Miller–Dieker syndrome

Miller–Dieker syndrome
Classification and external resources
Specialty medical genetics
ICD-9-CM 758.33
OMIM 247200
DiseasesDB 29494
MeSH D054221

Miller–Dieker syndrome (abbreviated MDS), Miller–Dieker lissencephaly syndrome (MDLS), and chromosome 17p13.3 deletion syndrome[1] is a micro deletion syndrome characterized by congenital malformations (a physical defect detectable in an infant at birth which can involve many different parts of the body including the brain, hearts, lungs, liver, bones, or intestinal tract). In this case, it is usually mainly the brain being affected. The congenital malformation can be genetic random and of unknown origin. The malformation is in fact characterized by lissencephaly (smooth brain). MDS is a contiguous gene syndrome, as well, which is a disorder due to the deletion of multiple gene loci that are adjacent to one another. The disorder arises from the deletion of part of the small arm of chromosome 17p (which includes both the LIS1 and 14-3-3 epsilon genes), leading to partial monosomy. There may be unbalanced translocations (i.e. 17q:17p or 12q:17p), or the presence of a ring chromosome 17.

This syndrome should not be confused with Miller syndrome, an unrelated rare genetic disorder, or Miller Fisher syndrome, a form of Guillain–Barré syndrome.

Early detection

With the use of prenatal ultrasonographic imaging, early detection of abnormal brain development in the fetus with MDS can be seen. At birth, facial dysmorphism can be present in the infant. Young children, when affected, can suffer from feeding difficulties, severe intellectual disability, developmental delay, and seizures. An early way to detect this syndrome in children can be by brain MRI which can show the image of smooth brain, also called lissencephaly.[2] Children with this syndrome may remain underdiagnosed because of how rare it is, and how common it is to have facial features that appear to be dysmorphic. They are highly variable and not easily recognizable because this syndrome shares distinct external features (phenotype) similar to more common syndromes. Lack of relevant family history can also prevent suspicion in many cases. FDNA provides a service that in turn increases the chances of detecting these distinct characteristics, which, when shown to a geneticist, can assist in reaching the right medical diagnosis. If a couple has had one child with MDS, they can be offered prenatal diagnosis in future pregnancies. This option is particularly important for the 20% of MDS families where one parent carries a balanced chromosome rearrangement. The risk for these couples to have another affected child depends on the exact type of chromosome rearrangement present and may be as high as 25-33%. For families in which both parents' chromosomes are normal, the risk of having another child with MDS is low (1% or less). Either chorionic villus sampling (CVS) or amniocentesis can be used early in a pregnancy to obtain a small sample of cells from the developing embryo for chromosome studies. Early prenatal diagnosis by ultrasound is not reliable because the brain is normally smooth until later in pregnancy. Couples who are considering prenatal diagnosis should discuss the risks and benefits of this type of testing with a geneticist or genetic counselor.

Visuals of the brain

The brain is usually grossly abnormal in outline when someone is diagnosed with Miller–Dieker syndrome. Only a few shallow sulci and shallow Sylvian fissures are seen; this takes on an hourglass or figure-8 appearance on the axial imaging. The thickness and measurement for a person without MDS is 3–4 mm. With MDS, a person's cortex is measured at 12–20 mm.


The brain is abnormally smooth, with fewer folds and grooves. The face, especially in children, has distinct characteristics including a short nose with upturned nares, thickened upper lip with a thin vermilion upper border, frontal bossing, small jaw, low-set posteriorily rotated ears, sunken appearance in the middle of the face, widely spaced eyes, and hypertelorism. The forehead is prominent with bitemporal hollowing.[3]

Characteristics that are not visual include mental retardation, pre- and postnatal growth retardation, epilepsy, and reduced lifespan.

Failure to thrive, feeding difficulties, seizures, and decreased spontaneous activity are often seen, and death often occurs in infancy and childhood. Also, multiple abnormalities of the brain, kidneys, and gastrointestinal tract (the stomach and intestines) can occur.

Cause and genetics

MDS is a microdeletion syndrome. It involves loss of the gene PAFAH1B1 on chromosome 17 which is responsible for the syndrome's characteristic sign of lissencephaly. The loss of another gene, YWHAE, in the same region of chromosome 17 increases the severity of the lissencephaly in patients with Miller–Dieker syndrome. Additional genes in the deleted region are likely to contribute to the varied features of Miller–Dieker syndrome.[4]

It may be a random event during the formation of reproductive cells or in early fetal development or due familial chromosomal rearrangement called chromosomal translocation. In less than 20%, inheritance is through an autosomal dominant pattern. The parent is usually unaffected, but carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. Increased rate of unexplained fetal loss may be observed in MDS carriers with balanced translocations although they may be otherwise asymptomatic.[5] However, they can become also unbalanced as they are passed to the next generation. Miller–Dieker syndrome is usually not inherited. The deletion event occurs randomly during gametogenesis (formation of eggs or sperm) or in early foetal development. Therefore, no history of the disorder is usually seen in their families.


