Wrinkly skin syndrome

The predominant clinical symptoms of wrinkly skin syndrome are wrinkled and inelastic skin over the face, backs of hands/fingers, tops of feet, and abdomen; delayed closure of the fontanelle (baby's soft spot), and increased palmar and plantar creases in the hands and feet, respectively. Fewer elastic fibers are present in the papillary dermis and fragmented elastic fibers in the reticular dermis are observed. Epidermal samples from the same patient subjected to electron microscopy revealed that elastin fibers display abnormally high levels of fragmentation and clumping of microfibrils, with little amorphous elastin. Within collagen bundles, collagen fibrils are of irregular shape and thickness. These disruptions of the connective tissue play a role in the elasticity of the skin and wrinkling. == Mechanism ==

Importance of the ATP6V0A2 pump Vacuolar ATPases (V-ATPase) regulate the pH of the subcellular compartments found within the endosomal membrane system. V-ATPases are multiprotein complexes composed of two functional domains, a V0 domain, and a V1 domain. The V1 domain catalyzes the hydrolysis of ATP to power the pumping of protons through the V0 channel, which spans the lipid bilayer of endosomal compartments. Vacuolar ATPases are also localized within the plasma membrane of both renal cells and osteoclasts. In the Golgi, proteins undergo extensive post-translational modifications (PTMs). In the context of WSS, the most significant PTM events are the glycosylation of proteins comprising the extracellular matrix (ECM) of epidermal cells. The two types of glycosylation events in the Golgi are N-linked glycosylation and O-linked glycosylation. Glycosylation of proteins destined for secretion occurs through the forward movement of proteins throughout the Golgi apparatus. The proteins destined for secretion are then trafficked to the plasma membrane in secretory vesicles. Retrograde (backward) transport in the Golgi apparatus is also important. To retain the enzymes responsible for protein glycosylation in the correct regions of the Golgi, there must be retrograde transport of these enzymes back into the Golgi apparatus. The process of secreting tropoelastin from the cell is dependent on the acidic pH of vesicles. It is thought that increased pH levels (lower acidity) lead to the premature aggregation (coacervation) of tropoelastin inside the vesicle. The process of coacervation is thought to be essential for proper elastin assembly in the ECM. Coacervation must occur outside of the cell within the ECM (the ECM has a more alkaline environment than the vesicle) for proper elastic fiber assembly. However, defective ATP6V0A2 pumps in the vesicle increase the lumenal pH of the vesicle, leading to premature coacervation and defective elastic fiber assembly. The abnormal assembly and glycosylation of proteins used to make elastic fibers explains the connective tissue phenotypes associated with ARCL2 and WSS but does not explain the neurodevelopmental disorders or growth defects of these patients (18). Elastin is not required for brain or bone growth. However, it is believed that abnormal/impaired secretion of the brain and bone-specific ECM proteins caused by dysregulation of Golgi acidification is what leads to the neural and skeletal defects in ARCL2. == Diagnosis ==

Accurate diagnosis of wrinkly skin syndrome generally requires specialized dermatological assessment. In addition to assessment of clinical physical symptoms, diagnosis may be aided by: • X-rays to identify joint abnormalities • ophthalmologic evaluation of hypertelorism, down slanting eyes, and myopia • brain MRI scans to evaluate the degree of microcephaly • genetic screening for congenital disorders of glycosylation (CDG) • skin biopsy and histological analysis • genetic screening for mutations in the ATP6VOA2 gene The pigmentation patterns observed in skin biopsies reveal a characteristic lack of elastic fibers in the papillary dermis and clumping of elastic fibers in the reticular dermis. However, the severity of skin abnormalities and facial dysmorphia is greater in cutis laxa type II. ==Management==

While there is no corrective cure for the disease, some symptoms can be managed therapeutically and/or monitored. Therapeutic treatment options include physical therapy to improve muscular development while patient growth and osteoporosis can be monitored via developmental assessments and bone density scans, respectively. ==Prognosis==

Long-term progression of this disorder varies between patients. Due to therapeutic interventions for developmental symptoms, long-term outcomes are improved by diagnosis of the disorder during childhood. In some cases, dermatological symptoms subside while associated neurological symptoms may worsen with age, including frequency of seizures and mental deterioration. == Epidemiology ==

As of January 2020, only ~ 30 cases of wrinkly skin syndrome have been reported. The majority of reported cases have come from Middle Eastern regions such as Iraq, Saudi Arabia, and Oman. Both males and females of Middle Eastern descent have been reported to be affected. Consanguineous (marriage of first-cousins) relationships are a prevalent feature of parents with children diagnosed with WSS. Such marriages and relationships are more common in Middle Eastern regions. Multiple children of the same parents have also been reported to be affected by WSS. There is currently insufficient epidemiological data to provide frequency of WSS occurrence in other ethnic groups. == History ==

Wrinkly skin syndrome is a very rare disease that was amenable to molecular diagnosis only recently. Consequently, the history of this disease has been minimally documented. However, in 1973, "wrinkly skin syndrome" received its name because of its characterized features of exceedingly wrinkled skin in the hands and feet in a number of related patients. In the same year, WSS was established as a new heritable disorder of connective tissue that appeared to be transmitted as an . In 1993, WSS was diagnosed in a mother and her son. Both patients displayed decreased elastic recoil of the skin and an increase in the number of palmar creases. In 1999, there were up to nine reported cases of WSS. In 2008, Kornak et al. investigated glycosylation of serum proteins with individuals with WSS and found that they had defects in N-glycosylation at the level of the Golgi apparatus. == See also ==