Ehlers-Danlos syndrome is a rare, heritable connective tissue disorder characterized by soft, hyperextensible skin, joint hypermobility, and tissue fragility, the severity of which can range from mild to severe. A 9-month-old male entire miniature Dachshund was presented following peracute tetraparesis. Neurological examination was suggestive of intracranial vestibular disease or high cervical myelopathy. MRI revealed atlantoaxial instability and subluxation, resulting in marked spinal cord compression at C1-C2, which was surgically stabilized. On discharge from the hospital, skin fragility was noted as the result of skin tearing during tape removal. A piece of full-thickness antebrachial skin was submitted for histopathology which showed changes consistent with Ehlers-Danlos syndrome. This case report describes the first case of atlantoaxial instability and subluxation in a dog as the result of a confirmed underlying collagenopathy.

UNASSIGNED: Pediatric rhegmatogenous retinal detachments, especially those presenting at birth or soon afterward, have a high likelihood of syndromic associations that can be confirmed by genetic testing.
UNASSIGNED: A 5-month-old child was found to have high myopia in the right eye (RE) with highly tessellated fundus, opalescent vitreous, and peripheral thinning. Left eye had a shallow retinal detachment for which he underwent belt buckling. The baby had an occipital skin tag. A provisional diagnosis of Stickler syndrome was made.
UNASSIGNED: On 1-month follow-up, left eye retina was attached and 360° laser barrage was done. Fluorescein angiography was done which revealed peripheral avascular retina in both eyes. MRI and genetic testing were suggestive of syndromic association. Genetic testing revealed pathogenic mutation in COL 18A1 suggestive of Knobloch syndrome in the baby, and both parents were found to be carriers of the same mutation. However, brain MRI showed features not pathognomonic of Knobloch syndrome.
UNASSIGNED: Although Knobloch syndrome is associated with vitreoretinal degeneration and high risk of retinal detachment, there seems to be no recommendation for prophylaxis in the other eye and therefore we preferred to observe the RE closely. A unique feature noted in our case was the peripheral avascular zone (PAZ). The PAZ could be contributed by multiple factors such as high myopia, or due to endostatin deficiency (which is a derivative of collagen XVIII) or an underlying WNT signalling abnormality.

An inflammatory collagenopathy of infancy characterized by subperiosteal bone hyperplasia is known as infantile cortical hyperostosis (ICH) or Caffey disease. A 10-day male infant presented to the hospital with leg swelling, excessive crying, and irritability since birth. He was born with the swallowed part of his tibia bone. The X-ray suggested hyperostosis of the bilateral tibia bone involving the anterior cortex, which is more prominent on the right side. The infant was clinically monitored and treated and discharged after the swelling was reduced. Again, he was admitted to the hospital at 10 weeks of life, and a similar thickening appeared on his left tibia. He was administered analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) and discharged under a follow-up schedule. The infant was monitored in the pediatric ward for the next seven days. The swelling and pain completely subsided one and a half weeks after hospitalization, and continued follow-up was suggested until the complete correction of the disease on an outpatient basis. This disease must be recognized and understood, and the clinical-radiological correlation is significant.

BACKGROUND: Stickler syndrome (SS) is a connective tissue disorder of fibrillary collagen with very variable clinical manifestations, including premature osteoarthritis and osteopenia. This musculoskeletal alteration may affect gait maturity or produce strength difficulties.
OBJECTIVE: Our aim was to describe the musculoskeletal characteristics, bone stiffness, gait kinematics, and kinetics of SS patients.
METHODS: This is a cross-sectional study of children and youngsters with SS recruited by telephone calls through the Spanish SS Association. All participants underwent an analysis of musculoskeletal characteristics, including a 3D gait analysis.
RESULTS: The sample included 26 SS patients, mainly boys (65.4%) with a median age of 11 (IQR 5-14). The manual muscle testing was normal in 88.5% of patients. The median distance covered in the 6-min walking test was 560.1 ± 113.4 m. Bone stiffness index scores were 70.9 ± 19.7 for children under 10 years and 88.3 ± 17.5 for children older than 10 years. The gait indicators GPS and GDI were: 7.4 ± 1.9 and 95.3 ± 9.7, respectively, for the left side and 6.8 ± 2.0 and 97.7 ± 9.5 for the right side, respectively.
CONCLUSIONS: In our series of patients with SS, we found muscle-articular involvement does not have a high impact on strength or gait problems. More work is needed to understand the effect of SS on the musculoskeletal system.

Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants in the COL6A2 gene (NM_001849.3) in a heterozygous state each in both cases: c.508_535delinsCTGTGG and c.1659_1660del (case 1) and c.1689del and c.1659_1660del (case 2). In two cases, the same nucleotide variant in the COL6A2 gene (c.1659_1660del) was observed. We have suggested that the variant c.1659_1660del may be common in the Ossetian-Digor population because two analyzed families have the same ancestry from the same subethnic group of Ossetians). The screening for an asymptomatic carriage of the nucleotide variant c.1659_1660del in 54 healthy donors from Ossetian-Digor population revealed that the estimated carrier frequency is 0.0093 (CI: 0.0002-0.0505), which is high for healthy carriers of the pathogenic variant. Molecular genetic, anamnestic data and clinical examination results allowed us to diagnose Ullrich muscular dystrophy in those affected boys. Genetic heterogeneity and phenotypic diversity of muscular dystrophies complicate diagnosis. It is important to make a differential diagnosis of such conditions and use HTS methods to determine the most accurate diagnosis.

Knobloch syndrome is a rare collagenopathy characterized by severe early onset myopia, retinal detachment, and occipital encephalocele with various additional manifestations due to biallelic changes in the COL18A1 gene. Here we reported a Chinese family with two affected siblings presented with antenatal occipital encephalocele, infantile onset retinal detachment, and pronounced high myopia at early childhood. Quartet whole exome sequencing was performed in this family and identified that both siblings carried novel compound heterozygous variants in the COL18A1 gene (NM_001379500.1): the maternally inherited variant c.1222-1G>A at the consensus acceptor splice site of intron 8, and the paternally inherited frameshift variant c.3931_3932delinsT p.(Gly1311Serfs*25) in the last exon. Both patients had successful surgical treatment for the occipital encephalocele soon after birth. They had normal neurocognitive outcome and good general conditions examined at the age of 7 years old for the elder sister and 4 years old for the younger brother. The younger brother developed infantile onset retinal detachment at 7 months of age while the sister had high myopia without signs of retinal detachment until 7 years old. This report expands the phenotype and genotype spectrum of Knobloch syndrome with antenatal and postnatal findings.

We report a newborn born to a consanguineous couple with antenatally detected dilatation of third ventricle, unilateral talipes, and intra uterine growth retardation. On examination, there was facial dysmorphism, hypotonia, encephalopathy, joint laxity and muscle hypertrophy in addition to left foot talipes. On evaluation, there were renal cortical cysts, rhizomelia, chondrodysplasia punctata and elevated muscle enzymes, along with a dilated third ventricle. As the phenotype was not consistent with any of the muscular dystrophies or the peroxisomal disorders, an exome sequencing was requested. It revealed a combination of Zellweger syndrome and Ullrich congenital muscular dystrophy type 1.

TANGO1 (transport and Golgi organization-1 homolog) encodes a transmembrane protein, which is located at endoplasmic reticulum (ER) exit sites where it binds bulky cargo, such as collagens, in the lumen and recruits membranes from the ER-Golgi intermediate compartment (ERGIC) to create an export route for cargo secretion. Mice lacking Mia3 (murine TANGO1 orthologue) show defective secretion of numerous procollagens and lead to neonatal lethality due to insufficient bone mineralization. Recently, aberrant expression of truncated TANGO1 in humans has been shown to cause a mild-to-moderate severe collagenopathy associated with dentinogenesis imperfecta, short stature, skeletal abnormalities, diabetes mellitus, and mild intellectual disability. We now show for the first time that complete loss of TANGO1 results in human embryonic lethality with near-total bone loss and phenocopies the situation of Mia3 -/- mice. Whole-exome sequencing on genomic DNA (gDNA) of an aborted fetus of Indian descent revealed a homozygous 4-base pair (4-bp) deletion in TANGO1 that is heterozygously present in both healthy parents. Parental fibroblast studies showed decreased TANGO1 mRNA expression and protein levels. Type I collagen secretion and extracellular matrix organization were normal, supporting a threshold model for clinical phenotype development. As such, our report broadens the phenotypic and mutational spectrum of TANGO1-related collagenopathies, and underscores the crucial role of TANGO1 for normal bone development, of which deficiency results in a severe-to-lethal form of osteochondrodysplasia. © 2021 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Osteogenesis imperfecta (OI) type II is a genetic connective tissue disorder characterized by bone fragility, severe skeletal deformities and shortened limbs. OI usually causes perinatal death of affected individuals. OI type II diagnosis in humans is established by the identification of heterozygous mutations in genes coding for collagens. The purpose of this study was to characterize the pathological phenotype of an OI type II-affected neonatal Holstein calf and to identify the causative genetic variant by whole-genome sequencing (WGS). The calf had acute as well as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis. Genetic analysis revealed a private heterozygous missense variant in COL1A1 (c.3917T>A) located in the fibrillar collagen NC1 domain (p.Val1306Glu) that most likely occurred de novo. This confirmed the diagnosis of OI type II and represents the first report of a pathogenic variant in the fibrillar collagen NC domain of COL1A1 associated to OI type II in domestic animals. Furthermore, this study highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for rare lethal genetic disorders in cattle.

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous collagenopathy characterized by ophthalmic, auditory, skeletal, and orofacial abnormalities. STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare. However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3.
Genetic analysis was performed using the next-generation sequencing of 166 genes associated with skeletal disorders and sequenced on an Ion Torrent S5 system with a minimum coverage of 100X. The two variants in the COL9A3 gene identified in the proband and the parents were confirmed by Sanger sequencing on an ABI3130xl sequencer.
We describe a novel case of autosomal recessive Stickler syndrome caused by two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter). The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs. Radiography revealed mild spondyloepiphyseal dysplasia.
This case further expands the mutational and phenotypic spectrum of COL9A-associated STL with a more severe presentation.