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Meckel syndrome, type 4(MKS4)

MedGen UID:
410003
Concept ID:
C1970161
Disease or Syndrome
Synonyms: CEP290-Related Meckel Syndrome; MECKEL-GRUBER SYNDROME, TYPE 4; MKS4
 
Gene (location): CEP290 (12q21.32)
 
Monarch Initiative: MONDO:0012626
OMIM®: 611134

Definition

Meckel syndrome is an autosomal recessive pre- or perinatal lethal disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly (summary by Baala et al., 2007). For a more complete phenotypic description and information on genetic heterogeneity of Meckel syndrome, see MKS1 (249000). [from OMIM]

Additional description

From MedlinePlus Genetics
Because of their serious health problems, most individuals with Meckel syndrome die before or shortly after birth. Most often, affected infants die of respiratory problems or kidney failure.

Other signs and symptoms of Meckel syndrome vary widely among affected individuals. Numerous abnormalities of the brain and spinal cord (central nervous system) have been reported in people with Meckel syndrome, including a group of birth defects known as neural tube defects. These defects occur when a structure called the neural tube, a layer of cells that ultimately develops into the brain and spinal cord, fails to close completely during the first few weeks of embryonic development. Meckel syndrome can also cause problems with development of the eyes and other facial features, heart, bones, urinary system, and genitalia.

Meckel syndrome is a disorder with severe signs and symptoms that affect many parts of the body. The most common features are enlarged kidneys with numerous fluid-filled cysts; an occipital encephalocele, which is a sac-like protrusion of the brain through an opening at the back of the skull; and the presence of extra fingers and toes (polydactyly). Most affected individuals also have a buildup of scar tissue (fibrosis) in the liver.  https://medlineplus.gov/genetics/condition/meckel-syndrome

Clinical features

From HPO
Renal cyst
MedGen UID:
854361
Concept ID:
C3887499
Disease or Syndrome
A fluid filled sac in the kidney.
Postaxial hand polydactyly
MedGen UID:
609221
Concept ID:
C0431904
Congenital Abnormality
Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Bile duct proliferation
MedGen UID:
120603
Concept ID:
C0267818
Disease or Syndrome
Proliferative changes of the bile ducts.
Anencephaly
MedGen UID:
8068
Concept ID:
C0002902
Congenital Abnormality
Anencephaly is a condition that prevents the normal development of the brain and the bones of the skull. This condition results when a structure called the neural tube fails to close during the first few weeks of embryonic development. The neural tube is a layer of cells that ultimately develops into the brain and spinal cord. Because anencephaly is caused by abnormalities of the neural tube, it is classified as a neural tube defect.\n\nBecause the neural tube fails to close properly, the developing brain and spinal cord are exposed to the amniotic fluid that surrounds the fetus in the womb. This exposure causes the nervous system tissue to break down (degenerate). As a result, people with anencephaly are missing large parts of the brain called the cerebrum and cerebellum. These brain regions are necessary for thinking, hearing, vision, emotion, and coordinating movement. The bones of the skull are also missing or incompletely formed.\n\nBecause these nervous system abnormalities are so severe, almost all babies with anencephaly die before birth or within a few hours or days after birth.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Meningocele
MedGen UID:
44356
Concept ID:
C0025299
Disease or Syndrome
Protrusion of the meninges through a defect of the skull or vertebral column.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Molar tooth sign on MRI
MedGen UID:
400670
Concept ID:
C1865060
Finding
An abnormal appearance of the midbrain in axial magnetic resonance imaging in which the elongated superior cerebellar peduncles give the midbrain an appearance reminiscent of a molar or wisdom tooth.
Encephalocele
MedGen UID:
1646412
Concept ID:
C4551722
Congenital Abnormality
A neural tube defect characterized by sac-like protrusions of the brain and the membranes that cover it through openings in the skull.
Agenesis of cerebellar vermis
MedGen UID:
1768774
Concept ID:
C5437781
Congenital Abnormality
Congenital absence of the vermis of cerebellum.
Dandy-Walker syndrome
MedGen UID:
4150
Concept ID:
C0010964
Disease or Syndrome
Dandy-Walker malformation is defined by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus. DWM is a heterogeneous disorder. The low empiric recurrence risk of approximately 1 to 2% for nonsyndromic DWM suggests that mendelian inheritance is unlikely (summary by Murray et al., 1985).
Bowing of the long bones
MedGen UID:
340849
Concept ID:
C1855340
Congenital Abnormality
A bending or abnormal curvature of a long bone.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.

