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Potocki-Shaffer syndrome

General Information (adopted from Orphanet):

Synonyms, Signs:	DEFECT11 SYNDROME PSS proximal 11p deletion syndrome P11pDS CHROMOSOME 11p11.2 DELETION SYNDROME 11p11.2 deletion
Number of Symptoms	28
OrphanetNr:	52022
OMIM Id:	601224
ICD-10:	Q93.5
UMLs:	C1832588
MeSH:	C538356
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence:	23 cases [Orphanet]
Inheritance:	Unknown [Orphanet]
Age of onset:	Neonatal Infancy [Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases:

Genetic multiple congenital anomalies/dysmorphic syndrome - variable intellectual deficit
-Rare genetic disease
Multiple congenital anomalies/dysmorphic syndrome - variable intellectual deficit
-Rare developmental defect during embryogenesis
Partial deletion of the short arm of chromosome 11
-Rare developmental defect during embryogenesis
-Rare genetic disease

Symptom Information: Sort by abundance

	Symptom Information	Symptom	Abundance	Pubmed	Source	DB Freq
1	(HPO:0000054)	Micropenis	5/6 [HPO]	8644736	IBIS	257 / 7739
2	(HPO:0004331)	Decreased skull ossification	Very frequent [Orphanet]			31 / 7739
3	(HPO:0000494)	Downslanted palpebral fissures		8644736	IBIS	328 / 7739
4	(HPO:0004439)	Craniofacial dysostosis	frequent [HPO]	8644736	IBIS	3 / 7739
5	(HPO:0000337)	Broad forehead		8644736	IBIS	116 / 7739
6	(HPO:0000431)	Wide nasal bridge		8644736	IBIS	290 / 7739
7	(HPO:0000348)	High forehead		8644736	IBIS	157 / 7739
8	(HPO:0002645)	Wormian bones	3/6 [HPO]	8644736	IBIS	65 / 7739
9	(HPO:0000262)	Turricephaly				38 / 7739
10	(HPO:0002714)	Downturned corners of mouth	8/9 [HPO]	15852040	IBIS	98 / 7739
11	(HPO:0000430)	Underdeveloped nasal alae		8644736	IBIS	90 / 7739
12	(HPO:0000506)	Telecanthus	4/9 [HPO]	8644736	IBIS	156 / 7739
13	(HPO:0002697)	Parietal foramina	9/11 [HPO]	8644736	IBIS	12 / 7739
14	(HPO:0000248)	Brachycephaly	6/9 [HPO]	8644736	IBIS	222 / 7739
15	(HPO:0000322)	Short philtrum	6/9 [HPO]	15852040	IBIS	130 / 7739
16	(HPO:0003196)	Short nose		8644736	IBIS	264 / 7739
17	(HPO:0005338)	Sparse lateral eyebrow	6/9 [HPO]	15852040	IBIS	21 / 7739
18	(HPO:0000286)	Epicanthus	4/9 [HPO]	8644736	IBIS	371 / 7739
19	(HPO:0001250)	Seizures	2/11 [HPO]	8644736	IBIS	1245 / 7739
20	(HPO:0001249)	Intellectual disability	7/10 [HPO]	8644736	IBIS	1089 / 7739
21	(HPO:0000954)	Single transverse palmar crease	5/6 [HPO]	8644736	IBIS	162 / 7739
22	(HPO:0001156)	Brachydactyly syndrome	5/8 [HPO]	15852040	IBIS	180 / 7739
23	(HPO:0002762)	Multiple exostoses	10/10 [HPO]	8644736	IBIS	6 / 7739
24	(HPO:0100777)	Exostoses	Very frequent [Orphanet]			32 / 7739
25	(HPO:0005650)	Cutaneous syndactyly between fingers 2 and 5	rare [HPO]			1 / 7739
26	(HPO:0001252)	Muscular hypotonia	5/9 [HPO]	8644736	IBIS	990 / 7739
27	(HPO:0001466)	Contiguous gene syndrome				8 / 7739
28	(HPO:0012758)	Neurodevelopmental delay	Very frequent [Orphanet]			949 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol	Variation	Clinical significance	Reference

Additional Information:

Clinical Description OMIM

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 ... 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.

Symptoms & Signs

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