly discovered pathological features that is uniquely demonstrated in the affected layers of DUH1 and DUH4 patients. In this review, DUH is further divided into four subtypes according the causative genes and their mutational sites, and the mutation regions described in the previous reports. To make an accurate diagnosis, we suggest that Sanger sequencing or the target region sequencing (TRS) to the candidate causative genes related melanogenesis may be the most effective and convenient method of clinical diagnosis or/and prenatal diagnosis for DUH and DUH-like patients. More importantly, heterozygous distribution or mosaic-like distribution of melanin can be utilized for differential diagnosis of DUH. We also investigate the underlying molecular mechanism to form mosaic-like melanin in the affected layers of hyper- and/or hypo-pigmented macules from DUH1 and DUH4 patients. This review provides a molecular and pathological delineation of four types of DUH and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis.

First records of pigmentation anomalies in the marsh deer at its southernmost stronghold: a warning message?

First records of pigmentation anomalies in the marsh deer at its southernmost stronghold: a warning message?

Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next-generation sequencing.

Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. A total of 24 patients from 21 Han-Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.

Pigmentary mosaicism as a recurrent clinical manifestation in three new patients with mosaic trisomy 12 diagnosed postnatally: cases report and literature review

BackgroundTo date, only twenty-one cases diagnosed postnatally with mosaic trisomy 12 have been reported. The most frequent phenotypic manifestations are developmental delay, dysmorphic facial features, congenital heart defects, digital alterations, and pigmentary disorders. In the present report, detailed clinical and genetic profiles of three unrelated new patients with mosaic trisomy 12 are described and compared with previously reported cases.Case presentationIn the present report, we include the clinical, cytogenetic, and molecular description of three Mexican patients diagnosed postnatally with mosaic trisomy 12. At phenotypic level, the three patients present with developmental delay, dysmorphic facial features, congenital heart defects and skin pigmentary anomalies. Particularly, patient 1 showed unique eye alterations as bilateral distichiasis, triple rows of upper lashes, and digital abnormalities. In patient 2 redundant skin, severe hearing loss, and hypotonia were observed, and patient 3 presented with hypertelorism and telecanthus. Hyperpigmentation with disseminated pigmentary anomalies is a common trait in all of them. The cytogenetic study was carried out under the strict criteria of analysis, screening 50–100 metaphases from three different tissues, showing trisomy 12 mosaicism in at least one of the three different tissues analyzed. With SNParray, the presence of low-level mosaic copy number variants not previously detected by cytogenetics, and uniparental disomy of chromosome 12, was excluded. STR markers allowed to confirm the absence of uniparental disomy as well as to know the parental origin of supernumerary chromosome 12.ConclusionsThe detailed clinical, cytogenetic, and molecular description of these three new patients, contributes with relevant information to delineate more accurately a group of patients that show a heterogeneous phenotype, although sharing the same chromosomal alteration. The possibility of detecting mosaic trisomy 12 is directly associated with the sensitivity of the methodology applied to reveal the low-level chromosomal mosaicism, as well as with the possibility to perform the analysis in a suitable tissue.

Toxic Epidermal Necrolysis: A Clinical and Therapeutic Review

Toxic Epidermal Necrolysis is a rare dermatological condition with high mortality and serious consequences on its survivors. Despite having been first described in 1956, its pathophysiology remains uncertain, mainly regarding its mechanisms, although it seems that certain apoptosis pathways are pivotal in starting keratinocytes’ apoptosis and in activating T cells, especially those mediated by tumour necrosis factor, Fas-FasL and granulysin. In general, its aetiology and presentation are consensual, being defined as a generalized necrolysis of the epidermis that occurs as an uncontrolled immune response to a specific drug or one of its metabolites, highlighting cotrimoxazole and allopurinol as the most important. This necrolysis leads to a massive shedding of the epidermal layer of the skin, with stronger incidences in the torso, upper limbs and face. Its complications tend to be severe, noting that septic ones are responsible for over half of the disease’s mortality. Nearly all survivors develop long-term sequelae, namely hypertrophic scarring and skin pigmentation anomalies. Regarding treatment, many different opinions arise, including contradictory ones, regarding more importantly immunomodulation therapies that have been the focus of several studies through the years. It is safe to state that supportive therapy is the only modality that has significantly strong evidence backing its efficacy in reducing mortality and improving prognosis, which have improved in the past years as general health care quality increased. In conclusion, it is imperative to say that more research is needed for new potential therapies with large study populations and more scientific rigor. Likewise, investigation towards its basic pathophysiology should also be promoted, mainly at a biomolecular level, allowing for an improved prevention of this illness.

