Chromosome 10q22.3-Q23.2 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr10: 81.6-88.9 Mb, NCBI36).

Description

The 10q22.3-q23.2 region is characterized by a complex set of low-copy repeats (LCRs), which can give rise to various genomic changes mediated by nonallelic homologous recombination (NAHR). Recurrent deletions of chromosome 10q22.3-q23.2, including the BMPR1A gene (601299) have been associated with dysmorphic facies, developmental delay, and multiple congenital anomalies. Some patients with deletions that extend distally to include the PTEN gene (601728) have a more severe phenotype with infantile/juvenile polyposis, macrocephaly, dysmorphic facial features, and developmental delay (summary by van Bon et al., 2011).

Clinical Features

Alliman et al. (2010) reported 4 unrelated patients with a recurrent interstitial deletion of chromosome 10q22.3-q23.2, including the BMPR1A gene but not the PTEN gene. All had mild dysmorphic features, and 3 had developmental delay. Three also had poor feeding and failure to thrive. None had polyposis. Van Bon et al. (2011) noted that the deletion in these patients occurred between LCR3 and LCR4.

Van Bon et al. (2011) reported 5 additional unrelated patients with heterozygous interstitial recurrent deletion of 10q22.3-q23.2 between LCR3 and LCR4. Three were de novo, 1 was inherited from a presumably unaffected mother, and the fifth was unknown. All had loss of the BMPR1A gene, but none had loss of the PTEN gene. All patients had variable degrees of developmental delay, 4 with speech delay, and all had variable dysmorphic features, including low-set ears, hypertelorism, broad nose, and flat nasal bridge. Other features were more variable, and included atrial and ventricular septal defects (1 patient), broad thumbs and halluces and breast aplasia (1 patient), high-arched palate, seizures, and Chiari I malformation (1 patient), and scoliosis, kyphosis, cafe-au-lait spots, and heart valve regurgitation (1 patient). None had polyposis. Van Bon et al. (2011) postulated involvement of the NRG3 gene (605533) in the patient with breast aplasia and involvement of the BMPR1A gene in those with heart defects. These patients were detected within a cohort of 30,991 individuals with mental retardation and/or multiple congenital anomalies, yielding a frequency of 0.016%.

Chromosome 10q22-q24 Deletion Associated with Juvenile Polyposis

Jacoby et al. (1997) reported a patient with juvenile polyposis at age 3 years and multiple congenital anomalies who had a de novo interstitial deletion of chromosome 10q22.3-q24.1. Other clinical features included short stature, short hands and feet, broad nasal tip and long philtrum, widely spaced canthi, hypoplastic ears, small head, and redundant neck skin. There were also a small umbilical hernia, hypoplastic oblique muscles with bilateral abdominal bulging laterally, and prominent venous patterning on thorax and abdomen. Motor and language skills were developmentally delayed.

Arch et al. (1997) identified an interstitial deletion of 10q23.2-q24.1, including the PTEN gene, in a patient with onset of juvenile polyposis at age 18 months. He also had macrocephaly, dysmorphic facial features, and psychomotor retardation.

Delnatte et al. (2006) described 4 unrelated children with juvenile polyposis of infancy. These children were heterozygous for de novo germline deletion encompassing the PTEN and BMPR1A genes. Extradigestive features of some of the children suggested Bannayan-Riley-Ruvalcaba syndrome. The authors considered it unsurprising that the clinical presentation of juvenile polyposis of infancy should alternatively suggest the diagnosis of BRRS or JPS, since the description of families with both Cowden syndrome and BRRS suggested that modifying factors influence the expression of the PTEN gene defect. Delnatte et al. (2006) hypothesized that juvenile polyposis of infancy is a contiguous gene deletion syndrome caused by the deletion of these 2 genes and that the severity of the disease reflects cooperation between these 2 tumor suppressor genes.

Salviati et al. (2006) reported a patient who had an interstitial deletion of chromosome 10 that was associated with a significantly milder phenotype than the patients reported by Delnatte et al. (2006). She had mildly dysmorphic features and developmental delay. Her first episode of mild rectal bleeding occurred at the age of 5 years. Colonoscopy performed at age 6 years detected multiple (more than 15) polyps throughout the entire length of the colon. Histology of resected lesions was compatible with juvenile polyps. A high-resolution karyotype detected an interstitial deletion of chromosome 10q23. The patient of Salviati et al. (2006) did not have any of the features of infantile juvenile polyposis, i.e., onset before age 2 years, severe bleeding, diarrhea, protein-losing enteropathy, inanition, and rectal prolapse. Furthermore, polyps were found only in the colon. She also did not show clinical signs typical of Cowden syndrome or BRR syndrome. In a reply to Salviati et al. (2006), Sanlaville et al. (2006) suggested that the findings in the patient of Salviati et al. (2006) were compatible with the interpretation provided by Delnatte et al. (2006), assuming some mechanism had increased expression levels of some critical genes on the remaining chromosome correcting the haploinsufficiency in the 10q22.3-q23 region and leading to an attenuated phenotype.

