SWNTS1
MCID: SCH077
MIFTS: 38

Schwannomatosis 1 (SWNTS1)

Categories: Cancer diseases, Genetic diseases, Neuronal diseases
Data Licensing
For inquiries, contact:

Aliases & Classifications for Schwannomatosis 1

MalaCards integrated aliases for Schwannomatosis 1:

Name: Schwannomatosis 1 57 73 28 5 71
Schwannomatosis-1, Susceptibility to 57 28
Schwannomatosis, Somatic 57 28
Swnts1 57 73
Neurilemmomatosis, Congenital Cutaneous 57
Congenital Cutaneous Neurilemmomatosis 73
Schwannomatosis-1 57
Schwannomatosis 71

Characteristics:


Inheritance:

Autosomal dominant 57

OMIM®:

57 (Updated 08-Dec-2022)
Miscellaneous:
variable expressivity
incomplete penetrance
germline and somatic mutations contribute to this disorder


Classifications:



External Ids:

OMIM® 57 162091
OMIM Phenotypic Series 57 PS162091
MeSH 43 D009442
SNOMED-CT via HPO 69 126962006 404022001 985004
UMLS 71 C1335929 C4048809

Summaries for Schwannomatosis 1

OMIM®: 57 Schwannomatosis, also known as neurilemmomatosis, first reported by Niimura (1973) as neurofibromatosis type 3, is characterized by multiple cutaneous neurilemmomas and spinal schwannomas, without acoustic tumors or other signs of neurofibromatosis I (NF1; 162200) or neurofibromatosis II (NF2; 101000). In neurilemmomas, the tumor consists of Schwann cells. Some patients may develop meningiomas (van den Munckhof et al., 2012). (162091) (Updated 08-Dec-2022)

MalaCards based summary: Schwannomatosis 1, also known as schwannomatosis-1, susceptibility to, is related to neurilemmomatosis and schwannomatosis 2. An important gene associated with Schwannomatosis 1 is SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1). The drugs Tanezumab and Analgesics have been mentioned in the context of this disorder. Affiliated tissues include spinal cord, brain and peripheral nerve, and related phenotypes are meningioma and spinal cord tumor

UniProtKB/Swiss-Prot: 73 A cancer syndrome in which patients develop multiple non-vestibular schwannomas, benign neoplasms that arise from Schwann cells of the cranial, peripheral, and autonomic nerves.

Related Diseases for Schwannomatosis 1

Diseases in the Schwannomatosis 1 family:

