Cerebral White Matter Lesions and Dysmorphisms: Signs Suggestive of 6p25 Deletion Syndrome—Literature Review

Abstract

Deletion of the region including chromosome 6p25 has been defined as a syndrome, with more than 68 reported cases. Individuals affected by the syndrome exhibit variable findings, including developmental delay and intellectual disability, cardiac anomalies, dysmorphic features, and—less commonly—skeletal and renal malformations. Ocular and hearing abnormalities are the most notable presenting features. The region encompasses more than 15 genes, of which the FOX group is the most likely causal factor of the clinical manifestations. We report the case of a 2-year-old child with developmental delay, generalized hypotonia, facial dysmorphism, and anomalies involving malformations of the eyes, heart, teeth, and skeleton. The magnetic resonance imaging (MRI) of the child's brain displayed cerebral anomalies involving the white matter, perivascular spaces, and corpus callosum. Array-CGH (comparative genomic hybridization) analysis displayed a de novo partial deletion of the short arm of chromosome 6, extending 5.13 Mb from nt 407.231 to nt 5.541.179. In infancy, neuroradiologic findings of abnormalities in the cerebral white matter and other neurologic anomalies elsewhere in the brain, in association with dysmorphisms and malformations, are highly suggestive of the diagnosis of 6p25 deletion syndrome. When these anomalies are found, the syndrome must be included in the differential diagnosis of disorders affecting the cerebral white matter.

Keywords

white matter anomalies - developmental delay - dysmorphic features - 6p25 syndrome - ocular lesions

Ethical Approval

The authors have no ethical conflicts to disclose.

• References

• 1 de Vos IJ, Stegmann AP, Webers CA, Stumpel CT. The 6p25 deletion syndrome: an update on a rare neurocristopathy. Ophthalmic Genet 2017; 38 (02) 101-107
• 2 Mirza G, Williams RR, Mohammed S. , et al. Refined genotype-phenotype correlations in cases of chromosome 6p deletion syndromes. Eur J Hum Genet 2004; 12 (09) 718-728
• 3 Beby F, Des Portes V, Till M, Mottolese C, Denis P. Chromosome 6p25 deletion syndrome: report of a case with optic disc coloboma and review of published ophthalmic findings. Ophthalmic Genet 2012; 33 (04) 240-248
• 4 Gould DB, Jaafar MS, Addison MK. , et al. Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: relevance to ocular dysgenesis and hearing impairment. BMC Med Genet 2004; 5: 17
• 5 de Sousa P, Kennedy A, Lalani HHS. A novel unbalanced translocation between the short arms of chromosomes 6 and 16 in a newborn girl: clinical features and management. Clin Case Rep 2018; 6 (07) 1282-1286
• 6 Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS. Fox's in development and disease. Trends Genet 2003; 19 (06) 339-344
• 7 Tepperberg JH, Rao KW, Albright SG, Kaiser-Rogers K, Powell CM. Deletion 6(p25.1) in a child with mild dysmorphic features and absence of major eye malformations: implications for the localization of genes involved in ocular development. Am J Hum Genet 1994; 55: A680
• 8 Davies AF, Mirza G, Sekhon G. , et al. Delineation of two distinct 6p deletion syndromes. Hum Genet 1999; 104 (01) 64-72
• 9 Anderlid BM, Schoumans J, Hallqvist A. , et al. Cryptic subtelomeric 6p deletion in a girl with congenital malformations and severe language impairment. Eur J Hum Genet 2003; 11: 89-92
• 10 Chen KM, Cherry AM, Hahn JS, Enns GM. Mild developmental delay in terminal chromosome 6p deletion. Am J Med Genet A 2004; 129A [phone]
• 11 Lin RJ, Cherry AM, Chen KC, Lyons M, Hoyme HE, Hudgins L. Terminal deletion of 6p results in a recognizable phenotype. Am J Med Genet A 2005; 136 (02) 162-168
• 12 Delahaye A, Khung-Savatovsky S, Aboura A. , et al. Pre- and postnatal phenotype of 6p25 deletions involving the FOXC1 gene. Am J Med Genet A 2012; 158A (10) 2430-2438
• 13 Aldinger KA, Lehmann OJ, Hudgins L. , et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet 2009; 41 (09) 1037-1042
• 14 Shen J, Scheffer DI, Kwan KY, Corey DP. SHIELD: an integrative gene expression database for inner ear research. Database (Oxford) 2015; 2015: bav071
• 15 Weegerink NJ, Swinnen FK, Vanakker OM, Casselman JW, Dhooge IJ. Phenotype of a Belgian family with 6p25 deletion syndrome. Ann Otol Rhinol Laryngol 2016; 125 (09) 734-745
• 16 Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet 2018; 93 (06) 1123-1130
• 17 Song W, Hu X. The rare Axenfeld-Rieger syndrome with systemic anomalies: a case report and brief review of literature. Medicine (Baltimore) 2017; 96 (33) e7791
• 18 Rao A, Padhy D, Sarangi S, Das G. Angle Closure Scoring System (ACSS): a scoring system for stratification of angle closure disease. PLoS One 2016; 27: 11:e0160209
• 19 Lehmann OJ, Ebenezer ND, Ekong R. , et al. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Invest Ophthalmol Vis Sci 2002; 43 (06) 1843-1849
• 20 DeScipio C. The 6p subtelomere deletion syndrome. Am J Med Genet C Semin Med Genet 2007; 145C [phone]
• 21 Nakane T, Kousuke N, Sonoko H. , et al. 6p subtelomere deletion with congenital glaucoma, severe mental retardation, and growth impairment. Pediatr Int 2013; 55 (03) 376-381
• 22 Maclean K, Smith J, St Heaps L. , et al. Axenfeld-Rieger malformation and distinctive facial features: clues to a recognizable 6p25 microdeletion syndrome. Am J Med Genet A 2005; 132A [phone]
• 23 Martinet D, Filges I, Besuchet Schmutz N. , et al. Subtelomeric 6p deletion: clinical and array-CGH characterization in two patients. Am J Med Genet A 2008; 146A (16) 2094-2102
• 24 Law CJ, Fisher AM, Temple IK. Distal 6p deletion syndrome: a report of a case with anterior chamber eye anomaly and review of published reports. J Med Genet 1998; 35 (08) 685-689
• 25 van der Knaap MS, Kriek M, Overweg-Plandsoen WC. , et al. Cerebral white matter abnormalities in 6p25 deletion syndrome. Am J Neuroradiol 2006; 27 (03) 586-588
• 26 Vernon HJ, Bytyci Telegrafi A, Batista D, Owegi M, Leigh R. 6p25 microdeletion: white matter abnormalities in an adult patient. Am J Med Genet A 2013; 161A [phone]
• 27 Williams III DW, Elster AD. Cranial MR imaging in hypomelanosis of Ito. J Comput Assist Tomogr 1990; 14 (06) 981-983
• 28 Fryburg JS, Lin KY, Matsumoto J. Abnormal head MRI in a neurologically normal boy with hypomelanosis of Ito. Am J Med Genet 1996; 66 (02) 200-203
• 29 Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72 (08) 750-759
• 30 Fichera M, Failla P, Saccuzzo L. , et al. Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy. Hum Genet 2019; 138 (02) 187-198
• 31 van der Knaap MS, Vermeulen G, Barkhof F, Hart AA, Loeber JG, Weel JF. Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection. Radiology 2004; 230 (02) 529-536