Waardenburg syndrome associated neurotrophic keratopathy in a child treated with neurotization surgery

Waardenburg syndrome (WS) is a genetic disorder characterized by congenital sensorineural hearing loss and pigmentary anomalies in the iris, hair, and skin. Ocular findings in WS include telecanthus, iris heterochromia, congenital cataracts, dry eye, and strabismus. To our knowledge, we report the first case of neurotrophic cornea in a patient with WS.

EP263: A pathogenic deletion at 13q32.1q33.1 presenting with bilateral sensorineural hearing loss and pigmentation anomalies, mimicking Waardenburg syndrome

13q deletion syndrome is caused by structural and functional monosomy of the long arm of chromosome 13. Individuals with partial deletions of 13q have a wide spectrum of clinical phenotypes, including mild to severe intellectual disability, growth retardation, craniofacial dysmorphism, hand and foot anomalies, brain, cardiac and renal defects. Previous reports suggest that deletions including the 13q32 band are associated with severe congenital malformations. The ZIC2 gene maps to this critical distal region at 13q32.2 and has been considered a possible candidate for brain malformations, such as holoprosencephaly and Dandy-Walker malformation. We present an individual with a 7.9 Mb deletion on chromosome 13, encompassing almost all of band q32, with a relatively mild phenotype. An 11-month-old term male was seen in the medical genetic clinic regarding concerns for possible Waardenburg Syndrome. He presented with bilateral sensorineural hearing loss at 9 months of age and was noted to have multiple hypopigmented lesions on both his feet and chest. Prenatal and post- natal course was unremarkable with normal growth and development. Physical examination revealed mild dysmorphic features such as borderline, low set and posteriorly rotated ears with folded upper helixes and a broad nasal bridge. Hypopigmented lesions consistent with leukoderma was noted over the anterior chest wall, abdominal wall and medial aspect of his right thigh. Family history was positive for a maternal cousin with similar hypopigmented lesions and maternal great, great grandmother with early premature graying of hair. There was no family history of congenital hearing loss or birth defects. A chromosomal microarray (CMA) was performed and revealed a 7.9 megabase pathogenic deletion at chromosome 13q32.1q33.1, involving 65 genes. This deletion encompasses the ZIC2 gene which is associated with holoprosencephaly. This was an unexpected finding and further imaging studies to evaluate for cardiac, renal and brain malformations have been planned. Deletions of 13q are rare and additional cases are needed to better understand the genotype-phenotype correlation. We present an atypical case of a 13q deletion syndrome associated with mild dysmorphism, bilateral sensorineural hearing loss and leukoderma. There have been suggestions that distal deletions are associated with a more severe clinical phenotype and proximal deletions causes less severe major anomalies. This case broadens the clinical spectrum of 13q deletion syndrome as hearing loss is an uncommon finding and dermatological involvement has not been previously reported. There have been one prior report indicating that the loss of Zic2 function results in impaired inner ear development in mice and may be a candidate gene that contributes to the genetics of hearing loss in humans. Additionally, although the region deleted on the long arm of chromosome 13 involves the ZIC2 gene, this patient appears to be growing and developing normally. These findings suggest regions outside of band 13q32 likely contribute to the severe congenital malformations previously associated with distal 13q deletions.

First report of albinism in a lactating female of the chestnut long-tongued bat Lionycteris spurrelli Thomas, 1913 (Chiroptera, Phyllostomidae)

Abstract Albinism is a genetic disorder that causes pigmentation anomalies. Even though supposedly rare in free-living mammals, cases of albinism have been reported worldwide, particularly in bats. In this article we present a new case of albinism in a Lionycteris spurrelli Thomas, 1913. The individual, observed in an Amazon region iron ore cave, in Northern Brazil, was a lactating female with a dark-brown pelage pup.

GM3 synthase deficiency in non-Amish patients

PurposeBiallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known. MethodsWe collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD. ResultsWe identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients’ plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss. ConclusionThe phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum.

