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Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities(NEDHFS)

MedGen UID:
1824058
Concept ID:
C5774285
Disease or Syndrome
Synonym: NEDHFS
 
Gene (location): PGM2L1 (11q13.4)
 
Monarch Initiative: MONDO:0859347
OMIM®: 620191

Definition

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities (NEDHFS) is an autosomal recessive disorder characterized by severe global developmental delay with impaired intellectual development and poor or absent speech. Affected individuals have dysmorphic facies, including large abnormally shaped ears and strabismus, hypotonia, and dry skin with keratosis pilaris. Some patients develop seizures. Metabolic studies are unremarkable (Morava et al., 2021). [from OMIM]

Clinical features

From HPO
Inborn organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Deep palmar crease
MedGen UID:
387849
Concept ID:
C1857539
Finding
Excessively deep creases of the palm.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Overfolded helix
MedGen UID:
325239
Concept ID:
C1837731
Finding
A condition in which the helix is folded over to a greater degree than normal. That is, excessive curling of the helix edge, whereby the free edge is parallel to the plane of the ear.
Large earlobe
MedGen UID:
334979
Concept ID:
C1844573
Finding
Increased volume of the earlobe, that is, abnormally prominent ear lobules.
Protruding ear
MedGen UID:
343309
Concept ID:
C1855285
Finding
Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective).
Prominent antitragus
MedGen UID:
369349
Concept ID:
C1968811
Finding
Increased anterosuperior prominence of the area between the bottom of the incisura and the inner margin of the antihelix.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Pica
MedGen UID:
45917
Concept ID:
C0031873
Mental or Behavioral Dysfunction
An appetite for and the persistent ingestion of non-food substances such as clay. In order to diagnose pica, this behavior must have persisted over a period of at least one month.
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.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
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.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Eczematoid dermatitis
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Abnormal isoelectric focusing of serum transferrin
MedGen UID:
413671
Concept ID:
C2749688
Finding
Glycosylated transferrin concentrations can be measured in serum as a marker of N-linked glycosylation fidelity. In the traditional nomenclature for congenital disorders of glycosylation, absence of entire glycans was designated type I, and loss of one or more monosaccharides as type II. These terms are retained for historical reasons but for new annotations the precise glycosylation defect should be recorded.
Abnormal circulating acylcarnitine concentration
MedGen UID:
1684872
Concept ID:
C5139063
Finding
Any deviation from the normal concentration in the blood circulation of an acylcarnitine, which is produced by reversible esterification of the 3-hydroxyl group of carnitine.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Prominent nose
MedGen UID:
98423
Concept ID:
C0426415
Finding
Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
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.
Pointed chin
MedGen UID:
336193
Concept ID:
C1844505
Finding
A marked tapering of the lower face to the chin.
Prominent nasal tip
MedGen UID:
383839
Concept ID:
C1856118
Finding
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased 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).
Underdeveloped nasolabial fold
MedGen UID:
866872
Concept ID:
C4021227
Anatomical Abnormality
Reduced bulkiness of the crease or fold of skin running from the lateral margin of the nose, where nasal base meets the skin of the face, to a point just lateral to the corner of the mouth (cheilion or commissure).
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Keratosis pilaris
MedGen UID:
82664
Concept ID:
C0263383
Disease or Syndrome
An anomaly of the hair follicles of the skin that typically presents as small, rough, brown folliculocentric papules distributed over characteristic areas of the skin, particularly the outer-upper arms and thighs.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Hypertrichosis cubiti-short stature syndrome
MedGen UID:
870835
Concept ID:
C4025295
Finding
Hairy elbows is a rare form of localized hypertrichosis. The lanugo type of hair usually appears in infancy, becomes coarser during early childhood, and regresses at adolescence (summary by Visser et al., 2002).
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.

Recent clinical studies

Etiology

Mor-Shaked H, Salah S, Yanovsky-Dagan S, Meiner V, Atawneh OM, Abu-Libdeh B, Elpeleg O, Harel T
Clin Genet 2021 Apr;99(4):577-582. Epub 2021 Jan 13 doi: 10.1111/cge.13920. PMID: 33410501
Gossai N, Biegel JA, Messiaen L, Berry SA, Moertel CL
Am J Med Genet A 2015 Dec;167A(12):3186-91. Epub 2015 Sep 14 doi: 10.1002/ajmg.a.37356. PMID: 26364901
Grebe TA, Clericuzio C
Am J Med Genet 2000 Nov 13;95(2):135-43. PMID: 11078563
de Vries BB, Fryns JP, Butler MG, Canziani F, Wesby-van Swaay E, van Hemel JO, Oostra BA, Halley DJ, Niermeijer MF
J Med Genet 1993 Sep;30(9):761-6. doi: 10.1136/jmg.30.9.761. PMID: 8411072Free PMC Article

