SSMED
MCID: SHR082
MIFTS: 32

Short Stature, Microcephaly, and Endocrine Dysfunction (SSMED)

Categories: Genetic diseases, Immune diseases

Aliases & Classifications for Short Stature, Microcephaly, and Endocrine Dysfunction

MalaCards integrated aliases for Short Stature, Microcephaly, and Endocrine Dysfunction:

Name: Short Stature, Microcephaly, and Endocrine Dysfunction 57 72 29 6
Ssmed 57 72
Stature, Short, Microcephaly, and Endocrine Dysfunction 39

Characteristics:

OMIM®:

57 (Updated 20-May-2021)
Inheritance:
autosomal recessive

Miscellaneous:
endocrine and neurologic defects may become apparent later in life


HPO:

31
short stature, microcephaly, and endocrine dysfunction:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Short Stature, Microcephaly, and Endocrine Dysfunction

OMIM® : 57 In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015). (616541) (Updated 20-May-2021)

MalaCards based summary : Short Stature, Microcephaly, and Endocrine Dysfunction, also known as ssmed, is related to microcephalic primordial dwarfism-insulin resistance syndrome and fanconi anemia, complementation group a. An important gene associated with Short Stature, Microcephaly, and Endocrine Dysfunction is XRCC4 (X-Ray Repair Cross Complementing 4), and among its related pathways/superpathways is DNA Double-Strand Break Repair. Affiliated tissues include eye, kidney and thyroid, and related phenotypes are cataract and sensorineural hearing impairment

UniProtKB/Swiss-Prot : 72 Short stature, microcephaly, and endocrine dysfunction: A disease characterized by short stature and microcephaly apparent at birth, progressive postnatal growth failure, and endocrine dysfunction. In affected adults endocrine features include hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus. Variable features observed in some patients are progressive ataxia, and lymphopenia or borderline leukopenia.

Related Diseases for Short Stature, Microcephaly, and Endocrine Dysfunction

Diseases related to Short Stature, Microcephaly, and Endocrine Dysfunction via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 microcephalic primordial dwarfism-insulin resistance syndrome 9.6 XRCC4 XRCC2
2 fanconi anemia, complementation group a 9.5 XRCC4 XRCC2

Symptoms & Phenotypes for Short Stature, Microcephaly, and Endocrine Dysfunction

Human phenotypes related to Short Stature, Microcephaly, and Endocrine Dysfunction:

31 (show top 50) (show all 55)
# Description HPO Frequency HPO Source Accession
1 cataract 31 occasional (7.5%) HP:0000518
2 sensorineural hearing impairment 31 occasional (7.5%) HP:0000407
3 truncal obesity 31 occasional (7.5%) HP:0001956
4 clinodactyly 31 occasional (7.5%) HP:0030084
5 nystagmus 31 very rare (1%) HP:0000639
6 ataxia 31 very rare (1%) HP:0001251
7 dysarthria 31 very rare (1%) HP:0001260
8 gait disturbance 31 very rare (1%) HP:0001288
9 microcephaly 31 very rare (1%) HP:0000252
10 cryptorchidism 31 very rare (1%) HP:0000028
11 ectopic kidney 31 very rare (1%) HP:0000086
12 dilated cardiomyopathy 31 very rare (1%) HP:0001644
13 renal hypoplasia 31 very rare (1%) HP:0000089
14 pes cavus 31 very rare (1%) HP:0001761
15 hypotelorism 31 very rare (1%) HP:0000601
16 disproportionate short-limb short stature 31 very rare (1%) HP:0008873
17 unilateral renal agenesis 31 very rare (1%) HP:0000122
18 sensory axonal neuropathy 31 very rare (1%) HP:0003390
19 impaired smooth pursuit 31 very rare (1%) HP:0007772
20 diabetes mellitus 31 HP:0000819
21 hypothyroidism 31 HP:0000821
22 global developmental delay 31 HP:0001263
23 inguinal hernia 31 HP:0000023
24 delayed speech and language development 31 HP:0000750
25 cognitive impairment 31 HP:0100543
26 immunodeficiency 31 HP:0002721
27 anemia 31 HP:0001903
28 intrauterine growth retardation 31 HP:0001511
29 lymphopenia 31 HP:0001888
30 micropenis 31 HP:0000054
31 long face 31 HP:0000276
32 deeply set eye 31 HP:0000490
33 ventriculomegaly 31 HP:0002119
34 prominent nasal bridge 31 HP:0000426
35 high forehead 31 HP:0000348
36 dysmetria 31 HP:0001310
37 sensory neuropathy 31 HP:0000763
38 dysdiadochokinesis 31 HP:0002075
39 convex nasal ridge 31 HP:0000444
40 high pitched voice 31 HP:0001620
41 triangular face 31 HP:0000325
42 acanthosis nigricans 31 HP:0000956
43 long nose 31 HP:0003189
44 broad-based gait 31 HP:0002136
45 sparse hair 31 HP:0008070
46 sloping forehead 31 HP:0000340
47 misalignment of teeth 31 HP:0000692
48 insulin resistance 31 HP:0000855
49 broad nasal tip 31 HP:0000455
50 limb undergrowth 31 HP:0009826

