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

Miller syndrome

Reviewed August 2010

What is Miller syndrome?

Miller syndrome is a rare condition that mainly affects the development of the face and limbs. The severity of this disorder varies among affected individuals.

Children with Miller syndrome are born with underdeveloped cheek bones (malar hypoplasia) and a very small lower jaw (micrognathia). They often have an opening in the roof of the mouth (cleft palate) and/or a split in the upper lip (cleft lip). These abnormalities frequently cause feeding problems in infants with Miller syndrome. The airway is usually restricted due to the micrognathia, which can lead to life-threatening breathing problems.

People with Miller syndrome often have eyes that slant downward, eyelids that turn out so the inner surface is exposed (ectropion), and a notch in the lower eyelids called an eyelid coloboma. Many affected individuals have small, cup-shaped ears, and some have hearing loss caused by defects in the middle ear (conductive hearing loss). Another feature of this condition is the presence of extra nipples. Miller syndrome does not affect a person's intelligence, although speech development may be delayed due to hearing impairment.

Individuals with Miller syndrome have various bone abnormalities in their arms and legs. The most common problem is absent fifth (pinky) fingers and toes. Affected individuals may also have webbed or fused fingers or toes (syndactyly) and abnormally formed bones in the forearms and lower legs. People with Miller syndrome sometimes have defects in other bones, such as the ribs or spine.

Less commonly, affected individuals have abnormalities of the heart, kidneys, genitalia, or gastrointestinal tract.

How common is Miller syndrome?

Miller syndrome is a rare disorder; it is estimated to affect fewer than 1 in 1 million newborns. At least 30 cases have been reported in the medical literature.

What genes are related to Miller syndrome?

Mutations in the DHODH gene cause Miller syndrome. This gene provides instructions for making an enzyme called dihydroorotate dehydrogenase. This enzyme is involved in producing pyrimidines, which are building blocks of DNA, its chemical cousin RNA, and molecules such as ATP and GTP that serve as energy sources in the cell. Specifically, dihydroorotate dehydrogenase converts a molecule called dihydroorotate to a molecule called orotic acid. In subsequent steps, other enzymes modify orotic acid to produce pyrimidines.

Miller syndrome disrupts the development of structures called the first and second pharyngeal arches. The pharyngeal arches are five paired structures that form on each side of the head and neck during embryonic development. These structures develop into the bones, skin, nerves, and muscles of the head and neck. In particular, the first and second pharyngeal arches develop into the jaw, the nerves and muscles for chewing and facial expressions, the bones in the middle ear, and the outer ear. It remains unclear exactly how DHODH gene mutations lead to abnormal development of the pharyngeal arches in people with Miller syndrome.

Development of the arms and legs is also affected by Miller syndrome. Each limb starts out as a small mound of tissue called a limb bud, which grows outward. Many different proteins are involved in the normal shaping (patterning) of each limb. Once the overall pattern of a limb is formed, detailed shaping can take place. For example, to create individual fingers and toes, certain cells self-destruct (undergo apoptosis) to remove the webbing between each digit. The role dihydroorotate dehydrogenase plays in limb development is not known. It is also unknown how mutations in the DHODH gene cause bone abnormalities in the arms and legs of people with Miller syndrome.

Related Gene(s)

Changes in this gene are associated with Miller syndrome.


How do people inherit Miller syndrome?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of Miller syndrome?

These resources address the diagnosis or management of Miller syndrome and may include treatment providers.

  • Foundation for Nager and Miller Syndromes (
  • Genetic Testing Registry: Miller syndrome (

You might also find information on the diagnosis or management of Miller syndrome in Educational resources and Patient support.

General information about the diagnosis ( and management ( of genetic conditions is available in the Handbook. Read more about genetic testing (, particularly the difference between clinical tests and research tests (

To locate a healthcare provider, see How can I find a genetics professional in my area? ( in the Handbook.

Where can I find additional information about Miller syndrome?

You may find the following resources about Miller syndrome helpful. These materials are written for the general public.

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

What other names do people use for Miller syndrome?

  • Genee-Wiedemann acrofacial dysostosis
  • Genee-Wiedemann syndrome
  • postaxial acrofacial dysostosis (POADS)

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines ( and How are genetic conditions and genes named? ( in the Handbook.

What if I still have specific questions about Miller syndrome?

Ask the Genetic and Rare Diseases Information Center (

What glossary definitions help with understanding Miller syndrome?

apoptosis ; ATP ; autosomal ; autosomal recessive ; bud ; cell ; cleft palate ; conductive hearing loss ; dehydrogenase ; DNA ; embryonic ; enzyme ; gastrointestinal ; gene ; genitalia ; GTP ; hypoplasia ; inherited ; lower jaw ; micrognathia ; molecule ; palate ; pyrimidines ; recessive ; RNA ; syndactyly ; syndrome ; tissue

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


  • Biesecker LG. Exome sequencing makes medical genomics a reality. Nat Genet. 2010 Jan;42(1):13-4. doi: 10.1038/ng0110-13. (
  • Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr. 2007 Jun;137(6 Suppl 2):1656S-1661S. Review. (
  • Gurrieri F, Kjaer KW, Sangiorgi E, Neri G. Limb anomalies: Developmental and evolutionary aspects. Am J Med Genet. 2002 Dec 30;115(4):231-44. Review. (
  • Neumann L, Pelz J, Kunze J. A new observation of two cases of acrofacial dysostosis type Genée-Wiedemann in a family--remarks on the mode of inheritance: report on two sibs. Am J Med Genet. 1996 Sep 6;64(4):556-62. (
  • Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13. (
  • Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 2010 Apr 30;328(5978):636-9. doi: 10.1126/science.1186802. Epub 2010 Mar 10. (


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: August 2010
Published: February 1, 2016