Alternative titles; symbols
SNOMEDCT: 702346005; ORPHA: 52022; DO: 0111687;
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38) : 11:43,400,001-48,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Potocki-Shaffer syndrome | 601224 | Autosomal dominant | 4 |
A number sign (#) is used with this entry Potocki-Shaffer syndrome is a contiguous gene deletion syndrome involving genes on chromosome 11p11.2.
Potocki-Shaffer syndrome is a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p12-p11.2 region and is characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses (168500), and biparietal foramina (609597) (summary by Swarr et al., 2010).
Bartsch et al. (1996) described a contiguous gene syndrome due to deletion in the proximal short arm of chromosome 11 in 8 patients belonging to 4 families. One patient had been reported by Lorenz et al. (1990) as an unusual case of acrocephalosyndactyly. Three of the patients had been reported by Shaffer et al. (1993). Bartsch et al. (1996) used microsatellite markers to characterize the extent of the deletion in each case. In addition to multiple exostoses and enlarged parietal foramina, 5 of the 8 patients showed brachycephaly with a somewhat turricephalic skull shape. The patient reported by Lorenz et al. (1990) and 1 of the patients reported by Shaffer et al. (1993) were described in the original publications to have a Saethre-Chotzen-like phenotype (101400). Cutaneous syndactyly between fingers 2 and 5 was present in the first of these 2 patients. The absence of craniofacial dysostosis in 1 family with the contiguous gene syndrome that showed enlarged parietal foramina and multiple exostoses and in families with autosomal inheritance of isolated enlarged parietal foramina suggested that there is a specific 11p gene involved in craniofacial dysostosis. Five of the patients were severely retarded but 3 patients from 1 family were mentally normal; thus, a specific mental retardation gene may be involved in the deletion. No evidence of imprinting was found; deletions of paternal origin were found in 2 patients and of maternal origin in 5. Bartsch et al. (1996) studied the deletions by cytogenetic and/or molecular methods and found them to be located between the centromere and D11S914 in a region of approximately 20 cM. Their study confirmed the presence of a multiple exostoses gene on 11p and suggested that the gene for isolated foramina parietalia permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region.
Potocki and Shaffer (1996) reported an additional patient with an 11p12-p11.2 deletion. Cytogenetic and molecular analysis demonstrated a de novo, paternally derived deletion for markers tightly linked to the EXT2 locus (133701).
Using FISH, Wu et al. (2000) tested for the presence or heterozygous deletion of a BAC clone containing ALX4 (605420) on 11p in 2 patients with the Potocki-Shaffer syndrome and found that the clone was deleted in these patients. The authors stated that the involvement of Alx4 in murine skull development (Qu et al., 1997), its bone-specific expression pattern, the finding that Alx4 is a dosage-sensitive gene in the mouse, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, supported the contention that ALX4 is a candidate gene for parietal foramina in the Potocki-Shaffer syndrome. Mavrogiannis et al. (2001) identified ALX4 as the gene which in haploid state causes the parietal foramina in proximal 11p deletion syndrome.
Hall et al. (2001) described an instructive family in which members in 5 generations had the Potocki-Shaffer syndrome with multiple exostoses and biparietal foramina but no mental retardation or craniofacial abnormalities. They showed that the EXT2 gene and the ALX4 gene were deleted, thus accounting for the multiple exostoses and biparietal foramina, respectively. The results indicated that the genes related to mental retardation and craniofacial abnormalities that sometimes occur in this syndrome must be located outside of the D11S1785-D11S1385 region.
Chuang et al. (2005) reported a family with inherited Potocki-Shaffer syndrome. The phenotypically normal mother had an interstitial deletion of chromosome 11 (11p11.2-p11.12) with neocentric marker chromosome formation. The marker chromosome contained the deleted material on 11p11.2 and was probably a ring. The patient inherited a maternal deleted chromosome 11 but not the marker chromosome, thus resulting in an unbalanced karyotype along with the phenotype of Potocki-Shaffer syndrome. Chuang et al. (2005) concluded that the deleted region in this case, 11p11.2-p11.12, was a previously unreported site of constitutional neocentromere formation and that this was also the first report describing deletion of 11p11.2-p11.12 and neocentromere formation resulting in inherited Potocki-Shaffer syndrome.
