Autosomal recessive cutis laxa type 2, classic type
General Information (adopted from Orphanet):
Synonyms, Signs:
CUTIS LAXA, DEBRE TYPE
CUTIS LAXA WITH BONE DYSTROPHY
CUTIS LAXA WITH GROWTH AND DEVELOPMENTAL DELAY
ARCL2A
CUTIS LAXA WITH JOINT LAXITY AND RETARDED DEVELOPMENT
CUTIS LAXA WITH CONGENITAL DISORDER OF GLYCOSYLATION
ARCL2
ARCL2, classic type
ARCL2, Debré type
Autosomal recessive cutis laxa type 2, Debré type
Autosomal recessive cutis laxa type II represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted ... Autosomal recessive cutis laxa type II represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type II), and ARCL2B, those without a metabolic disorder (summary by Morava et al., 2009). Van Maldergem et al. (2008) concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder. For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100). - Genetic Heterogeneity of Cutis Laxa Type II ARCL2A is caused by mutation in the ATP6V0A2 gene. ARCL2B (612940) is caused by mutation in the PYCR1 gene (179035).
Fittke (1942) described a 10.5-month-old female whose skin from birth had been in loose, redundant folds. The face was spared, however. On stretching, the skin returned only slowly to its original position. The skeletal system showed widely persistent ... Fittke (1942) described a 10.5-month-old female whose skin from birth had been in loose, redundant folds. The face was spared, however. On stretching, the skin returned only slowly to its original position. The skeletal system showed widely persistent fontanels, slight oxycephaly, and dislocation of one hip. The parents were not known to be related but lived in an area of Europe where most persons were related in some degree. The mother, aged 25 years, had long suffered from 'weak knee joints.' An 8-year-old cousin of the proband showed the same skin changes, as well as pigeon breast, static scoliosis, and flat feet. The fontanels had not closed until the third year. The case of Debre et al. (1937) may be identical. Theopold and Wildhack (1951) restudied Fittke's family and demonstrated consanguinity of the parents of the affected cousin. Reisner et al. (1971) described 2 sisters with congenital cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. The parents were first cousins. The authors suggested that the severe form may occur only or mainly in females because it is lethal to the male fetus. They also suggested that this disorder is unusually frequent in Saudi Arabia. Sakati et al. (1983) reported 6 cases, bringing the reported total to 13, all female, and raised the question of X-linked dominant lethal in the hemizygous male. However, Philip (1978) observed a case in a male infant. Fitzsimmons et al. (1985) and Goldblatt et al. (1988) also reported males with this special cutis laxa syndrome. Allanson et al. (1986) reported an affected girl with first-cousin parents of Saudi Arabian extraction. Ogur et al. (1990) reported the cases of Turkish brother and sister. Van Maldergem et al. (1989) pictured a 23-month-old patient born to Turkish first-cousin parents. Facial features included a bossing of the forehead, reversed-V eyebrows, and downward slant of palpebral fissures. The patient also had enormous bilateral inguinal hernias. Imaizumi et al. (1994) described a nineteenth case; the ratio of males to females was 5 to 14. Their patient, a 5-year-old boy, had pre- and postnatal growth retardation, delayed motor development, cutis laxa, delayed closure of large fontanels, congenital hip dislocation, and characteristic facies. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, Morava et al. (2005) performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome. They described 5 patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay, and neurologic findings. Three of these 5 children had an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans, and 2 of these patients had bilateral pachygyria on brain MRI. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were identified in the FBLN5 gene (604580). Morava et al. (2005) concluded that these patients had a unique combined glycosylation defect with a distinct clinical phenotype and that a combined defect of glycosylation may be a causative factor in autosomal recessive congenital cutis laxa. Morava et al. (2008) described 10 patients with cutis laxa and congenital disorder of glycosylation, including 3 patients reported by Morava et al. (2005). Clinical features included transient feeding problems in infancy, late closure of the fontanelles, and variable central nervous system involvement including hypotonia, developmental delay, mental retardation, seizures, microcephaly, pachygyria, and myopia. All patients had dysmorphic facial features with downslanting palpebral fissures, midface hypoplasia, anteverted nares, short nose and small mouth. Other features included congenital hip dislocation and joint hyperlaxity. Skin biopsy showed decreased amounts of elastin and abnormal elastin structure. Biochemical analysis showed a combined defect of N- and O-glycosylation. All patients had mutations in the ATP6V0A2 gene (Kornak et al., 2008). Van Maldergem et al. (2008) reported 11 patients from 9 families with the Debre type of cutis laxa, which was confirmed by genetic analysis of the ATP6V0A2 in all patients except 1. All had dysmorphic craniofacial features, most commonly including large anterior fontanel, prominent supraorbital ridges and nasal root, downslanting palpebral fissures, and coarse hair. Four patients had microcephaly. The skin showed generalized overfolding and wrinkling, but no hyperelasticity, and skin biopsies showed a sparse elastin network. Connective tissue problems were common, and included inguinal hernia, hip dislocation, and high myopia. There tended to be improvement of cutis laxa throughout childhood. All had mental retardation that varied in severity, and 5 patients developed refractory seizures. Transferrin isoelectric focusing showed CDG type II. Brain imaging was performed in 9 patients, 8 of whom showed a cobblestone-like malformation predominantly in the posterior frontal, perisylvian, and parietal regions. It resembled polymicrogyria, but the cortical ribbon appeared smooth in some areas and irregular in others. These cortical malformations were reminiscent of those observed in the alpha-dystroglycanopathies, such as Walker-Warburg syndrome (see, e.g., MDDGA1, 236670). Two patients had a Dandy-Walker malformation. Morava et al. (2009) reviewed the spectrum of clinical features of the various autosomal recessive syndromes associated with cutis laxa, including ARCL1 (219100), ARCL2, de Barsy syndrome (219150), X-linked cutis laxa (304150), WSS, geroderma osteodysplasticum (GO; 231070), and Costello syndrome (218040). - Relationship to Wrinkly Skin Syndrome Zlotogora (1999) pointed out that the 2 sisters reported by Reisner et al. (1971) as one of the first examples of the syndrome of cutis laxa with growth and developmental delay were reported later, along with their newborn brother, as examples of WSS. Conformation that these 2 syndromes represent variable presentations of one disorder may be provided by the report of Ogur et al. (1990) on 2 affected Turkish sibs. The boy was severely affected with the classic form of cutis laxa and developmental delay, while his sister showed improvement with the years and at the age of 6.5 years presented with a relatively mild disease, including cutaneous manifestations similar to those found in the wrinkly skin syndrome. Another source of confusion is that some of the children reported with recessive infantile cutis laxa with growth and developmental delay were, in fact, affected with Costello syndrome (see later). Since the wrinkly skin syndrome is not a true form of cutis laxa (Azuri et al., 1999), Zlotogora (1999) suggested use of the designation 'wrinkly skin syndrome' for all of the patients who were reported as affected with either one or the other of these 2 syndromes.
