Homozygous mutation in ELMO2 may cause Ramon syndrome

Abstract

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made. Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

“…Ramon syndrome is an extremely rare condition with six unrelated families reported so far (de Pina‐Neto et al, 1998; Mehawej et al, 2018; Pina‐Neto et al, 1986; Pridmore, Baraitser, & Leonard, 1992; Ramon et al, 1967; Suhanya, Aggarwal, Mohideen, Jayachandran, & Ponniah, 2010). Subject 3 had clinical features overlapping those of individuals with Ramon syndrome, such as intellectual disability, seizures, gingival overgrowth, cherubism, and left optic disc pallor (Mehawej et al, 2018; Parkin & Law, 2001; Pina‐Neto et al, 1986; Pridmore et al, 1992; Ramon et al, 1967; Suhanya et al, 2010). Subjects 1 and 2 also presented with the typical clinical triad of intellectual disability, seizures, and gingival overgrowth, although a possible diagnosis of cherubism was not confirmed by CT scan and/or histopathology.…”

“…Nevertheless, clinical features of Subjects 1–3 do overlap the core phenotype of Ramon syndrome, possibly implying that biallelic TBC1D2B variants underlie this rare disorder. However, a homozygous missense variant in ELMO2 (MIM# 606421) has recently been reported in two siblings with clinical features suggestive of Ramon syndrome (Mehawej et al, 2018). ELMO2 controls the activation of the small Rho GTPase Rac1 to modulate actin cytoskeleton remodeling and microtubule dynamics (Jackson, Ivanova, & Dagnino, 2015; Toret, Collins, & Nelson, 2014).…”

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

“…Loss of function variations in ELMO2 (OMIM * 606421), in the form of small insertions or deletions have been associated with a rare malformative condition known as vascular malformation, primary intraosseous (VMPI, OMIM # 606893) [ 139 ]. However, a homozygous missense variant in ELMO2 has been recently reported in a young girl with intellectual disability, seizures, dysmorphic features, and associated syndromic manifestations suggestive of Ramon syndrome [ 140 ]. The (p.Ile606Ser) variant (NM_182764.2) localizes to the atypical Pleckstrin homology domain of ELMO2 involved in the interaction with the DOCK proteins, suggesting that a dysregulation of the activity of these GEFs possibly leading to an abnormal Rac1 function might be a relevant underlying pathogenic mechanism in ELMO2 -related disorder [ 140 , 141 ].…”

“…However, a homozygous missense variant in ELMO2 has been recently reported in a young girl with intellectual disability, seizures, dysmorphic features, and associated syndromic manifestations suggestive of Ramon syndrome [ 140 ]. The (p.Ile606Ser) variant (NM_182764.2) localizes to the atypical Pleckstrin homology domain of ELMO2 involved in the interaction with the DOCK proteins, suggesting that a dysregulation of the activity of these GEFs possibly leading to an abnormal Rac1 function might be a relevant underlying pathogenic mechanism in ELMO2 -related disorder [ 140 , 141 ]. These emerging disease associations support a role of ELMO genes in the pathogenesis of human conditions with a primary neurological involvement.…”

Syndromes with gingival fibromatosis: A systematic review

“…Besides GF, individuals with Ramon syndrome also presented with maxillary fibrous dysplasia, epilepsy, mental deficiency, hypertrichosis, stunted growth, rheumatoid arthritis, and retinal changes. At present, the molecular etiology of Ramon syndrome is unknown, but a recent report described a mutation in the ELMO2 gene in a girl diagnosed with Ramon syndrome (Mehawej et al., 2018).…”