Chromosome 2q37 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome involving several genes on chromosome 2q37.2.

Description

Patients with chromosome 2q37 deletion syndrome show highly variable clinical manifestations likely resulting from different deletion sizes and deletions of different genes. Variable clinical features included brachydactyly type E (BDE), affecting the metacarpals and metatarsals (in about 50% of patients), short stature, mild to moderate intellectual disability, behavioral abnormalities, and dysmorphic facial features. However, many individuals with deletions do not show cognitive deficits (summary by Villavicencio-Lorini et al., 2013, Wheeler et al., 2014, Jean-Marcais et al., 2015).

Clinical Features

Wilson et al. (1995) reported 5 unrelated patients with a phenotype resembling the physical anomalies found in Albright hereditary osteodystrophy (AHO; see 103580). Variable features included short stature, stocky build, mental retardation, brachymetaphalangia, and eczema. Soft tissue ossification was absent, and there were no abnormalities in parathyroid hormone or calcium metabolism. These patients, unlike some patients with AHO features, had normal levels of Gs-alpha (139320).

Williams et al. (2010) reported 6 unrelated patients with brachydactyly-mental retardation syndrome, including 4 with deletions of chromosome 2q37 that involved the HDAC4 gene and 2 with point mutations in the HDAC4 gene (605314.0001 and 605314.0002, respectively). Several of the cases had been referred on suspicion of having the Smith-Magenis syndrome (182290), and 4 patients had previously been reported by Wilson et al. (1995), Aldred et al. (2004), and Williams et al. (2010). The 2 patients with HDAC4 point mutations were described in detail. The first patient was a French Canadian woman, born of nonconsanguineous parents, who showed feeding difficulties in infancy and progressively delayed psychomotor development. Subvalvular aortic stenosis was identified at 4 months, and she received a mitral valve replacement and permanent pacemaker at age 5 years. Physical examination at age 13.5 years showed dysmorphic features, including midface hypoplasia, broad face and nose, brachycephaly, frontal bossing, downturned lower lip, and upslanted eyes. She also had hyporeflexia, a wide-based gait, and sensorineural hearing loss. Behavioral features included decreased sensitivity to pain, onychotillomania, hyperactivity, a decreased attention span, and sleep abnormalities. At age 25, she was obese. She had with bilateral proximal placement of the third, fourth, and fifth fingers, bilateral proximally placed fourth toes, and bilateral widely spaced first, second, and third toes. Radiographs confirmed brachydactyly type E (BDE), with shortened metacarpals and metatarsals. Family history was unremarkable. The second patient was a 16-year-old Caucasian female with obesity and intellectual disability. She had poor feeding in infancy and delayed psychomotor development. Dysmorphic features included a small chin, large asymmetrically placed ears, bitemporal narrowing, and narrow palpebral fissures. Neurologic and behavioral abnormalities included aggressive tantrum-like behavior, decreased sensitivity to pain, head banging, self-biting, skin picking resulting in scarring, stereotypies, food-seeking behaviors, and sleep disturbances. Musculoskeletal features include hypotonia, hypermobility, pes planus, and type E brachydactyly with mild shortening of metacarpals and metatarsals three through five. The 4 other patients with chromosome 2q37 deletions had similar features and the absence of hearing loss and congenital heart malformation. Variable features included short stature in 2, seizures in 1, and obesity/overweight in 2.

Clinical Variability

Villavicencio-Lorini et al. (2013) reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. Dysmorphic features included coarse facies with high-arched eyebrows, deep-set eyes, narrow palpebral fissures, broad, depressed nasal bridge, and everted full lips. The proband had sleeping difficulties and aggressive behavior. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (607556) genes. Villavicencio-Lorini et al. (2013) concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE.

Ogura et al. (2014) reported 2 unrelated male patients with different interstitial deletions of 2q37.3 involving multiple genes. One patient (patient 1) was a 16-year-old Japanese boy with BDE, dysmorphic facial features, delayed psychomotor development, and moderate intellectual disability. He had a heterozygous 3.2-Mb deletion that included the HDAC4 gene. The other patient (patient 2) was a 5-year-old Japanese boy with mildly delayed language and mild behavioral issues, including obsessive tendencies and mild attention impairment, as well as poor fine motor skills; he did not have BDE. He had a 2.3-Mb deletion that did not include the HDAC4 gene. Both patients also had disabilities in visuospatial perception. All 4 parents declined genetic analysis.

Jean-Marcais et al. (2015) reported a father and his 3 children who had brachydactyly type E, short stature, and normal cognitive development associated with an inherited heterozygous interstitial deletion of 2q37.3. The proband, who was one of the children, had bilateral shortening of metacarpals IV and V, bilateral shortening of metatarsals III, IV, and V, and mild short stature. Her brother had brachymetatarsy without brachymetacarpy, and her 3-year-old sister had short stature without visible brachymetacarpy or brachymetatarsy. The father had shortening of metacarpals and metatarsals IV and V, and mild short stature. The father and proband had similar dysmorphic features, including depressed nasal bridge, hypoplastic nasal alae, sparse arched eyebrows, and prominent columella. Several family members on the father's side reportedly had short stature and brachymetarcarpy/brachymetatarsy. None of the individuals had intellectual disability or behavioral abnormalities. The deletion was between 491 and 813 kb and included the HDAC4 and TWIST2 genes, as well as 2 noncoding RNAs (MGC16025 and FLJ43879) and 3 microRNAs (MIR4269, MIR4441, and MIR4440). DNA from additional possibly affected family members on the paternal side was not available. The report indicated that haploinsufficiency of HDAC4 and the surrounding critical region is not always associated with cognitive defects.

Cytogenetics

Of 5 patients with AHO-like features, Wilson et al. (1995) identified cytogenetically visible de novo deletions of 2q37 in 4, and showed deletion of 2q37 by a combination of highly polymorphic molecular markers and fluorescence in situ hybridization in 1. Wilson et al. (1995) noted that brachydactyly type E (113300) is difficult to distinguish from AHO (Ablow et al., 1977; Poznanski et al., 1977) and suggested that brachydactyly type E is due to a mutation in the 2q37 region.

Independently, Phelan et al. (1995) found a small terminal deletion of chromosome 2 in 4 unrelated patients with AHO-like features. They interpreted the findings as indicative of the existence of a gene locus in the 2q37 region important in the pathogenesis of AHO. Giardino et al. (2003) narrowed the candidate region to 2q37-qter by deletion mapping in a patient with an unbalanced cryptic translocation t(2;6)(q37.3;q26).

Shrimpton et al. (2004) described 3 patients with an AHO-like phenotype associated with a deletion involving the 2q37.3 region. They suggested that haploinsufficiency of GPR35 (602646), which is located in this region, could be responsible for the disorder in these patients. Shrimpton et al. (2004) noted that short third and fourth metacarpals were present in 2 of the patients.

In the course of describing patients with BDMR and deletions of chromosome 2q37.3, Williams et al. (2010) reported 1 patient with a 2.68-Mb terminal deletion distal to and not including the HDAC4 gene. The patient had minor craniofacial abnormalities, developmental delay, obesity, autistic behaviors, and a history of seizures, but no evidence of metacarpal or metatarsal shortening and no evidence of cardiac or other major organ defect, supporting the conclusion that deletion of the HDAC4 gene is specifically necessary for the brachydactyly type E phenotype. The results also suggested that other clinical features in patients with chromosome 2q37 deletion syndrome likely have a complex etiology, and that multiple genes may contribute to the full phenotypic spectrum.

Molecular Genetics

By analyzing the breakpoints and overlapping regions of patients with BDMR and deletions of chromosome 2q37.3, Williams et al. (2010) narrowed the critical region to about 200 kb and identified HDAC4 as the critical gene that determines the phenotype. Two unrelated patients with BDMR were found to have de novo heterozygous mutations specifically interrupting the HDAC4 gene (605314.0001 and 605314.0002, respectively). The findings indicated that haploinsufficiency for HDAC4 results in BDMR. Quantitative RT-PCR analysis showed that lymphocytes from the 2 BDMR patients with point mutations had decreased expression of RAI1 (607642), which is mutant in SMS. These findings provided a link to the overlapping phenotypes in these 2 disorders.

Wheeler et al. (2014) provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene and 2 noncoding RNA sequences (MGC16025 and LOC150935) and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment. Wheeler et al. (2014) suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability.