Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

Abstract

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.

Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

“…Although the precise incidence of infantile hemangiomas remains unknown, a reasonable estimate is that they occur in 4-5% of infants [12,13]. us, even with the addition of the two cases reported here to the two found among 95 cases of OFCD drawn from 66 families, the prevalence of OFCD would not exceed statistical expectations (4/97 � 4.12%) [4]. However, infants do not usually get the type of infantile hemangiomas described in these cases, i.e., large (>5 cm) forehead/scalp hemangiomas.…”

“…Infantile hemangiomas have not been labeled as a key characteristic of OFCD or other BCOR-related disorders. Along with two previously published cases, we report two new cases of infantile hemangioma in OFCD [4]. e precise characteristics of infantile hemangiomas including location and size are important to note, but such features may be poorly recalled as a "birth mark that went away" if the child is evaluated later in life.…”

“…Currently, the molecular basis of PHACE syndrome is unknown but is suspected to involve somatic mosaic mutation, a phenomenon that has been described in mothers of affected daughters with OFCD [19]. Given that infantile hemangioma is a benign neoplasm that exceedingly rarely transforms to angiosarcoma, along with the recognition that BCOR functions as a tumor suppressor gene implicated in sarcomas as well as some hematologic malignancies (with one reported case of T-cell lymphoma reported in a male with Lenz microphthalmia [4]), systematic investigation of BCOR and PHACE patients may provide important insights into human development and tumorigenesis [20]. BCOR copy number reductions and focal deletions have been reported rarely in retinoblastomas, especially occurring later in childhood [21,22].…”

“…A recently reported case series noted the presence of hemangiomas in two affected individuals [4]. One was a female with OFCD due to monoallelic BCOR frameshift mutation.…”

MRI ofCapn15knockout mice and analysis of Capn 15 distribution reveal possible roles in brain development and plasticity

“…All statistical analyses were corrected for multiple comparisons, utilizing the false discovery rate technique (52) with a 5% threshold. Whole Exome Sequencing Fifty-six individuals from 55 families within the cohort were screened by whole exome sequencing (WES) as described previously (53,54)…”