Ehlers-Danlos syndrome (EDS) is a congenital disorder affecting connective tissue. Patients diagnosed with EDS may present with joint instability, and in human medicine, an increased risk of cranial cruciate rupture has been described. A few therapeutic options for these patients have been described, with no evident superiority of one technique due to small study groups. Cranial cruciate rupture has never been described in a dog with EDS. This is a case report of an 11-month-old Maltese diagnosed with bilateral cruciate ligament rupture and classical EDS with a previously undescribed heterozygous COL5A1 missense variant that underwent stifle stabilization.

Diaphragmatic rupture is an uncommonly seen complication of classical Ehlers-Danlos syndrome (cEDS). There have been no documented cases of diaphragmatic hernia in newborns having cEDS. This case study discusses a male infant delivered through spontaneous vertex delivery to a mother with cEDS. No evidence of a diaphragmatic hernia was found 6 days before delivery when an ultrasound scan to monitor a ventricular septal defect was carried out. Postnatally, the infant displayed signs of severe respiratory distress. A chest radiograph revealed a diaphragmatic hernia. The surgical team found and corrected a small posterolateral diaphragmatic defect on the third day of life. This resulted in a good recovery following management of a complication of chylothorax. The mother was known to have cEDS and bidirectional sequencing of the patient's lymphocyte DNA detected the heterozygous pathogenic familial variant COL1A1 c.934C > T;p.(Arg312Cys). This variant has been previously reported in cases of cEDS. Other COL1A1 variants are known to be associated with arthrochalasia-type EDS and osteogenesis imperfecta, but no COL1A1 variants have been associated previously with congenital diaphragmatic hernia or diaphragmatic rupture. The familial variant impacts the highly conserved arginine residue in the Gly-X-Y triplet motif of the Type-I collagen protein. It has been reported in various families as a rare cause of autosomal-dominant cEDS. This case report details the patient's journey, including images of radiographs, highlighting a rare but important complication of spontaneous vertex delivery for individuals with cEDS. We also include a literature review on diaphragmatic hernia and rupture in classical EDS.

Ehlers-Danlos syndromes (EDSs) are a group of connective tissue disorders with diverse clinical and genetic profiles. Classical Ehlers-Danlos syndrome (cEDS), the second most common type, is characterised by skin hyperextensibility, atrophic scars and joint hypermobility, primarily due to mutations in COL5A1 and COL5A2 genes. We report a case of an infant with severe cEDS presenting with motor developmental delay, joint hyperextensibility and cranio-cervical instability. Genetic analysis identified a novel heterozygous missense mutation in COL5A1 (c.386G>T) and a non-segregating variant in COL1A2. The child's clinical features were more severe compared with his mother and grandmother, highlighting the variable expression of cEDS. Treatment included vitamin D and iron supplementation, physiotherapy and avoidance of excessive stretching. The child later required surgical intervention for cervical dislocation. This case emphasises the importance of clinical examination of family members and targeted genetic testing along with individualised management for severe cEDS presentations.

Human patients with Ehlers-Danlos syndrome (EDS) are categorized into subtypes based on causative genetic variants and phenotypes. The classical form of EDS, primarily caused by variants in COL5A1 or COL5A2, is a very common subtype in people but is poorly characterized in dogs. Describe likely causal COL5A1 variants in dogs with classical EDS, summarize clinical histories, discuss potential disease mechanisms, and draw conclusions about disease prognosis. Seven client-owned dogs that exhibited clinical signs of classical EDS. Clinical information was recorded from medical records and communication with attending veterinarians and dog owners. To identify potential causal gene sequence variants whole-genome sequence analyses (n = 6) or Sanger sequencing (n = 1) were performed on DNA isolated from the probands. Pathological abnormalities in skin biopsy samples were assessed using histology and electron microscopy in 3 dogs. Six distinct heterozygous COL5A1 sequence variants were identified. The most common clinical signs included fragile skin (n = 7), hyperextensible skin (n = 7), joint hypermobility (n = 6), and atrophic scars (n = 5). The median age at last follow-up or death was 12 years (range, 6.5-14 years). Ultrastructural abnormalities in dermal collagen differed among dogs with different COL5A1 variants. We describe the genotypic and phenotypic spectrum of the classical subtype of EDS by identifying 6 novel COL5A1 variants in conjunction with detailed clinical histories that included long-term follow-up information in 7 dogs.

