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Intellectual disability, autosomal dominant 20(NEDHSIL)

MedGen UID:
462050
Concept ID:
C3150700
Disease or Syndrome
Synonyms: NEDHSIL; NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE
 
Gene (location): MEF2C (5q14.3)
 
Monarch Initiative: MONDO:0013266
OMIM®: 613443

Definition

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL) is characterized by global developmental delay with hypotonia, poor motor development with limited walking, impaired intellectual development with poor or absent speech, and behavioral abnormalities. Almost all affected individuals demonstrate repetitive stereotypic hand movements that can be categorized as hyperkinetic and resembling those of Rett syndrome (RTT; 312750). About 80% of patients develop various types of seizures that may be refractory to treatment. Additional features may include dysmorphic facial features, particularly dysplastic ears, poor eye contact, episodic hyperventilation, tendency to infection, and abnormalities on brain imaging, such as enlarged ventricles, thin corpus callosum, and delayed myelination (summary by Vrecar et al., 2017, Paciorkowski et al., 2013). [from OMIM]

Clinical features

From HPO
Single transverse palmar crease
MedGen UID:
96108
Concept ID:
C0424731
Finding
The distal and proximal transverse palmar creases are merged into a single transverse palmar crease.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
2-3 toe syndactyly
MedGen UID:
1645640
Concept ID:
C4551570
Congenital Abnormality
Syndactyly with fusion of toes two and three.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Motor stereotypies
MedGen UID:
21318
Concept ID:
C0038271
Individual Behavior
Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
Dilated fourth ventricle
MedGen UID:
376050
Concept ID:
C1847117
Finding
An abnormal dilatation of the fourth cerebral ventricle.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
Abnormal periventricular white matter morphology
MedGen UID:
435926
Concept ID:
C2673431
Finding
A structural abnormality of the myelinated axons (white matter) located near the cerebral ventricles.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Lobulated tongue
MedGen UID:
140914
Concept ID:
C0431564
Congenital Abnormality
Multiple indentations and/or elevations on the edge and/or surface of the tongue producing an irregular surface contour.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Anatomical Abnormality
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.
Short chin
MedGen UID:
784514
Concept ID:
C3697248
Finding
Decreased vertical distance from the vermilion border of the lower lip to the inferior-most point of the chin.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.

Professional guidelines

PubMed

D'Onofrio G, Accogli A, Severino M, Caliskan H, Kokotović T, Blazekovic A, Jercic KG, Markovic S, Zigman T, Goran K, Barišić N, Duranovic V, Ban A, Borovecki F, Ramadža DP, Barić I, Fazeli W, Herkenrath P, Marini C, Vittorini R, Gowda V, Bouman A, Rocca C, Alkhawaja IA, Murtaza BN, Rehman MMU, Al Alam C, Nader G, Mancardi MM, Giacomini T, Srivastava S, Alvi JR, Tomoum H, Matricardi S, Iacomino M, Riva A, Scala M, Madia F, Pistorio A, Salpietro V, Minetti C, Rivière JB, Srour M, Efthymiou S, Maroofian R, Houlden H, Vernes SC, Zara F, Striano P, Nagy V
Hum Genet 2023 Jul;142(7):909-925. Epub 2023 May 14 doi: 10.1007/s00439-023-02552-2. PMID: 37183190Free PMC Article
Miroševič Š, Khandelwal S, Sušjan P, Žakelj N, Gosar D, Forstnerič V, Lainšček D, Jerala R, Osredkar D
Int J Mol Sci 2022 Oct 19;23(20) doi: 10.3390/ijms232012564. PMID: 36293418Free PMC Article
Chen CA, Bosch DG, Cho MT, Rosenfeld JA, Shinawi M, Lewis RA, Mann J, Jayakar P, Payne K, Walsh L, Moss T, Schreiber A, Schoonveld C, Monaghan KG, Elmslie F, Douglas G, Boonstra FN, Millan F, Cremers FP, McKnight D, Richard G, Juusola J, Kendall F, Ramsey K, Anyane-Yeboa K, Malkin E, Chung WK, Niyazov D, Pascual JM, Walkiewicz M, Veluchamy V, Li C, Hisama FM, de Vries BB, Schaaf C
Genet Med 2016 Nov;18(11):1143-1150. Epub 2016 Mar 17 doi: 10.1038/gim.2016.18. PMID: 26986877

