Two novel heterozygous exonic deletions lead to Chanarin-Dorfman syndrome in a patient with congenital ichthyosis, sensorineural hearing loss, and liver dysfunction.

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.

Otological problems in ichthyosis: A literature review.

BACKGROUND: Ichthyoses are a rare group of keratinization disorders characterized by scaling of the skin due to an impaired barrier function. Few studies have addressed ear involvement in patients with ichthyosis, although it is a probably underestimated aspect of the disease. OBJECTIVE: This study aims to provide an overview of the otological manifestations in ichthyosis and propose specific treatment options. METHODS: Articles were collected using PubMed, EMBASE, and Web of Science. A total of 53 articles were included in this literature review. RESULTS: The most common ear problem in patients with ichthyosis is scale accumulation in the ear canals, which can lead to conductive hearing loss and increases the risk of ear infections. Furthermore, some types of ichthyosis are associated with outer ear malformations. Lastly, sensorineural hearing loss is common in syndromic forms of ichthyosis. CONCLUSIONS: Otological problems are present in all types of ichthyoses and their treatment is challenging. The involvement of ear, nose, and throat specialists in the routine care of ichthyosis patients is essential for early identification and treatment of these manifestations. More research is needed to provide more insight into the otological problems in ichthyosis and to ameliorate treatment options.

A Brazilian case of IFAP syndrome with severe congenital ichthyosis and limb malformations caused by a rare variant in MBTPS2.

OBJECTIVE: The classic triad, which defines IFAP syndrome, is ichthyosis follicularis, alopecia, and photophobia. It is a rare X-linked genetic disorder characterized by multiple congenital anomalies with variable severity, caused by pathogenic variants in the MBTPS2 gene, which encodes a zinc metalloprotease that is essential for normal development. This study aimed to report a case of a Brazilian patient with IFAP syndrome presenting skeletal anomalies, which is a rare finding among patients from different families. CASE DESCRIPTION: We describe a male proband with IFAP syndrome showing severe ichthyosis congenita, cryptorchidism, limb malformation, and comprising the BRESHECK syndrome features. Using whole-exome sequencing, we identified a rare missense variant in hemizygosity in the MBTPS2 gene, which had not been identified in other family members. COMMENTS: This is the first diagnosis of IFAP syndrome in Brazil with a molecular investigation. The present case study thus expands our knowledge on the mutational spectrum of MBPTS2 associated with IFAP syndrome.

Ichthyosis uteri associated with squamous cell carcinoma of the endometrium - a case report.

BACKGROUND: Ichthyosis uteri is an extremely rare condition in which the entire or extensive parts of endometrial lining are replaced by stratified squamous epithelium. Malignant potential of this entity is unclear and its association with dysplastic changes and primary squamous cell carcinoma of the endometrium and endometrial adenocarcinoma has been reported. However, lack of data makes difficult to interpret the significance of neoplasms arising from this condition. PATIENTS AND METHODS: We report a case of ichthyosis uteri associated with squamous cell carcinoma of the endometrium in a 62-year-old female who presented with postmenopausal bleeding and thin endometrium on ultrasound. RESULTS: Endometrial curettage was performed and revealed high grade squamous intraepithelial lesion. The patient underwent total laparoscopic hysterectomy with bilateral salpingo-oophorectomy and bilateral pelvic lymph node dissection. Microscopic examination of sections revealed squamous cell cancer along with extensive replacement of the endometrial lining by stratified squamous epithelium, consistent with ichthyosis uteri. CONCLUSION: If ichthyosis uteri is suspected we recommend hysterectomy in order to rule out possibility of coexisting carcinoma. Also, thin endometrium in women with postmenopausal bleeding does not reliably exclude endometrial cancer.

Evaluation of neurodevelopmental symptoms in 10 cases of neonatal ichthyosis and sclerosing cholangitis syndrome.

Neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome is an extremely rare entity with only 19 patients described in the literature. We report an extended family with the disorder and investigate the association of neurodevelopmental symptoms. Patients with CLDN1 mutations, and specifically « the Moroccan¼ c.200_201delTT deletion, may be an increased risk for neurodevelopmental symptoms such as learning disabilities, mental retardation, and language delay.

Mood symptoms, neurodevelopmental traits, and their contributory factors in X-linked ichthyosis, ichthyosis vulgaris and psoriasis.