Professional guidelines

PubMed

Erger F, Brüchle NO, Gembruch U, Zerres K
Arch Gynecol Obstet 2017 Apr;295(4):897-906. Epub 2017 Mar 10 doi: 10.1007/s00404-017-4336-6. PMID: 28283827
Barisic I, Boban L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Bergman JE, Braz P, Draper ES, Haeusler M, Khoshnood B, Klungsoyr K, Pierini A, Queisser-Luft A, Rankin J, Rissmann A, Verellen-Dumoulin C
Eur J Hum Genet 2015 Jun;23(6):746-52. Epub 2014 Sep 3 doi: 10.1038/ejhg.2014.174. PMID: 25182137Free PMC Article

Curated

Salonen R, Kestilä M, Bergmann C
Eur J Hum Genet 2011 Jul;19(7) Epub 2011 Feb 2 doi: 10.1038/ejhg.2010.255. PMID: 21368913Free PMC Article

Recent clinical studies

Etiology

Simonini C, Floeck A, Strizek B, Mueller A, Gembruch U, Geipel A
Arch Gynecol Obstet 2022 Jul;306(1):71-83. Epub 2021 Oct 1 doi: 10.1007/s00404-021-06265-7. PMID: 34596737Free PMC Article
Watson CM, Crinnion LA, Berry IR, Harrison SM, Lascelles C, Antanaviciute A, Charlton RS, Dobbie A, Carr IM, Bonthron DT
BMC Med Genet 2016 Jan 4;17:1. doi: 10.1186/s12881-015-0265-z. PMID: 26729329Free PMC Article
Park E, Lee JM, Ahn YH, Kang HG, Ha II, Lee JH, Park YS, Kim NK, Park WY, Cheong HI
Pediatr Nephrol 2016 Jan;31(1):113-9. Epub 2015 Aug 11 doi: 10.1007/s00467-015-3185-4. PMID: 26260382
Seidahmed MZ, Abdelbasit OB, Shaheed MM, Alhussein KA, Miqdad AM, Samadi AS, Khalil MI, Al-Mardawi E, Salih MA
Saudi Med J 2014 Dec;35 Suppl 1(Suppl 1):S49-56. PMID: 25551112Free PMC Article
Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K, Golzio C, Lacoste T, Besse L, Ozilou C, Moutkine I, Hellman NE, Anselme I, Silbermann F, Vesque C, Gerhardt C, Rattenberry E, Wolf MT, Gubler MC, Martinovic J, Encha-Razavi F, Boddaert N, Gonzales M, Macher MA, Nivet H, Champion G, Berthélémé JP, Niaudet P, McDonald F, Hildebrandt F, Johnson CA, Vekemans M, Antignac C, Rüther U, Schneider-Maunoury S, Attié-Bitach T, Saunier S
Nat Genet 2007 Jul;39(7):875-81. Epub 2007 Jun 10 doi: 10.1038/ng2039. PMID: 17558409

