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. 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. 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. 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.

De Barsy syndrome (DBS) is an exceedingly rare autosomal recessively inherited genetic disorder that manifests as premature aging with progeroid features. Typically, the skin loses its elasticity, causing laxity, wrinkling, and sagging. Other characteristics include ophthalmological, orthopedic, and neurological abnormalities. As of 2011, only 27 DBS cases had been recorded. This paper reports the case of a two-day-old female infant who was referred to the pediatrics department with complaints of lax skin, a progeroid appearance, a short stature, hazy corneas, and bilateral claw-like hands with thin overlapping fingers. She also had features of pectus excavatum and visible veins over her chest and abdomen. There was a history of third-degree consanguineous parents in this patient. This patient was diagnosed with De Barsy syndrome due to findings on the Verhoeff Van Gieson staining, which demonstrated a marked decrease in elastic tissue fibers. Palliative care was recommended for this infant. We report this case considering its extreme rarity.

This report describes a very rare case of progeroid syndrome of De Barsy (Cutis laxa-corneal clouding syndrome). A 2 year-old child presented to the pediatric ophthalmology outpatients with bilateral congenital corneal opacification along with dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint. The child underwent a detailed ophthalmic work up and systemic evaluation by a clinical geneticist. Ophthalmic management in the form of bilateral sequential penetrating keratoplasties and a left eye trabeculectomy for medically uncontrolled angle-closure glaucoma was performed. Visual rehabilitation with glasses and amblyopia therapy is ongoing. Histopathology of the corneal button revealed loss of the bowman's layer which was replaced by a fibrous pannus while the stroma showed loss of stromal lamellar architecture with anterior and mid stroma showing vascularization. Genetic testing confirmed a mutation in the PYCR1 gene for a homozygous autosomal recessive cutis laxa type IIB. Although rare, De Barsy syndrome is an important cause of corneal opacification at birth with multiple systemic abnormalities that requires intervention.

Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the skin, but may show systemic elastolysis. Mendelian forms are often pleiotropic in nature and classified upon systemic manifestations and mode of inheritance. Though impaired elastogenesis is a common denominator in all Mendelian forms of CL, the underlying gene defects are diverse and affect structural components of the elastic fiber or impair metabolic pathways interfering with cellular trafficking, proline synthesis, or mitochondrial functioning. In this chapter we provide a detailed overview of the clinical and molecular characteristics of the different cutis laxa types and review the latest insights on elastic fiber assembly and homeostasis from both human and animal studies.

De Barsy syndrome is an autosomal recessive condition characterized by an progeroid appearance with distinctive facial features and cutis laxa. Ophthalmological, orthopedic, and neurological anomalies are generally also present. This syndrome is rare and the complex therapeutic management, from a surgical but also rehabilitative point of view, has not been recognized. The aim of this paper is to describe a possible rehabilitative protocol, after an orthopedic surgical treatment, in a child with De Barsy Syndrome. A 6-year-old boy was born with a congenital bilateral hip dysplasia associated with bilateral congenital foot deformity (vertical talus). Moreover, he showed stereotypic dyskinetic movements and psychomotor delay with cognitive impairment and absent language; the sitting position was maintained with orthoses to support the trunk control and the standing position was not acquired. He was treated with pinstripe knee-highs for the foot and double nappy for the hips. At 19 months old, he underwent a two stage surgical approach for a bilateral pronated valgus foot with severe talonavicular subluxation. Satisfactory hip range of motion was achieved by conservative treatment alone. Afterwards, for the foot laxity and the flat-pronated foot corrective shoes were prescribed. The main rehabilitative goals were: attention improvement, visual exploration for foot-eye and hand-eye coordination, encourage the essential prerequisites of language, controlling the upright position using support, improving hip-knee-foot relationship, improving load transfer between the right and left sides of the body, and bimanual coordination. The rehabilitation process lasted six months, three times a week, for a time from 30 minutes to 60 minutes per session. The results were encouraging and the patient acquired the possibility of sitting with the indicated postural system, the possibility of assuming an upright position and taking a few steps with the aid of rollator with a postural stabilization system for the pelvis.