Wolcott-Rallison syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: WRS
Early-onset diabetes mellitus with multiple epiphyseal dysplasia
IDDM-MED syndrome
Wolcott-Rallison syndrome
MED-IDDM syndrome
Number of Symptoms 118
OrphanetNr: 1667
OMIM Id: 226980
ICD-10: E10
UMLs: C0432217
MeSH: C536739
MedDRA:
Snomed: 254066006

Prevalence, inheritance and age of onset:

Prevalence: < 60 cases [Orphanet]
Inheritance: Autosomal recessive
[Orphanet]
Age of onset: Neonatal
Infancy
[Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases: AARSKOG SYNDROME, AUTOSOMAL DOMINANT
 -AARSKOG SYNDROME, AUTOSOMAL DOMINANT
Other rare diabetes mellitus
 -Rare endocrine disease
Rare genetic diabetes mellitus
 -Rare genetic disease
Spondyloepiphyseal dysplasia and spondyloepimetaphyseal dysplasia
 -Rare bone disease
 -Rare developmental defect during embryogenesis
 -Rare genetic disease

Comment:

Wolcott Rallison syndrome is an autosomal recessive disorder characterised by infantile onset diabetes, multiple epiphyseal dysplasia, growth retardation, exocrine pancreatic dysfunction, osteopenia, developmental delay, hypothyroidism, acute liver failure, renal failure, cardiomegaly, cerebellar cortical dysplasia and early death. The molecular defect is localised to the EIF‐2AK3 gene on chromosome 2p12 which regulates protein synthesis and folding. The resultant misfolded proteins increase the stress in the endoplasmic reticulum of various tissues leading to cell death by apoptosis which explains the various phenotypic features (PMID: 23869298). Wolcott-Rallison syndrome is a form of monogenic diabetes caused by mutations in EIF2AK3 (PMID:21127150).

