Chromosome 3q13.31 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene syndrome on chromosome 3q13.31 (chr3:103.32-128.18 Mb).

Description

The chromosome 3q13.31 deletion syndrome is characterized by marked developmental delay, characteristic facies with a short philtrum and protruding lips, and abnormal male genitalia (Molin et al., 2012).

Patients with Primrose syndrome (PRIMS; 259050) exhibit features overlapping those of the chromosome 3q13.31 deletion syndrome but also have ossified ear cartilage, severe muscle wasting, and abnormalities of glucose metabolism resulting in insulin-resistant diabetes mellitus in adulthood. Primrose syndrome is caused by mutation in the ZBTB20 gene (606025) on chromosome 3q13.

Clinical Features

Ogilvie et al. (1998) reported an unrelated girl and boy with interstitial deletions at chromosome 3q12-q21 (see CYTOGENETICS). The 4-year-old girl, who had no speech, was born at term but was hypotonic and a poor feeder. She first walked at age 3 years and had a broad-based gait, but no ataxia in her hand movements. She was myopic and had a broad face and high-arched palate, as well as an unusual palmar crease on 1 hand. The boy had been delivered by cesarean section at 37 weeks' gestation due to fetal distress and had apneic episodes in the neonatal period. He was hypotonic at birth and exhibited marked plagiocephaly; 2 central cysts were seen on cranial ultrasound, and agenesis of the corpus callosum was later confirmed. Examination at age 17 months showed over-folded ears, pointed chin, broad forehead, prominent supraorbital ridges, relative midface hypoplasia, and prominent nostrils. He had developed scoliosis, lordosis, and kyphosis; his genitalia were normal, but he had a hypoplastic pelvis and was very thin. He was profoundly retarded and had no speech. Neither patient exhibited blepharophimosis.

Molin et al. (2012) described the clinical features of 15 patients with deletions in the proximal long arm of chromosome 3, 1 of whom was the girl previously reported by Ogilvie et al. (1998), and also reviewed 13 previously reported patients with deletions on the proximal long arm of chromosome 3. The major characteristics in 24 patients who shared the shortest region of overlap included significant developmental delay, muscular hypotonia, high-arched palate, and recognizable facial features including short philtrum and protruding lips. Brain and central nervous system anomalies included agenesis of the corpus callosum in 5 patients, ventriculomegaly in 3, and alobar holoprosencephaly in 1. Abnormal genitalia were found in the majority of males, with several having micropenis. In addition, a postnatal growth pattern above the mean was apparent.

Cytogenetics

By G-banding of DNA from peripheral lymphocytes of 2 unrelated children with dysmorphic features and severe psychomotor retardation, Ogilvie et al. (1998) identified an apparently identical interstitial deletion, with breakpoints established at 3q12-q21. Analysis of chromosomes from both sets of parents showed normal karyotypes.

Molin et al. (2012) studied 14 novel patients with deletions of chromosome 3q11-q23 and compared them to 14 previously reported cases with deletions in the same region. Molecular investigation revealed that the deletions mapped within 3q12-q21.3 and ranged in size from 580 kb to 22.4 Mb. Most of the deletions had different breakpoints, although 4 cases had breakpoints in close proximity. The deletions were shown to be de novo in the 13 cases for which parental DNA was available. The shortest region of overlapping deletion (SRO), shared by 24 of the patients, was a 580-kb segment at 3q13.31. Molin et al. (2012) noted that of the 5 genes located in that interval, DRD3 (126451) and ZBTB20 (606025) were strong candidate genes for developmental delay.

Shuvarikov et al. (2013) reported 9 patients with recurrent 3.4-Mb de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All had hypotonia as well as language and motor delays; 8 patients had mild to moderate cognitive delays, 7 showed abnormal behavior, and 3 exhibited autism spectrum disorders. Common facial features included downslanting palpebral fissures with epicanthal folds, slightly bulbous nose, prominent lower lip, and relative macrocephaly. DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination between HERV-H elements (see 604109) as a mechanism of deletion formation.

Rasmussen et al. (2014) studied 2 patients with de novo chromosomal rearrangements at 3q13.31 causing haploinsufficiency of the ZBTB20 gene (606025). A 13-year-old Brazilian boy with developmental delay, attention deficit-hyperactivity disorder, psychosis, Tourette syndrome, and autistic traits had a balanced reciprocal translocation t(3;18)(q13.31;q22.1). The chromosome 3 breakpoint separated upstream noncoding exons and gene regulatory elements from the downstream coding exons of the ZBTB20 gene, whereas the fully balanced chromosome 18 breakpoint was located in an intergenic region. A 3-year-old Portuguese boy with developmental delay and autism had a 1.3-Mb microdeletion at 3q13.31 that truncated the ZBTB20 gene in intron 4 and encompassed the GAP43 (162060) and LSAMP (603241) genes as well. Both boys exhibited characteristic facial dysmorphic features of 3q13.31 deletion syndrome, including downslanting palpebral fissures, full lower lip, and prominent ears, but neither had genital anomalies.