The disease may be diagnosed by cytogenetic techniques like fluorescence in situ hybridization (FISH), testing for a microdeletion at LIS1.[6]


While no cure for MDS is available yet, many complications associated with this condition can be treated, and a great deal can be done to support or compensate for functional disabilities. Because of the diversity of the symptoms, it can be necessary to see a number of different specialists and undergo various examinations, including:


Most individuals with this condition do not survive beyond childhood. Individuals with MDS usually die in infancy. Because they do not live to the age where they can reproduce, they cannot transmit MDS to their offspring.


Miller-Dieker occurs in less than one in 100000 people and can occur in all races.


MDS was named for the two physicians, J. Miller and H. Dieker, who independently described the condition in the 1960s. The hallmark of MDS is lissencephaly, a condition in which the outer layer of the brain, the cerebral cortex, is abnormally thick and lacks the normal convolutions (gyri). In some areas of the brain, gyri are fewer in number but wider than normal (pachygyri). Other areas lack gyri entirely (agyri). Normally, during the third and fourth months of pregnancy, the brain cells in the baby multiply and move to the surface of the brain to form the cortex. Lissencephaly is caused by a failure of this nerve cell migration. MDS is often called Miller-Dieker lissencephaly syndrome. It is named for James Q. Miller[7] and H. Dieker.[8] JQ Miller described the disease and in 1969 H Dieker emphasized that it should also take the name lissencephaly syndrome because several malformations occur beyond the brain itself. When MDS was described in the beginning, geneticists assumed it followed an autosomal recessive pattern of inheritance. In the early 1990s, several patients with Miller–Dieker syndrome were found to be missing a small portion of the chromosome 17. (17p13.3) (a partial deletion).


  1. Huang, HC; Bautista, SL; Chen, BS; Chang, KP; Chen, YJ; Wuu, SW (1996). "Miller-Dieker syndrome with microdeletion of chromosome 17p13.3: report of one case.". Zhonghua Minguo xiao er ke yi xue hui za zhi [Journal]. Zhonghua Minguo xiao er ke yi xue hui. 38 (6): 472–6. PMID 9473821.
  2. Chong, SS; Pack, SD; Roschke, AV; Tanigami, A; Carrozzo, R; Smith, AC; Dobyns, WB; Ledbetter, DH (February 1997). "A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3.". Human Molecular Genetics. 6 (2): 147–55. doi:10.1093/hmg/6.2.147. PMID 9063734.
  3. Herman, T E; Siegel, M J (April 2008). "Miller–Dieker syndrome, type 1 lissencephaly". Journal of Perinatology. 28 (4): 313–315. doi:10.1038/
  4. Dobyns, WB; Das, S; Pagon, RA; Adam, MP; Ardinger, HH; Wallace, SE; Amemiya, A; Bean, LJH; Bird, TD; Dolan, CR; Fong, CT; Smith, RJH; Stephens, K (1993). "LIS1-Associated Lissencephaly/Subcortical Band Heterotopia". PMID 20301752.
  5. Pollin, TI; Dobyns, WB; Crowe, CA; Ledbetter, DH; Bailey-Wilson, JE; Smith, AC (6 August 1999). "Risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the Miller-Dieker syndrome (MDS) critical region in chromosome 17p13.3.". American Journal of Medical Genetics. 85 (4): 369–75. doi:10.1002/(SICI)1096-8628(19990806)85:43.3.CO;2-C. PMID 10398263.
  6. Izumi K, Kuratsuji G, Ikeda K, Takahashi T, Kosaki K (2007). "Partial deletion of LIS1: a pitfall in molecular diagnosis of Miller-Dieker syndrome". Pediatr. Neurol. 36 (4): 258–60. doi:10.1016/j.pediatrneurol.2006.11.015. PMID 17437911.
  7. Miller JQ (1963). "Lissencephaly in 2 siblings". Neurology. 13: 841–50. doi:10.1212/wnl.13.10.841. PMID 14066999.
  8. Dieker, H.; Edwards, R. H.; ZuRhein, G. et al. The lissencephaly syndrome. In: Bergsma, D. : The Clinical Delineation of Birth Defects: Malformation Syndromes. New York: National Foundation-March of Dimes (pub.) II 1969. Pp. 53-64.
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