MDFPMR
MCID: MCR321
MIFTS: 33

Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation (MDFPMR)

Categories: Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

MalaCards integrated aliases for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

Name: Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation 57 72 36 29 6
Mdfpmr 57 72
Megalencephaly-Severe Kyphoscoliosis-Overgrowth Syndrome 58

Characteristics:

Orphanet epidemiological data:

58
megalencephaly-severe kyphoscoliosis-overgrowth syndrome
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Neonatal;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset at birth


HPO:

31
macrocephaly, dysmorphic facies, and psychomotor retardation:
Inheritance autosomal recessive inheritance
Onset and clinical course congenital onset


Classifications:

Orphanet: 58  
Rare neurological diseases
Developmental anomalies during embryogenesis


Summaries for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

OMIM® : 57 Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) is an autosomal recessive neurodevelopmental disorder characterized by large head and somatic overgrowth apparent at birth followed by global developmental delay. Affected individuals have characteristic dysmorphic facial features and persistently large head, but increased birth weight normalizes with age. Additional neurologic features, including seizures, hypotonia, and gait ataxia, may also occur. Patients show severe intellectual impairment (summary by Ortega-Recalde et al., 2015). (617011) (Updated 05-Apr-2021)

MalaCards based summary : Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation, also known as mdfpmr, is related to tuberous sclerosis 1 and alacrima, achalasia, and mental retardation syndrome. An important gene associated with Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation is HERC1 (HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 1), and among its related pathways/superpathways is Ubiquitin mediated proteolysis. Affiliated tissues include bone and spinal cord, and related phenotypes are hypertelorism and intellectual disability, severe

KEGG : 36 Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) is a rare autosomal recessive overgrowth syndrome. HERC1 mutations in individuals with MDFPMR have been reported. HERC1 is believed to be involved in intracellular membrane trafficking and ubiquitinization. It is also presumed to play a regulatory role in the mTOR pathway.

UniProtKB/Swiss-Prot : 72 Macrocephaly, dysmorphic facies, and psychomotor retardation: An autosomal recessive syndrome characterized by large head and somatic overgrowth, intellectual disability, and facial dysmorphism. Seizures, hypotonia and ataxic gait are observed in some patients.

Related Diseases for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Diseases related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 tuberous sclerosis 1 9.9
2 alacrima, achalasia, and mental retardation syndrome 9.9
3 tuberous sclerosis 9.9
4 schizoaffective disorder 9.9
5 overgrowth syndrome 9.9

Graphical network of the top 20 diseases related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:



Diseases related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Symptoms & Phenotypes for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Human phenotypes related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