In 12 families with diagnoses of either autosomal recessive cutis laxa type II or wrinkly skin syndrome, Kornak et al. (2008) identified 10 different loss-of-function mutations in the ATP6V0A2 gene. The mutations resulted in abnormal glycosylation of serum ... In 12 families with diagnoses of either autosomal recessive cutis laxa type II or wrinkly skin syndrome, Kornak et al. (2008) identified 10 different loss-of-function mutations in the ATP6V0A2 gene. The mutations resulted in abnormal glycosylation of serum proteins (CDG II) and caused an impairment of Golgi trafficking in fibroblasts from affected individuals. The results indicated that the alpha-2 subunit of the proton pump has an important role in the Golgi function. Leao-Teles et al. (2010) stated that 1 of the patients studied by Kornak et al. (2008) and found to have a mutation in the ATP6V0A2 gene (patient 'CoFe') displayed the full clinical picture of the De Barsy syndrome (see 219150), including cutis laxa, facial dysmorphism, dwarfism, psychomotor retardation, dystonia, congenital hip dysplasia, and corneal dystrophy requiring repeated corneal transplantation. Leao-Teles et al. (2010) suggested that a subgroup of patients with De Barsy syndrome belongs to the spectrum of ATP6V0A2-associated CDG, and recommended that mutations in the ATP6V0A2 gene be sought in patients diagnosed with De Barsy syndrome. Morava et al. (2010) noted that none of their cohort of 6 patients with De Barsy syndrome had N-linked or O-linked glycosylation abnormalities nor mutations in ATP6V0A2; they stated that further description and photographs of patient CoFe would be helpful, since corneal abnormalities with a movement disorder would widen the range of symptoms evoking glycosylation studies in patients with cutis laxa. In 13 patients with ARCL2, Fischer et al. (2012) identified 17 ATP6V0A2 mutations: 1 mutation of the start codon, 3 missense mutations, 3 nonsense mutations, 3 splice site mutations, 3 in-frame deletions, and 4 frameshift mutations; 14 of the mutations were novel. All mutations but 1 were found in homozygous or compound heterozygous state. A heterozygous mutation was detected at the genomic as well as the cDNA level in a 40-year-old patient (patient 2), but a pronounced nonsense-mediated decay of the ATP6V0A2 mRNA in fibroblasts corroborated an ATP6V0A2-related ARCL2. Fischer et al. (2012) suggested that the second mutation most probably resided in noncoding regions not included in the mutation screening. This patient, who was described as the oldest affected individual reported to that time, showed a strikingly progressive phenotype leading to kyphoscoliosis, facial coarsening, mild to moderate mental retardation, and seizures without progression.
ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end. ...
DiagnosisClinical Diagnosis ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end. ATP6V0A2-related cutis laxa is diagnosed in individuals with the characteristic signs of cutis laxa: Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groinDroopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features Skin that when extended does not display hyperelasticity (as in the Ehlers-Danlos syndromes) but rather keeps its consistencyOther evidence of a generalized connective tissue disorderEnlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age one year)Congenital dislocation of the hipsInguinal hernias High myopiaBruch’s membrane ruptureCentral nervous system (CNS) abnormalities. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Cortical malformation. Abnormally thick (5-10 mm) cortex has subtle vertical streaks that appear smooth in some areas and irregular in others, resembling either lissencephaly or polymicrogyria, particularly the cortical malformation of GPR56-associated fronto-parietal cobblestone-like cortical malformation (see Polymicrogyria Overview) or muscle-eye-brain (MEB) disease (see Congenital Muscular Dystrophy Overview), except that white matter changes are more prominent in the two latter conditions. This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes them from true polymicrogyria.Cerebellar malformation ranges from mild cerebellar vermis hypoplasia to classic Dandy-Walker malformation, including severe hypoplasia and upward rotation of the vermis, cystic enlargement of the fourth ventricle, and enlarged posterior fossa.TestingSerum sialotransferrin isoelectric focusing (IEF). Findings in ATP6V0A2-related cutis laxa:Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: Disialotransferrin: 2.5%-9.8%Trisialotransferrin: 3.4%-13.7%These findings, which are also observed in type 2 congenital disorder of glycosylation (CDG type 2), support the diagnosis of ATP6V0A2-related cutis laxa [Morava et al 2005, Wopereis et al 2005, Morava et al 2008, Guillard et al 2009] (see Congenital Disorders of Glycosylation Overview). Note: In the authors’ experience, all probands had a CDG type 2 sialotransferrin IEF pattern; however, it has been observed that infants may have a normal transferrin isofocusing profile in the first months of life, but develop the typical transferrin abnormality later on. In these infants, the apolipoprotein C-III isofocusing was already abnormal in the first months of life [Morava et al 2005, Wopereis et al 2005].Serum apolipoprotein C III isoelectric focusing (IEF) reveals the following changes of altered O-glycosylation:Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues Increased amounts of monosialotransferrin. Normal ranges depend on age. In adults: monosialotransferrin: 43%-69%; disialotransferrin: 23%-50%.Abnormal O-glycosylation is supportive of the diagnosis, but a normal or inconclusive result does eliminate the possibility of ATP6V0A2-related cutis laxa. In the authors’ experience, comparing the findings in the parents with those