Symptoms via clinical synopsis from OMIM®:

57 (Updated 20-May-2021)
Head And Neck Eyes:
nystagmus
hypotelorism
deep-set eyes
cataracts (rare)
slowing of eye pursuits

Endocrine Features:
diabetes mellitus
hypothyroidism
insulin resistance
multinodular thyroid hypertrophy

Head And Neck Head:
microcephaly

Growth Height:
short stature

Genitourinary Kidneys:
ectopic kidney
unilateral renal agenesis
small kidneys

Neurologic Peripheral Nervous System:
sensory neuropathy

Head And Neck Nose:
long nose
broad nasal tip
beaked nose
high nasal bridge

Skeletal Limbs:
short limbs

Head And Neck Teeth:
malpositioned teeth

Metabolic Features:
dyslipidemia
mildly elevated glucose

Head And Neck Ears:
hearing loss, sensorineural (rare)

Skeletal Feet:
pes cavus (rare)

Muscle Soft Tissue:
hypotrophic type 2 muscle fibers

Immunology:
no clinical signs of immunodeficiency

Neurologic Central Nervous System:
dysarthria
cognitive impairment
dysmetria
simplified gyral pattern
developmental delay
more
Genitourinary External Genitalia Male:
inguinal hernia
micropenis

Skeletal Skull:
microcephaly

Genitourinary Internal Genitalia Male:
cryptorchidism

Head And Neck Face:
long face
high forehead
triangular face
sloping forehead
small chin

Skin Nails Hair Skin:
acanthosis nigricans

Voice:
high-pitched voice

Skeletal Hands:
clinodactyly (rare)

Growth Other:
intrauterine growth failure
truncal obesity, mild (in some patients)

Chest Breasts:
absent thelarche

Cardiovascular Heart:
cardiomyopathy, dilated (rare)

Skin Nails Hair Hair:
fine, sparse hair

Hematology:
lymphopenia, mild
anemia, persistent

Neoplasia:
gastrointestinal stromal tumor of jejunum (rare)
thalamic glioma, low grade (rare)

Clinical features from OMIM®:

616541 (Updated 20-May-2021)

MGI Mouse Phenotypes related to Short Stature, Microcephaly, and Endocrine Dysfunction:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 neoplasm MP:0002006 8.62 XRCC2 XRCC4

Drugs & Therapeutics for Short Stature, Microcephaly, and Endocrine Dysfunction

Search Clinical Trials , NIH Clinical Center for Short Stature, Microcephaly, and Endocrine Dysfunction

Genetic Tests for Short Stature, Microcephaly, and Endocrine Dysfunction

Genetic tests related to Short Stature, Microcephaly, and Endocrine Dysfunction:

# Genetic test Affiliating Genes
1 Short Stature, Microcephaly, and Endocrine Dysfunction 29 XRCC4

Anatomical Context for Short Stature, Microcephaly, and Endocrine Dysfunction

MalaCards organs/tissues related to Short Stature, Microcephaly, and Endocrine Dysfunction:

40
Eye, Kidney, Thyroid

Publications for Short Stature, Microcephaly, and Endocrine Dysfunction

Articles related to Short Stature, Microcephaly, and Endocrine Dysfunction:

# Title Authors PMID Year
1
XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency. 6 57
26255102 2015
2
Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability. 57 6
25839420 2015
3
A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy. 57 6
25872942 2015
4
An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome. 57 6
25742519 2015
5
Mutations in the NHEJ component XRCC4 cause primordial dwarfism. 57 6
25728776 2015
6
Genomic analysis of primordial dwarfism reveals novel disease genes. 57 6
24389050 2014
7
Response of motor complications in Cockayne syndrome to carbidopa-levodopa. 57 6
18695064 2008
8
Improvement of Anti-Hyperlipidemic Activity and Oral Bioavailability of Fluvastatin Via Solid Self-Microemulsifying Systems and Comparative with Liquisolid Formulation. 61
30033871 2018

