Miller-Dieker syndrome (MDS), is a disorder with abnormal neuronal migration during brain development due to an underlying deletion at chromosome 17p13.3 [1]. This rare disease features classic lissencephaly (smooth brain), which is characterized by agyria (absence of brain convolutions) or frontal pachygyria (few brain convolutions) [1]. MDS also consists of microcephaly and profound facial dysmorphisms such as a prominent forehead, bitemporal hollowing, down-slanting palpebral fissures, short nose accompanied by upturned nares, protuberant upper lip, downturned vermillion border, and micrognathia [2] [3]. Occasionally, other anomalies like congenital heart malformations, genitourinary defects, and omphalocele may also be present [4] [5].

MDS is associated with a very poor prognosis. Affected children have severe developmental retardation and are at risk of dying within a few years of life [2] [3]. Complications include severe neurologic and mental delay, epilepsy, growth restriction, as well as trouble with feeding [2] [6].

• Single Transverse Palmar Crease

  transverse palmar crease 0000954 Thick upper lip vermilion Full upper lip Increased volume of upper lip Plump upper lip Prominent upper lip Thick upper lip [ more ] 0000215 Wide nasal bridge Broad nasal bridge Broad nasal root Broadened nasal bridge [rarediseases.info.nih.gov]

• Axillary Freckling

  The mother had café-au-lait spots, and axillary freckling. [ncbi.nlm.nih.gov]

• Unilateral Ptosis

  The proband was determined at birth owing to the presence of multiple congenital anomalies, including low birth weight, microcephaly, agenesis of the corpus callosum, lissencephaly, cerebral atrophy, unilateral ptosis, polydactyly, and omphalocele. [ncbi.nlm.nih.gov]

• Reduced Fetal Movement

  History of polyhydramnios, intrauterine growth retardation and reduced fetal movements are associated with MDS. [ijcasereportsandimages.com]

• Psychomotor Retardation

  She underwent surgical closure of patent ductus arteriosus after birth; during development, she displayed psychomotor retardation, language impairment, and short stature. [elsevier.es]

  retardation and infant death. [eyewiki.aao.org]

• Upturned Nares

  However, hypotonia and abnormal facial morphology including prominent forehead, a short nose with upturned nares and protuberant upper lip were developed gradually as he got older. [synapse.koreamed.org]

  Miller-Dieker syndrome: A congenital malformation syndrome characterized by lissencephaly ("smooth brain") and a characteristic facial appearance with a prominent forehead with bitemporal hollowing, short nose with upturned nares, thickened upper lip [medicinenet.com]

  MDS also consists of microcephaly and profound facial dysmorphisms such as a prominent forehead, bitemporal hollowing, down-slanting palpebral fissures, short nose accompanied by upturned nares, protuberant upper lip, downturned vermillion border, and [symptoma.com]

  All had severe type I lissencephaly with grossly normal cerebellum and a distinctive facial appearance consisting of prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw. [ncbi.nlm.nih.gov]

An infant with the clinical presentation discussed above or a fetus with suspicious findings observed on prenatal ultrasonography warrants a full workup that consists of patient/fetal and family history, a detailed physical exam of the infant, and the appropriate studies discussed below.

Prenatal testing

Obstetric ultrasonography can detect MDS prenatally if performed during late second trimester or later by an experienced operator [1]. Ultrasound scans on fetuses with this disease reveal findings such as a smooth gyral pattern consistent with lissencephaly, ventriculomegaly, other brain abnormalities, intrauterine growth restriction (IUGR), and polyhydramnios [7] [8]. Additionally, congenital anomalies such as omphalocele and heart defects are also identified prenatally [5].

Amniocentesis or chorionic villus sampling (CVS) and subsequent cytogenic analysis can confirm the diagnosis in a fetus suspected to have MDS.

Postnatal imaging

A study reviewing brain computerized tomography (CT) scans and magnetic resonance imaging (MRI) of affected infants demonstrate features such as smooth cerebral hemispheres and a remarkable figure of eight appearance [3]. Frequent findings include a thickened cortex, enlarged cavum septi pellucidi, and diminished or absent corpus callosum [3]. Furthermore, enlarged ventricles and midline calcifications may also be observed [3]. Another study also reported lissencephaly and agenesis of the corpus callosum on CT imaging [9].

Cytogenetic analysis

Patients suspected to have MDS should undergo chromosomal analysis with fluorescence in situ hybridization (FISH) in order to confirm the deletion of the 17p13.3 locus. MDS is associated with multiple genes including LIS1, YWHAE, and CRK in addition to contiguous genes that would contribute to the manifestations of severe forms of the disease [10] [11].

Other

Distinct electroencephalogram (EEG) results associated with MDS include abnormally high amplitude,and rhythmic slow activities [9].

