Pathologic Lower Extremity Fractures in Children With Alagille Syndrome

Abstract

Objectives In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, one of the leading inherited causes of pediatric cholestatic liver disease. Methods Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance or The Children’s Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to one question, and details characterizing each patient’s medical, growth, and fracture history were obtained through chart review and telephone contact. Results Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures/10,000 person years (95% CI = 206.5, 698.0) and 127.6 femur fractures/10,000 person-years (95% CI = 42.4, 297.7). There were no differences in gender, age distribution or organ system involvement between the fracture and no-fracture groups. Conclusions Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. While this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and to explore factors contributing to bone fragility in these children.

Mutations in NOTCH2 in families with Hajdu-Cheney syndrome

“…ALGS can include skeletal defects, typically butterfly vertebrae, and mineralization defects and while shortened phalanges have been reported, these are not caused by acro-osteolysis as they are in HCS. An increase in lower limb fractures in ALGS patients has been noted, consistent with the hallmark bone weakening observed in HCS [Bales et al, 2010]. It seems likely that the very different presentations of NOTCH2 mutations in HCS versus ALGS are allele-specific and reflect different effects on protein function.…”

NOTCH signaling in skeletal progenitors is critical for fracture repair

“…Management of these pathological lower extremity fractures in Alagille syndrome patients can sometimes be challenging, with reports of recurrent fractures in some patients and poor healing outcomes and/ or postfracture deformities in others (50,51). Therefore, it may be important to assess BMSC status and CFU-F frequency in the BM of Alagille patients with complicated fracture repair scenarios and to consider BMSC or BM aspirate treatments to repair and unification and may also provide the basis for developing cell-and/or molecular-based therapeutics aimed at challenging skeletal repair and nonunion scenarios.…”

“…It is of note that children with Alagille syndrome caused by JAG1 or NOTCH2 mutations have an especially high risk of lower extremity fractures, originally thought to be due to altered bone development and metabolism brought on by improper calcium, vitamin, and mineral regulation and/or altered osteoblast differentiation or function (50). Management of these pathological lower extremity fractures in Alagille syndrome patients can sometimes be challenging, with reports of recurrent fractures in some patients and poor healing outcomes and/ or postfracture deformities in others (50,51).…”

The developmental biology of genetic Notch disorders

“…This imbalance leads to spine defects and the formation of butterfly vertebrae, a characteristic feature of Alagille syndrome (Emerick et al, 1999;Youngstrom et al, 2016). Furthermore, both clinical and genome-wide association studies indicate a positive correlation between mutations in JAG1 and decreased bone mineral density and osteoporotic fractures (Bales et al, 2010;Kung et al, 2010). The formation of craniofacial bone, which arises from intramembranous ossification of neural crest (NC)-derived mesenchyme, also requires Jag1: its deletion in NC cells disrupts mesenchymal differentiation and leads to abrogated mineralization and deformities of the craniofacial skeleton + stalk cells proliferate to form the vessel trunk.…”