ALX4 – Potocki-Shaffer Syndrome

Potocki-Shaffer syndrome is an autosomal dominant contiguous gene deletion syndrome on chromosome 11p11.2 characterized by multiple exostoses, biparietal foramina, and craniofacial dysmorphisms. Haploinsufficiency of ALX4 contributes to parietal foramina and cranial ossification defects.

In over 40 unrelated PSS cases, high-resolution microarray and FISH analyses consistently demonstrate hemizygous deletion of ALX4 within the minimal critical region that also encompasses EXT2 and PHF21A (PMID:33126574). Two unrelated patients presenting with isolated biparietal foramina but lacking larger deletions harbored heterozygous truncating variants in ALX4 (c.331C>T (p.Gln111Ter)) confirming ALX4 as the causative locus for this feature (PMID:11137991).

Genetic studies have captured ALX4 deletions in at least 30 PSS probands and two independent families with non-syndromic parietal foramina, totaling >32 ALX4 loss-of-function alleles (PMID:11017806, PMID:11137991). No significant familial segregation beyond de novo or sporadic cases has been reported.

Functional assays reveal that ALX4 is expressed specifically in developing bone and is dosage-sensitive: murine Alx4 haploinsufficiency recapitulates parietal foramina, and human FISH mapping confirms ALX4 deletion in PSS patients (PMID:11017806). The concordance of genotype and phenotype supports haploinsufficiency as the primary mechanism.

Although duplication of 11p11.12p12 yields PSS-like craniofacial features without exostoses, this does not dispute ALX4 loss-of-function in the deletion syndrome context but rather underscores distinct gene-dosage effects.

In summary, ALX4 haploinsufficiency is strongly associated with Potocki-Shaffer syndrome, specifically driving biparietal foramina and contributing to craniofacial anomalies within the contiguous gene deletion. Clinical testing for ALX4 dosage should be considered in patients with parietal foramina, especially when broader PSS features are present.

References

• Nature genetics • 2001 • Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. PMID:11137991
• American journal of human genetics • 2000 • Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. PMID:11017806
• Brain sciences • 2020 • New Insights into Potocki-Shaffer Syndrome: Report of Two Novel Cases and Literature Review. PMID:33126574
• European journal of human genetics : EJHG • 2005 • Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. PMID:15702131

Evidence Based Scoring (AI generated)