Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: A review of the literature and description of three new cases.

Microphthalmia with brain and digital anomalies (MCOPS6, MIM# 607932) is an autosomal dominant disorder caused by loss-of-function variants or large deletions involving BMP4, which encodes bone morphogenetic protein 4, a member of the TGF-ß protein superfamily. BMP4 has a number of roles in embryonic development including neurogenesis, lens induction, development of cartilage and bone, urogenital development, limb and digit patterning, hair follicle regeneration, as well as tooth formation. In addition to syndromic microphthalmia, BMP4 variants have been implicated in non-syndromic cleft lip with or without cleft palate and congenital healed cleft lip indicating different allelic presentations. MCOPS6 subjects may also lack some of the major phenotypic hallmarks of the disorder, including microphthalmia, indicating variable expressivity. As only a handful of individuals with MCOPS6 have been described, we review the clinical findings in previously reported cases with either deletions or loss-of-function variants in BMP4. We describe three new cases, including two subjects with novel deletions and one subject with a likely pathogenic de novo nonsense variant [c.1052C>G, p.(S351*)] in BMP4. One of the subjects had dual molecular diagnoses including a co-occurring microdeletion at 17q21.31 associated with Koolen de Vries syndrome, which has a partially overlapping disease phenotype. None of these individuals had clinically apparent microphthalmia or anopthalmia, which have been reported in a majority of previously described cases. One subject had exophthalmia and strabismus, while another had bilateral Peters anomaly and sclerocornea, thus expanding the phenotype associated with BMP4 loss-of-function variants.

The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency.

Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA.