Chromosome 4q21 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.

Clinical Features

Harada et al. (2002) described a 6.7-year-old Japanese girl with severe postnatal short stature, dolichocephaly, hypertelorism, long philtrum, small mouth, defect of bilateral lower incisors, pathologic attrition of all teeth, bilateral sensorineural deafness with bilateral ear canal stenosis, and muscle hypotonia. She also had severe psychomotor retardation with absence of speech.

Friedman et al. (2006) reported an 18-year-old woman with extremely short stature, deep-set eyes with narrow palpebral fissures, low-set straight eyebrows, narrow nasal root and bridge, prominent columella with receding alae nasi, short philtrum and thin, downturned lips, small hands and feet, severe hypotonia, marked pes planus, mild scoliosis, and severe cognitive impairment.

Bonnet et al. (2010) described 9 patients, ranging in age from 9 months to 23 years, who had a distinctive phenotype including neonatal muscular hypotonia, severe psychomotor retardation with absent or severely delayed speech, marked progressive growth restriction, and distinctive facial features involving a broad forehead, frontal bossing, hypertelorism, short philtrum, and downturned corners of the mouth. The 2 youngest patients still had measurements within the normal range, whereas the other 7 displayed postnatal short stature with conserved head circumference. Brain imaging was abnormal in 8 of the 9 patients, demonstrating cerebral hypoplasia with ventricular dilation in 5 individuals and cerebellar anomalies in 3.

Cytogenetics

In a 6.7-year-old Japanese girl with severe psychomotor retardation, severe postnatal short stature, and hypotonia, Harada et al. (2002) identified a de novo deletion of chromosome 4q21.1-q22.2 located 81 Mb to 95.8 Mb from 4pter, a region containing at least 30 genes.

In an 18-year-old woman with severe cognitive impairment, extreme short stature, and severe hypotonia, Friedman et al. (2006) identified a de novo 11.1-Mb deletion of chromosome 4q21.1-q22.1 between rs1493182 to rs1586340.

In 9 patients with a common phenotype comprised of severe psychomotor retardation, severe growth restriction, hypotonia, distinctive facial features, and variable brain anomalies, Bonnet et al. (2010) identified overlapping de novo deletions of chromosome 4q21. The boundaries and sizes of the 9 deletions were different, but a 1.37-Mb critical interval was defined containing 5 genes, of which the PRKG2 (601591) and RASGEF1B (614532) genes were considered to be the most promising candidates.