Schwannomatosis 2

Diseases related to Schwannomatosis 1 via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 58)
# Related Disease Score Top Affiliating Genes
1 neurilemmomatosis 31.3 SMARCB1 NF2
2 schwannomatosis 2 11.0
3 full schwannomatosis 9.9 SMARCB1 NF2
4 posterior pituitary gland neoplasm 9.9 SMARCB1 NF2
5 childhood meningioma 9.9 SMARCB1 NF2
6 peripheral nerve schwannoma 9.9 SMARCB1 NF2
7 pineal region meningioma 9.9 SMARCB1 NF2
8 cerebral falx meningioma 9.9 SMARCB1 NF2
9 parasagittal meningioma 9.9 SMARCB1 NF2
10 cerebral convexity meningioma 9.9 SMARCB1 NF2
11 optic nerve sheath meningioma 9.9 SMARCB1 NF2
12 plexiform schwannoma 9.9 SMARCB1 NF2
13 olfactory groove meningioma 9.9 SMARCB1 NF2
14 cerebellopontine angle tumor 9.9 SMARCB1 NF2
15 anterior cranial fossa meningioma 9.9 SMARCB1 NF2
16 cellular schwannoma 9.9 SMARCB1 NF2
17 chordoid meningioma 9.9 SMARCB1 NF2
18 brain meningioma 9.9 SMARCB1 NF2
19 transitional meningioma 9.9 SMARCB1 NF2
20 atypical neurofibroma 9.8 SMARCB1 NF2
21 secretory meningioma 9.8 SMARCB1 NF2
22 optic nerve neoplasm 9.8 SMARCB1 NF2
23 melanotic neurilemmoma 9.8 SMARCB1 NF2
24 neurilemmoma 9.8 SMARCB1 NF2
25 schwannoma of twelfth cranial nerve 9.8 SMARCB1 NF2
26 hypoglossal nerve disease 9.8 SMARCB1 NF2
27 rhabdoid meningioma 9.8 SMARCB1 NF2
28 skull base meningioma 9.8 SMARCB1 NF2
29 spinal canal and spinal cord meningioma 9.8 SMARCB1 NF2
30 spinal meningioma 9.8 SMARCB1 NF2
31 meningothelial meningioma 9.8 SMARCB1 NF2
32 spinal cord ependymoma 9.8 SMARCB1 NF2
33 clear cell meningioma 9.8 SMARCB1 NF2
34 skull base cancer 9.8 SMARCB1 NF2
35 fibrous meningioma 9.8 SMARCB1 NF2
36 cranial nerve malignant neoplasm 9.8 SMARCB1 NF2
37 intracranial meningioma 9.8 SMARCB1 NF2
38 anaplastic ependymoma 9.8 SMARCB1 NF2
39 spinal cancer 9.8 SMARCB1 NF2
40 plexiform neurofibroma 9.8 SMARCB1 NF2
41 high grade ependymoma 9.8 SMARCB1 NF2
42 cerebral ventricle cancer 9.8 SMARCB1 NF2
43 neurofibromatosis, type ii 9.8 SMARCB1 NF2
44 neurofibromatosis 9.8 SMARCB1 NF2
45 cerebrum cancer 9.8 SMARCB1 NF2
46 supratentorial cancer 9.8 SMARCB1 NF2
47 spindle cell sarcoma 9.8 SMARCB1 NF2
48 acoustic neuroma 9.8 SMARCB1 NF2
49 neuroma 9.8 SMARCB1 NF2
50 atypical teratoid rhabdoid tumor 9.7 SMARCB1 NF2

Graphical network of the top 20 diseases related to Schwannomatosis 1:



Diseases related to Schwannomatosis 1

Symptoms & Phenotypes for Schwannomatosis 1

Human phenotypes related to Schwannomatosis 1:

30
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 meningioma 30 HP:0002858
2 spinal cord tumor 30 HP:0010302
3 schwannoma 30 HP:0100008

Symptoms via clinical synopsis from OMIM®:

57 (Updated 08-Dec-2022)
Skeletal Spine:
schwannomas

Skin Nails Hair Skin:
schwannomas

Neoplasia:
meningiomas
multiple schwannomas

Skeletal Limbs:
schwannomas

Neurologic Central Nervous System:
spinal tumors
absence of vestibular schwannomas at age greater than 18 years
meningiomas

Clinical features from OMIM®:

162091 (Updated 08-Dec-2022)

GenomeRNAi Phenotypes related to Schwannomatosis 1 according to GeneCards Suite gene sharing:

25
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Decreased viability GR00055-A-3 9.56 NF2
2 Decreased viability GR00221-A-1 9.56 SMARCB1
3 Decreased viability GR00221-A-2 9.56 SMARCB1
4 Decreased viability GR00221-A-3 9.56 NF2 SMARCB1
5 Decreased viability GR00249-S 9.56 NF2 SMARCB1
6 Decreased viability GR00381-A-1 9.56 SMARCB1
7 Increased proliferation GR00094-A 8.62 NF2 SMARCB1

Drugs & Therapeutics for Schwannomatosis 1

Drugs for Schwannomatosis 1 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 6)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Tanezumab Investigational Phase 2 880266-57-9
2 Analgesics Phase 2
3 Immunoglobulins Phase 2
4 Antibodies Phase 2
5 Mitogens Phase 2
6
Lysine Approved, Nutraceutical 56-87-1 5962

