Case Report: Non-ossifying fibromas with pathologic fractures in a patient with NONO-associated X-linked syndromic intellectual developmental disorder

Abstract

The NONO gene encodes a nuclear protein involved in transcriptional regulation, RNA synthesis and DNA repair. Hemizygous loss-of function, de novo or maternally inherited variants in NONO have been associated with an X-linked syndromic intellectual developmental disorder-34 (OMIM # 300967), characterized by developmental delay, intellectual disability, hypotonia, macrocephaly, elongated face, structural abnormalities of corpus callosum and/or cerebellum, congenital heart defect and left ventricular non-compaction cardiomyopathy. Few patients have been described in the literature and the phenotype data are limited. We report a 17-year-old boy with dolihocephaly, elongated face, strabismus, speech and motor delay, intellectual disability, congenital heart defect (ASD, VSD and Ebstein’s anomaly), left ventricular non-compaction cardiomyopathy, bilateral inguinal hernia and cryptorchidism. Additional features included recurrent fractures due to multiple non-ossifying fibromas, thrombocytopenia, and renal anomalies. Exome sequencing revealed a de novo pathogenic variant (NM_001145408.2: c.348+2_ 348+15del) in intron 5 of the NONO gene. Renal anomalies and thrombocytopenia have been rarely reported in patients with NONO—X-linked intellectual disability syndrome, while recurrent fractures due to multiple non-ossifying fibromas have not previously been associated with this syndrome. The phenotypic spectrum of NONO—X-linked intellectual disability syndrome may be broader than currently known.

X-linked intellectual developmental disorder with onset of neonatal heart failure: A case report and literature review

“…The PubMed, Embase, HGMD, Chinese National Knowledge Infrastructure, and WanFang databases were searched from inception to August 2023 using the following keywords: “X-linked intellectual developmental disorder”, “ NONO gene”, “congenital heart disease” or “X-linked”, “Intellectual development disorder”, and “congenital heart disease”. This resulted in the extraction of 12 articles written in English, reporting 22 cases of MRXS34 caused by pathogenic variants in the NONO gene [ [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] ]. Thus, including the present case, 23 cases were reviewed ( Table 1 ).…”

“…All patients were male. The age at diagnosis ranged from infant to adult, with two patients diagnosed at birth, most in infancy, and the latest diagnosis was at 29 years old [ 8 ].Two patients of severe ventricular dysfunction at 78 days [ 8 ] and 3 months respectively [ 12 ], while one died of unknown causes at the age of 17 [ 11 ]. The remainders are alive.…”

“…Macrocephaly is a cardinal feature and becomes more prominent with age. In addition, several reported patients showed developmental malformations of the urinary system, thrombocytopenia, non-ossifying fibroma, and other symptoms, suggesting that the phenotypic spectrum of X-linked intellectual disability syndromes may be wider than currently recognized [ 11 ]. Affected children showed feeding difficulties and reflux during their first few years and thus their growth should be carefully monitored.…”

Established and Evolving Roles of the Multifunctional Non-POU Domain-Containing Octamer-Binding Protein (NonO) and Splicing Factor Proline- and Glutamine-Rich (SFPQ)

“…The top line shows, to scale, the coding (yellow) and noncoding (blue) exons of NONO located at Xq13.1.The numerals a-p denote the positions of pathologic point and/or deletion mutations within coding regions; q denotes the deletion of exons 1-3, which includes part of the 5 ′ noncoding region. Details of the various mutations and their clinical ramifications are provided in references[52,53,[92][93][94][95].…”