This case report describes a fetus with achondrogenesis type II, a severe and lethal type II collagen disorder, presenting with micrognathia and hydrops. Prenatal evaluation with 2D/3D ultrasound, followed by postmortem imaging and pathological examination, confirmed the diagnosis. Genetic testing revealed a heterozygous COL2A1 mutation (1703G>A; Gly516Ser, exon 24). The significance of this study lies in the identification of a missense mutation in COL2A1 associated with achondrogenesis type II. This report highlights that the condition may present with hydrops and craniofacial anomalies, establishing this variant as a pathogenic mutation associated with the disorder.

The COL2A1 gene encodes the α1 chain of type II collagen, a critical structural component in cartilage and the extracellular matrix. Mutations in this gene are associated with type II collagenopathies, including achondrogenesis type II (ACG2), a severe skeletal dysplasia characterized by perinatal lethality. This study aims to identify and characterize the molecular basis of a COL2A1 mutation in a patient presenting with ACG2 features and to elucidate the pathogenic mechanism of the mutation. A newborn with clinical signs of ACG2 underwent whole-exome sequencing (WES) for genetic analysis. Structural modeling was performed using AlphaFold2 to assess the mutation's impact on the collagen triple-helix. Functional studies were conducted using HEK-293 and C28/I2 cells transfected with wild-type or mutant COL2A1 to evaluate collagen synthesis and secretion via immunoblotting and ELISA. WES identified a heterozygous missense mutation in COL2A1 gene (NM_001844.5: c.1584G>C, p.Glu532Gln). Structural modeling predicted that the mutation disrupted the stability of the triple-helix. Functional assays demonstrated increased synthesis and impaired secretion of type II collagen in cells expressing the mutant COL2A1 gene. The identified COL2A1 mutation (p.Glu532Gln) may lead to disrupted collagen structure and secretion, contributing to the pathogenesis of ACG2. These findings advance the understanding of COL2A1-related disorders and highlight the molecular mechanisms underlying type II collagenopathies. The purpose of this GeneReview is to: 1.. Describe the clinical characteristics of type II collagen disorders; 2.. Provide an evaluation strategy to identify the genetic cause of a type II collagen disorder in a proband; 3.. Review the differential diagnosis of type II collagen disorders with a focus on genetic conditions; 4.. Review management of type II collagen disorders; 5.. Inform genetic counseling of family members of an individual with a type II collagen disorder.

This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe skeletal anomalies, craniofacial deformities, and thoracic abnormalities, suggesting a complex and severe skeletal dysplasia, potentially type IA Achondrogenesis-a lethal autosomal recessive condition marked by ossification delay. This case highlights the significance of advanced genetic testing, such as next-generation sequencing (NGS) and whole-genome sequencing (WGS), in diagnosing and understanding skeletal dysplasias. Skeletal dysplasias represent a group of genetic disorders that affect osteogenesis. The prevalence of this condition is 1 in 4000 births. Sadly, 25% of affected infants are stillborn, and around 30% do not survive the neonatal period. There is a wide range of rare skeletal dysplasias, each with its own specific recurrence risk, dysmorphic expression, and implications for neonatal survival and quality of life. When skeletal dysplasia is incidentally discovered during routine ultrasound screening in a pregnancy not known to be at risk of a specific syndrome, a systematic examination of the limbs, head, thorax, and spine is necessary to reach the correct diagnosis. Prenatal diagnosis of skeletal dysplasia is crucial for providing accurate counselling to future parents and facilitating the proper management of affected pregnancies. An accurate diagnosis can be a real challenge due to the wide spectrum of clinical presentations of skeletal dysplasia but advances in imaging technologies and molecular genetics have improved accuracy. Additionally, some of these skeletal dysplasias may present clinical overlap, making it especially difficult to distinguish. After the 11th revision of genetic skeletal disorder nosology, there are 771 entities associated with 552 gene mutations. The most common types of skeletal dysplasia are thanatophoric dysplasia, osteogenesis imperfect, achondroplasia, achondrogenesis, and asphyxiating thoracic dystrophy.

We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or lethal phenotypes are identifiable in the prenatal period and the pregnancy can be terminated. Perinatal autopsy and posmortem X-rays are crucial in providing a definitive diagnosis. The number of cases confirmed by genetic testing is increasing. We report our own experience with genetic skeletal disorders based on 41 illustrative fetal and neonatal cases which we encountered over a 10-year period. Thanatophoric dysplasia and osteogenesis imperfecta represent approximately half of the cases coming to autopsy. Achondrogenesis type 2 and hypochondrogenesis, short-rib dysplasia, chondrodysplasia punctata, campomelic dysplasia and achondroplasia are less common. Skeletal dysplasias with autosomal recessive inheritance are the least frequent, e.g. perinatally lethal hypophophatasia, achondrogenesis type 1A, diastrophic dysplasia/atelosteogenesis type 2 or mucolipidosis type 2 (I cell disease). Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. Death occurs prenatally or shortly after birth. The diagnosis of ACG1B is established in a proband with characteristic clinical, radiologic, and histopathologic features. Identification of biallelic pathogenic variants in SLC26A2 on molecular genetic testing can confirm the diagnosis. Treatment of manifestations: Palliative care for live-born neonates. ACG1B is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC26A2 pathogenic variants. Once the SLC26A2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.