of the index case is most helpful in identifying the reduction of the main band. Skin biopsy with orcein staining Light microscopy is normal.Electron microscopy (EM). Rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities. Note: EM studies require a high level of expertise and are only available in specialized centers.The EM findings strongly support the diagnosis of ATP6V0A2-related cutis laxa but are also seen in De Barsy syndrome [Guerra et al 2004] (see Differential Diagnosis). EM findings differ from the misassembly of elastin fibers observed in FBLN5-associated cutis laxa. Molecular Genetic Testing Genes. ATP6V0A2 is the only gene associated with ATP6V0A2-related cutis laxa.Clinical testing Sequence analysis. Thus far diagnosis of ATP6V0A2-related cutis laxa has been confirmed in no more than 55 individuals by ATP6V0A2 sequencing. In individuals with cutis laxa and a clear CDG type 2 sialotransferrin IEF pattern, mutation detection rate is high; however, it is possible that in a subset of affected individuals, exon or whole-gene deletions (which cannot be detected by sequence analysis) are present. When parental consanguinity is present, detection of homozygosity for ATP6V0A2 polymorphic markers may provide an incentive for full-sequence analysis of the gene. Deletion/duplication analysis. Hucthagowder et al [2009] identified deletion of exon 16 in four unrelated individuals of Middle Eastern origin in their cohort of 17 affected individuals from 16 families.Table 1. Summary of Molecular Genetic Testing Used in ATP6V0A2-Related Cutis LaxaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityATP6V0A2Sequence analysisSequence variants 2UnknownClinicalDeletion/ duplication analysis 3Deletion/ duplication of one or more exons or the whole gene1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy Confirming/establishing the diagnosis in a proband. The diagnosis of ATP6V0A2-related cutis laxa is established in individuals who meet clinical diagnostic criteria and have two disease-causing mutations in ATP6V0A2. Abnormal results on biochemical studies (sialotransferrin IEF and apolipoprotein CIII IEF) and skin biopsy increase the probability of finding an ATP6V0A2 mutation. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in ATP6V0A2.
ATP6V0A2-related cutis laxa spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end; these two phenotypes were thought to be distinct clinical entities until their molecular genetic nature was determined. Children with Debré-type cutis laxa have more severe developmental and neurologic abnormalities and a less severe cutaneous phenotype than children with wrinkly skin syndrome. In ATP6V0A2-related cutis laxa the skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. ...
Natural History ATP6V0A2-related cutis laxa spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end; these two phenotypes were thought to be distinct clinical entities until their molecular genetic nature was determined. Children with Debré-type cutis laxa have more severe developmental and neurologic abnormalities and a less severe cutaneous phenotype than children with wrinkly skin syndrome. In ATP6V0A2-related cutis laxa the skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. At birth, hypotonia, over-folded skin, and distinctive facial features are present. Enlarged fontanelles are invariably present in infants with Debré-type cutis laxa. During childhood, facial features and the thick or coarse hair may become quite distinctive. Nearly all affected children described to date have had delayed developmental milestones and intellectual disability. Most have borderline microcephaly with head circumference in the range of -2 to -3 standard deviations. Despite delays in developmental milestones and language, affected children are said to be cheerful and outgoing.Many children have a degenerative course including cognitive decline that begins about the end of the first decade. Generalized or partial complex seizures begin between ages eight and 12 years. Six of eight children fulfilling diagnostic criteria for Debré-type cutis laxa developed seizures by their mid-teens. Note: By contrast, a lower rate of seizures was observed in a cohort of children with autosomal cutis laxa (regardless of accompanying signs and symptoms) and abnormal IEF [Morava et al 2005, Morava et al 2008] and a cohort of children from Oman [Rajab et al 2008]. An explanation could be age-related bias of ascertainment, given that most children in these two cohorts were young.Neurologic regression (with or without seizures) can include spasticity and cerebellar signs and symptoms (ataxia, slurred speech). Some adolescents become wheelchair bound. High myopia (> -5 diopters) has been observed in the majority of affected individuals. One Portuguese individual had an unclassified corneal dysplasia requiring engraftment; a Belgian individual had unilateral rupture of Bruch’s membrane rupture. Strabismus has been observed in nearly half of the patients.A unique individual with mild brain dysgenesis and compound heterozygosity for ATP6V0A2 mutations had a normal IQ with no history of seizures, and was doing well in mainstream school at age 15 years [Van Maldergem et al 2008].Pulmonary emphysema does not occur.Wrinkly skin syndrome (WSS) includes many features of Debré-type cutis laxa but is milder [Gazit et al 1973]. Usually, affected individuals have only mild developmental delay without subsequent neurodegeneration. The skin shows tighter wrinkles and the changes in facial features are milder [Al-Gazali et al 2001]. In one of the four WSS families from Oman described recently, the father of an index patient appeared to be affected as well, as determined by molecular genetic testing after subtle signs of WSS were noted during clinical examination [Rajab et al 2008].
