June 18, 2018
Years published: 1992, 1997, 2002, 2015, 2018
NORD gratefully acknowledges Daniela V. Luquetti, MD, PhD, Assistant Professor, Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, for assistance in the preparation of this report.
Miller syndrome, also known as postaxial acrofacial dysostosis, is a rare genetic disorder characterized by craniofacial malformations occurring along with abnormalities of the arms, hands and/or feet. Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Limb abnormalities may include incomplete development, webbing (syndactyly), and/or closure or absence of certain fingers and/or toes; and/or improper development and/or abnormal fusion of bones in the forearms (radioulnar synostosis), causing the forearms to appear unusually short. Additional physical abnormalities can occur in some cases. Intelligence is not affected. Miller syndrome is inherited in an autosomal recessive pattern caused by mutations in the DHODH gene.
Miller syndrome was first described in the medical field between 1969 and 1979 through several independent reports. The disorder is refereed by several names derived from some of the physicians who first reported the disorder including M. Miller, H.R. Wiedemann, and E. Genee. Some researchers believe that Miller syndrome represents a distinct entity under the broader term of “postaxial acrofacial dysostosis,” which would include other disorders with similar and overlapping craniofacial and limb abnormalities, but ultimately distinct symptoms.
The specific symptoms associated with Miller syndrome may vary from one person to another. Affected individuals may develop a variety of craniofacial and limb abnormalities. Most abnormalities are noticeable at birth.
Common craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); narrowing of the back of the nasal cavity (choanal atresia); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Additional craniofacial findings can include a gap of missing tissue in the upper lip (cleft lip), a broad bridge of the nose, downward-slanting palpebral fissures (which means that the opening between the eyelids slants downward), partial or total absence of the eyelashes of the lower eyelids, and lower eyelids that are turned (inverted) outwards so that the inner surface is exposed (ectropion).
Micrognathia and choanal atresia may contribute to difficulty breathing and/or feeding difficulties. Some affected individuals develop hearing loss due to improper conduction of sound from the outer or middle ear to the inner ear (conductive hearing loss). Hearing impairment may cause speech development to be delayed when not treated.
Individuals with Miller syndrome also have various abnormalities affecting the arms and legs including absence or abnormality of either the fifth or both the fourth and fifth fingers of the hands and toes of the feet and, in some cases, the ulna and/or the fibula may be underdeveloped. The ulna is the forearm bone on the pinky side of the arm; the fibula is the outer and narrower long bone of the lower legs, thus the medical term “postaxial” which refers to fourth and fifth fingers or toes; as well as the ulna and fibula. This can cause the forearms and/or the lower legs to appear short. Additional symptoms can occur including webbing (syndactyly) of the fingers and toes, underdevelopment of the thumbs, and the formation of an abnormal bone or soft tissue connection between the ulna and the radius, two main bones of the forearm (radioulnar synostosis).
In some cases, additional symptoms develop including growth deficiency after birth (postnatal growth deficiency), a sunken breastbone so that the chest appears ‘scooped out’ (pectus excavatum), rib defects, and extra (accessory) nipples. Affected infants may have hips that dislocate easily and may potentially be dislocated at birth. Affected male infants may have undescended testicles (cryptorchidism).
Some individuals have kidney, gastrointestinal or heart abnormalities. Kidney abnormalities may include the backflow of urine from the bladder to the kidneys (kidney reflux). Gastrointestinal abnormalities can include abnormal positioning of the intestines (midgut malrotation) and narrowing of the opening that connects the stomach to the duodenum, the first part of the small intestine (pyloric stenosis). Heart defects can include ventricular septal defects (VSDs), which are also known as a ‘hole in the heart’. VSDs are characterized by an abnormal opening in the wall (septum) that separates the lower chambers of the heart (ventricles).
Miller syndrome is caused by mutations in the dihydroorotate dehydrogenase (DHODH) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The DHODH gene contains instructions for creating (encoding) the enzyme dihydroorotate dehydrogenase. Mutations in this gene result in a deficiency of functional dihydroorotate dehydrogenase. This enzyme plays a role in the production (biosynthesis) of pyrimidine, which are compounds found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and certain molecules within the body. The exact underlying manner that decreased levels of functional dihydroorotate dehydrogenase contributes to the specific symptoms associated with Miller syndrome is not fully understood. Research into the underlying causes and genetic aspects of this disorder is ongoing.
Miller syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Miller syndrome is a rare disorder with an estimated prevalence of approximately 1 case per 1 million newborns. Because cases may go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Fewer than 75 cases have been described in the medical literature. Males and females are affected in equal numbers.
A diagnosis of Miller syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Many of the associated abnormalities are present at birth (congenital).
Specialized x-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormal smallness of the jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia).
Molecular genetic testing can confirm a diagnosis of Miller syndrome. Molecular genetic testing can detect a mutation the DHODH gene, but is available only as a diagnostic service at specialized laboratories.
The treatment of Miller syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, pediatric ear, nose and throat specialists (pediatric otolaryngologists), specialists in diagnosing and treating eye disorders (ophthalmologists), specialists in diagnosing and treating ear disorders (otologists), specialists in treating hearing loss (audiologists), specialists in treating kidney disorders (nephrologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Affected individuals may benefit from referral to a craniofacial center where a team of experienced specialists will coordinate care.
Specific treatment may consist of surgery to create a small opening in the throat, through which a small tube is inserted to assist with breathing. Additional jaw surgery may also be necessary to improve breathing. In addition, it might be also necessary to create a small opening in the stomach to allow the insertion of a feeding tube in infants experiencing difficulty eating in order to maintain proper nutrition.
Surgery may be required to correct abnormalities of the limbs, and eyes. Surgery and/or speech therapy may be necessary when cleft palate or cleft lip is present. Congenital heart defects often require surgical intervention.
Early intervention with appropriate physical, occupational, and speech therapy services is important in ensuring that affected children reach their full potential. Physical and occupational therapy may be necessary to aid in walking and using one’s hands. Speech therapy may be of benefit for individuals with speech development delays due to hearing loss. Hearing loss may require the use of a hearing aid.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Jones KL, Jones MC, del Campo Casanelles. Eds. Miller Syndrome (Postaxial Acrofacial Dysostosis Syndrome). In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:342.
Wulfsberg EA. Miller Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:222-223.
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Fang JX, Uchiumi T, Yagi M, et al. Protein instability and functional defects caused by mutations of dihydro-orotate dehydrogenase in Miller syndrome patients. Biosci Rep. 2012;32:631-639. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497730/
Kinoshita F, Kondoh T, Komori K, et al. Miller syndrome with novel dihydroorotate dehydrogenase gene mutations. Pediatr Int. 2011;53:587-591. http://www.ncbi.nlm.nih.gov/pubmed/21851494
Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a Mendelian disorder. Nat Genet. 2010;42:30-35. https://www.nature.com/articles/ng.499
Trainor PA, Andrews BT. 2013. Facial dysostoses: Etiology, pathogenesis and
management. Am J Med Genet Part C Semin Med Genet 163C:283–294.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:263750; Last Update: 01/07/2015. Available at: http://omim.org/entry/263750 Accessed June 18, 2018.
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