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.

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.

[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.

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.

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.

SOPH syndrome in three affected individuals showing similarities with progeroid cutis laxa conditions in early infancy.

Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.

Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG.

Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. >100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542T>G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H+-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the ß-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1.

The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz-Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.

Geroderma osteodysplasticum: Histological features and the role of panel-based exome sequencing in diagnosis.

Geroderma osteodysplasticum (GO) has clinical and histological features that overlap with other causes of wrinkly skin. Here we present the case of a child diagnosed with GO following exome sequencing of a panel of genes covering the wide differential diagnosis. The histological features of the overlapping conditions are presented, highlighting the utility of panel testing for conditions of this type. This is relevant to many genetic conditions and can influence ongoing management as exemplified by this case.

Cutaneous disorders characterized by elastolysis or loss of elastic tissue.

Along with collagen, elastic fibers are integral components of cutaneous connective tissue. A decrease in elastic fibers or loss thereof has been described in a number of clinically distinct skin diseases, both hereditary and acquired. In disorders associated with inflammation, elastophagocytosis is an important histological hallmark. Treatment is generally difficult.

[Clinical and genetic analysis of a patient with cutis laxa].

OBJECTIVE To identify potential mutation in a patient with cutis laxa through exome sequencing of genetic disease-related genes and explore its clinical and genetic features. METHODS Clinical data was collected for the proband and her parents. Exome sequencing was carried out on the proband. Suspected mutations were verified by Sanger sequencing. RESULTS Exome sequencing identified a compound heterozygous mutation of the ATP6V0A2 gene, c.187C>T (p.R63X) and c.1189G>C (p.A397P), in the proband. The mutations were respectively inherited from the father and mother. The patient was diagnosed with autosomal recessive cutis laxa type 2A (ARCL2A). CONCLUSION A case with ARCL2A was diagnosed. The novel mutation has expanded the spectrum of ATP6V0A2 mutations. Exome sequencing is a useful tool for the diagnosis of complex genetic diseases.

Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica.

Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient's clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions.

Generalized acquired cutis laxa type 1: a case report and brief review of literature.

Cutis laxa, clinically characterized by loose and pendulous skin related to loss of elastic tissue, is a rare heterogeneous condition. It is classified into congenital and acquired types. We report a case of generalized acquired cutis laxa type 1 in a young man following pruritic urticarial plaques. We have done a brief review of literature.

[Pseudoxanthoma elasticum-like disease with deficiency of vitamin K-dependent clotting factors and cutis laxa features]. / Pseudoxanthome élastique variant avec déficit en facteurs de coagulation vitamine K-dépendants et perte d'élasticité cutanée.

BACKGROUND: Pseudoxanthoma elasticum (PXE)-like syndrome is characterized by the association of PXE and cutis laxa (CL) features with a deficiency of vitamin K-dependent clotting factors. It was first described in 1971 and was identified as a distinct genetic entity in 2007 with analysis of the GGCX (γ-glutamyl carboxylase) gene, which is involved in congenital deficiency in vitamin K-dependent clotting factors. Here we report a new case of this extremely rare syndrome. PATIENTS AND METHODS: A 23-year-old female patient was seen for the emergence of loose and redundant skin following extensive weight loss. She also presented a deficiency of vitamin K-dependent clotting factors. Physical examination revealed excessive, leathery skin folds in the axillary and neck regions. A skin biopsy revealed polymorphous and fragmented elastic fibers in the reticular dermis. These were mineralized, as was demonstrated by Von Kossa staining. The clinical features of CL associated with the histopathological features of PXE and vitamin K-dependent clotting factor deficiency led us to a diagnosis of PXE-like syndrome. A molecular study of the GGCX gene showed compound heterozygosity. DISCUSSION: The GGCX gene is usually responsible for PXE-like syndrome. GGCX encodes a γ-glutamyl carboxylase necessary for activation of gla-proteins. Gla-proteins are involved both in coagulation factors in the liver and in the prevention of ectopic mineralization of soft tissues. Uncarboxylated forms of gla-proteins in fibroblast would thus enable mineralization and fragmentation of elastic fibers.

Autosomal recessive cutis laxa type 2A (ARCL2A) mimicking Ehlers-Danlos syndrome by its dermatological manifestations: report of three affected patients.

Through a survey of more than 20 patients with a specific subgroup of autosomal recessive congenital cutis laxa (ARCL), namely ATP6V0A2-related cutis laxa, we noted that the clinical findings on three patients included pretibial pseudo-ecchymotic skin lesions very similar to those found in classical Ehlers-Danlos syndrome. The finding is apparently age-related, occurring during the second decade in two of the three patients.

Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2.

The disorder comprising Macrocephaly, Alopecia, Cutis laxa, and Scoliosis has been designated MACS syndrome. It is a rare condition, inherited in an autosomal recessive pattern. Three families from different ethnic origins have so far been reported and were all linked to homozygous mutations in RIN2, a gene encoding the Ras and Rab interactor 2 protein involved in cell trafficking. We describe herein the fourth family with MACS syndrome in two siblings carrying a novel homozygous mutation, c.1878_1879insC in exon 8 of the RIN2 gene, which predicts p.Ile627Hisfs*7. We also report on additional findings not previously described in MACS syndrome, including bronchiectasis and hypergonadotropic hypogonadism. Finally, our overall data support the argument that RIN2 syndrome is a more appropriate name for the disorder.