Mulvihill-Smith Syndrome (MSS) is a clinically complex and genetically unsolved nano-rare disorder with only 12 patients reported in the literature. Most patients (91%) have immunological impairments, succumb to infection, and might develop cancer later in life. Its pathogenesis remains elusive and therapeutic options are limited. We used single-cell MULTI-omics (sc-MULTI-omics), combining transcriptomics (gene expression, TCR, and BCR repertoire) and proteogenomic (Cellular Indexing of Transcriptomes and Epitopes by Sequencing; CITE-seq), to decipher the pathophysiology of nano-rare disease patient. We report a new patient who is a 16-year-old girl. She had an increased leukocyte counts and typical manifestations of MSS such as short stature, older appearance, multiple pigmented nevi, microcephaly, monolateral keratoconus, Marcus-Gunn syndrome, hearing loss, vitamin D deficiency, mild hypercortisolism, and diabetes mellitus with very high insulin resistance (T3DM). sc-MULTI-omics CITE-seq showed that the MSS patient had increased central memory CD4+ T cells as well as effector memory CD8+ T cells, whilst reduced naïve T cells (both CD4+ and CD8+ T cells). Furthermore, we identified genes and pathways associated with the progeria-like phenotype, inflammation, and cancer progression, which may contribute to the clinical signs of MSS. sc-MUTLI-omics CITE-seq analyses improve our understanding of complex human disease pathophysiology and provides an alternative approach in personalized medicine in nano-rare disease.

Mulvihill-Smith syndrome is a rare sporadic condition that was first recognized in 1975. A total of 11 cases have been described in the literature. The aim of this study was to describe the orofacial signs and dental anomalies, their frequency, and the relationship between Mulvihill-Smith syndrome and other progeroid syndromes via a review of the literature. A systematic PubMed search was performed to retrieve articles published between 1975 and the present day that described patients affected by Mulvihill-Smith syndrome. The search identified 14 articles, and data on 11 patients were extracted from the selected articles. A total of 7 patients (63.6%) affected by Mulvihill-Smith syndrome were described as having a typical "bird" face. Dental abnormalities, including irregular shape, enamel defects, hypodontia, and taurodontism, were described in 6 patients (54.5%). All patients (100%) had multiple pigmented nevi on the face and a lack or thinning of subcutaneous tissue around the neck and face. Three patients with Mulvihill-Smith syndrome exhibited early onset of tumors of the gastrointestinal tract, including the tongue. Mulvihill-Smith syndrome is a clinically complex disease that may be caused by a single gene mutation. Numerous different tissues of the body are affected. This analysis of the orofacial signs may help clinicians to diagnose this rare pathology.

Mulvihill-Smith syndrome is a rare progeroid syndrome of sporadic nature. Previously reported ophthalmological findings include astigmatism, myopia, endothelial dystrophy, keratoconus, cataract, band keratopathy, meibomian gland dysfunction, dry eye disease, amblyopia, and allergic conjunctivitis. The proband, a 25-year-old male subject diagnosed with Mulvihill-Smith syndrome in childhood developed retinal changes with onset of adulthood. The retinal changes were monitored for progression with fundus photography, electrodiagnostic tests, and spectral domain optical coherence tomography. The fundus examination revealed grossly normal looking retina with dull foveal reflex. The optical coherence tomography scan of the retina revealed diffuse thickening, schisis, and folding of retinal layers in both eyes. The structural changes in retina were progressive with wrinkling of inner retinal layers and loss of foveal contour as observed over 3 years. The electrodiagnostic tests revealed normal photoreceptor-retinal pigment epithelial interface. This is the first report of retinal features in Mulvihill-Smith syndrome. These ocular changes coincided with other systemic changes with the onset of adulthood. These changes may indicate the natural history of retinal features in this progeria syndrome with short life span. The detailed analysis and progression of structural changes in retina is possible with optical coherence tomography.