Other disorders characterized by cutis laxa are summarized in Table 2....
Differential DiagnosisOther disorders characterized by cutis laxa are summarized in Table 2.FBLN5-related cutis laxa (ARCL1) is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Intrafamilial variability in age of onset is observed. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death. Inheritance is autosomal recessive. EFEMP2 (FBLN4)-related cutis laxa (ARCL1). Based on reports of two affected individuals, EFEMP2-related cutis laxa appears to comprise arachnodactyly and arterial tortuosity with a predisposition for aneurysms and dissections [Hucthagowder et al 2006, Dasouki et al 2007]. The cutis laxa and emphysema are similar in EFEMP2- or FBLN5-related cutis laxa; however, to date the diaphragmatic changes and arterial aneurysms appear to be more predominant in EFEMP2-related cutis laxa. Inheritance is autosomal recessive.ELN-related cutis laxa (ADCL) was historically considered a strictly cutaneous disorder without systemic involvement; however, it is now known that persons with ELN mutations can also have aortic aneurysms that require aortic root replacement or lead to aortic rupture in early adulthood. The aortic pathology of these aneurysms is indistinguishable from that of Marfan syndrome. It remains to be seen whether ELN is mutated in persons with thoracic aortic aneurysms and aortic dissections (TAAD) [Urban et al 2005] (see Thoracic Aortic Aneurysms and Aortic Dissections). Inheritance is autosomal dominant.Gerodermia osteodysplastica (GO). Onset occurs in infancy or early childhood (for review, see Nanda et al [2008]). Children appear older than their age because of sagging cheeks and jaw hypoplasia. Skin wrinkling is less severe and is confined to the dorsum of the hands and feet and to the abdomen when in the sitting position. A generalized connective tissue weakness leads to frequent hip dislocation and hernias; however, GO can be distinguished from other types of cutis laxa by the presence of osteopenia/osteoporosis and fractures, most commonly vertebral compression fractures, but also fractures of the long bones. Mental development is in the normal range. In contrast to Debré-type cutis laxa, fontanelle size and closure are normal; positioning of the palpebral fissures is normal; and disease manifestations do not become milder with age. Mutations in GORAB (formerly SCYL1BP1) are causative [Hennies et al 2008]. A GO-like phenotype, but in most cases with intellectual disability, can be caused by mutations in PYCR1 (see below).De Barsy syndrome. Characterized by a progeroid appearance, pre- and postnatal growth retardation, moderate to severe intellectual disability, corneal clouding or cataracts, and generalized cutis laxa [Guerra et al 2004]. The progeroid appearance is not caused by skin sagging, but rather by a hypoplasia of the dermis. Joint hyperlaxity, pseudo-athetoid movements, and hyperreflexia are observed. Inheritance is autosomal recessive. In a number of individuals who received this diagnosis mutations in PYCR1 were identified [Reversade et al 2009] (see following).PYCR1-related cutis laxa (ARCL2B). Mutations in PYCR1 cause a phenotype which shares many similarities with GO, with wrinkly skin syndrome and with De Barsy syndrome. Affected individuals have a common facial gestalt with triangular face, hypomimia, large everted ears and a cutis laxa more pronounced in extremities. About 95% of affected individuals show intellectual disability. Hypoplasia of the corpus callosum is common. The protein is involved in proline biosynthesis in mitochondria [Reversade et al 2009].ALDH18A1-related cutis laxa. A syndrome of IUGR, cataracts, postnatal growth failure and developmental delay with cutis laxa has been described in