58 31 (show top 50) (show all 67)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hypertelorism 58 31 hallmark (90%) Very frequent (99-80%) HP:0000316
2 intellectual disability, severe 58 31 hallmark (90%) Very frequent (99-80%) HP:0010864
3 prominent forehead 58 31 hallmark (90%) Very frequent (99-80%) HP:0011220
4 arachnodactyly 58 31 hallmark (90%) Very frequent (99-80%) HP:0001166
5 long face 58 31 hallmark (90%) Very frequent (99-80%) HP:0000276
6 sparse eyebrow 58 31 hallmark (90%) Very frequent (99-80%) HP:0045075
7 broad eyebrow 58 31 hallmark (90%) Very frequent (99-80%) HP:0011229
8 overgrowth 58 31 hallmark (90%) Very frequent (99-80%) HP:0001548
9 macrocephaly 58 31 frequent (33%) Frequent (79-30%) HP:0000256
10 megalencephaly 58 31 frequent (33%) Frequent (79-30%) HP:0001355
11 high palate 58 31 frequent (33%) Frequent (79-30%) HP:0000218
12 global developmental delay 58 31 frequent (33%) Frequent (79-30%) HP:0001263
13 macrotia 58 31 frequent (33%) Frequent (79-30%) HP:0000400
14 mandibular prognathia 58 31 frequent (33%) Frequent (79-30%) HP:0000303
15 absent speech 58 31 frequent (33%) Frequent (79-30%) HP:0001344
16 kyphoscoliosis 58 31 frequent (33%) Frequent (79-30%) HP:0002751
17 disproportionate tall stature 58 31 frequent (33%) Frequent (79-30%) HP:0001519
18 slender build 58 31 frequent (33%) Frequent (79-30%) HP:0001533
19 downslanted palpebral fissures 58 31 frequent (33%) Frequent (79-30%) HP:0000494
20 upslanted palpebral fissure 58 31 frequent (33%) Frequent (79-30%) HP:0000582
21 low-set, posteriorly rotated ears 58 31 frequent (33%) Frequent (79-30%) HP:0000368
22 large for gestational age 58 31 frequent (33%) Frequent (79-30%) HP:0001520
23 gait ataxia 58 31 frequent (33%) Frequent (79-30%) HP:0002066
24 difficulty walking 58 31 frequent (33%) Frequent (79-30%) HP:0002355
25 drooling 58 31 frequent (33%) Frequent (79-30%) HP:0002307
26 long foot 58 31 frequent (33%) Frequent (79-30%) HP:0001833
27 bilateral tonic-clonic seizure 31 frequent (33%) HP:0002069
28 pes planus 58 31 occasional (7.5%) Occasional (29-5%) HP:0001763
29 joint laxity 58 31 occasional (7.5%) Occasional (29-5%) HP:0001388
30 cerebral cortical atrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0002120
31 micropenis 58 31 occasional (7.5%) Occasional (29-5%) HP:0000054
32 ventriculomegaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0002119
33 malar flattening 58 31 occasional (7.5%) Occasional (29-5%) HP:0000272
34 prominent nasal bridge 58 31 occasional (7.5%) Occasional (29-5%) HP:0000426
35 triangular face 58 31 occasional (7.5%) Occasional (29-5%) HP:0000325
36 limitation of joint mobility 58 31 occasional (7.5%) Occasional (29-5%) HP:0001376
37 cerebellar hypoplasia 58 31 occasional (7.5%) Occasional (29-5%) HP:0001321
38 neonatal hypoglycemia 58 31 occasional (7.5%) Occasional (29-5%) HP:0001998
39 asymmetry of the thorax 58 31 occasional (7.5%) Occasional (29-5%) HP:0001555
40 communicating hydrocephalus 58 31 occasional (7.5%) Occasional (29-5%) HP:0001334
41 high myopia 58 31 occasional (7.5%) Occasional (29-5%) HP:0011003
42 long neck 58 31 occasional (7.5%) Occasional (29-5%) HP:0000472
43 metopic synostosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0011330
44 facial hypotonia 58 31 occasional (7.5%) Occasional (29-5%) HP:0000297
45 lumbar hyperlordosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0002938
46 impaired social interactions 58 31 occasional (7.5%) Occasional (29-5%) HP:0000735
47 diffuse white matter abnormalities 58 31 occasional (7.5%) Occasional (29-5%) HP:0007204
48 shallow orbits 58 31 occasional (7.5%) Occasional (29-5%) HP:0000586
49 severe expressive language delay 58 31 occasional (7.5%) Occasional (29-5%) HP:0006863
50 thick corpus callosum 58 31 occasional (7.5%) Occasional (29-5%) HP:0007074

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Head And Neck Head:
macrocephaly

Head And Neck Face:
frontal bossing
prominent forehead
long face
triangular face
prognathism
more
Head And Neck Eyes:
hypertelorism
proptosis
downslanting palpebral fissures
upslanting palpebral fissures
sparse eyebrows

Skeletal:
joint laxity
joint limitation
normal bone age

Head And Neck Nose:
prominent nasal bridge

Head And Neck Neck:
long neck

Skeletal Feet:
flat feet
large feet

Growth Weight:
increased birth weight

Growth Other:
somatic overgrowth apparent since birth
asthenic habitus as adult

Skeletal Limbs:
elongated limbs

Neurologic Central Nervous System:
intellectual disability
megalencephaly
global developmental delay
ventriculomegaly
seizures (in some patients)
more
Skeletal Spine:
scoliosis
kyphosis
lordosis