Recent clinical studies

Etiology

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Tafazoli A, Eshraghi P, Pantaleoni F, Vakili R, Moghaddassian M, Ghahraman M, Muto V, Paolacci S, Golyan FF, Abbaszadegan MR
Adv Med Sci 2018 Mar;63(1):87-93. Epub 2017 Sep 26 doi: 10.1016/j.advms.2017.07.001. PMID: 28957739
Castori M, Valiante M, Pascolini G, Leuzzi V, Pizzuti A, Grammatico P
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Diagnosis

Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, Kao CY, Wang Y, Xia F, Eng CM, Benn P
Ultrasound Obstet Gynecol 2022 Jan;59(1):33-39. doi: 10.1002/uog.23756. PMID: 34358384Free PMC Article
Fortea J, Zaman SH, Hartley S, Rafii MS, Head E, Carmona-Iragui M
Lancet Neurol 2021 Nov;20(11):930-942. doi: 10.1016/S1474-4422(21)00245-3. PMID: 34687637Free PMC Article
Raviglione F, Douzgou S, Scala M, Mingarelli A, D'Arrigo S, Freri E, Darra F, Giglio S, Bonaglia MC, Pantaleoni C, Mastrangelo M, Epifanio R, Elia M, Saletti V, Morlino S, Vari MS, De Liso P, Pavaine J, Spaccini L, Cattaneo E, Gardella E, Møller RS, Marchese F, Colonna C, Gandioli C, Gobbi G, Ram D, Palumbo O, Carella M, Germano M, Tonduti D, De Angelis D, Caputo D, Bergonzini P, Novara F, Zuffardi O, Verrotti A, Orsini A, Bonuccelli A, De Muto MC, Trivisano M, Vigevano F, Granata T, Bernardina BD, Tranchina A, Striano P
Seizure 2021 May;88:60-72. Epub 2021 Mar 30 doi: 10.1016/j.seizure.2021.03.025. PMID: 33831796
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Mol Med Rep 2016 Jul;14(1):33-40. Epub 2016 May 4 doi: 10.3892/mmr.2016.5209. PMID: 27150940Free PMC Article

Therapy

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J Med Case Rep 2019 Dec 24;13(1):381. doi: 10.1186/s13256-019-2274-6. PMID: 31870441Free PMC Article
Matevosyan NR
Arch Gynecol Obstet 2016 Jan;293(1):87-99. Epub 2015 Jun 11 doi: 10.1007/s00404-015-3770-6. PMID: 26063342

Prognosis

Cheng C, Yang F, Zhao S, Chen X
BMC Med Genomics 2023 Dec 18;16(1):331. doi: 10.1186/s12920-023-01778-3. PMID: 38111042Free PMC Article
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Rafii MS
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Moog U, van Mierlo I, van Schrojenstein Lantman-de Valk HM, Spaapen L, Maaskant MA, Curfs LM
Am J Med Genet C Semin Med Genet 2007 Aug 15;145C(3):293-301. doi: 10.1002/ajmg.c.30142. PMID: 17640047

Clinical prediction guides

Cheng C, Yang F, Zhao S, Chen X
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Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, Kao CY, Wang Y, Xia F, Eng CM, Benn P
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Dommergues M, Candilis D, Becerra L, Thoueille E, Cohen D, Viaux-Savelon S
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Am J Med Genet A 2021 Jun;185(6):1649-1665. Epub 2021 Mar 30 doi: 10.1002/ajmg.a.62124. PMID: 33783954Free PMC Article
Chilton I, Okur V, Vitiello G, Selicorni A, Mariani M, Goldenberg A, Husson T, Campion D, Lichtenbelt KD, van Gassen K, Steinraths M, Rice J, Roeder ER, Littlejohn RO, Srour M, Sebire G, Accogli A, Héron D, Heide S, Nava C, Depienne C, Larson A, Niyazov D, Azage M, Hoganson G, Burton J, Rush ET, Jenkins JL, Saunders CJ, Thiffault I, Alaimo JT, Fleischer J, Groepper D, Gripp KW, Chung WK
Am J Med Genet A 2020 May;182(5):962-973. Epub 2020 Feb 7 doi: 10.1002/ajmg.a.61505. PMID: 32031333

Recent systematic reviews

Miroševič Š, Khandelwal S, Sušjan P, Žakelj N, Gosar D, Forstnerič V, Lainšček D, Jerala R, Osredkar D
Int J Mol Sci 2022 Oct 19;23(20) doi: 10.3390/ijms232012564. PMID: 36293418Free PMC Article

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