PHF21A Related Disorder: Description of a New Case.

PHF21A (PHD finger protein 21A) gene, located in the short arm of chromosome 11, encodes for BHC80, a component of the Lysine Specific Demethylase 1, Corepressor of REST (LSD1-CoREST) complex. BHC80 is mainly expressed in the human fetal brain and skeletal muscle and acts as a modulator of several neuronal genes during embryogenesis. Data from literature relates PHF21A variants with Potocki-Shaffer Syndrome (PSS), a contiguous gene deletion disorder caused by the haploinsufficiency of PHF21A, ALX4, and EXT2 genes. Clinical cardinal features of PSS syndrome are multiple exostoses (due to the EXT2 involvement), biparietal foramina (due to the ALX4 involvement), intellectual disability, and craniofacial anomalies (due to the PHF21A involvement). To date, to the best of our knowledge, a detailed description of PHF21A-related disorder clinical phenotype is not described in the literature; in fact, only 14 subjects with microdeletion frameshift or nonsense variants concerning only PHF21A gene have been reported. All reported cases did not present ALX4 or EXT2 variants, and their clinical features did not fit with PSS diagnosis. Herein, by using Exome sequencing, and Sanger sequencing of the region of interest, we describe a case of a child with a paternally inherited (mosaicism of 5%) truncating variant of the PHF21A gene (c.649_650del; p.Gln217ValfsTer6), and discuss the new evidence. In conclusion, these patients showed varied clinical expressions, mainly including the presence of intellectual disability, epilepsy, hypotonia, and dysmorphic features. Our study contributes to describing the genotype-phenotype spectrum of patients with PHF21A-related disorder; however, the limited data in the literature have been unable to provide a precise diagnostic protocol for patients with PHF21A-related disorder.

Novel Pathogenic Variant (c.1171A>T) in PHF21A in a Female with Intellectual Disability and Craniofacial Anomalies.

Background: PHF21A, along with EXT2 and ALX4, is one of the causative genes of Potocki-Shaffer syndrome (PSS), a rare contiguous disorder involving chromosome region11p11.2. PHF21A has been associated with intellectual developmental disorders and craniofacial anomalies and suggested as a candidate for more extended phenotypes. However, variants in PHF21A and its associated phenotypes are yet to be fully explored, since reports on cases with variants affecting this gene are few worldwide. We present a novel heterogeneous variant in PHF21A in a 26-year-old Korean female. Methods: The patient's clinical manifestations were recorded and physical examination, cognitive assessment, brain imaging, metabolic screening, and cytogenetic testing including whole exome sequencing were pursued. Results: Whole exome sequencing identified a de novo nonsense variant c.1171A>T (p.Lys391Ter), affecting the AT-hook domain. The patient showed an extended phenotypic spectrum along with intellectual developmental disorders and craniofacial anomalies, such as attention-deficit hyperactivity disorder, epilepsy, overgrowth, and hypotonia. Variants affecting the AT-hook domain are few in PSS, however, the phenotypic spectrum of the patient was in line with previously reported cases. Conclusion: This case further reinforced and adds to the extended data on the phenotypes associated with PHF21A haploinsufficiency.

Multiple Osteochondromas Comorbid With Enlarged Parietal Foramina, Elongated Styloid Processes, and Tibiofibular Synostosis.

OBJECTIVES: This study investigates a unique case of multiple osteochondromas (MO) comorbid with enlarged parietal foramina and correlates the findings with the existing literature. The aim of this study is to provide a deeper understanding of anatomic variation for physicians. METHODS: A 66-year-old White male donor was examined during a routine cadaveric dissection performed by medical students in an anatomy laboratory. Detailed exploration of the skeleton and organs was performed, and photographs were taken. Tissue samples were obtained from multiple outgrowths, and histopathologic examination was done. RESULTS: Bilateral bony growths were noted rising from the long bones of the upper and lower extremities (femur, tibia, fibula, and radius). An accessory muscle was found to be associated with the left radial bony growth. Histopathologic examination was positive for osteochondroma. Inspection of the skull revealed enlarged parietal foramina. Other findings included tibiofibular synostosis, abnormally shaped vertebral bodies and ribs, and elongated styloid processes of the skull. CONCLUSIONS: In combination with the histopathologic examination, the case report and literature review elucidate a more precise clinical picture for those affected with MO or similar disorders. This report also emphasizes the necessity of further investigation of the pathogenesis of MO and Potocki-Shaffer syndrome.

Hypertension in Potocki-Shaffer syndrome: A case report.

Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome caused by heterozygous deletion of 11p11.2p12. Typical features described in patients with PSS include developmental delay, intellectual disability, multiple cartilaginous exostoses, biparietal foramina, craniofacial abnormalities, and genitourinary anomalies. While hypertension has been noted in three patients with PSS, it has not been described in most patients with this syndrome. This report details the evaluation and treatment of a teenager with PSS who presented on several occasions during childhood with elevated blood pressure measurements. The renin level was elevated, likely indicating a secondary cause for the HTN. The patient's BP responded to monotherapy with Angiotensin Converting Enzyme Inhibitor (ACEI).

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism.

Background: PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods: Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results: We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. Conclusion: Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.

Transcriptome Analysis Revealed Impaired cAMP Responsiveness in PHF21A-Deficient Human Cells.

Potocki-Shaffer Syndrome is a rare neurodevelopmental syndrome associated with microdeletion of a region of Chromosome 11p11.2. Genetic evidence has implicated haploinsufficiency of PHF21A, a gene that encodes a histone-binding protein, as the likely cause of intellectual disability and craniofacial abnormalities in Potocki-Shaffer Syndrome. However, the molecular consequences of reduced PHF21A expression remain elusive. In this study, we analyzed by RNA-Sequencing (RNA-Seq) two patient-derived cell lines with heterozygous loss of PHF21A compared to unaffected individuals and identified 1,885 genes that were commonly misregulated. The patient cells displayed down-regulation of key pathways relevant to learning and memory, including Cyclic Adenosine Monophosphate (cAMP)-signaling pathway genes. We found that PHF21A is required for full induction of a luciferase reporter carrying cAMP-responsive elements (CRE) following stimulation by the cAMP analog, forskolin. Finally, PHF21A-deficient patient-derived cells exhibited a delayed induction of immediate early genes following forskolin stimulation. These results suggest that an impaired response to cAMP signaling might be involved in the pathology of PHF21A deficiency. This article is part of a Special Issue entitled: [SI: Molecules & Cognition].

Potocki-Shaffer syndrome in a child without intellectual disability-The role of PHF21A in cognitive function.

Potocki-Shaffer syndrome is a contiguous gene deletion syndrome involving 11p11.2p12 and characterized by multiple exostoses, biparietal foramina, genitourinary anomalies in males, central nervous system abnormalities, intellectual disability, and craniofacial abnormalities. Current literature implicates haploinsufficiency of three genes (ALX4, EXT2, and PHF21A) in causing some of the cardinal features of PSS. We report a patient with multiple exostoses, biparietal foramina, and history of mild developmental delay. Cognitive and behavioral testing supported formal diagnoses of anxiety, verbal dyspraxia, articulation disorder, and coordination disorder, without intellectual disability. His facial features, though distinctive, were not typical of those observed in PSS. As the chromosomal deletion does not encompass PHF21A, this case lends further support that haploinsufficiency of PHF21A contributes to the intellectual disability and craniofacial abnormalities in PSS and that there are other genes in the region which likely contribute to the behavioral phenotype in this syndrome. © 2017 Wiley Periodicals, Inc.

Congenital biparietal foramina presenting with multiple concussions.

We report a man with biparietal foramina secondary to Potocki-Shaffer syndrome. This is due to incomplete ossification of parietal bones secondary to haploinsuffiency of ALX4 gene. He presented with multiple episodes of concussion following minimal head trauma. Cranioplasty was performed to close the skull defects with the aim of preventing further concussion and permanent traumatic brain injury.

A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.

In Potocki-Shaffer syndrome (PSS), the full phenotypic spectrum is manifested when deletions are at least 2.1 Mb in size at 11p11.2. The PSS-associated genes EXT2 and ALX4, together with PHF21A, all map to this region flanked by markers D11S1393 and D11S1319. Being proximal to EXT2 and ALX4, a 1.1 Mb region containing 12 annotated genes had been identified by deletion mapping to explain PSS phenotypes except multiple exostoses and parietal foramina. Here, we report a male patient with partial PSS phenotypes including global developmental delay, craniofacial anomalies, minor limb anomalies, and micropenis. Using microarray, qPCR, RT-qPCR, and Western blot analyses, we refined the candidate gene region, which harbors five genes, by excluding two genes, SLC35C1 and CRY2, which resulted in a corroborating role of PHF21A in developmental delay and craniofacial anomalies. This microdeletion contains the least number of genes at 11p11.2 reported to date. Additionally, we also discuss the phenotypes observed in our patient with respect to those of published cases of microdeletions across the Potocki-Shaffer interval.

The first Korean patient with Potocki-Shaffer syndrome: a rare cause of multiple exostoses.

Potocki-Shaffer syndrome (PSS, OMIM #601224) is a rare contiguous gene deletion syndrome caused by haploinsufficiency of genes located on the 11p11.2p12. Affected individuals have a number of characteristic features including multiple exostoses, biparietal foramina, abnormalities of genitourinary system, hypotonia, developmental delay, and intellectual disability. We report here on the first Korean case of an 8-yr-old boy with PSS diagnosed by high resolution microarray. Initial evaluation was done at age 6 months because of a history of developmental delay, hypotonia, and dysmorphic face. Coronal craniosynostosis and enlarged parietal foramina were found on skull radiographs. At age 6 yr, he had severe global developmental delay. Multiple exostoses of long bones were detected during a radiological check-up. Based on the clinical and radiological features, PSS was highly suspected. Subsequently, chromosomal microarray analysis identified an 8.6 Mb deletion at 11p11.2 [arr 11p12p11.2 (Chr11:39,204,770-47,791,278)×1]. The patient continued rehabilitation therapy for profound developmental delay. The progression of multiple exostosis has being monitored. This case confirms and extends data on the genetic basis of PSS. In clinical and radiologic aspect, a patient with multiple exostoses accompanying with syndromic features, including craniofacial abnormalities and mental retardation, the diagnosis of PSS should be considered.

Potocki-Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype.

Frontonasal dysplasia (FND) is a genetically heterogeneous malformation spectrum with marked hypertelorism, broad nasal tip and bifid nose. Only a small number of genes have been associated with FND phenotypes until now, the first gene being EFNB1, related to craniofrontonasal syndrome (CFNS) with craniosynostosis in addition, and more recently the aristaless-like homeobox genes ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively. We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. While molecular investigations did not reveal mutations in any of the known genes, ALX4, ALX3, ALX1 and EFNB1, comparative genomic hybridization (array CGH) techniques showed a large heterozygous de novo deletion at 11p11.12p12, encompassing the ALX4 gene. Deletions in this region have been described in patients with Potocki-Shaffer syndrome (PSS), characterized by biparietal foramina, multiple exostoses, and intellectual disability. Although the patient reported herein manifests some overlapping features of FND and PPS, it is likely that the observed phenotype maybe due to a second unidentified mutation in the ALX4 gene. The phenotype will be discussed in view of the deleted region encompassing the ALX4 gene.