BACKGROUND: High rates of adverse mood/neurodevelopmental traits are seen in multiple dermatological conditions, and can significantly affect patient quality of life. Understanding the sex-specific nature, magnitude, impact and basis of such traits in lesser-studied conditions like ichthyosis, is important for developing effective interventions. AIM: To quantify and compare relevant psychological traits in men with X-linked ichthyosis (XLI, n = 54) or in XLI carrier women (n = 83) and in patients with ichthyosis vulgaris (IV, men n = 23, women n = 59) or psoriasis (men n = 30, women n = 122), and to identify factors self-reported to contribute most towards depressive, anxious and irritable phenotypes. METHODS: Participants recruited via relevant charities or social media completed an online survey of established questionnaires. Data were analysed by sex and skin condition, and compared with general population data. RESULTS: Compared with the general population, there was a higher rate of lifetime prevalence of mood disorder diagnoses across all groups and of neurodevelopmental disorder diagnoses in the XLI groups. The groups exhibited similarly significant elevations in recent mood symptoms (Cohen d statistic 0.95-1.28, P < 0.001) and neurodevelopmental traits (d = 0.31-0.91, P < 0.05) compared with general population controls, and self-reported moderate effects on quality of life and stigmatization. There were strong positive associations between neurodevelopmental traits and recent mood symptoms (r > 0.47, P < 0.01), and between feelings of stigmatization and quality of life, particularly in men. Numerous factors were identified as contributing significantly to mood symptoms in a condition or sex-specific, or condition or sex-independent, manner. CONCLUSION: We found that individuals with XLI, IV or psoriasis show higher levels of mood disorder diagnoses and symptoms than matched general population controls, and that the prevalence and severity of these is similar across conditions. We also identified a number of factors potentially conferring either general or condition-specific risk of adverse mood symptoms in the three skin conditions, which could be targeted clinically and/or through education programmes. In clinical practice, recognizing mood/neurodevelopmental problems in ichthyosis and psoriasis, and addressing the predisposing factors identified by this study should benefit the mental health of affected individuals.

Malnutrition in children with ichthyosis: Recommendations for monitoring from a multidisciplinary clinic experience.

BACKGROUND: Short stature has been reported in congenital ichthyoses (CI), but few data exist on patients' nutritional status. OBJECTIVE: To describe the nutritional status at the first evaluation of children and young adults with CI. METHODS: Prospective observational study of patients assessed at a multidisciplinary clinic. Clinical variables and ichthyosis severity were collected. Anthropometric assessment was made by measuring weight and height, and nutritional status was classified based on the World Health Organization definitions for malnutrition. Analytical assessment included markers of nutritional status, fat-soluble vitamins, and micronutrients. RESULTS: We included 50 patients with a median age of 5 years (IQR, 1.6-10.3). Undernutrition was found in 32% of patients, and 75% of the undernourished children presented growth impairment. Younger children and those with severe ichthyoses were the most affected. Micronutrient deficiencies were found in 60% of patients. Deficiencies of selenium (34%), iron (28%), vitamin D (22%), and zinc (4%) were the most frequent findings. LIMITATIONS: Our small sample includes a heterogeneous group of ichthyoses. CONCLUSION: Children with CI appear to be at risk of undernutrition, especially at younger ages. Nutritional deficiencies are common and should be monitored. Growth failure in children with ichthyosis could be caused by undernutrition and aggravated by nutritional deficiencies.

Reporte de caso: Manejo anestésico en un paciente pediátrico con ictiosis más deshidratación grave / Case report: Anesthetic management of an infant patient with ichthyosis plus severe dehydration

INTRODUCTION: Ichthyosis are hereditary disorders of keratinization which are characterized for the presence of hyperkeratosis and/or peeling. This disorder group can put in danger the life of the patient because of the severe alteration of the skin barrier, associated with a severe transdermic loss of water, different grades of hypothermia and a hypernatremic dehydration. OBJECTIVE: Introducing the clinic case of an infant patient with the diagnosis of ichthyosis plus severe dehydration who is scheduled for placement of CVC. CLINICAL CASE: Male infant, 3 months old, with the diagnosis of ichthyosis and severe dehydration, scheduled for placement of CVC. CONCLUSIONS: Due to the urgency of our patient, who presented severe dehydration, an inhaled general anesthesia with sevoflurane and oxygen was decided, without instrumenting the airway which in these patients has the risk of being potentially difficult, from the placement of the face mask itself, until finding lesions within the oral cavity, ventilatory assis- tance should be maintained by the pediatric anesthesiologist, once venous access is achieved, the fluids restitution is performed with loads of 10 to 20 ml/kg of the patient's weight, hyperthermia was controlled with physical means.