Head And Neck Ears:
macrotia
low-set ears
posteriorly rotated ears
large ears

Skeletal Hands:
arachnodactyly
large hands

Growth Height:
tall stature

Muscle Soft Tissue:
hypotonia

Head And Neck Mouth:
high-arched palate

Neurologic Behavioral Psychiatric Manifestations:
poor social interaction

Chest External Features:
asymmetric thorax

Clinical features from OMIM®:

617011 (Updated 05-Apr-2021)

Drugs & Therapeutics for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Search Clinical Trials , NIH Clinical Center for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Genetic Tests for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Genetic tests related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

# Genetic test Affiliating Genes
1 Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation 29 HERC1

Anatomical Context for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

MalaCards organs/tissues related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

40
Bone, Spinal Cord

Publications for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Articles related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

# Title Authors PMID Year
1
A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum. 57 6
27108999 2016
2
A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy. 6 57
26153217 2016
3
Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability. 57 6
26138117 2015
4
A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism. 61 6
32921582 2020
5
HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study. 57
27147983 2016
6
The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction. 57
25746226 2015
7
Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase. 57
20041218 2009

Variations for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

ClinVar genetic disease variations for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

6 (show all 29)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 HERC1 NM_003922.4(HERC1):c.13559G>A (p.Gly4520Glu) SNV Pathogenic 243011 rs769677823 GRCh37: 15:63915976-63915976
GRCh38: 15:63623777-63623777
2 HERC1 NM_003922.4(HERC1):c.9748C>T (p.Arg3250Ter) SNV Pathogenic 188045 rs753780877 GRCh37: 15:63948409-63948409
GRCh38: 15:63656210-63656210
3 HERC1 NM_003922.4(HERC1):c.4906-2A>C SNV Pathogenic 208859 rs797045141 GRCh37: 15:63988540-63988540
GRCh38: 15:63696341-63696341
4 HERC1 NM_003922.4(HERC1):c.2625G>A (p.Trp875Ter) SNV Pathogenic 243010 rs879253786 GRCh37: 15:64026944-64026944
GRCh38: 15:63734745-63734745
5 HERC1 NM_003922.4(HERC1):c.14072G>C (p.Arg4691Pro) SNV Pathogenic 984952 GRCh37: 15:63907989-63907989
GRCh38: 15:63615790-63615790
6 HERC1 NM_003922.4(HERC1):c.6586C>T (p.Arg2196Ter) SNV Pathogenic 992326 GRCh37: 15:63970528-63970528
GRCh38: 15:63678329-63678329
7 ERC1 NM_178040.4(ERC1):c.3037dup (p.Leu1013fs) Duplication Likely pathogenic 804463 rs1592108170 GRCh37: 12:1553736-1553737
GRCh38: 12:1444570-1444571
8 HERC1 NM_003922.4(HERC1):c.4847T>G (p.Met1616Arg) SNV Uncertain significance 931722 GRCh37: 15:63990985-63990985
GRCh38: 15:63698786-63698786
9 HERC1 NM_003922.4(HERC1):c.6949C>A (p.Leu2317Ile) SNV Uncertain significance 1028680 GRCh37: 15:63970165-63970165
GRCh38: 15:63677966-63677966
10 HERC1 NM_003922.4(HERC1):c.776G>T (p.Gly259Val) SNV Uncertain significance 1028681 GRCh37: 15:64067047-64067047
GRCh38: 15:63774848-63774848
11 HERC1 NM_003922.4(HERC1):c.8617C>T (p.Arg2873Cys) SNV Uncertain significance 1028682 GRCh37: 15:63956732-63956732
GRCh38: 15:63664533-63664533
12 HERC1 NM_003922.4(HERC1):c.9439G>A (p.Val3147Ile) SNV Uncertain significance 1028683 GRCh37: 15:63950903-63950903
GRCh38: 15:63658704-63658704
13 HERC1 NM_003922.4(HERC1):c.9900T>A (p.Asn3300Lys) SNV Uncertain significance 1028684 GRCh37: 15:63948125-63948125
GRCh38: 15:63655926-63655926