Menko et al. (2008) reported 4 additional unrelated patients with 10q23 microdeletions encompassing both the BMPR1A and the PTEN genes. The clinical phenotype varied somewhat, but generally included psychomotor retardation, macrocephaly, facial dysmorphism, and early childhood onset of symptomatic juvenile polyposis. Two of the patients had documented upper gastrointestinal tract involvement. Other variable features included congenital heart defects, hypotonia, and cleft palate. Only 1 patient had onset of polyposis before age 2 years and severe symptoms requiring colectomy at that time, and another patient had an unusual disease course, with death from metastatic rectal cancer at age 25 years. FISH and multiplex ligation-dependent probe amplification (MLPA) showed deletions ranging in size from 2.88 to 4.26 Mb. The common region deleted in these 4 patients and in previously reported patients was 1.47 Mb, including at least 10 known genes. There was no clear correlation between deletion size and age at onset or disease severity. Menko et al. (2008) concluded that the phenotypes associated with 10q23 deletions are not restricted to severe infantile juvenile polyposis, but also include childhood-onset cases with macrocephaly, retardation, mild gastrointestinal symptoms, and possibly early-onset colorectal cancer.

Babovic et al. (2010) reported a girl with infantile polyposis, macrocephaly, delayed psychomotor development, and hypotonia associated with a 2.5-Mb deletion at chromosome 10q23.2-q23.31. At age 14 years, she developed bilateral mucinous cystadenoma of the ovaries, a neoplastic condition that had not previously been described in association with deletion of chromosome 10q23. The authors also noted that the patient had pronounced polyps on her tonsils, which may be used as a diagnostic clue.

Van Bon et al. (2011) reported a patient (patient 6) with a de novo 4.7-Mb interstitial deletion of chromosome 10q22.3-q23.3, including the BMPR1A and PTEN genes and involving LCR4. The patient had juvenile polyposis, macrocephaly, and hyperactivity. She also had 2 shorter regions of copy number loss at LCR3.

Chromosome 10q22-q23 Deletion

Van Bon et al. (2011) reported 2 unrelated patients with small interstitial deletions of chromosome 10q22.3-q23.3 region. One patient (patient 7) had a 0.2-Mb intragenic deletion of the GRID1 gene (610659). He had multiple congenital anomalies, including diaphragmatic eventration, undescended testes, heart defects, and dysmorphic features, but normal development. The other patient (patient 8) had a 30-kb deletion outside of the LCR regions. He had developmental delay, autism, absent speech, and seizures. He inherited the deletion from his father; although several family members had a psychiatric disorder, the intragenic deletion found in this patient and his father did not segregate in the rest of the family.

Cytogenetics

Recurrent Deletion of Chromosome 10q22.3-q23.1

Balciuniene et al. (2007) described the patient reported by Arch et al. (1997) and 2 other patients with cognitive and behavioral abnormalities due to chromosome 10q22-q23 deletion. They suggested that the 10q22.3-q23.32 region should be added to the list of genomic regions affected by recurring rearrangements. They related the breakpoint in each family to the organization of complex low-copy repeats (LCRs) located in the proximity of the deletions. The breakpoints in 2 of the families mapped within LCR3 and LCR4, whereas the deletion in the family of Arch et al. (1997) removed the telomeric LCR4 and had a complex noncontiguous structure. Balciuniene et al. (2007) proposed that the LCRs in this region increased susceptibility to chromosomal rearrangements.

Chromosome 10q22.3-q23.2 Duplication

Van Bon et al. (2011) also reported 3 patients, including 2 sibs, with duplication of chromosome 10q22.3-q23.2 involving LCR3 and LCR4. All had developmental delay and variable dysmorphic features. The sibs inherited the duplication from an unaffected mother. Three additional patients had nonrecurrent duplications in this region that did not involve LCR3 and LCR4; 1 had developmental delay with dysmorphic features, 1 had dysmorphic features only, and the third had multiple congenital anomalies.