Type I acquired cutis laxa: Report of a unique progressive case and short review.

Cutis laxa is a rare connective tissue disorder, characterized by a reduced number and abnormal properties of elastic fibers throughout the dermis, creating a clinical appearance of premature aging. It can be subdivided into inherited and acquired, the latter rarer than the former, and skin involvement may be localized or generalized. The etiology of acquired cutis laxa (ACL) remains unknown and there is no definitive treatment. We present the case of a 30-year-old man diagnosed with type I ACL with progressive systemic involvement at the renal, pulmonary, and digestive levels. Histological analysis of the skin revealed reduction and fragmentation of elastic fibers. Immunosuppressive treatment was started with prednisone, cyclophosphamide, and rituximab, with which a complete response to proteinuria was achieved and the progression of lung damage was limited. Autoimmune, infectious, and neoplastic diseases were ruled out.

Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families.

BACKGROUND: Autosomal recessive cutis laxa type 2A (ARCL2A; OMIM: 219200) is characterized by neurovegetative, developmental and progeroid elastic skin anomalies. It is caused by biallelic variation in ATPase, H+ transporting V0 subunit A2 (ATP6V0A2; OMIM: 611716) located on chromosome 12q24.31. Autosomal recessive cutis laxa type 3A (ARCL3A; OMIM: 219150) is another subclinical type characterized by short stature, ophthalmological abnormalities and a progeria-like appearance. The ARCL3A is caused by loss of function alterations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1; OMIM: 138250) gene located at chromosome 10q24.1. METHODS: Whole-exome sequencing (WES), and Sanger sequencing were performed for molecular diagnosis. 3D protein modeling was performed to investigate the deleterious effect of the variant on protein structure. RESULTS: In this study, clinical and molecular diagnosis were performed for two families, ED-01 and DWF-41, which displayed hallmark features of ARCL2A and ARCL3A, respectively. Three affected individuals in the ED-01 family (IV-4, IV-5 and V-3) displayed sagging loose skin, down-slanting palpebral fissures, excessive wrinkles on the abdomen, hands and feet, and prominent veins on the trunk. Meanwhile the affected individuals in the DWF-41 family (V-2 and V-3) had progeroid skin, short stature, dysmorphology, low muscle tone, epilepsy, lordosis, scoliosis, delayed puberty and internal genitalia. WES in the index patient (ED-01: IV-4) identified a novel homozygous deletion (NM_012463.3: c.1977_1980del; p.[Val660LeufsTer23]) in exon 16 of the ATP6V0A2 while in DWF-41 a novel homozygous missense variant (NM_001323413.1:c.1867G>A; p.[Asp623Asn]) in exon 15 of the ALDH18A1 was identified. Sanger validation in all available family members confirmed the autosomal recessive modes of inheritances in each family. Three dimensional in-silico protein modeling suggested deleterious impact of the identified variants. Furthermore, these variants were assigned class 1 or "pathogenic" as per guidelines of American College of Medical Genetics 2015. Screening of ethnically matched healthy controls (n = 200 chromosomes), excluded the presence of these variations in general population. CONCLUSIONS: To the best of our knowledge, this is the first report of ATP6V0A2 and ALDH18A1 variations in the Pakhtun ethnicity of Pakistani population. The study confirms that WES can be used as a first-line diagnostic test in patients with cutis laxa, and provides basis for population screening and premarital testing to reduce the diseases burden in future generations.

Autosomal dominant cutis laxa and critical stenosis of the left main coronary artery in a 21-year-old female with an intronic mutation in the elastin gene.

Cutis laxa (CL) is a rare, inherited or acquired connective tissue disorder characterized by abnormal elastic fibers causing loose and redundant skin and a prematurely aged appearance. The syndrome has been associated with hypertension, but cases with early-onset ischemic heart disease have never been described. Here, we report a 21-year-old Danish female with activity-related shortness of breath and oedema of the lower extremities. The patient had a clinical diagnosis of autosomal dominant CL, but no genotyping had been performed prior to the index admission. The patient was diagnosed with ischemic heart disease, based on results of non-invasive cardiovascular imaging (including MRI and PET-CT) followed by invasive treatment of a critical left main coronary artery stenosis. Subsequent referral to genetic testing revealed a likely pathogenic intronic variant in ELN. This case report includes the clinical findings and relates these to known molecular mechanisms of CL.

A novel deletion mutation in the ATP6V0A2 gene in an Iranian patient affected by autosomal recessive cutis laxa.

Cutis laxa (CL) can be caused by mutations in a number of genes. Cutis laxa with autosomal recessive inheritance due to mutations in several genes, including mutations in the ATP6V0A2 gene, causes autosomal recessive cutis laxa type 2A (ARCL2A). The ATP6V0A2 gene encodes the a2 subunit in the V-ATPases pump. The V-ATPases are located in the membrane of some organelles, including the Golgi or some vesicles, and act as ATP-dependent proton pumps to pH adjustment intracellular segments. Mutations in the ATP6V0A2 gene consist present in ARCL2A patients. We present the case of a 12-year-old girl who was referred to Rasad Laboratory (Tehran, Iran) at the age of 5 with a set of symptoms of congenital disorders. Her clinical phenotype contains distal symmetrical sensory and motor polyneuropathy, loose joints, large nasal roots, growth delay, and wrinkled skin. Also, there was a history of the parental marriage of consanguinity. A potentially pathogenic homozygous deletion mutation was detected in the ATP6V0A2 gene related to ARCL2A. This mutation has not been reported in the other patients with ARCL2A. A novel homozygous deletion mutation in ATP6V0A2 is supposed to be the reason for disease in our proband.