Patients with classical Ehlers Danlos syndrome (cEDS) suffer impaired wound healing and from scars formed after injuries that are atrophic and difficult to close surgically. Haploinsufficiency in COL5A1 creates systemic morphological and functional alterations in the entire body. We investigated mechanisms that impair wound healing from corneal lacerations (full thickness injuries) in a mouse model of cEDS (Col5a1+/-). We found that collagen V reexpression in this model is upregulated during corneal tissue repair and that wound healing is delayed, impaired, and results in large atrophic corneal scars. We noted that in a matrix with a 50 % content of collagen V, activation of latent Transforming Growth Factor (TGF) β is dysregulated. Corneal myofibroblasts with a haploinsufficiency of collagen V failed to mechanically activate latent TGF β. Second harmonic imaging microscopy showed a disorganized, undulated, and denser collagen matrix in our Col5a1+/- model that suggested alterations in the extracellular matrix structure and function. We hypothesize that a regenerated collagen matrix with only 50 % content of collagen V is not resistant enough mechanically to allow adequate activation of latent TGF β by fibroblasts and myofibroblasts. Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft, velvety, or doughy to the touch. In addition, the skin is hyperextensible, meaning that it extends easily and snaps back after release. The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching, thinning, and pigmentation of scars is characteristic, leading to the presence of atrophic and/or hemosiderotic scars. Easy bruising is also a hallmark of cEDS. GJH is present in most but not all affected individuals, evidenced by the presence of a Beighton score of five or greater, either on examination or historically. Joint instability complications may comprise sprains and dislocations/subluxations. Mild muscle hypotonia with delayed motor development, fatigue and muscle cramps, and some skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus) are regularly observed. While aortic root dilatation and mitral valve prolapse are seen in cEDS, they are rarely clinically significant. Arterial aneurysm and rupture have been reported in a few individuals with cEDS. The diagnosis of cEDS is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in COL1A1, COL5A1, or COL5A2 identified by molecular genetic testing. Treatment of manifestations: Dermal wounds are closed without tension, preferably in two layers. For other wounds, deep stitches are applied generously; cutaneous stitches are left in place twice as long as usual; and the borders of adjacent skin are carefully taped to prevent stretching of the scar. Young children with skin fragility can wear pads or bandages over the forehead, knees, and shins to avoid skin tears. Older children can wear soccer pads or ski stockings with shin padding during activities. Braces as needed to improve joint stability; referral to orthopedist, rheumatologist, or physical therapist and occupational therapist as needed. Mobility devices as needed. Adjust sleep surface as needed to improve sleep quality and decrease pain. Those with hypotonia, joint instability, and chronic pain may need to adapt lifestyles accordingly. Anti-inflammatory drugs may alleviate joint pain. Children with hypotonia and delayed motor development benefit from physiotherapy. Non-weight-bearing exercise promotes muscle strength and coordination. Ascorbic acid (vitamin C) may reduce bruising. DDAVP® (desmopressin) may be useful to normalize bleeding time. Cardiovascular manifestations are treated in a standard manner. Surveillance: Assess for skin fragility, joint instability, occupational and physical therapy needs, mobility issues, and pain at each visit or as needed. Evaluation for hypotonia and motor development at each visit in infants and children. Assess for easy bruising and/or prolonged bleeding at each visit. Evaluation of clotting factors if severe easy bruising is present. Yearly echocardiogram when aortic dilatation and/or mitral valve prolapse are present. Agents/circumstances to avoid: Sports with heavy joint strain. Classic EDS is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with cEDS have an affected parent; approximately 50% of individuals diagnosed with cEDS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with cEDS has a 50% chance of inheriting the pathogenic variant. Once the cEDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.