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Genetics Home Reference: your guide to understanding genetic conditions     A service of the U.S. National Library of Medicine®


Reviewed April 2014

What is the official name of the ALX4 gene?

The official name of this gene is “ALX homeobox 4.”

ALX4 is the gene's official symbol. The ALX4 gene is also known by other names, listed below.

What is the normal function of the ALX4 gene?

The ALX4 gene provides instructions for making a protein that is 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 and face, particularly the formation of the nose, which begins around the fourth week of development. This protein is also involved in the formation of skin layers, but its role in this process is poorly understood. 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) and movement (migration), ensuring that cells grow and stop growing at specific times and that they are positioned correctly during development.

Does the ALX4 gene share characteristics with other genes?

The ALX4 gene belongs to a family of genes called homeobox (homeoboxes).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? ( in the Handbook.

How are changes in the ALX4 gene related to health conditions?

enlarged parietal foramina - caused by mutations in the ALX4 gene

A few mutations in the ALX4 gene have been identified in people with enlarged parietal foramina type 2. This condition is characterized by enlarged openings (foramina) in the two bones that make up much of the top and sides of the skull (the parietal bones). The mutations involved in this condition include a change of one protein building block (amino acid) in the ALX4 protein and deletions of one or more DNA building blocks (nucleotides) from the gene. These genetic changes result in the production of an unstable ALX4 protein that cannot bind to DNA. A nonfunctional ALX4 protein impairs the regulation of cell proliferation; cell maturation and specialization (differentiation); and the balance of cell survival and self-destruction in certain areas of the skull. These impairments of cell function lead to problems with bone formation (ossification) in the skull, which cause enlarged parietal foramina.

frontonasal dysplasia - caused by mutations in the ALX4 gene

At least four mutations in the ALX4 gene have been found to cause frontonasal dysplasia. ALX4 gene mutations cause a form of the disorder called frontonasal dysplasia type 2. In addition to facial malformations, this type can include features such as genital abnormalities in males, hair loss (alopecia), and enlarged parietal foramina (described above). The ALX4 gene mutations that cause frontonasal dysplasia type 2 severely reduce or eliminate the function of the ALX4 protein. As a result, the protein cannot bind to DNA and regulate gene function, which leads to poorly controlled cell proliferation and migration during development. This abnormal cell growth and movement leads to malformations in the middle of the face, particularly affecting the nose, which leads to openings (clefts) in the nose. This abnormal development can also interfere with the proper formation of the skull, which likely contributes to enlarged parietal foramina. In some individuals, ALX4 gene mutations impair the function of hair follicles under the skin causing alopecia, but the mechanism is unclear.

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

Potocki-Shaffer syndrome - caused by mutations in the ALX4 gene

A mutation resulting in the deletion of the ALX4 gene causes a condition called Potocki-Shaffer syndrome. People with this condition have enlarged parietal foramina (described above) and multiple benign bone tumors (exostoses). Other signs and symptoms seen in some people with Potocki-Shaffer syndrome include intellectual disability, developmental delay, distinctive facial features, vision problems, and defects in the heart, kidneys, and urinary tract.

Potocki-Shaffer syndrome (also called proximal 11p deletion 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 enlarged parietal foramina. This feature occurs because a shortage of the ALX4 transcription factor caused by deletion of the gene disrupts several cellular processes and impairs proper bone formation (ossification). The loss of another gene, EXT2, in the same region of chromosome 11 underlies the multiple exostoses. The loss of additional genes in the deleted region likely contributes to the other features of Potocki-Shaffer syndrome.

Where is the ALX4 gene located?

Cytogenetic Location: 11p11.2

Molecular Location on chromosome 11: base pairs 44,260,438 to 44,319,220

(Homo sapiens Annotation Release 107, GRCh38.p2) (NCBI (

The ALX4 gene is located on the short (p) arm of chromosome 11 at position 11.2.

The ALX4 gene is located on the short (p) arm of chromosome 11 at position 11.2.

More precisely, the ALX4 gene is located from base pair 44,260,438 to base pair 44,319,220 on chromosome 11.

See How do geneticists indicate the location of a gene? ( in the Handbook.

Where can I find additional information about ALX4?

You and your healthcare professional may find the following resources about ALX4 helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the ALX4 gene or gene products?

  • FPP
  • homeodomain transcription factor ALX4
  • KIAA1788
  • PFM
  • PFM2

See How are genetic conditions and genes named? ( in the Handbook.

What glossary definitions help with understanding ALX4?

alopecia ; amino acid ; benign ; bone formation ; cell ; cell proliferation ; chromosome ; deletion ; developmental delay ; differentiation ; disability ; DNA ; dysplasia ; embryonic ; exostoses ; gene ; homeobox ; homeodomain ; mutation ; ossification ; proliferation ; protein ; proximal ; spectrum ; syndrome ; transcription ; transcription factor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.


  • Antonopoulou I, Mavrogiannis LA, Wilkie AO, Morriss-Kay GM. Alx4 and Msx2 play phenotypically similar and additive roles in skull vault differentiation. J Anat. 2004 Jun;204(6):487-99. (
  • Gene Review: Enlarged Parietal Foramina (
  • Hall CR, Wu Y, Shaffer LG, Hecht JT. Familial case of Potocki-Shaffer syndrome associated with microdeletion of EXT2 and ALX4. Clin Genet. 2001 Nov;60(5):356-9. (
  • Kayserili H, Altunoglu U, Ozgur H, Basaran S, Uyguner ZO. Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations. Am J Med Genet A. 2012 Jan;158A(1):236-44. doi: 10.1002/ajmg.a.34390. Epub 2011 Dec 2. (
  • 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. (
  • Mavrogiannis LA, Antonopoulou I, Baxová A, Kutílek S, Kim CA, Sugayama SM, Salamanca A, Wall SA, Morriss-Kay GM, Wilkie AO. Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nat Genet. 2001 Jan;27(1):17-8. (
  • NCBI Gene (
  • 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. Review. (
  • 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. (
  • 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. Epub 2000 Oct 3. (
  • 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. (
  • Wuyts W, Waeber G, Meinecke P, Schüler 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. Review. (


The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? ( in the Handbook.

Reviewed: April 2014
Published: February 1, 2016