INTRODUCCIÓN: Las ictiosis son trastornos hereditarios de la queratinización caracterizadas por la presencia de hiperqueratosis y/o descamación. Este grupo de patologías pueden poner en peligro la vida del paciente debido a la severa alteración de la barrera cutánea, asociada a intensa pérdida transepidérmica de agua, diferentes grados de hipotermia y la deshidratación hipernatrémica. OBJETIVO: Presentar un caso clínico de paciente lactante menor con diagnóstico de ictiosis, cursando un cuadro grave por deshidratación, al que se le instala un CVC. CASO CLÍNICO: Lactante masculino, 3 meses de edad, con diagnóstico de ictiosis y deshidratación grave programado para colocación de CVC. CONCLUSIONES: Debido a la urgencia del paciente quien presentaba un caso de deshidratación severa se decide anestesia general inhalada con sevoflurano y oxígeno, sin instrumentación de la vía área, la cual en estos pacientes tiene el riesgo de ser potencialmente difícil, desde la propia colocación de la mascarilla facial hasta encontrar lesiones dentro de la cavidad oral; se debe mantener la asistencia ventilatoria por el anestesiólogo pediatra, una vez logrado el acceso venoso se procede a la restitución hídrica con cargas de 10 a 20 ml/kg de peso del paciente, el control de la hipertermia fue con medios físicos.

Congenital ichthyosis in Prader-Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD.

Prader-Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11-q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader-Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15-related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co-occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15-related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.

Novel progressive acrodysostosis-like skeletal dysplasia, cerebellar atrophy, and ichthyosis.

Acrodysostosis refers to a rare heterogeneous group of bone dysplasias that share skeletal features, hormone resistance, and intellectual disability. Two genes have been associated with acrodysostosis with or without hormone resistance (PRKAR1A and PDE4D). Severe intellectual disability has been reported with acrodysostosis but brain malformations and ichthyosis have not been reported in these syndromes. Here we describe a female patient with acrodysostosis, intellectual disability, cerebellar hypoplasia, and lamellar ichthyosis. The patient has an evolving distinctive facial phenotype and childhood onset ataxia. X-rays showed generalized osteopenia, shortening of middle and distal phalanges, and abnormal distal epiphysis of the ulna and radius. Brain magnetic resonance imaging showed cerebellar atrophy without other brainstem abnormalities. Genetic workup included nondiagnostic chromosomal microarray and skeletal dysplasia molecular panels. These clinical findings are different from any recognized form of acrodysostosis syndrome. Whole exome sequencing did not identify rare or predicted pathogenic variants in genes associated with known acrodysostosis, lamellar ichthyosis, and other overlapping disorders. A broader search for rare alleles absent in healthy population databases and controls identified two heterozygous truncating alleles in FBNL7 and PPM1M genes, and one missense allele in the NPEPPS gene. Identification of additional patients is required to delineate the mechanism of this unique disorder.

1-O-Alkylglycerol accumulation reveals abnormal ether glycerolipid metabolism in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an inherited metabolic disease characterized by ichthyosis, spasticity, intellectual disability and deficient oxidation and accumulation of of fatty aldehydes and alcohols. We investigated whether excess fatty alcohols in SLS are diverted into biosynthesis of ether glycerolipids (eGLs) by measuring the 1-O-alkylglycerol (AG) backbone of eGLs in stratum corneum, plasma and red blood cells (RBCs). In all tissues, saturated and monounsaturated AGs were detected. In stratum corneum from SLS patients, saturated AGs (C15-C20) were increased 97-fold (range: 86- to 169-fold) compared to controls. AGs were largely (67 ± 9%) derived from neutral esterified eGLs (i.e. alkyl-diacylglyerol) and free non-esterified AGs (28 ± 10%), but very little from plasmalogens (3 ± 5%). Plasma from SLS patients had 2-fold more C18:0-AG (p < 0.005) and 40% less C16:1-AG (p < 0.01) than controls but the total concentration of AGs was not increased, and the AG profile in RBCs from SLS subjects was normal. All AGs were profoundly reduced in plasma and RBCs from patients with Zellweger spectrum disorder, who have impaired eGL (i.e. plasmalogen) synthesis. The striking accumulation of AGs in stratum corneum of SLS patients constitutes a novel lipid biomarker for this disease, and may contribute to the pathogenesis of the ichthyosis. Measurement of AGs is a simple and convenient method to assess global synthesis of eGLs and potentially identify patients with defects in their metabolism.

Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome.

PURPOSE: To describe the presentation and management of limbal stem cell dysfunction in ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome. METHODS: A retrospective case report. RESULTS: A 6-day-old male infant was diagnosed with IFAP syndrome based on family history and a mutation detected in the MBTPS2 gene. Initial examination showed hyperkeratotic eyelids, madarosis, and lagophthalmos, but otherwise clear corneas. He developed bilateral central corneal epithelial defects spontaneously 6 months later, which were managed with aggressive lubrication, prophylactic antibiotics, and bilateral permanent lateral tarsorrhaphies at 7 months of age. During the procedure, the patient was noted to have bilateral limbal thickening, peripheral corneal pannus with underlying stromal scarring, and late fluorescein staining of the corneal surface. Anterior segment optical coherence tomography demonstrated a significantly abnormal and hyperreflective epithelial surface overlying a thinned corneal stroma, suggestive of limbal stem cell dysfunction. The corneal surface was maintained with lubrication and tarsorrhaphy and has remained stable since. CONCLUSIONS: The progressive conjunctivalization, spontaneous epithelial defects, and anterior segment optical coherence tomography features are highly suggestive of limbal stem cell dysfunction in IFAP syndrome. Optimizing the ocular surface is of importance in the management of children with this rare disease.

Uncrossed corticospinal tracts in a patient with ichthyosis and hemiparesis: a case report.

BACKGROUND: Anomalies of pyramidal tract decussation are rare phenomena that can be caused by ectodermal dysplasia. Herein, we describe a patient with ichthyosis who exhibited ipsilateral hemiparesis after stroke and whose neuroimaging results showed evidence of motor control being provided by the ipsilateral motor cortex. CASE PRESENTATION: A 24-year-old right-handed man presented with skin abnormalities, sudden-onset left hemiparesis, and dysarthria. He exhibited a mild-to-moderate left-sided weakness (grade 4 on the Medical Research Council scale). Magnetic resonance imaging revealed an acute infarct in the left corona radiata. Diffusion tensor imaging revealed uncrossed corticospinal tracts. Next-generation sequencing identified heterozygous FLG mutations. The patient was diagnosed with cerebral infarction and ichthyosis vulgaris and was treated with aspirin (100 mg/d). His symptoms gradually dissipated. CONCLUSIONS: This case suggests that pyramidal decussation anomalies can be associated with ichthyosis. Patients with ichthyosis should therefore be evaluated for nerve involvement.

Mutation in ALOX12B likely cause of POI and also ichthyosis in a large Iranian pedigree.

Premature ovarian insufficiency (POI) is a clinically and etiologically heterogeneous disorder characterized by menstrual irregularities and elevated levels of FSH before age of 40 years. Genetic anomalies are among the recognized causes of POI. Here, we aimed to identify the genetic cause of POI in an inbred pedigree with nine POI and two ichthyosis-affected members. Inheritance of POI and ichthyosis were, respectively, dominant and recessive. Reproduction-related information and measurements of relevant hormones were obtained. Genetic studies included homozygosity mapping, linkage analysis, exome sequencing, and screening of candidate variants. A mutation within ALOX12B, which is a known ichthyosis causing gene, was identified as cause of ichthyosis. ALOX12B encodes a protein involved in steroidogenesis and lipid metabolism. Considering the importance of steroidogenesis in reproduction functions, the possibility that the ALOX12B mutation is also cause of POI was considered. Screenings showed that the mutation segregated with POI status. Linkage analysis with respect to POI identified a single strongly linked locus (LOD > 3) that includes ALOX12B. Exome sequencing on POI-affected females identified the mutation in ALOX12B and also a sequence variation in SPNS2 within the linked locus. A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree.