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ALX4 gene
URL of this page: https://medlineplus.gov/genetics/gene/alx4/

ALX4 gene

ALX homeobox 4

Normal Function

The ALX4 gene provides instructions for making a member of the homeobox protein family. Homeobox proteins direct the formation of body structures during early embryonic development. The ALX4 protein is necessary for normal development of the head.

The ALX4 protein is a transcription factor, which means that it attaches (binds) to DNA and controls the activity of certain genes. Specifically, the protein controls the activity of genes that regulate cell growth and division (proliferation), cell maturation and specialization (differentiation), cell movement (migration), and cell survival. The ALX4 protein also interacts with other transcription factors to help regulate these functions and ensure that cells start and stop growing at specific times and that they are positioned correctly during development.

Health Conditions Related to Genetic Changes

Enlarged parietal foramina

Changes in the ALX4 gene have been found to cause enlarged parietal foramina. Genetic changes that cause disease are called pathogenic variants. Enlarged parietal foramina is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. Openings in the parietal bones are normal during fetal development, but they usually close before birth. In people with this condition, the parietal foramina remain enlarged and may persist after birth. ALX4 gene variants cause a form of the condition known as enlarged parietal foramina type 2.

 Pathogenic variants in the ALX4 gene can cause cells to produce a version of the ALX4 protein that cannot bind to DNA. This impairs the regulation of multiple genes, and several cell processes are disrupted. The skull seems to be particularly sensitive to changes in ALX4 protein activity during early development. Specifically, the cells in the skull that are involved in bone formation (ossification) cannot function normally, leading to a lack of bone in certain areas of the skull and enlarged parietal foramina.

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Frontonasal dysplasia

Pathogenic variants in the ALX4 gene also cause a condition called frontonasal dysplasia. This condition is characterized by abnormal development of structures in the head and face. ALX4 gene variants cause a form of the condition called frontonasal dysplasia type 2. In addition to the facial features typically seen in people with frontonasal dysplasia, people with type 2 may also have genital abnormalities, hair loss (alopecia), and enlarged parietal foramina.

The ALX4 gene variants that are associated with frontonasal dysplasia type 2 cause cells to produce versions of the ALX4 protein that have a severely reduced function or cannot function at all. As a result, the protein cannot bind to DNA and regulate gene activity. This leads to poorly controlled cell proliferation and migration during development, resulting in abnormal formation of structures in the head and face. In some individuals, ALX4 gene variants impair the function of hair follicles and lead to alopecia.

Because enlarged parietal foramina can be a feature of frontonasal dysplasia type 2, and because the two conditions are caused by variants in the same gene, it is unclear whether these conditions are distinct disorders or part of a disease spectrum.

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Potocki-Shaffer syndrome

Certain genetic changes that affect the ALX4 gene are associated with a condition called Potocki-Shaffer syndrome. This condition affects the development of the bones, brain, and other tissues. Characteristic bone abnormalities include enlarged parietal foramina and multiple noncancerous bone tumors (osteochondromas). Other signs and symptoms seen in people with Potocki-Shaffer syndrome include intellectual disabilities, developmental delays, and distinctive facial features.

Potocki-Shaffer syndrome is caused by a deletion of genetic material from the short (p) arm of chromosome 11. In people with this condition, a loss of the ALX4 gene within this region is responsible for the enlarged parietal foramina. This feature occurs because a shortage of the ALX4 protein disrupts several cellular processes and impairs ossification.

The loss of additional genes in the deleted region likely contributes to the other features of Potocki-Shaffer syndrome. For example, the loss of the EXT2 gene results in multiple osteochondromas, and the deletion of the PHF21A gene causes intellectual disabilities and distinctive facial features.

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Other Names for This Gene

  • homeodomain transcription factor ALX4
  • KIAA1788
  • PFM

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Cain B, Yuan Z, Thoman E, Kovall RA, Gebelein B. The ALX4 dimer structure provides insight into how disease alleles impact function. Nat Commun. 2025 May 23;16(1):4800. doi: 10.1038/s41467-025-59728-9. Citation on PubMed
  • Griessenauer CJ, Veith P, Mortazavi MM, Stewart C, Grochowsky A, Loukas M, Tubbs RS. Enlarged parietal foramina: a review of genetics, prognosis, radiology, and treatment. Childs Nerv Syst. 2013 Apr;29(4):543-7. doi: 10.1007/s00381-012-1982-7. Epub 2012 Dec 4. Citation on PubMed
  • Kayserili H, Uz E, Niessen C, Vargel I, Alanay Y, Tuncbilek G, Yigit G, Uyguner O, Candan S, Okur H, Kaygin S, Balci S, Mavili E, Alikasifoglu M, Haase I, Wollnik B, Akarsu NA. ALX4 dysfunction disrupts craniofacial and epidermal development. Hum Mol Genet. 2009 Nov 15;18(22):4357-66. doi: 10.1093/hmg/ddp391. Epub 2009 Aug 19. Citation on PubMed
  • Mavrogiannis LA, Wilkie AOM. Enlarged Parietal Foramina. 2004 Mar 30 [updated 2025 Jun 26]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1128/ Citation on PubMed
  • Romeike BF, Wuyts W. Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature. Clin Neuropathol. 2007 Jan-Feb;26(1):1-11. doi: 10.5414/npp26001. Citation on PubMed
  • Wakui K, Gregato G, Ballif BC, Glotzbach CD, Bailey KA, Kuo PL, Sue WC, Sheffield LJ, Irons M, Gomez EG, Hecht JT, Potocki L, Shaffer LG. Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki-Shaffer syndrome. Eur J Hum Genet. 2005 May;13(5):528-40. doi: 10.1038/sj.ejhg.5201366. Citation on PubMed
  • Wu YQ, Badano JL, McCaskill C, Vogel H, Potocki L, Shaffer LG. Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Am J Hum Genet. 2000 Nov;67(5):1327-32. doi: 10.1016/S0002-9297(07)62963-2. Epub 2000 Oct 3. Citation on PubMed or Free article on PubMed Central
  • Wuyts W, Cleiren E, Homfray T, Rasore-Quartino A, Vanhoenacker F, Van Hul W. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J Med Genet. 2000 Dec;37(12):916-20. doi: 10.1136/jmg.37.12.916. Citation on PubMed or Free article on PubMed Central
  • Wuyts W, Waeber G, Meinecke P, Schuler H, Goecke TO, Van Hul W, Bartsch O. Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects. Eur J Hum Genet. 2004 May;12(5):400-6. doi: 10.1038/sj.ejhg.5201163. Citation on PubMed

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