Bosma arhinia microphthalmia syndrome: Clinical report and review of the literature.

Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males.

Can Anal Cytology Be a Tool in Following Patients Treated for Squamous Cell Carcinoma of the Anus?

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is associated with human papillomavirus infection and preceded by high-grade squamous intraepithelial lesions (HSIL). Following successful treatment, the standard of care is to surveille for local recurrence with both anoscopy and digital rectal examination. While high-resolution anoscopy (HRA) has been shown to identify HSIL during the surveillance period, it requires specialized training and resources.1 The burden of these resources may be reduced by conducting surveillance with anal cytology. We studied 2 questions: (1) Can anal cytology identify HSIL in patients after successful treatment of SCCA? (2) Can HSIL be found with anal cytology after completion of chemoradiation for SCCA? METHODS: Patient charts were queried for diagnosis of SCCA. Patients were excluded if they were not successfully treated for cure or if patients had not been seen in the surveillance period of 5 years following treatment. Descriptive statistics were elucidated. RESULTS: 104 patient charts met inclusion criteria. 81 were surveilled using standard of care, while 23 were followed with standard of care plus anal cytology. 5 patients followed with cytology demonstrated HSIL. 2/5 were found via cytology, 1/5 via HRA, and 2/5 patients via exam under anesthesia and biopsy. DISCUSSION: This study demonstrated that HSIL was identified cytologically in the surveillance period. There may be utility in using anal cytology to identify HSIL in patients during this period in lieu of the specialized resources required for HRA. This may allow dysplasia to be treated with excision and fulguration prior to redevelopment of SCCA.

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

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.