Miller–Dieker syndrome, also called Miller–Dieker lissencephaly syndrome (MDLS) or chromosome 17p13.3 deletion syndrome, is a micro deletion syndrome characterized by
congenital malformation
A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
s. Congenital malformations are physical defects detectable in an infant at birth which can involve many different parts of the body, including the brain, heart, lungs, liver, bones, or intestinal tract.
MDS is a contiguous gene syndrome – a disorder due to the deletion of multiple gene loci 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
Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing.
Human monosomy
Human conditions due to monosomy:
* Turner syndrome – Females ...
. There may be unbalanced translocations (e.g., 17q:17p or 12q:17p), or the presence of a
ring chromosome
A ring chromosome is an aberrant chromosome whose ends have fused together to form a ring. Ring chromosomes were first observed in ''Drosphila'' by Lilian Vaughan Morgan in 1926 and in maize by Barbara McClintock in 1931. A ring chromosome is den ...
Guillain–Barré syndrome
Guillain–Barré syndrome (GBS) is a rapid-onset Paralysis, muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation ...
.
Presentation
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 posteriorly rotated ears, sunken appearance in the middle of the face, and
hypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...
of eyes. The forehead is prominent with bitemporal hollowing. Children typically also have
microcephaly
Microcephaly (from Neo-Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...
intellectual disabilities
Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
, pre- and postnatal growth retardation,
epilepsy
Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, and reduced lifespan. Children may also experience breathing problems,
dysphagia
Dysphagia is difficulty in swallowing. Although classified under " symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right.
It may be a sensation that suggests difficulty in the passage of solids or l ...
, feeding problems,
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...
,
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles. ...
, and muscle stiffness.
Failure to thrive
Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
, feeding difficulties,
seizures
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
and decreased spontaneous activity are often seen.
Death
Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...
usually occurs in
infancy
In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...
and childhood.
Multiple abnormalities of the brain, kidneys, and gastrointestinal tract (the stomach and intestines) may occur.
Cause
MDS is a microdeletion syndrome involving loss of the gene
PAFAH1B1
Platelet-activating factor acetylhydrolase IB subunit alpha or Lisencephaly protein-1 (LIS-1) is an enzyme that in humans is encoded by the ''PAFAH1B1'' gene. The protein plays an important role in regulating the motor protein dynein.
Function ...
on
chromosome 17
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
which is responsible for the syndrome's characteristic sign of
lissencephaly
Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...
. 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.
It may be a random event during the formation of reproductive cells or in early fetal development or due to familial chromosomal rearrangement called chromosomal translocation. In less than 20% of cases an unaffected parent carries a particular 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 those who have these suspectible balanced translocations although they may be otherwise asymptomatic. However, these translocations 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.
Diagnosis
The disease may be diagnosed by cytogenetic techniques like
fluorescence in situ hybridization
Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed by ...
(FISH), testing for a
microdeletion
In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...
at LIS1.
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 have feeding difficulties, severe intellectual disability, developmental delay, and seizures. MRI facilitates early detection of this syndrome in children by revealing a "smooth brain" image, also called lissencephaly.
Children with this syndrome may remain underdiagnosed because of rarity and the prevalence of facial features that appear to be dysmorphic. The syndrome shares distinct external features (
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
) similar to more common syndromes. Lack of relevant family history may delay diagnosis.
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 screening in future pregnancies. This option is particularly important for the few (less than 20%) MDS families where one parent carries a balanced chromosome rearrangement. The risk of these couples having another child with MDS depends on the exact type of chromosomal 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 are usually advised to 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.
Treatment
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:
* Developmental evaluation
* Cardiologists evaluation
* Otolaryngology
* Treatment of seizures
* Urologic evaluation
* Genetic counseling: though MDS is usually random and without a family history, a balanced chromosomal translocation in one of the parents can greatly raise the chances of a child of theirs being affected. If parents with an affected child are planning another pregnancy, they are usually advised to visit a genetic counselor for further information.
This disease is fairly uncommon, and treatment is scarce.
Prognosis
Most individuals with this condition do not survive beyond childhood. Individuals with MDS usually die in infancy and therefore do not live to the age where they can reproduce and transmit MDS to their offspring.
Due to more accurate diagnosis by
MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
and improved management of symptoms with medical treatments including
gastrostomy
A gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression.
Typically this would include an incision in the patient's epigastrium as part of a formal operation. When originall ...
(feeding tubes), suction machines,
seizure
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
medications,
tracheostomy
Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision on the front of the neck to open a direct airway to the trachea. The resulting stoma (hole) can serve independently as an airway ...
, and management of secretions, more children are surviving into adulthood and have a better quality of life. Development of skills and core strength may be improved with physical therapy, but improvement is limited by the severity of the condition. Some children may be able to sit up, crawl, or say a few basic words, but most are severely developmentally delayed and remain at the level of infants for their lifetime. At all ages the most common cause of death is pneumonia, often after multiple cases have weakened the respiratory function.
Epidemiology
Miller-Dieker occurs in less than one in 100,000 people and can occur in all races.
Given this statistic, it is conclusive that roughly 75000 people worldwide are affected by MDS.
History
MDS was named for the two physicians, James Q. Miller and H. Dieker.,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. 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.
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 initially described, 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 chromosome 17. (17p13.3) (a partial deletion).