Cutis laxa type 2A

Overview

Cutis laxa type 2A is a rare, inherited condition that affects the body's connective tissues. Connective tissues provide structure and support to many parts of the body, including the skin, joints, blood vessels, and internal organs. In individuals with cutis laxa type 2A, the connective tissue is less elastic and more fragile than usual. This leads to the characteristic loose, sagging, and wrinkled skin that gives the condition its name, which means 'loose skin' [PMID:24637152].

Beyond the skin, cutis laxa type 2A can also affect the skeletal system, leading to developmental delays, and sometimes impact other organ systems. The severity of the condition can vary significantly among affected individuals. It is one of several forms of cutis laxa, distinguished by its specific genetic cause and pattern of inheritance.

Symptoms & clinical features

The most notable feature of cutis laxa type 2A is the appearance of loose, inelastic skin, often giving an aged look, particularly on the face, neck, and trunk [PMID:30130985]. This skin laxity may be noticeable from birth or develop in early infancy. Individuals may also experience joint hypermobility, where joints extend beyond their normal range of motion, or joint contractures, where joints become stiff and have limited movement.

Other typical features include developmental delays, which can affect motor skills, speech, and intellectual development. Skeletal abnormalities are common, such as abnormal curvature of the spine (scoliosis) and bone fragility. Some individuals may have unique facial features [PMID:25287515]. Less commonly, issues affecting the heart, lungs, or digestive system may occur, though these are typically more prominent in other forms of cutis laxa.

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Affected organs

Cutis laxa type 2A primarily affects organs rich in connective tissue. The skin is prominently affected, displaying laxity and reduced elasticity. The skeletal system is also significantly involved, leading to abnormalities in bone structure and joint movement. The brain might be impacted, contributing to developmental delays and intellectual disability. Connective tissue in other organs like the eyes and gastrointestinal tract can also be affected, though severe complications in these systems are less typical for type 2A compared to other cutis laxa types.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Cutis laxa type 2A can present with a wide spectrum of severity, from relatively mild to more severe forms impacting multiple body systems. The primary risks relate to the laxity of connective tissue, which can lead to complications such as hernias, eye problems, and, less frequently, issues with blood vessel integrity or organ function. Developmental delays are a common concern, and the degree can vary.

The overall prognosis depends on the specific constellation of symptoms and their severity. While some individuals may lead relatively independent lives with supportive care, others might require more extensive medical management. The exact prevalence of cutis laxa type 2A is not well established, but it is considered a very rare condition.

Genetic causes

Cutis laxa type 2A is caused by pathogenic variants in the ATP6V0A2 gene. This gene provides instructions for making a protein that is a crucial component of an enzyme called V-ATPase. V-ATPases are proton pumps located in the membranes of cellular compartments, such as lysosomes and the Golgi apparatus. These pumps are essential for maintaining the correct acidity (pH) within these compartments.

The ATP6V0A2 protein plays a vital role in processes that modify other proteins, particularly a process called glycosylation. Glycosylation is the attachment of sugar molecules to proteins and lipids, which is critical for their proper function and structure, especially in connective tissues. When the ATP6V0A2 gene has pathogenic variants, the V-ATPase cannot function correctly, disrupting the pH balance in cellular compartments. This, in turn, impairs glycosylation pathways, leading to the production of abnormal or improperly structured connective tissue components, resulting in the signs and symptoms of cutis laxa type 2A [PMID:25287515].

• ATP6V0A2
  ATPase H+ transporting V0 subunit a2
  The ATP6V0A2 gene provides instructions for a component of a vital enzyme complex, the vacuolar H+-ATPase (V-ATPase), which is crucial for cellular pH regulation and protein modification.

Inheritance pattern

Cutis laxa type 2A follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the pathogenic gene variant - one from each parent - to develop the condition. People who have only one copy of the pathogenic variant are called carriers; they typically do not show symptoms of the condition themselves but can pass the variant on to their children.

If both parents are carriers, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two pathogenic variants and therefore develop cutis laxa type 2A. There is a 50% (1 in 2) chance that their child will be a carrier like them, and a 25% chance that their child will inherit two typical copies of the gene and not be affected or a carrier.

Diagnosis & testing

Diagnosing cutis laxa type 2A typically begins with a clinical evaluation based on the characteristic physical features, particularly the loose skin, developmental delays, and skeletal anomalies. Due to its rarity and variable presentation, a definitive diagnosis often requires genetic testing. The NHS Genomic Medicine Service (GMS) offers genomic testing for rare conditions like cutis laxa type 2A.

A referral to a clinical genetics service is usually made by a GP or paediatrician when cutis laxa is suspected. Genetic testing involves analysing a blood or saliva sample to identify pathogenic variants in the ATP6V0A2 gene. This testing is covered by the NHS and falls under specific R-codes for rare disease diagnosis. A confirmed genetic diagnosis can help clarify the specific type of cutis laxa and guide management strategies.

Management & lifestyle

There is currently no cure for cutis laxa type 2A, so management focuses on addressing specific symptoms and improving quality of life. Management is typically multidisciplinary, involving various specialists such as paediatricians, dermatologists, orthopaedic surgeons, neurologists, and physiotherapists.

Physical therapy and occupational therapy can help address developmental delays and improve motor skills. Orthopaedic interventions may be needed for skeletal issues or joint problems. Skin care focuses on protecting fragile skin and, in some cases, reconstructive surgery might be considered for severe skin laxity. Regular monitoring for potential complications involving internal organs may also be part of the care plan. The overall approach is tailored to the individual's specific needs, aiming to minimise complications and support development.

UK care pathway

In the UK, suspected cases of cutis laxa type 2A would typically be referred by a general practitioner or specialist to a regional clinical genetics service within the NHS Genomic Medicine Service (GMS). Genetic counsellors, as part of the clinical genetics team, play a vital role in discussing the implications of genetic testing, explaining inheritance patterns, and providing support. Genomic testing for individuals with suspected cutis laxa and related conditions is available via the NHS GMS, often covered by specific PanelApp R-codes for rare disease diagnoses.

Related conditions

Other forms of cutis laxa exist, such as cutis laxa type 1 (autosomal dominant or recessive) and cutis laxa type 3, which involve different genes and can have varying clinical features, sometimes with more severe systemic involvement. Ehlers-Danlos syndromes are another group of connective tissue disorders that can present with joint hypermobility and skin fragility, leading to some overlap in symptoms. However, the specific pattern of skin laxity and systemic involvement, along with genetic testing results, helps to differentiate cutis laxa type 2A from these conditions.

Frequently asked questions

References

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2. Morlino S, Nardella G, Castellana S. Review of clinical and molecular variability in autosomal recessive cutis laxa 2A. American journal of medical genetics. Part A. 2021. PMID: 33369135
3. Cohen R, Halevy A, Aharoni S. Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A. Neurogenetics. 2016. PMID: 27631729
4. Abdullah M, Alabduljalil T. NOVEL RETINAL FINDINGS IN A PATIENT WITH AUTOSOMAL RECESSIVE CUTIS LAXA TYPE 2A. Retinal cases & brief reports. 2024. PMID: 36728588
5. Zaman Q, Iftikhar A, Rehman G. Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families. The journal of gene medicine. 2023. PMID: 37119015
6. Greally MT, Kalis NN, Agab W. Autosomal recessive cutis laxa type 2A (ARCL2A) mimicking Ehlers-Danlos syndrome by its dermatological manifestations: report of three affected patients. American journal of medical genetics. Part A. 2014. PMID: 24478233
7. Shafagh Shishavan N, Morovvati S. A novel deletion mutation in the ATP6V0A2 gene in an Iranian patient affected by autosomal recessive cutis laxa. Irish journal of medical science. 2023. PMID: 36520350