Symptom Information: Sort by abundance 

1
 (HPO:0000083) Renal insufficiency Occasional [Orphanet] 232 / 7739
2
 (HPO:0000112) Nephropathy Occasional [Orphanet] 92 / 7739
3
 (HPO:0005280) Depressed nasal bridge 381 / 7739
4
 (HPO:0000218) High palate 356 / 7739
5
 (HPO:0000252) Microcephaly Occasional [Orphanet] 832 / 7739
6
 (HPO:0000582) Upslanted palpebral fissure 185 / 7739
7
 (HPO:0000316) Hypertelorism 644 / 7739
8
 (HPO:0002705) High, narrow palate 308 / 7739
9
 (HPO:0004467) Preauricular pit 39 / 7739
10
 (HPO:0001270) Motor delay Frequent [Orphanet] 322 / 7739
11
 (HPO:0002133) Status epilepticus Occasional [Orphanet] 59 / 7739
12
 (HPO:0001276) Hypertonia 317 / 7739
13
 (HPO:0001328) Specific learning disability Frequent [Orphanet] 114 / 7739
14
 (HPO:0002121) Absence seizures Occasional [Orphanet] 62 / 7739
15
 (HPO:0001288) Gait disturbance Frequent [Orphanet] 318 / 7739
16
 (HPO:0001263) Global developmental delay Frequent [Orphanet] 853 / 7739
17
 (HPO:0011097) Epileptic spasms Occasional [Orphanet] 45 / 7739
18
 (HPO:0001250) Seizures Occasional [Orphanet] 1245 / 7739
19
 (HPO:0001249) Intellectual disability Frequent [Orphanet] 1089 / 7739
20
 (HPO:0100543) Cognitive impairment Frequent [Orphanet] 230 / 7739
21
 (HPO:0011147) Typical absence seizures Occasional [Orphanet] 33 / 7739
22
 (HPO:0100651) Type I diabetes mellitus 44 / 7739
23
 (HPO:0000819) Diabetes mellitus 23869298 IBIS 131 / 7739
24
 (HPO:0005978) Type II diabetes mellitus Very frequent [Orphanet] 68 / 7739
25
 (HPO:0000821) Hypothyroidism Occasional [Orphanet] 23869298 IBIS 141 / 7739
26
 (HPO:0010230) Cone-shaped epiphyses of the phalanges of the hand 34 / 7739
27
 (HPO:0003172) Abnormality of the pubic bone Frequent [Orphanet] 5 / 7739
28
 (HPO:0003311) Hypoplasia of the odontoid process 34 / 7739
29
 (HPO:0000773) Short ribs Frequent [Orphanet] typical [HPO] 70 / 7739
30
 (HPO:0002749) Osteomalacia Very frequent [Orphanet] 24 / 7739
31
 (HPO:0002857) Genu valgum Frequent [Orphanet] 144 / 7739
32
 (HPO:0002827) Hip dislocation Frequent [Orphanet] 94 / 7739
33
 (HPO:0002868) Narrow iliac wings Frequent [Orphanet] 15 / 7739
34
 (HPO:0002644) Abnormality of pelvic girdle bone morphology Frequent [Orphanet] 31 / 7739
35
 (HPO:0008134) Irregular tarsal ossification 2 / 7739
36
 (HPO:0002748) Rickets Very frequent [Orphanet] 41 / 7739
37
 (HPO:0010583) Ivory epiphyses 4 / 7739
38
 (HPO:0011927) Short digit Frequent [Orphanet] 17 / 7739
39
 (HPO:0003071) Flattened epiphysis 14 / 7739
40
 (HPO:0000944) Abnormality of the metaphyses Very frequent [Orphanet] 141 / 7739
41
 (HPO:0010579) Cone-shaped epiphysis Very frequent [Orphanet] hallmark [HPO] 54 / 7739
42
 (HPO:0010306) Short thorax Frequent [Orphanet] 10 / 7739
43
 (HPO:0001552) Barrel-shaped chest Frequent [Orphanet] typical [HPO] 31 / 7739
44
 (HPO:0006110) Shortening of all middle phalanges of the fingers 7 / 7739
45
 (HPO:0004236) Irregular carpal bones 3 / 7739
46
 (HPO:0000888) Horizontal ribs Frequent [Orphanet] typical [HPO] 12 / 7739
47
 (HPO:0000939) Osteoporosis Very frequent [Orphanet] 129 / 7739
48
 (HPO:0003272) Abnormality of the hip bone 3 / 7739
49
 (HPO:0001216) Delayed ossification of carpal bones Frequent [Orphanet] typical [HPO] 30 / 7739
50
 (HPO:0000926) Platyspondyly Frequent [Orphanet] 150 / 7739
51
 (HPO:0002757) Recurrent fractures Occasional [Orphanet] 47 / 7739
52
 (HPO:0003301) Irregular vertebral endplates 25 / 7739
53
 (HPO:0004349) Reduced bone mineral density 165 / 7739
54
 (HPO:0010665) Bilateral coxa valga Frequent [Orphanet] 4 / 7739
55
 (HPO:0001498) Carpal bone hypoplasia 17 / 7739
56
 (HPO:0002654) Multiple epiphyseal dysplasia 8 / 7739
57
 (HPO:0000914) Shield chest 14 / 7739
58
 (HPO:0003307) Hyperlordosis Occasional [Orphanet] 122 / 7739
59
 (HPO:0001385) Hip dysplasia Frequent [Orphanet] 242 / 7739
60
 (HPO:0009803) Short phalanx of finger Frequent [Orphanet] 79 / 7739
61
 (HPO:0002808) Kyphosis Occasional [Orphanet] 289 / 7739
62
 (HPO:0004565) Severe platyspondyly Frequent [Orphanet] typical [HPO] 13 / 7739
63
 (HPO:0005257) Thoracic hypoplasia Frequent [Orphanet] typical [HPO] 79 / 7739
64
 (HPO:0005930) Abnormality of epiphysis morphology Very frequent [Orphanet] 119 / 7739
65
 (HPO:0002750) Delayed skeletal maturation Frequent [Orphanet] 250 / 7739
66
 (HPO:0001156) Brachydactyly syndrome Frequent [Orphanet] 180 / 7739
67
 (HPO:0100255) Metaphyseal dysplasia Very frequent [Orphanet] hallmark [HPO] 26 / 7739
68
 (HPO:0002812) Coxa vara Frequent [Orphanet] 58 / 7739
69
 (HPO:0002673) Coxa valga Frequent [Orphanet] 57 / 7739
70
 (HPO:0010585) Small epiphyses 16 / 7739
71
 (HPO:0000938) Osteopenia Very frequent [Orphanet] 23869298 IBIS 138 / 7739
72
 (HPO:0004279) Short palm Frequent [Orphanet] 323 / 7739
73
 (HPO:0002656) Epiphyseal dysplasia 23869298 IBIS 25 / 7739
74
 (HPO:0005743) Avascular necrosis of the capital femoral epiphysis Frequent [Orphanet] 17 / 7739
75
 (HPO:0100625) Enlarged thorax Frequent [Orphanet] typical [HPO] 15 / 7739
76
 (HPO:0006462) Generalized bone demineralization Very frequent [Orphanet] 11 / 7739
77
 (HPO:0009381) Short finger Frequent [Orphanet] 45 / 7739
78
 (HPO:0002659) Increased susceptibility to fractures Occasional [Orphanet] 110 / 7739
79
 (HPO:0002938) Lumbar hyperlordosis Occasional [Orphanet] occasional [HPO] 73 / 7739
80
 (HPO:0002611) Cholestatic liver disease Occasional [Orphanet] 19 / 7739
81
 (HPO:0100626) Chronic hepatic failure Frequent [Orphanet] 7 / 7739
82
 (HPO:0001396) Cholestasis Occasional [Orphanet] 136 / 7739
83
 (HPO:0002594) Pancreatic hypoplasia Occasional [Orphanet] 5 / 7739
84
 (HPO:0001738) Exocrine pancreatic insufficiency Occasional [Orphanet] 23 / 7739
85
 (HPO:0000952) Jaundice Occasional [Orphanet] 105 / 7739
86
 (HPO:0100800) Aplasia/Hypoplasia of the pancreas Occasional [Orphanet] 8 / 7739
87
 (HPO:0002910) Elevated hepatic transaminases Frequent [Orphanet] 158 / 7739
88
 (HPO:0012092) Abnormality of exocrine pancreas physiology Occasional [Orphanet] 23869298 IBIS 9 / 7739
89
 (HPO:0012115) Hepatitis Occasional [Orphanet] 24 / 7739
90
 (HPO:0006554) Acute hepatic failure Frequent [Orphanet] 23869298 IBIS 20 / 7739
91
 (HPO:0006274) Reduced pancreatic beta cells 2 / 7739
92
 (HPO:0002240) Hepatomegaly Frequent [Orphanet] 467 / 7739
93
 (HPO:0001511) Intrauterine growth retardation Occasional [Orphanet] 23869298 IBIS 358 / 7739
94
 (HPO:0004322) Short stature Very frequent [Orphanet] 1232 / 7739
95
 (HPO:0003510) Severe short stature Very frequent [Orphanet] 90 / 7739
96
 (HPO:0001640) Cardiomegaly 23869298 IBIS 81 / 7739
97
 (HPO:0001875) Neutropenia Frequent [Orphanet] 83 / 7739
98
 (HPO:0001874) Abnormality of neutrophils Frequent [Orphanet] 47 / 7739
99
 (HPO:0011897) Neutrophillia Frequent [Orphanet] 4 / 7739
100
 (HPO:0001943) Hypoglycemia Occasional [Orphanet] 131 / 7739
101
 (HPO:0002718) Recurrent bacterial infections Frequent [Orphanet] 75 / 7739
102
 (HPO:0002719) Recurrent infections Frequent [Orphanet] 107 / 7739
103
 (HPO:0010978) Abnormality of immune system physiology Frequent [Orphanet] 148 / 7739
104
 (HPO:0002721) Immunodeficiency Frequent [Orphanet] 97 / 7739
105
 (OMIM) Small, irregular carpal centers 1 / 7739
106
 (HPO:0001302) Pachygyria Occasional [Orphanet] 60 / 7739
107
 (HPO:0002536) Abnormal cortical gyration Occasional [Orphanet] 72 / 7739
108
 (HPO:0008278) Cerebellar cortical atrophy 23869298 IBIS 2 / 7739
109
 (HPO:0002126) Polymicrogyria Occasional [Orphanet] 64 / 7739
110
 (OMIM) Bowing distal radii and ulnae 1 / 7739
111
 (OMIM) Small flattened epiphyses (distal femora and proximal tibiae) 3 / 7739
112
 (HPO:0001339) Lissencephaly Occasional [Orphanet] 30 / 7739
113
 (HPO:0002269) Abnormality of neuronal migration Occasional [Orphanet] 10 / 7739
114
 (HPO:0007227) Macrogyria Occasional [Orphanet] 9 / 7739
115
 (OMIM) Small, irregular tarsal centers 1 / 7739
116
 (Orphanet:29660) Abnormal hepatic enzymes/transaminases Frequent [Orphanet] 2 / 7739
117
 (OMIM) Reabsorption of capital femoral epiphyses 1 / 7739
118
 (OMIM) Hypoplastic distal and middle phalanges 3 / 7739

Associated genes:

EIF2AK3

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis, and growth retardation develop at a later age. Other frequent multisystem manifestations include hepatic and renal dysfunction, mental retardation, ...
Clinical Description OMIM Wolcott and Rallison (1972) described 2 brothers and a sister with infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. Demineralization of bone with multiple fractures, tooth discoloration, and skin abnormalities were also noted. The parents were not related. Extracellular collagen ...
Molecular genetics OMIM In 2 consanguineous families with Wolcott-Rallison syndrome, Delepine et al. (2000) identified different mutations in the EIF2AK3 (604032.0001; 604032.0002) that segregated with the disorder in each family.

In one of the sibs with Wolcott-Rallison syndrome reported by ...