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Immunotherapy Targeting Neurofibromatosis or Schwannomatosis Recruiting NCT04085159 Phase 1, Phase 2
2 A Phase 2 Randomized, Double-blind, Placebo-Controlled Study of the Analgesic Efficacy and Safety of the Subcutaneous Administration of the Anti-NGF Antibody Tanezumab in Subjects With Moderate to Severe Pain Due to Schwannomatosis Active, not recruiting NCT04163419 Phase 2 Tanezumab;Placebo
3 Relationship Between Psychosocial Factors, Health Literacy, Quality of Life and Satisfaction With Medical Visits in Adults With Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis Completed NCT02435628
4 Resiliency Training for Patients With Neurofibromatosis Via Videoconferencing With Skype Completed NCT02298270
5 Neurofibromatosis (NF) Registry Portal Funded by Children's Tumor Foundation Recruiting NCT01885767
6 Resiliency Training for Adults With Neurofibromatosis Via Live Videoconferencing Recruiting NCT03406208
7 Tazemetostat Expanded Access Program for Adults With Solid Tumors Temporarily not available NCT03874455 Tazemetostat

Search NIH Clinical Center for Schwannomatosis 1

Genetic Tests for Schwannomatosis 1

Genetic tests related to Schwannomatosis 1:

# Genetic test Affiliating Genes
1 Schwannomatosis 1 28 NF2 SMARCB1
2 Schwannomatosis, Somatic 28
3 Schwannomatosis-1, Susceptibility to 28

Anatomical Context for Schwannomatosis 1

Organs/tissues related to Schwannomatosis 1:

MalaCards : Spinal Cord, Brain
ODiseA: Peripheral Nerve, Brain

Publications for Schwannomatosis 1

Articles related to Schwannomatosis 1:

(show all 23)
# Title Authors PMID Year
1
Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri. 57 5
22038540 2012
2
Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. 57 5
20930055 2011
3
Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. 57 5
19582488 2010
4
Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. 57 5
19124645 2009
5
Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. 57 5
18285426 2008
6
Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. 57 5
18072270 2008
7
Germline mutation of INI1/SMARCB1 in familial schwannomatosis. 57 5
17357086 2007
8
Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. 57 5
9399891 1997
9
Neurofibromatosis 2 and neurilemmomatosis gene are identical. 57 5
7798645 1995
10
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. 5
25525159 2015
11
Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2. 57
16287142 2005
12
Familial schwannomatosis: exclusion of the NF2 locus as the germline event. 57
12821741 2003
13
Phenotypic variability associated with 14 splice-site mutations in the NF2 gene. 5
9605590 1998
14
Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study. 57
9120449 1997
15
Schwannomatosis: a clinical and pathologic study. 57
8780094 1996
16
Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. 57
7747758 1994
17
Neurofibromatosis 2 in the pediatric age group. 57
8355853 1993
18
A clinical study of type 2 neurofibromatosis. 57
1484939 1992
19
Congenital neurilemmomatosis. 57
1583187 1992
20
A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. 62
28365909 2017
21
Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. 62
27958595 2016
22
Epithelioid Schwannomas: An Analysis of 58 Cases Including Atypical Variants. 62
26752543 2016
23
Diagnosis, Management, and New Therapeutic Options in Childhood Neurofibromatosis Type 2 and Related Forms. 62
26706012 2015

Variations for Schwannomatosis 1

ClinVar genetic disease variations for Schwannomatosis 1:

5 (show top 50) (show all 52)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 SMARCB1 NM_003073.5(SMARCB1):c.143C>T (p.Pro48Leu) SNV Pathogenic
30202 rs387906811 GRCh37: 22:24133992-24133992
GRCh38: 22:23791805-23791805
2 NF2 NM_000268.4(NF2):c.125_126insG (p.Gly43fs) INSERT Pathogenic
3299 rs587776564 GRCh37: 22:30032750-30032751
GRCh38: 22:29636761-29636762
3 NF2 NM_000268.4(NF2):c.205_211del (p.Lys69fs) DEL Pathogenic
3300 rs587776565 GRCh37: 22:30032830-30032836
GRCh38: 22:29636841-29636847
4 NF2 NM_000268.4(NF2):c.363+1G>A SNV Pathogenic
635372 rs1601583839 GRCh37: 22:30035202-30035202
GRCh38: 22:29639213-29639213
5 SMARCB1 NM_003073.5(SMARCB1):c.233-2_237del DEL Pathogenic
8029 GRCh37: 22:24135742-24135748
GRCh38: 22:23793555-23793561
6 NF2 NC_000022.11:g.(29668447_29671826)_(29681601_?)del DEL Pathogenic
3298 GRCh37:
GRCh38: 22:29668447-29681601
7 SMARCB1 NM_003073.5(SMARCB1):c.747dup (p.Thr250fs) DUP Pathogenic
1686219 GRCh37: 22:24159071-24159072
GRCh38: 22:23816884-23816885
8 SMARCB1 NM_003073.5(SMARCB1):c.307_346del (p.Asn103fs) DEL Pathogenic
1686218 GRCh37: 22:24135818-24135857
GRCh38: 22:23793631-23793670
9 SMARCB1 NM_003073.5(SMARCB1):c.92A>T (p.Glu31Val) SNV Pathogenic
8031 rs267607072 GRCh37: 22:24129448-24129448
GRCh38: 22:23787261-23787261
10 SMARCB1 NM_003073.5(SMARCB1):c.629-361_795+2103dup DUP Pathogenic
8030 GRCh37: 22:24158592-24158593
GRCh38: 22:23816405-23816406
11 SMARCB1 NM_003073.5(SMARCB1):c.203_216delinsTACC (p.His68fs) INDEL Pathogenic
8028 rs587776679 GRCh37: 22:24134052-24134065
GRCh38: 22:23791865-23791878
12 SMARCB1 NM_003073.5(SMARCB1):c.34C>T (p.Gln12Ter) SNV Pathogenic
8026 rs74315513 GRCh37: 22:24129390-24129390
GRCh38: 22:23787203-23787203
13 SMARCB1 NM_003073.5(SMARCB1):c.568C>T (p.Arg190Trp) SNV Likely Pathogenic
825898 rs1601405064 GRCh37: 22:24145549-24145549
GRCh38: 22:23803362-23803362
14 SMARCB1 NM_003073.5(SMARCB1):c.607G>A (p.Ala203Thr) SNV Uncertain Significance
340912 rs762962010 GRCh37: 22:24145588-24145588
GRCh38: 22:23803401-23803401
15 SMARCB1 NM_003073.5(SMARCB1):c.987-4G>C SNV Uncertain Significance
340915 rs745773662 GRCh37: 22:24175755-24175755
GRCh38: 22:23833568-23833568
16 SMARCB1 NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu) SNV Uncertain Significance
410706 rs779769475 GRCh37: 22:24134007-24134007
GRCh38: 22:23791820-23791820
17 SMARCB1 NM_003073.5(SMARCB1):c.*100C>G SNV Uncertain Significance
903097 rs1363655817 GRCh37: 22:24176467-24176467
GRCh38: 22:23834280-23834280
18 SMARCB1 NM_003073.5(SMARCB1):c.309C>T (p.Asn103=) SNV Uncertain Significance
532975 rs145695677 GRCh37: 22:24135822-24135822
GRCh38: 22:23793635-23793635