two pedigrees. Joint hyperlaxity is apparently a common feature. This autosomal recessive syndrome falls within de Barsy syndrome spectrum. It is associated with mutations in ALDH18A1, previously known as P5CS, encoding delta-1-pyrroline-5-carboxylate synthase (P5CS) [Baumgartner et al 2000, Baumgartner et al 2005, Bicknell et al 2008].LTBP4-related cutis laxa. Urban et al [2009] described four patients with cutis laxa, a phenotype resembling pulmonary associated cutis laxa (EFEMP2- and FBLN5-related). A characteristic of this subtype is the severity of associated malformations, including major congenital heart disease, severe pulmonary hypertension, thought to be the consequence of pulmonary arteries stenosis, diaphragmatic hernia and multiple bladder diverticulae with vesicoureteral reflux were causative of life-threatening complications and short life span. The authors observed prolonged survival in a girl who ultimately died of multiple brain abscesses at age 14 years.Telecanthus, epicanthus, and a droopy facial appearance are very similar to that seen in EFEMP2- and FBLN5-related CLLTBP4 encodes a protein which plays a role in assembly of elastin fibres.RIN2-related cutis laxa. Mutations in RIN2 cause MACS syndrome (macrocephaly, alopecia, cutis laxa, scoliosis), displaying a very characteristic facial gestalt [Basel-Vanagaite et al 2009]. Cutis laxa is mild and mostly manifests as redundant skin at the face. Mild intellectual disability is only present in some affected individuals.Table 2. Disorders to Consider in the Differential Diagnosis of Cutis LaxaView in own windowDisease Name Gene SymbolOMIMInheritanceClinical FindingsCutis laxaEmphysemaAneurysmsDevelopmental delayALDH18A1–related cutis laxaALDH18A1 612652AR+--++FBLN5-related cutis laxaFBLN5219100AR ++++++--EFEMP2-related cutis laxaEFEMP2 (FBLN4)219100AR+++++++-ARCL2AATP6V0A2278250 219200AR++--++ADCLELN or FBLN5123700AD+++-GOGORAB231070AR+ +---De Barsy syndrome (PYCR1-related progeroid syndrome)PYCR1219150AR+--+++ARCL2BPYCR1612940AR+-_+++LTBP4-related cutis laxaLTBP4613177AR+++++RIN2-related cutis laxaRIN2613075AR+--+/-
To establish the extent of disease in an individual diagnosed with ATP6V0A2-related cutis laxa, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with ATP6V0A2-related cutis laxa, the following evaluations are recommended:Ortolani sign for detection of hip dislocation. Hip ultrasound examination as needed based on clinical findings.Pelvic x-ray (one time only) to identify hip dysplasia in the event that hip dislocation has not been treated properly.Assessment for inguinal herniasOphthalmologic examination, including refraction (for myopia), slit-lamp examination, fundus examination. Note: Slit-lamp examination allows diagnosis of corneal dysplasia, which was present in one individual. Brain MRI EEG if seizures are suspectedEchocardiogram to look for evidence of floppy valves or more severe valvular dysplasia that can often be observed in a connective tissue disorderTreatment of ManifestationsThe following are appropriate:Repair of inguinal hernia(s)Routine management of hip dislocationRoutine management of refractive errorsAntiepileptic drugs (AEDs): valproate. Because treatment with valproate is often unsuccessful, carbamazepine can serve as a second-line drug and levetiracetam as a third-line drug. Or a combination of AEDs can be used. Psychological help as needed for self-image issuesSurveillancePerform annual ophthalmologic examination, including refraction for evidence of myopia (which can be progressive) and fundus examination to inspect Bruch’s membrane.