Chromosome 9p Deletion Syndrome

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

Also see chromosome 9p24.3 deletion syndrome (154230), which results in 46,XY gonadal dysgenesis.

Clinical Features

Alfi et al. (1973) reported 2 unrelated patients with partial deletion of the short arm of chromosome 9. Common clinical features included trigonocephaly, flattened occiput, prominent forehead, broad flat nasal bridge, anteverted nares, malformed external ears, hypertelorism, and hypertonia. One had a patent ductus arteriosus, and the other had ventricular septal defect. One child had an omphalocele, a left diaphragmatic hernia, and inguinal hernias. Both infants had delayed psychomotor development. Cytogenetic studies on family members indicated that the mother and several maternal relatives of the first patient and the father of the second patient carried a similar deletion of 9p.

Hoo et al. (1982) observed a kindred with several cases of mental retardation attributable to deletion of the terminal band of 9p (p24). Chromosomal translocation was sought because of the high frequency of mental retardation in the family. High resolution cytogenetics showed a tiny translocation between 9p and 20p in presumptively balanced translocation carriers. The clinical features fitted well with the previously described 9p- syndrome based on patients with more extensive deletions. In addition to mental retardation, these clinical features were delayed motor development, trigonocephaly, wide nasal bridge, large upper lip, high-arched palate, long fingers and toes due to elongation of the second phalanx, flat feet, and dermatoglyphic peculiarities. Shashi et al. (1994) described choanal atresia in a patient with the 9p- syndrome; Huret et al. (1988) had earlier reported the association in a single case.

Swinkels et al. (2008) reported 13 presumably unrelated Dutch patients with 9p syndrome. Ages ranged from 3 months to 42 years; there were 8 females and 5 males. The most common clinical features, occurring in more than 50% of patients, included developmental and psychomotor delay, trigonocephaly, flat midface, short palpebral fissures, highly arched eyebrows, low-set ears, short flat nose with anteverted nostrils, thin upper lip, long philtrum, high palate, micrognathia, short neck, enlarged internipple distance, tapering fingers, flat feet, and hypotonia. Speech was delayed, but improved with age. Seven of 13 patients had cardiac murmurs presumed to be due to patent ductus arteriosus, ventricular septal defect, atrial septal defect, tricuspid valve insufficiency, and coarctation of the aorta. Three of 5 males had hypospadias and micropenis. All patients had a normal height.

Cytogenetics

Christ et al. (1999) used high-resolution cytogenetics, FISH analysis, and PCR to evaluate the cytogenetic breakpoints in 24 patients with 9p deletion syndrome. Nine of 10 different breakpoints identified were within a 5-Mb region on chromosome 9p23-p22 between D9S1869 and D9S162. Eight unrelated patients had a breakpoint between D9S274 and D9S285, suggesting a breakage hotspot. However, 12 patients had 7 different breakpoints localized to a more proximal 2-Mb region on chromosome 9p22. The combined data indicated that the critical region for the 9p deletion syndrome mapped to a 4 to 6-Mb region in 9p23-p22 between D9S286 to D9S285. All patients with a break centromeric to D9S274 showed a consensus 9p deletion phenotype. Swinkels et al. (2008) noted that the candidate region reported by Christ et al. (1999) actually encompassed about 8 Mb, based on revised genome data.

In a 2-year-old Japanese boy with clinical characteristics of monosomy 9p syndrome, Kawara et al. (2006) identified complex chromosomal rearrangements involving 7 breakpoints in chromosomes 2 and 9, including a 6.6-Mb deletion at 9p23-p22.3. These data, together with previous studies, narrowed the shortest region of overlap for the syndrome to a 4.7-Mb interval from the BAC clone RP11-933C16 to D9S285. The patient also had brown hair and relatively light skin color, which the authors postulated may have resulted from deletion of the TYRP1 gene (115501) on 9p23 since mutations in that gene can result in albinism (see, e.g. 203290).

Faas et al. (2007) reported a girl with clinical features of the 9p syndrome in whom cytogenetic analysis and array comparative genomic hybridization showed a 14.8-Mb loss from 9pter to 9p22.3 and a 50.9-Mb gain from 9p22.3 to 9q12 that appeared to be an inverted duplication. Combined with the results of Kawara et al. (2006), this allowed Faas et al. (2007) to refine the critical region to a 3.5-Mb interval containing at least 7 genes.

By analysis of breakpoints from 13 Dutch patients with 9p deletions Swinkels et al. (2008) narrowed the candidate region for 9p deletion syndrome to 300 kb on chromosome 9p22.3. The region overlapped that of Christ et al. (1999) and Kawara et al. (2006), but differed from that of Faas et al. (2007), whose patient also had a duplication. Five of the 13 patients reported by Swinkels et al. (2008) did not have all of the consensus phenotypic features, lacking trigonocephaly, long philtrum, and micrognathia; these patients had more distal 9p breakpoints compared to the other patients. Sequencing analysis of a candidate gene CER1 (603777), which lies outside of the candidate region, did not identify any causative mutations.

Mapping

Barbaro et al. (2009) noted that separate regions of deletion on chromosome 9 had been identified for 46,XY gonadal dysgenesis (154230) and monosomy 9p deletion syndrome: 9p24.3, extending from the DMRT genes (602424; 604935) to the telomere for the former, and 9p23-p22.3 for the latter.

Using high-density chromosome 9-specific arrays, Vissers et al. (2011) reanalyzed the deletion breakpoints of 4 patients with syndromic metopic craniosynostosis and de novo copy number variation (CNV) involving chromosome 9p22.3, 3 of whom were previously studied by Swinkels et al. (2008). Two of the patients' rearrangements contained deletion breakpoints within the FREM1 gene (608944), deleting exons 7 to 37 and 10 to 37, respectively; in the remaining 2 patients, the FREM1 gene was entirely deleted. Vissers et al. (2011) concluded that the CNV data were consistent with a model in which haploinsufficiency of FREM1 is associated with metopic craniosynostosis (see 614485).

Animal Model

Vissers et al. (2011) studied C57BL/6J mice carrying the ENU-generated Frem1 (608944) (bat) mutation, which is thought to represent a hypomorphic allele rather than a null allele. Morphometric analysis of skulls from homozygous and heterozygous mutant mice demonstrated craniofacial malformations consistent with the craniofacial features seen in the 9p22 deletion syndrome, in particular, metopic craniosynostosis and midface asymmetry and/or hypoplasia. The penetrance of the phenotypes in mice correlated to mutant gene dosage.