Diagnosis

Simonini C, Fröschen EM, Nadal J, Strizek B, Berg C, Geipel A, Gembruch U
Arch Gynecol Obstet 2023 Oct;308(4):1287-1300. Epub 2022 Oct 31 doi: 10.1007/s00404-022-06814-8. PMID: 36310336Free PMC Article
Simonini C, Floeck A, Strizek B, Mueller A, Gembruch U, Geipel A
Arch Gynecol Obstet 2022 Jul;306(1):71-83. Epub 2021 Oct 1 doi: 10.1007/s00404-021-06265-7. PMID: 34596737Free PMC Article
Turkyilmaz A, Geckinli BB, Alavanda C, Arslan Ates E, Buyukbayrak EE, Eren SF, Arman A
Genet Test Mol Biomarkers 2021 Jun;25(6):445-451. Epub 2021 Jun 4 doi: 10.1089/gtmb.2020.0311. PMID: 34096792
Watson CM, Crinnion LA, Berry IR, Harrison SM, Lascelles C, Antanaviciute A, Charlton RS, Dobbie A, Carr IM, Bonthron DT
BMC Med Genet 2016 Jan 4;17:1. doi: 10.1186/s12881-015-0265-z. PMID: 26729329Free PMC Article
Park E, Lee JM, Ahn YH, Kang HG, Ha II, Lee JH, Park YS, Kim NK, Park WY, Cheong HI
Pediatr Nephrol 2016 Jan;31(1):113-9. Epub 2015 Aug 11 doi: 10.1007/s00467-015-3185-4. PMID: 26260382

Prognosis

Miyamoto S, Nakamura K, Kato M, Nakashima M, Saitsu H
Ann Hum Genet 2023 Jul;87(4):196-202. Epub 2023 Mar 27 doi: 10.1111/ahg.12507. PMID: 36970932
Aydin Ozturk P, Asena M, Katar S, Ozturk U
Pediatr Neurosurg 2019;54(4):277-280. Epub 2019 Jul 1 doi: 10.1159/000500766. PMID: 31261150
Erger F, Brüchle NO, Gembruch U, Zerres K
Arch Gynecol Obstet 2017 Apr;295(4):897-906. Epub 2017 Mar 10 doi: 10.1007/s00404-017-4336-6. PMID: 28283827
Park E, Lee JM, Ahn YH, Kang HG, Ha II, Lee JH, Park YS, Kim NK, Park WY, Cheong HI
Pediatr Nephrol 2016 Jan;31(1):113-9. Epub 2015 Aug 11 doi: 10.1007/s00467-015-3185-4. PMID: 26260382
Zhang D, Aravind L
Cell Cycle 2012 Oct 15;11(20):3861-75. Epub 2012 Sep 14 doi: 10.4161/cc.22068. PMID: 22983010Free PMC Article

Clinical prediction guides

Miyamoto S, Nakamura K, Kato M, Nakashima M, Saitsu H
Ann Hum Genet 2023 Jul;87(4):196-202. Epub 2023 Mar 27 doi: 10.1111/ahg.12507. PMID: 36970932
Simonini C, Fröschen EM, Nadal J, Strizek B, Berg C, Geipel A, Gembruch U
Arch Gynecol Obstet 2023 Oct;308(4):1287-1300. Epub 2022 Oct 31 doi: 10.1007/s00404-022-06814-8. PMID: 36310336Free PMC Article
Simonini C, Floeck A, Strizek B, Mueller A, Gembruch U, Geipel A
Arch Gynecol Obstet 2022 Jul;306(1):71-83. Epub 2021 Oct 1 doi: 10.1007/s00404-021-06265-7. PMID: 34596737Free PMC Article
Park E, Lee JM, Ahn YH, Kang HG, Ha II, Lee JH, Park YS, Kim NK, Park WY, Cheong HI
Pediatr Nephrol 2016 Jan;31(1):113-9. Epub 2015 Aug 11 doi: 10.1007/s00467-015-3185-4. PMID: 26260382
Barisic I, Boban L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Bergman JE, Braz P, Draper ES, Haeusler M, Khoshnood B, Klungsoyr K, Pierini A, Queisser-Luft A, Rankin J, Rissmann A, Verellen-Dumoulin C
Eur J Hum Genet 2015 Jun;23(6):746-52. Epub 2014 Sep 3 doi: 10.1038/ejhg.2014.174. PMID: 25182137Free PMC Article

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