[Analysis of clinical features and genetic variants in a child with autosomal recessive cutis laxa due to variants of ATP6V0A2 gene].

OBJECTIVE: To explore the clinical characteristics and genetic basis for a child featuring autosomal recessive cutis laxa (ARCL). METHODS: Clinical data of the patient was collected. Trio-whole exome sequencing (trio-WES) was carried out for the proband, his sister and parents. Candidate variant was verified by Sanger sequencing. RESULTS: The 5 years and 2 month old child, was 109.5 cm tall (40% centile) and 14.2 kg in weight (< 3% centile). Physical examination discovered facial dysmorphisms including downslanting palpebral fissure, hypertelorism, broad nasal bridge, prominent forehead, long philtrum, obvious loose and wrinkled of abdominal and groin skin. He also had previous history of cryptorchidism and umbilical hernia. Trio-WES revealed that the child harbored compound heterozygous variants c.1421_1424delAGTC (p.Val476Thrfs*71) and c.2293+1G>A of the ATP6V0A2 gene, both of which were unreported previously. In addition to our patient, 75 cases of ATP6V0A2 gene-related ARCL have so far been diagnosed, with main features including cutis laxa [100% (75/75)], facial dysmorphism [78.7% (59/75)] and delayed closure/large anterior fontanelle [65.3% (49/75)]. Typical facial features have included downslanting palpebral fissures [57.3% (43/75)], broad nasal bridge [40.0% (30/75)] and long face [34.7% (26/75)]. CONCLUSION: Patients presenting with generalized skin wrinkling, facial dysmorphism, delayed closure/large anterior fontanelle, mental retardation, global developmental disabilities and seizures should be considered for ATP6V0A2 gene-related ARCL. Exome sequencing may facilitate the identification of genetic etiology, to confirm the diagnosis.

[Sweet syndrome of childhood with acquired cutis laxa (Marshall syndrome) as primary manifestation of Takayasu arteritis]. / Sweet-Syndrom des Kindesalters mit erworbener Cutis laxa (Marshall-Syndrom) als Erstmanifestation einer Takayasu-Arteriitis.

A special form of the rare infantile Sweet syndrome (acute febrile neutrophilic dermatosis) is facultative healing in the form of postinflammatory elastolysis with acquired cutis laxa, named "Marshall" syndrome after the authors who first described it. We report the case of a 3-year-old child in whom the cutaneous manifestation led to diagnosis of Takayasu arteritis. Postinflammatory elastolysis with acquired cutis laxa is a clinically relevant cutaneous indicator of life-threatening cardiovascular complications such as aortitis, aortic aneurysm, coronary stenosis and heart failure in children with Sweet's syndrome. Cutis laxa usually precedes cardiac complications or, as in our case, occurs simultaneously; thus, immediate cardiac and rheumatologic examinations are important to initiate systemic therapy with anti-inflammatory and immunomodulatory agents early to prevent complications.

Acquired cutis laxa type II (Marshall syndrome) in a 3-month-old boy.

Acquired cutis laxa type II (Marshall syndrome) is a post-inflammatory elastolysis occurring in infancy and childhood. It is challenging to treat with very few effective treatment options available. Herein, we describe the case of a 3-month-old boy with acquired cutis laxa type II secondary to a neutrophilic dermatosis. Early treatment of the initial inflammatory phase is essential to reduce the permanent sequelae.

Hemopericardium with cardiac tamponade as a rare presentation of a massive aortic aneurysm in a young child with autosomal recessive cutis laxa.

Aortic aneurysms are rare in the pediatric age group and are commonly caused by genetic disorders associated with vasculopathy, weakness and fragility of arterial walls with progressive dilatation or even rupture. We reported a giant aortic aneurysm involving the ascending aorta and aortic arch in a 20-month-old girl with autosomal recessive cutis laxa type 1B (ARCL1B) who presented with hemorrhagic pericardial effusion and tamponade (impending rupture). Successful surgical repair has been done through excision of the aneurysmal part and replacement by Hemashield graft with preservation of the aortic valve.

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype.

BACKGROUND: The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate. METHODS: We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondrial membrane potential, and redox balance in cultured fibroblasts of Patient 1. RESULTS: We found a novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in Patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiologic worsening was observed in the dHMN of Patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria. CONCLUSIONS: Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrate that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the pathogenic mechanism in ATP7A-related dHMN.

Review of clinical and molecular variability in autosomal recessive cutis laxa 2A.

ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), is a subtype of hereditary cutis laxa originally characterized by skin, skeletal, and neurological involvement, and a combined defect of N-glycosylation and O-glycosylation. The associated clinical spectrum subsequently expanded to a less severe phenotype dominated by cutaneous involvement. At the moment, ARCL2A was described in a few case reports and series only. An Italian adult woman ARCL2A with a phenotype restricted to skin and the two novel c.3G>C and c.1101dup ATP6V0A2 variants has been reported. A systematic literature review allowed us to identify 69 additional individuals from 64 families. Available data were scrutinized in order to describe the clinical and molecular variability of ARCL2A. About 78.3% of known variants were predicted null alleles, while 11 were missense and 2 affected noncanonical splice sites. Age at ascertainment appeared as the unique phenotypic discriminator with earlier age more commonly associated with facial dysmorphism (p .02), high/cleft palate (p .005), intellectual disability/global developmental delay (p .013), and seizures (p .024). No specific genotype-phenotype correlations were identified. This work confirmed the existence of an attenuated phenotype associated with ATP6V0A2 biallelic variants and offers an updated critique to the clinical and molecular variability of ARCL2A.