19 NF2 NM_000268.4(NF2):c.1701C>G (p.Asp567Glu) SNV Uncertain Significance
457904 rs1049732514 GRCh37: 22:30077554-30077554
GRCh38: 22:29681565-29681565
20 NF2 NM_000268.4(NF2):c.1619A>G (p.Asn540Ser) SNV Uncertain Significance
565467 rs774824164 GRCh37: 22:30077472-30077472
GRCh38: 22:29681483-29681483
21 NF2 NM_000268.4(NF2):c.1232G>A (p.Arg411His) SNV Uncertain Significance
527695 rs201214090 GRCh37: 22:30069367-30069367
GRCh38: 22:29673378-29673378
22 NF2 NM_000268.4(NF2):c.215T>C (p.Val72Ala) SNV Uncertain Significance
569354 rs1260510937 GRCh37: 22:30032840-30032840
GRCh38: 22:29636851-29636851
23 NF2 NM_000268.4(NF2):c.4G>T (p.Ala2Ser) SNV Uncertain Significance
638486 rs1601515682 GRCh37: 22:29999991-29999991
GRCh38: 22:29604002-29604002
24 SMARCB1 NM_003073.5(SMARCB1):c.*279G>A SNV Uncertain Significance
340921 rs886057287 GRCh37: 22:24176646-24176646
GRCh38: 22:23834459-23834459
25 SMARCB1 NM_003073.5(SMARCB1):c.*113C>T SNV Uncertain Significance
340920 rs886057286 GRCh37: 22:24176480-24176480
GRCh38: 22:23834293-23834293
26 SMARCB1 NM_003073.5(SMARCB1):c.-107A>G SNV Uncertain Significance
340910 rs886057284 GRCh37: 22:24129250-24129250
GRCh38: 22:23787063-23787063
27 SMARCB1 NM_003073.5(SMARCB1):c.-157G>A SNV Uncertain Significance
340905 rs886057281 GRCh37: 22:24129200-24129200
GRCh38: 22:23787013-23787013
28 SMARCB1 NM_003073.5(SMARCB1):c.-148T>C SNV Uncertain Significance
340907 rs886057283 GRCh37: 22:24129209-24129209
GRCh38: 22:23787022-23787022
29 SMARCB1 NM_003073.5(SMARCB1):c.-83C>T SNV Uncertain Significance
903043 rs1374186002 GRCh37: 22:24129274-24129274
GRCh38: 22:23787087-23787087
30 SMARCB1 NM_003073.5(SMARCB1):c.1118+8T>C SNV Uncertain Significance
902212 rs2030796889 GRCh37: 22:24175898-24175898
GRCh38: 22:23833711-23833711
31 SMARCB1 NM_003073.5(SMARCB1):c.*307A>G SNV Uncertain Significance
900606 rs2030874248 GRCh37: 22:24176674-24176674
GRCh38: 22:23834487-23834487
32 SMARCB1 NM_003073.5(SMARCB1):c.633G>A (p.Lys211=) SNV Uncertain Significance
900547 rs1930218305 GRCh37: 22:24158961-24158961
GRCh38: 22:23816774-23816774
33 SMARCB1 NM_003073.5(SMARCB1):c.*197A>C SNV Uncertain Significance
899472 rs1306414841 GRCh37: 22:24176564-24176564
GRCh38: 22:23834377-23834377
34 SMARCB1 NM_003073.5(SMARCB1):c.*159C>G SNV Uncertain Significance
899471 rs1022324232 GRCh37: 22:24176526-24176526
GRCh38: 22:23834339-23834339
35 SMARCB1 NM_003073.5(SMARCB1):c.696G>A (p.Thr232=) SNV Likely Benign
416321 rs145934279 GRCh37: 22:24159024-24159024
GRCh38: 22:23816837-23816837
36 SMARCB1 NM_003073.5(SMARCB1):c.*17C>T SNV Likely Benign
340918 rs372348692 GRCh37: 22:24176384-24176384
GRCh38: 22:23834197-23834197