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. ATP6V0A2-Related Cutis Laxa: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATP6V0A212q24.31V-type proton ATPase 116 kDa subunit a isoform 2ATP6V0A2 homepage - Mendelian genesATP6V0A2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for ATP6V0A2-Related Cutis Laxa (View All in OMIM) View in own window 219200CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIA; ARCL2A 278250WRINKLY SKIN SYNDROME; WSS 611716ATPase, H+ TRANSPORTING, LYSOSOMAL, V0 SUBUNIT A2; ATP6V0A2Molecular Genetic Pathogenesis Independent of the underlying molecular pathophysiology, all types of cutis laxa are characterized by alterations of elastic fibers, not collagen. In ultrastructural investigations elastic fibers are reduced in number and often appear fragmented. The assembly of elastic fibers, a complex mechanism, takes place in the extracellular space. According to the currently accepted model, microfibrillar proteins like the fibrillins first form a lattice with fibulins into which secreted tropoelastin is deposited and further processed [Kielty 2006]. Enzymes necessary for the conversion of tropoelastin into elastin are the lysyl oxidases, which form covalent crosslinks between elastin molecules. Elastic fibers not only increase the elasticity of the extracellular matrix, but also influence its architecture and regulate TGFβ-signaling.A complex mechanism underlies autosomal recessive cutis laxa Debré-type/ARCL2A. In contrast to ARCL1, the loss-of-function mutations do not affect an extracellular matrix protein, but a subunit of a v-type H+-ATPase that resides in endosomes as well as in the Golgi compartment [Hurtado-Lorenzo et al 2006, Pietrement et al 2006]. Proton pumps are universally expressed and allow pH regulation in the extracellular space and in many subcellular compartments [Forgac 2007]. In addition, there are indications that a subunit of the proton pump complex is directly involved in vesicle fusion [Peters et al 2001]. Evidence that suggests that a defect of the secretory pathway is the basis of the elastic fiber defect in ARCL2A is the following: Affected individuals show a glycosylation defect, which can be detected by IEF of serum transferrin [Kornak et al 2008].Cells from affected individuals display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.Normal allelic variants. ATP6V0A2 comprises 20 exons. Only two non-synonymous coding normal variants are found in ATP6V0A2 (see Table 3): rs7969410 (p.Arg685Gln) in exon 16 and rs17883456 (p.Ala813Val) in exon 19. Both have a frequency of approximately 2%.Pathologic allelic variants. ATP6V0A2 mutations are scattered over the entire coding sequence. Of the ten mutations described to date, four are splice-site mutations, three are nonsense mutations, and three are frameshift mutations [Kornak et al 2008]. The most 5’ residue affected is p.Arg63* and the most 3’ mutation is p.Gln765*. Both mutations have been found in several individuals [Author, unpublished observation].Table 3. Selected ATP6V0A2 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference SequencesNormalc.2302G>Ap.Arg685Gln NM_012463.2 NP_036595.2c.2686C>Tp.Alal813Val Pathologicc.187C>Tp.Arg63*c.294+1G>A--c.353_354delTGp.Lys117fs*144c.732-2A>G--c.839delCp.Thr280fs*285c.1324G>Tp.Glu442*c.1929delAp.Thr643fs*683c.2176-2_3delCA--c.2293C>Tp.Gln765*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. ATP6V0A2 encodes the a2 subunit of the v-type H+-ATPase complex. It is a membrane protein with eight to nine transmembrane helices that anchor the complex to the membrane and are directly involved in proton translocation [Marshansky 2007]. The protein resides in the Golgi compartment and in endosomes where it adjusts the luminal pH by transport of protons from the cytosol.Abnormal gene product. Most ATP6V0A2 mutations lead to severe protein truncation that most likely destabilizes the protein, leading to a loss of function [Kornak et al 2008].