Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

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Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

In a prospective, clinical study, the clinical utility of indocyanine green for intraoperative monitoring of free tissue transfer was evaluated. The study comprised 20 surgical patients undergoing elective microsurgical procedures. Indocyanine green angiography was performed intraoperatively, immediately after flap inset, and the operating team was blind to the fluoremetric findings. Thereafter, postoperative monitoring was done exclusively by clinical examination (color, temperature, time for recapillarization, and bleeding after puncture). Final outcome was compared with results of perioperative indocyanine (ICG)-imaging, and classified either as total flap loss, partial flap loss, or successful tissue transplantation. A total of 2 (10%) complications was recorded, and included one partial and one total flap loss. Both complications were detected by intraoperative ICG imaging. Another case of intraoperative subclinical arterial spasm at the place of microvascular anastomosis was revealed by dynamic ICG-videography. This flap did not develop postoperative complications. In conclusion, evaluation of perfusion by ICG imaging is feasible in all kinds of microsurgical flaps, irrespective of the type of tissue. Even though not meeting all the criteria of an ideal monitoring device, significant additional information can be obtained. In this study, cases with arterial spasm, venous congestion, and regional hypoperfusion were revealed by intraoperative ICG-videography. There was a strong correlation between intraoperative findings and clinical outcome.