14 HERC1 NM_003922.4(HERC1):c.10739G>A (p.Arg3580Gln) SNV Uncertain significance 1031369 GRCh37: 15:63941932-63941932
GRCh38: 15:63649733-63649733
15 HERC1 NM_003922.4(HERC1):c.11428T>G (p.Ser3810Ala) SNV Uncertain significance 1031370 GRCh37: 15:63935161-63935161
GRCh38: 15:63642962-63642962
16 HERC1 NM_003922.4(HERC1):c.12302G>A (p.Gly4101Asp) SNV Uncertain significance 1031371 GRCh37: 15:63928272-63928272
GRCh38: 15:63636073-63636073
17 HERC1 NM_003922.4(HERC1):c.1853A>C (p.Lys618Thr) SNV Uncertain significance 1031372 GRCh37: 15:64045206-64045206
GRCh38: 15:63753007-63753007
18 HERC1 NM_003922.4(HERC1):c.2319C>T (p.Asn773=) SNV Uncertain significance 795963 rs901441145 GRCh37: 15:64039958-64039958
GRCh38: 15:63747759-63747759
19 HERC1 NM_003922.4(HERC1):c.3574T>C (p.Cys1192Arg) SNV Uncertain significance 1032166 GRCh37: 15:64015549-64015549
GRCh38: 15:63723350-63723350
20 HERC1 NM_003922.4(HERC1):c.4631A>G (p.Lys1544Arg) SNV Uncertain significance 1032167 GRCh37: 15:63998984-63998984
GRCh38: 15:63706785-63706785
21 HERC1 NM_003922.4(HERC1):c.7088C>T (p.Ser2363Leu) SNV Uncertain significance 1032168 GRCh37: 15:63967299-63967299
GRCh38: 15:63675100-63675100
22 HERC1 NM_003922.4(HERC1):c.9869A>G (p.Gln3290Arg) SNV Uncertain significance 996983 GRCh37: 15:63948288-63948288
GRCh38: 15:63656089-63656089
23 HERC1 NM_003922.4(HERC1):c.-26-25134A>G SNV Uncertain significance 996984 GRCh37: 15:64092982-64092982
GRCh38: 15:63800783-63800783
24 HERC1 NM_003922.4(HERC1):c.11230C>T (p.Arg3744Trp) SNV Uncertain significance 1028676 GRCh37: 15:63935704-63935704
GRCh38: 15:63643505-63643505
25 HERC1 NM_003922.4(HERC1):c.3635A>T (p.Tyr1212Phe) SNV Uncertain significance 1028677 GRCh37: 15:64015488-64015488
GRCh38: 15:63723289-63723289
26 HERC1 NM_003922.4(HERC1):c.5944G>A (p.Glu1982Lys) SNV Uncertain significance 1028678 GRCh37: 15:63981892-63981892
GRCh38: 15:63689693-63689693
27 HERC1 NM_003922.4(HERC1):c.6109C>G (p.Pro2037Ala) SNV Uncertain significance 1028679 GRCh37: 15:63978674-63978674
GRCh38: 15:63686475-63686475
28 HERC1 NM_003922.4(HERC1):c.3374G>A (p.Gly1125Asp) SNV Uncertain significance 377238 rs80203202 GRCh37: 15:64017685-64017685
GRCh38: 15:63725486-63725486
29 HERC1 NM_003922.4(HERC1):c.3021+6C>T SNV Uncertain significance 547868 rs368315540 GRCh37: 15:64021690-64021690
GRCh38: 15:63729491-63729491

UniProtKB/Swiss-Prot genetic disease variations for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation:

72
# Symbol AA change Variation ID SNP ID
1 HERC1 p.Gly4520Glu VAR_076995 rs769677823

Expression for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Search GEO for disease gene expression data for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation.

Pathways for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Pathways related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation according to KEGG:

36
# Name Kegg Source Accession
1 Ubiquitin mediated proteolysis hsa04120

GO Terms for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

Cellular components related to Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 Golgi apparatus GO:0005794 8.62 HERC1 ERC1

Sources for Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation

3 CDC
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10 dbSNP
11 DGIdb
17 EFO
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19 FMA
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28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
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35 IUPHAR
36 KEGG
37 LifeMap
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44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
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53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
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71 UMLS via Orphanet
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