Discussion 

The discovery of the first gene responsible for recessive osteogenesis imperfecta in 2006 transformed the understanding of collagen‑related bone dysplasias. Although most cases of osteogenesis imperfecta result from dominant mutations in COL1A1 and COL1A2, the identification of additional genes involved in collagen modification, folding, and trafficking expanded the spectrum of recessive forms [1]. As these genetic subtypes accumulated, Sillence’s 1979 clinical phenotypic classification [2] evolved into a functional genetic classification that groups osteogenesis imperfecta according to the disrupted intracellular or extracellular metabolic pathway [3]:

• Group A: primary defects in collagen structure or processing
• Group B: defects in collagen post‑translational modification
• Group C: abnormalities in collagen folding and cross‑linking
• Group D: defects in ossification or mineralisation
• Group E: impaired osteoblast development leading to collagen insufficiency.

Within group C, Bruck syndrome represents a distinct entity characterized by congenital joint contractures and bone fragility, arising from defects in proteins essential for collagen cross‑linking and extracellular matrix stability.

In 1989, Viljoen et al. [4] described five children with congenital, symmetrical contractures of the knees, ankles, and feet, as well as the presence of Wormian bones and fractures resulting from minimal trauma. Because the contractures were evident at birth, all children were initially diagnosed with congenital arthrogryposis, a diagnosis that was later reconsidered once they began to walk and fractures appeared. Given the striking similarity to the case reported by Bruck in a German medical journal in 1897 [5], the authors proposed the term Bruck syndrome to designate this disorder. However, according to Ha‑Vinh et al. [6], the eponym is historically inaccurate, since Bruck’s original patient had osteogenesis imperfecta and developed joint contractures only later in life rather than congenitally.

The incidence of Bruck syndrome remains unknown. Fewer than 50 to 60 cases have been reported worldwide, supporting a prevalence well below 1 per 1,000,000 [7,8]. The disorder is genetically heterogeneous and results from biallelic pathogenic variants in FKBP10 or PLOD2, both of which encode proteins essential for the post‑translational maturation of type I collagen. Bruck syndrome type 1 (OMIM #259450) is caused by pathogenic variants in FKBP10, located on chromosome 17q21. This gene encodes FKBP65, a component of an endoplasmic reticulum chaperone complex that is crucial for the correct folding and stabilization of type I procollagen [9-11]. In contrast, Bruck syndrome type 2 (OMIM #609220) results from pathogenic variants in PLOD2 (chromosome 3q24), which encodes lysyl hydroxylase 2 (LH2). LH2 catalyzes the hydroxylation of lysine residues in the telopeptides of type I collagen, a modification required for the formation of intermolecular crosslinks and the mechanical stabilization of collagen fibrils [6,12-16]. Schwarze et al. [17] have reported that FKBP65 deficiency in patients with FKBP10 mutations in part leads to impaired LH2‑mediated hydroxylation of lysines in type I collagen telopeptides, which helps explain the phenotypic overlap between Bruck I (FKBP10) and Bruck II (PLOD2).

Postnatally, Bruck syndrome is characterized by bone fragility with recurrent fractures, particularly of the ribs and long tubular bones, often beginning in infancy or early childhood. Affected individuals typically present with multiple joint contractures and cutaneous pterygia. The contractures are congenital and associated with pterygia while the fractures are often of postnatal onset. Therefore, the contractures must be considered as a primary abnormality and not a complication of the fractures or the resulting immobilization [18]. Most patients have normal cognitive development and normal birth length, although some exhibit vertebral abnormalities such as platyspondyly, which may lead to short stature, disproportionate growth, and progressive spinal deformities [19,20]. Many reported patients also present with Wormian bones and congenital talipes, whereas blue sclerae are observed in only a minority of cases (approximately 25%). Camptodactyly and progressive scoliosis are common. There is marked inter‑ and intrafamilial variability, and the clinical phenotype alone does not reliably distinguish between Bruck syndrome types 1 and 2 [15, 21].

Prenatally, the condition has been diagnosed in a small number of cases [18,22-26]. It may present with severe micromelia, bowing or angulation of the long bones, fractures, reduced mineralization, and multiple joint contractures. Additional findings may include hypo-ossification of the calvarium, micrognathia and limb anomalies (clubbed feet). Thoracic hypoplasia and pulmonary insufficiency contribute to the poor prognosis in severe cases. Occasionally, abnormalities of the cardiac valvular structures have been reported in a fetus with Bruck syndrome, which underscores the need for ongoing echocardiographic evaluation throughout pregnancy in these patients [26]. In our case, the combination of severe micromelia, femoral bowing, fixed flexion contractures of the elbows and knees, and mild hypo-ossification of the calvarium raised suspicion for a lethal skeletal dysplasia within the osteogenesis imperfecta spectrum. Molecular testing confirmed a homozygous pathogenic PLOD2 variant, establishing the diagnosis of Bruck syndrome type 2. The recurrence of identical findings in two consecutive pregnancies, a pattern reported in several published cases, is consistent with autosomal recessive inheritance, conferring a 25% recurrence risk.

When both bone fragility and congenital joint contractures are identified prenatally, the differential diagnosis must first consider disorders that present these findings separately. Arthrogryposis is a key distinguishing feature that helps differentiate Bruck syndrome from classic forms of osteogenesis imperfecta as true congenital contractures are not characteristic of osteogenesis imperfecta. Although severe arthrogryposis multiplex congenita may lead to secondary skeletal remodeling, bone fragility, fractures, and generalized undermineralization are not expected. Campomelic dysplasia may show long‑bone bowing and limb positional abnormalities, but fractures and generalized osteopenia are uncommon, and contractures are usually less pronounced. Additional features such as characteristic facial morphology, hypoplastic scapulae, and possible sex reversal assist in differentiation between Campomelic dysplasia and Bruck syndrome [15]. Other rare bent bone dysplasias (e.g., Stüve‑Wiedemann syndrome, kyphomelic dysplasia) may present with limb bowing or contractures, but they typically lack the combination of multiple fractures, undermineralization, and generalized bone fragility that defines Bruck syndrome.

This case highlights the importance of early first and second trimester recognition of skeletal shortening combined with arthrogryposis, which should prompt targeted genetic testing and counselling. Early diagnosis enables informed parental decision-making, including the possibility of legal termination of pregnancy, and allows considerations of options such as early invasive testing or preimplantation genetic testing in future pregnancies.

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