Congenital Pigmentary Anomalies in the Newborn

Congenital pigmentary anomalies may be evident at birth or soon after, with some birthmarks becoming apparent later in infancy or early childhood. It is important to recognize various pigmentary anomalies in the neonate, most of which are benign but a subset of which are associated with cutaneous morbidity or systemic ramifications and require further evaluation. This review will focus on pigmentary mosaicism, congenital melanocytic nevi, nevus spilus, dermal melanocytosis, and pigmentary anomalies associated with neurofibromatosis type 1 (café au lait spots, freckling, plexiform neurofibromas, nevus anemicus), tuberous sclerosis (hypomelanotic macules), and incontinentia pigmenti.

215 Unambiguous evidence of melanocyte proliferation in plaque psoriasis

Melanocytes of the human epidermis are located in the stratum basale in a ratio of 1 melanocyte to 10 keratinocytes. Melanocytes do not divide in healthy epidermis, even after UVR stimulation. While psoriasis is characterised by keratinocyte hyperplasia, pigmentary anomalies can occur (hypopigmented Woronoff ring, hyperpigmentation). Curiously, the normal s.basale melanocyte to keratinocyte ratio is retained in the hyperplastic epidermis. This may infer a commensurate (compensatory) expansion in melanocyte number.

New records of pigmentary abnormalities in two species of birds in Cali, Colombia

We report two bird species with pigment anomalies, which were seen in Cali, Colombia in 2020. The individuals were, a female Shiny Cowbird (Molothrus bonariensis) with partial leucism, a female Ruddy Ground-Dove (Columbia talpacoti) with partial leucism and a young nestling of the same species, with albinism. The records reported here are the first of partial leucism and albinism for Columbia talpacoti and partial leucism for Molothrus bonariensis in Colombia.

A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy

BackgroundHereditary motor and sensory neuropathy, also referred to as Charcot–Marie–Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of “double trouble” overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2.Case presentationThe 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2.ConclusionsWe described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

Establishment of an iPSC line (CSUXHi004-A) from a patient with Waardenburg syndrome type I caused by a PAX3 splice mutation

Waardenburg Syndrome (WS) is a common autosomal dominant syndrome associated with hearing loss. Its clinical manifestations include hearing impairment and pigmentation anomalies. In this study, we generated an induced pluripotent stem cell (iPSC) line from the Epstein–Barr virus-immortalized B lymphocytes of a 6-year-old boy affected with WS type I, caused by a heterozygous splice site mutation in the PAIRED BOX GENE 3 (PAX3) (NM_181457.3: c.452-2A > G). The patient-specific iPSC line (CSUXHi004-A) carrying the same PAX3 mutation showed a normal karyotype, expressed pluripotent markers, and presented differentiation capacity in vitro. This method may be a useful tool for the in vitro modeling of WS.

Pigmentary anomalies and neurologic symptoms in two siblings.

Pigmentary anomalies and neurologic symptoms in two siblings.

De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role...

Seizures and Cardiomyopathy in a Patient with Pallister-Killian Syndrome due to Hexasomy 12p Mosaicism

Pallister-Killian syndrome (PKS) is a rare disorder presenting with developmental delay, numerous dysmorphic features, and skin pigmentation anomalies. It is caused by mosaic tetrasomy of the short arm of chromosome 12. In most instances, tetrasomy is due to a supernumerary isochromosome i(12)(p10). Although mitotic instability is a generally accepted behavior for supernumerary chromosomes, hexasomy 12p due to a gain of an isochromosome 12p, has been hardly ever reported. We report a 10 year follow-up on a girl with 2 copies of isochromosome consisting of the short arm of chromosome 12, who has craniofacial features seen in PKS, such as sparse hair with an unusual pattern, sparse eyebrows, lacrimal duct stenosis, submucous cleft palate, Pallister lip (a relatively long philtrum continuing into the vermillion border of the upper lip), narrow palate, and wide alveolar ridges. She also has other abnormalities, including unilateral renal dysgenesis, rectovaginal fistula, pre-axial polydactyly of the right hand, severe global developmental delay, and hypotonia as well as some features suggestive of mosaicism such as bilateral asymmetry, patchy areas of rough skin, and retinal mottling. Initial cytogenetic studies from peripheral blood showed a normal female karyotype. Further cytogenetic studies on a skin biopsy showed mosaicism with 2 copies of the supernumerary isochromosome 12p.