SMCHD1 mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier.

Arhinia, or congenital absence of the nose, is an exceedingly rare anomaly caused by pathogenic variants in the gene SMCHD1. Arhinia exhibits unique reconstructive challenges, as the midface is deficient in skeletal and soft tissue structures. The authors present 2 related patients with arhinia who harbor a novel SMCHD1 gene variant and illustrate their surgical midface and nasal construction. Targeted sequencing was carried out on DNA samples from the 2 affected patients, 1 anosmic and 1 healthy parent, to identify variants in exons 3 to 13 of SMCHD1. The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V. A staged surgical approach was applied. First, both patients underwent a LeFort II osteotomy and distraction osteogenesis to improve the projection of the midfacial segment, followed by tissue expansion of the forehead, and nasal construction with a forehead flap that was placed over a costochondral framework derived from rib cartilage. The novel gene variant could guide future investigations on genetic pathways and molecular processes that underly the physiological and pathologic development of the nose. Further investigations on the variable expressivity ranging from anosmia to arhinia could improve clinical genetic screens for risk stratification of individuals with anosmia on passing on arhinia to their children. Due to the exceptional rarity and complexity of congenital arhinia, most surgical approaches are developed on a single-case basis. This case series, albeit limited to 2 cases, is the largest pedigree of such cases in the literature. It highlights key principles of a staged approach to nasal construction in arhinia and discusses nuances and improvements learned between both patients. It subsequently offers an optimized guide to this surgical strategy.