New X‐linked mental retardation (XLMR) syndrome with distinct facial appearance and growth retardation

Abstract

We report on 2 brothers and their nephew with an apparently new X-linked mental retardation (XLMR) syndrome characterized by a distinct facial appearance, growth retardation, and severe mental retardation. The facial traits included triangular shape; bifrontal narrowness; malar flatness; blepharophimosis; very deeply set eyes; epicanthus inversus; bulbous nose; low hairline; low-set, deeply cupped, and protruding ears; short ill-defined philtrum; and thin tented upper lip. These facial anomalies are particularly striking and recognizable even at birth. The boys were small for gestational age and remained below -2 SD in growth parameters. With age, large joint contractures developed. Pectus excavatum was apparent at birth but became more obvious with age. Global developmental delay was evident in infancy. The brothers were nonverbal while their nephew spoke simple words. Optic atrophy, esotropia, nystagmus, and spastic diplegia were evident. They were self-abusive, hyperactive, and poorly coordinated. CT scans demonstrated atrophic hydrocephalus. No EEG abnormalities were detected. Karyotypes were 46,XY and fragile X negative. Routine chemistries; amino, organic, and uronic acids; oligosaccharides; lysosomal enzymes; and very long chain fatty acids were normal. Remarkable phenotypic similarity between these brothers and their nephew and lack of manifestations in their mothers makes X-linked recessive inheritance likely. This syndrome, which does not appear to have been reported previously, adds to the delineation of XLMR.

Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability

“…Mutations in HUWE1 are the cause of mental retardation, X-linked syndromic, Turner type [Online Mendelian Inheritance in Man (OMIM, http://www.ncbi.nlm.nih.gov/omim) #300706], Juberg-Marsidi syndrome [OMIM #309580] and Brooks-Wisniewski-Brown syndrome [OMIM #300612] [5,15–17]. Xp11.22 microduplication syndrome [OMIM #300705] is caused by duplication of HUWE1 and is characterized by mild to moderate intellectual disability [5].…”

HECT‐type E3 ubiquitin ligases in nerve cell development and synapse physiology

“…Interestingly, mutations in genes encoding HECT type E3 ligases and DUBs have been characterized in patients with intellectual disability, including X‐linked mental retardation syndromes. Huwe1 , encoded on the X chromosome, is mutated in patients with Brooks–Wisniewski–Brown syndrome [93,94]. The analysis of a brain specific Huwe1 KO uncovered defects in neurogenesis, which may be at the basis of the pathology [41,95].…”

Quantitative trait loci modulate ventricular size in the mouse brain

“…Hydrocephalus is associated with numerous negative effects in both children and adults, including intellectual disabilities, urinary incontinence, sexual impairment, epilepsy, visual impairment, and deafness (Simpson and Hemmer, 1993). There is a wide variety of inherited disorders associated with hydrocephalus, including ciliary dyskinesia (al-Shroof et al, 2001), Dandy-Walker malformation (Cavalcanti and Salomao, 1999;McKee et al, 2001), and a number of X-linked disorders (Brooks et al, 1994;Czarnecki et al, 1996;Kenwrick et al, 1996;Katsuragi et al, 2000).…”