McGaughran et al. (1995) reported a patient with the combination of 2 deletion syndromes, WAGR (194072) and Potocki-Shaffer syndrome. Bremond-Gignac et al. (2005) described a second case of the combination. The latter patient also had obesity which, in combination with WAGR, is referred to as WAGRO. The patient presented with aniridia, cataract, nystagmus, corneal ulcers, and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months of age. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses, and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion. The deletion included the EXT2 (608210), ALX4, WT1 (607102), and PAX6 (607108) genes.
Wakui et al. (2005) constructed a panel of 11p deletions using cell lines derived from 10 patients with Potocki-Shaffer syndrome, including 6 patients who were newly identified. Analysis of the deleted regions using FISH, microsatellite analysis, and DNA array-based comparative genomic hybridization demonstrated that the full spectrum of PSS manifests when deletions are at least 2.1 Mb, spanning from D11S1393 to D11D1385/D11S1319, and encompassing the EXT2 and ALX4 genes. However, 1 patient with parietal foramina retained the ALX4 gene, and Wakui et al. (2005) suggested that ALX4 in this patient was functionally haploinsufficient due to a position effect. Results from 2 patients without mental retardation suggested that a gene related to mental retardation may be located between D11S554 and D11S1385/D11S1319.
In a 3-generation family with Potocki-Shaffer syndrome without mental defect or learning difficulties, Mavrogiannis et al. (2006) mapped the outer limits of the chromosome 11p deletion at D11S4173 distally and D11S554 proximally. FISH mapping determined that the deleted segment was eccentrically placed with respect to the ALX4 gene. The findings delineated a mental retardation locus to within 1.1 Mb of 11p11.2 between D11S1361 and D11S1344, thus confirming the findings of Wakui et al. (2005).
Swarr et al. (2010) evaluated 6 individuals diagnosed with PSS by cytogenetic methods through a multidisciplinary protocol-driven clinical assessment combined with retrospective chart reviews. All 6 patients had developmental delay and intellectual disability; 3 of the 6 patients had autistic features, and another child had occasional aggressive and self-injurious behaviors. Myopia, strabismus, and mild to moderate sensorineural hearing loss were also common. The patients had similar dysmorphic features, including microcephaly, brachycephaly, epicanthus, and sparse eyebrows laterally, prominent nasal bridge with broad, depressed nasal tip, hypoplastic nares, short philtrum, downturned mouth, and micrognathia.
Kim et al. (2012) identified 3 patients with balanced translocations disrupting the PHF21A (608325) gene in the PSS critical region. The patients had intellectual disability and craniofacial anomalies seen in PSS but did not have other manifestations of the contiguous gene deletion syndrome. Kim et al. (2012) concluded that the PHF21A gene is responsible for the intellectual disability and craniofacial anomalies seen in PSS. One of these patients had been reported by Dollfus et al. (1998) as having a phenotype suggestive of Gillespie syndrome (206700); Kim et al. (2012) noted that the translocation in this patient disrupted both the PHF21A and the ARHGAP6 (300118) genes.
McCool et al. (2017) reported a boy with a deletion on chromosome 11p11.2 that involved the ALX4 and EXT2 genes, but not the PHF21A gene. He had multiple exostoses, biparietal foramina, and a history of mild developmental delay. On formal testing at age 6 years and 4 months, he had anxiety, verbal dyspraxia, articulation disorder, and coordination disorder, but no intellectual disability. The authors argued that the phenotype of this patient supported the notion that haploinsufficiency of the PHF21A genes contributes to the intellectual disability of PSS. See also IDDBCS (618725), an intellectual developmental disorder with some features overlapping those of PSS that results from mutation in the PHF21A gene.
Based on their study of 6 patients with Potocki-Shaffer syndrome and a review of 31 reported patients, Swarr et al. (2010) proposed the following recommendations: referral to early childhood intervention and developmental-behavioral specialist at the time of diagnosis; a full skeletal survey at the time of diagnosis or by age 3 years, whichever is later; a screening for strabismus and nystagmus by their primary care provider at every well-child examination; referral to a pediatric ophthalmologist by age 6 months or at the time of diagnosis, whichever is later; evaluation for sensorineural hearing loss by 3 months of age, if not done previously; and a behavioral audiogram at 1 year of age, and audiograms obtained annually thereafter, at least through the age of speech development. Swarr et al. (2010) also recommended that FISH studies be performed on the parents of children diagnosed with PSS to assess for a balanced chromosomal rearrangement that would increase recurrence risk of PSS in future offspring.
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