37 SMARCB1 NM_003073.5(SMARCB1):c.*15C>A SNV Likely Benign
340917 rs369400289 GRCh37: 22:24176382-24176382
GRCh38: 22:23834195-23834195
38 SMARCB1 NM_003073.5(SMARCB1):c.-17C>T SNV Benign
340911 rs372777519 GRCh37: 22:24129340-24129340
GRCh38: 22:23787153-23787153
39 SMARCB1 NM_003073.5(SMARCB1):c.*293C>T SNV Benign
340922 rs754865420 GRCh37: 22:24176660-24176660
GRCh38: 22:23834473-23834473
40 SMARCB1 NM_003073.5(SMARCB1):c.-117C>T SNV Benign
340908 rs11090285 GRCh37: 22:24129240-24129240
GRCh38: 22:23787053-23787053
41 SMARCB1 NM_003073.5(SMARCB1):c.897G>A (p.Ser299=) SNV Benign
126368 rs2229354 GRCh37: 22:24167513-24167513
GRCh38: 22:23825326-23825326
42 SMARCB1 NM_003073.5(SMARCB1):c.362+7C>T SNV Benign
239483 rs34746244 GRCh37: 22:24135882-24135882
GRCh38: 22:23793695-23793695
43 SMARCB1 NM_003073.5(SMARCB1):c.-184G>A SNV Benign
900500 rs563943196 GRCh37: 22:24129173-24129173
GRCh38: 22:23786986-23786986
44 SMARCB1 NM_003073.5(SMARCB1):c.-115C>T SNV Benign
340909 rs551328283 GRCh37: 22:24129242-24129242
GRCh38: 22:23787055-23787055
45 SMARCB1 NM_003073.5(SMARCB1):c.*33T>G SNV Benign
903096 rs11541580 GRCh37: 22:24176400-24176400
GRCh38: 22:23834213-23834213
46 SMARCB1 NM_003073.5(SMARCB1):c.-31C>T SNV Benign
903044 rs34276473 GRCh37: 22:24129326-24129326
GRCh38: 22:23787139-23787139
47 SMARCB1 NM_003073.5(SMARCB1):c.978C>T (p.Tyr326=) SNV Benign
388704 rs187488637 GRCh37: 22:24167594-24167594
GRCh38: 22:23825407-23825407
48 SMARCB1 NM_003073.5(SMARCB1):c.1032C>T (p.Gly344=) SNV Benign
416325 rs149451748 GRCh37: 22:24175804-24175804
GRCh38: 22:23833617-23833617
49 SMARCB1 NM_003073.5(SMARCB1):c.1A>G (p.Met1Val) SNV Benign
135257 rs367768260 GRCh37: 22:24129357-24129357
GRCh38: 22:23787170-23787170
50 SMARCB1 NM_003073.5(SMARCB1):c.628+13C>T SNV Benign
340913 rs184021903 GRCh37: 22:24145622-24145622
GRCh38: 22:23803435-23803435

Expression for Schwannomatosis 1

Search GEO for disease gene expression data for Schwannomatosis 1.

Pathways for Schwannomatosis 1

GO Terms for Schwannomatosis 1

Biological processes related to Schwannomatosis 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 positive regulation of cell differentiation GO:0045597 8.92 SMARCB1 NF2

Sources for Schwannomatosis 1

2 CDC
6 CNVD
8 Cosmic
9 dbSNP
10 DGIdb
16 EFO
17 ExPASy
18 FMA
19 GARD
27 GO
28 GTR
29 HMDB
30 HPO
31 ICD10
32 ICD10 via Orphanet
33 ICD11
34 ICD9CM
35 IUPHAR
36 LifeMap
38 LOVD
40 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
52 NINDS
53 Novoseek
55 ODiseA
56 OMIM via Orphanet
57 OMIM® (Updated 08-Dec-2022)
61 PubChem
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 Tocris
71 UMLS
72 UMLS via Orphanet
Content
Loading form....