New Insights into Potocki-Shaffer Syndrome: Report of Two Novel Cases and Literature Review

Abstract

Potocki-Shaffer syndrome (PSS) is a rare non-recurrent contiguous gene deletion syndrome involving chromosome 11p11.2. Current literature implies a minimal region with haploinsufficiency of three genes, ALX4 (parietal foramina), EXT2 (multiple exostoses), and PHF21A (craniofacial anomalies, and intellectual disability). The rest of the PSS phenotype is still not associated with a specific gene. We report a systematic review of the literature and included two novel cases. Because deletions are highly variable in size, we defined three groups of patients considering the PSS-genes involved. We found 23 full PSS cases (ALX4, EXT2, and PHF21A), 14 cases with EXT2-ALX4, and three with PHF21A only. Among the latter, we describe a novel male child showing developmental delay, café-au-lait spots, liner postnatal overgrowth and West-like epileptic encephalopathy. We suggest PSS cases may have epileptic spasms early in life, and PHF21A is likely to be the causative gene. Given their subtle presentation these may be overlooked and if left untreated could lead to a severe type or deterioration in the developmental plateau. If our hypothesis is correct, a timely therapy may ameliorate PSS phenotype and improve patients' outcomes. Our analysis also shows PHF21A is a candidate for the overgrowth phenotype.

Keywords: LSD-CoREST; PHF21A; Potocki-Shaffer; SCNA; epileptic encephalopathy; infantile spasms; intellectual disability; west syndrome.

Figure 1

Photography of patient 1 (Decipher 286390) at 20 years old. She has a high and broad forehead, sparse lateral eyebrows, long nose with prominent nasal bridge, short and smooth philtrum, thin lips, prominent chin with horizontal crease, quite large mouth, and a short neck. There is a large abduction and an external rotation of the two hips.

Figure 2

Electroencephalography (EEG): interictal hypsarrhythmia. Slow high voltage of delta and theta activity (circles on the left), mono/polymorphic preceded by multifocal PO (arrows on the left), PPO spike (arrows on the right).

Figure 3

Scheme for the 40 known deletions encompassing the Potocki-Shaffer syndrome (PSS) critical region. In red, the extension of the minimal deleted region. Vertical light blue lines indicate the borders of the critical PSS region, spanning the PHF21A, ALX4, and EXT2 genes. Black vertical lines indicate the redefined critical region for ID/DD in PSS: a ~1.1 Mb region containing 12 annotated genes between markers D11S554 and D11S1319 [22]. On the left side, the PAX6 and WT1 genes associated with Wilms’ tumor, aniridia, genitourinary anomalies/gonadoblastoma and mental retardation syndrome (WAGR). Note that some of the red bars indicate more than one case in the same family.