Diagnosis

Vinci M, Kursula P, Greco D, Elia M, Vetri L, Schepis C, Chiavetta V, Donadio S, Roccella M, Carotenuto M, Romano V, Calì F
Mol Genet Genomic Med 2022 Sep;10(9):e2012. Epub 2022 Jul 5 doi: 10.1002/mgg3.2012. PMID: 35789128Free PMC Article
Jinxiu L, Shuimei L, Ming X, Jonathan LC, Xiangju L, Wenyuan D
Medicine (Baltimore) 2020 Apr;99(16):e19813. doi: 10.1097/MD.0000000000019813. PMID: 32311999Free PMC Article
Gershlick DC, Ishida M, Jones JR, Bellomo A, Bonifacino JS, Everman DB
Hum Mol Genet 2019 May 1;28(9):1548-1560. doi: 10.1093/hmg/ddy423. PMID: 30624672Free PMC Article
Douglas G, Cho MT, Telegrafi A, Winter S, Carmichael J, Zackai EH, Deardorff MA, Harr M, Williams L, Psychogios A, Erwin AL, Grebe T, Retterer K, Juusola J
Am J Med Genet A 2018 Sep;176(9):1845-1851. Epub 2018 Jul 28 doi: 10.1002/ajmg.a.40368. PMID: 30055086
Uzak AS, Fryns JP, Dundar M
Genet Couns 2014;25(2):159-69. PMID: 25059014

Therapy

Jinxiu L, Shuimei L, Ming X, Jonathan LC, Xiangju L, Wenyuan D
Medicine (Baltimore) 2020 Apr;99(16):e19813. doi: 10.1097/MD.0000000000019813. PMID: 32311999Free PMC Article

Prognosis

Vinci M, Kursula P, Greco D, Elia M, Vetri L, Schepis C, Chiavetta V, Donadio S, Roccella M, Carotenuto M, Romano V, Calì F
Mol Genet Genomic Med 2022 Sep;10(9):e2012. Epub 2022 Jul 5 doi: 10.1002/mgg3.2012. PMID: 35789128Free PMC Article
Mor-Shaked H, Salah S, Yanovsky-Dagan S, Meiner V, Atawneh OM, Abu-Libdeh B, Elpeleg O, Harel T
Clin Genet 2021 Apr;99(4):577-582. Epub 2021 Jan 13 doi: 10.1111/cge.13920. PMID: 33410501
Niclass T, Le Guyader G, Beneteau C, Joubert M, Pizzuti A, Giuffrida MG, Bernardini L, Gilbert-Dussardier B, Bilan F, Egloff M
Am J Med Genet A 2020 Sep;182(9):2133-2138. Epub 2020 Jul 6 doi: 10.1002/ajmg.a.61734. PMID: 32633079
Douglas G, Cho MT, Telegrafi A, Winter S, Carmichael J, Zackai EH, Deardorff MA, Harr M, Williams L, Psychogios A, Erwin AL, Grebe T, Retterer K, Juusola J
Am J Med Genet A 2018 Sep;176(9):1845-1851. Epub 2018 Jul 28 doi: 10.1002/ajmg.a.40368. PMID: 30055086
Gossai N, Biegel JA, Messiaen L, Berry SA, Moertel CL
Am J Med Genet A 2015 Dec;167A(12):3186-91. Epub 2015 Sep 14 doi: 10.1002/ajmg.a.37356. PMID: 26364901

Clinical prediction guides

Vinci M, Kursula P, Greco D, Elia M, Vetri L, Schepis C, Chiavetta V, Donadio S, Roccella M, Carotenuto M, Romano V, Calì F
Mol Genet Genomic Med 2022 Sep;10(9):e2012. Epub 2022 Jul 5 doi: 10.1002/mgg3.2012. PMID: 35789128Free PMC Article
Yi S, Li M, Yang Q, Qin Z, Yi S, Xu J, Chen J, Wei H, Jiang Y, Wei R, Zhang Q, Yang C, Chen B, Luo J
J Mol Neurosci 2022 Jun;72(6):1293-1299. Epub 2022 May 10 doi: 10.1007/s12031-022-02010-0. PMID: 35536477
Douglas G, Cho MT, Telegrafi A, Winter S, Carmichael J, Zackai EH, Deardorff MA, Harr M, Williams L, Psychogios A, Erwin AL, Grebe T, Retterer K, Juusola J
Am J Med Genet A 2018 Sep;176(9):1845-1851. Epub 2018 Jul 28 doi: 10.1002/ajmg.a.40368. PMID: 30055086
Uzak AS, Fryns JP, Dundar M
Genet Couns 2014;25(2):159-69. PMID: 25059014
Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, Arcas J, Lopez-Martin V, Tendero A, Esquiroz JL, Pascual-Pascual SI
Brain Dev 1998 Jan;20(1):36-43. doi: 10.1016/s0387-7604(97)00097-1. PMID: 9533559

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