Variations for Short Stature, Microcephaly, and Endocrine Dysfunction

ClinVar genetic disease variations for Short Stature, Microcephaly, and Endocrine Dysfunction:

6 (show all 13)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 XRCC4 NM_003401.5(XRCC4):c.823C>T (p.Arg275Ter) SNV Pathogenic 208516 rs797045016 GRCh37: 5:82554426-82554426
GRCh38: 5:83258607-83258607
2 XRCC4 NM_003401.5(XRCC4):c.-10-1G>T SNV Pathogenic 208517 rs869320678 GRCh37: 5:82400728-82400728
GRCh38: 5:83104909-83104909
3 XRCC4 NM_003401.5(XRCC4):c.673C>T (p.Arg225Ter) SNV Pathogenic 208518 rs768825050 GRCh37: 5:82500668-82500668
GRCh38: 5:83204849-83204849
4 XRCC4 NM_003401.5(XRCC4):c.481C>T (p.Arg161Ter) SNV Pathogenic 208519 rs779773463 GRCh37: 5:82491754-82491754
GRCh38: 5:83195935-83195935
5 XRCC4 NM_003401.5(XRCC4):c.246T>G (p.Asp82Glu) SNV Pathogenic 208520 rs879255258 GRCh37: 5:82406953-82406953
GRCh38: 5:83111134-83111134
6 XRCC4 NM_003401.5(XRCC4):c.482G>A (p.Arg161Gln) SNV Pathogenic 208521 rs797045017 GRCh37: 5:82491755-82491755
GRCh38: 5:83195936-83195936
7 XRCC4 NM_003401.5(XRCC4):c.760del (p.Asp254fs) Deletion Pathogenic 208522 rs879255259 GRCh37: 5:82554363-82554363
GRCh38: 5:83258544-83258544
8 XRCC4 NM_003401.5(XRCC4):c.628A>T (p.Lys210Ter) SNV Likely pathogenic 667362 rs991596636 GRCh37: 5:82499516-82499516
GRCh38: 5:83203697-83203697
9 XRCC4 NM_003401.5(XRCC4):c.127T>C (p.Trp43Arg) SNV Likely pathogenic 127246 rs587779351 GRCh37: 5:82400865-82400865
GRCh38: 5:83105046-83105046
10 XRCC4 NM_003401.5(XRCC4):c.25del (p.His9fs) Deletion Likely pathogenic 208515 rs869320677 GRCh37: 5:82400762-82400762
GRCh38: 5:83104943-83104943
11 XRCC2 NM_005431.2(XRCC2):c.643C>T (p.Arg215Ter) SNV Likely pathogenic 30063 rs143153871 GRCh37: 7:152345927-152345927
GRCh38: 7:152648842-152648842
12 XRCC4 NM_003401.5(XRCC4):c.640G>A (p.Glu214Lys) SNV Uncertain significance 690381 rs746407658 GRCh37: 5:82500635-82500635
GRCh38: 5:83204816-83204816
13 XRCC4 NM_003401.5(XRCC4):c.356C>T (p.Pro119Leu) SNV Uncertain significance 690382 rs768175717 GRCh37: 5:82491629-82491629
GRCh38: 5:83195810-83195810

UniProtKB/Swiss-Prot genetic disease variations for Short Stature, Microcephaly, and Endocrine Dysfunction:

72
# Symbol AA change Variation ID SNP ID
1 XRCC4 p.Trp43Arg VAR_075822 rs587779351
2 XRCC4 p.Arg161Gln VAR_075823 rs797045017

Expression for Short Stature, Microcephaly, and Endocrine Dysfunction

Search GEO for disease gene expression data for Short Stature, Microcephaly, and Endocrine Dysfunction.

Pathways for Short Stature, Microcephaly, and Endocrine Dysfunction

Pathways related to Short Stature, Microcephaly, and Endocrine Dysfunction according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
11.62 XRCC4 XRCC2

GO Terms for Short Stature, Microcephaly, and Endocrine Dysfunction

Biological processes related to Short Stature, Microcephaly, and Endocrine Dysfunction according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cellular response to DNA damage stimulus GO:0006974 9.26 XRCC4 XRCC2
2 DNA repair GO:0006281 9.16 XRCC4 XRCC2
3 DNA recombination GO:0006310 8.96 XRCC4 XRCC2
4 response to X-ray GO:0010165 8.62 XRCC4 XRCC2

Sources for Short Stature, Microcephaly, and Endocrine Dysfunction

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 20-May-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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