• Rhythmic Slowing

  Other Distinct electroencephalogram (EEG) results associated with MDS include abnormally high amplitude,and rhythmic slow activities. [symptoma.com]

Management and treatment Management of children with MDS is symptomatic. [orpha.net]

Miller-Dieker syndrome is incurable, with no known prenatal treatment options. Postnatal treatment consists largely of antiepileptic therapy for seizure control and supportive care. [researchers.dellmed.utexas.edu]

Treatment is symptomatic and supportive. Source: Genetic and Rare Diseases Information Center (GARD), supported by ORDR-NCATS and NHGRI. [diseaseinfosearch.org]

The treatment of epilepsy: principles and practice. ‏ الصفحة 68 - Committee on Quality Improvement, Subcommittee on Febrile Seizures. Practice parameter: long-term treatment of the child with simple febrile seizures. [books.google.com]

Treatment - Miller-Dieker syndrome There is no cure for MDS and treatment is usually directed toward comfort measures. [checkorphan.org]

Treatment and prognosis The overall prognosis is poor with most fetuses not surviving beyond infancy. There may be recurrence rate of ~25% for future pregnancies. [radiopaedia.org]

An accurate diagnosis of MDS is important not only because it can provide a prognosis for the affected child, but because it can give parents an estimate of their risk for having another child with MDS. [checkorphan.org]

MDS is associated with a very poor prognosis. Affected children have severe developmental retardation and are at risk of dying within a few years of life. [symptoma.com]

Prognosis Most babies with Miller Dieker Syndrome die in the first three months of life and most infants are dead from complications of seizures, aspiration pneumonia etc. within two years of age. [nethealthbook.com]

We wish to emphasize that lissencephaly is etiologically non-specific and represents only one feature in this malformation syndrome. [ncbi.nlm.nih.gov]

Etiology Visible and submicroscopic deletions of 17p13.3, including the LIS1 gene, are found in almost 100% of patients. Management and treatment Management of children with MDS is symptomatic. [orpha.net]

Qualificadores Permitidos Inglês: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology [decs.bvs.br]

Summary Epidemiology MDS is undoubtedly a rare condition with a reported estimate of 1 cases per 100 000 live births, although incidence and prevalence are probably higher. [orpha.net]

In 1991, it was reported in the only published epidemiological study performed in the Dutch population that the prevalence was 11.7 per million live births. [accessanesthesiology.mhmedical.com]

Epidemiology of lissencephaly type 1. Neuroepidemiology 1991.10: 200-4. Guerrini R and Filippi T. Neuronal migration disorders, genetics and epileptogenesis. J Child neurol. 2005;20. 287-299. Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. [malattierare.toscana.it]

Histórica Inglês: 2008 Qualificadores Permitidos Inglês: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology [decs.bvs.br]

Epidemiology Miller-Dieker occurs in less than one in 100000 people and can occur in all races. History MDS was named for the two physicians, J. Miller and H. Dieker, who independently described the condition in the 1960s. [ipfs.io]

Refrigeration at 2° - 8° C may assist when a delay is not preventable. Do not freeze or place specimens directly on ice. [pathlabs.ufl.edu]

Treatment is based on the symptoms in each person and aims to prevent complications and control seizures. [malacards.org]

Prevention - Miller-Dieker syndrome Not supplied. Diagnosis - Miller-Dieker syndrome MDS is not the only disorder associated with lissencephaly. [checkorphan.org]

A little boy born with a rare brain disease that prevented him from being able to cry or feed properly, has died at just eight weeks old. [dailymail.co.uk]

[…] diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology GE genetics HI history IM immunology ME metabolism MI microbiology MO mortality NU nursing PS parasitology PA pathology PP physiopathology PC prevention [decs.bvs.br]

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2. Atwal PS, Macmurdo C. A Case of Concurrent Miller-Dieker Syndrome (17p13.3 Deletion) and 22q11.2 Deletion Syndrome. J Pediatr Genet. 2015;4(4):201-203.
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5. Chitayat D, Toi A, Babul R, et al. Omphalocele in Miller–Dieker syndrome: expanding the phenotype. Am J Med Genet. 1997;69(3): 293–298.
6. Cardoso C, Leventer RJ, Ward HL, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet. 2003;72(4):918–30.
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9. Sharief N, Craze J, Summers D, Butler L, Wood CB. Miller-Dieker syndrome with ring chromosome 17. Arch Dis Child. 1991;66(6):710-2.
10. Ghai S, Fong KW, Toi A, et al. Prenatal US and MR imaging findings of lissencephaly: review of fetal cerebral sulcal development. Radiographics. 2006;26(2):389-405.
11. Toyo-oka K, Shionoya A, Gambello MJ, et al. 14–3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003;34(3):274-85.