MCID: HST017
MIFTS: 38

Histiocytosis-Lymphadenopathy Plus Syndrome

Categories: Genetic diseases, Rare diseases, Liver diseases, Ear diseases, Immune diseases

Aliases & Classifications for Histiocytosis-Lymphadenopathy Plus Syndrome

MalaCards integrated aliases for Histiocytosis-Lymphadenopathy Plus Syndrome:

Name: Histiocytosis-Lymphadenopathy Plus Syndrome 53 49 24 71 28 13
Histiocytosis with Joint Contractures and Sensorineural Deafness 53 49 71 69
Faisalabad Histiocytosis 53 49 71
H Syndrome 53 49 71
Hjcd 53 49 71
Pigmented Hypertrichosis with Insulin-Dependent Diabetes Mellitus 53 71
Sinus Histiocytosis and Massive Lymphadenopathy 53 71
Slc29a3 Spectrum Disorder 49 24
Phid 53 71
Shml 53 71
Hyperpigmentation, Cutaneous, with Hypertrichosis, Hepatosplenomegaly, Heart Anomalies, and Hypogonadism with or Without Hearing Loss 53
Histiocytosis and Lymphadenopathy with or Without Cutaneous, Cardiac, and/or Endocrine Features, Joint Contractures, and/or Deafness 53
Cutaneous Hyperpigmentation with Hypertrichosis Hepatosplenomegaly Heart Anomalies and Hypogonadism with or Without Hearing Loss 71
Histiocytosis and Lymphadenopathy with or Without Cutaneous Cardiac and/or Endocrine Features Joint Contractures and/or Deafness 71
Pigmented Hypertrichosis with Insulin-Dependent Diabetes Mellitus; Phid 53
Histiocytosis with Joint Contractures and Sensorineural Deafness; Hjcd 53
Sinus Histiocytosis and Massive Lymphadenopathy; Shml 53
Rosai-Dorfman Disease, Familial 53
Familial Rosai-Dorfman Disease 71
Histiocytosis, Sinus 41
Slc29a3 Disorder 24
Hlas 71

Characteristics:

OMIM:

53
Inheritance:
autosomal recessive

Miscellaneous:
very variable phenotype, with some patients having many features and others only a few


HPO:

31
histiocytosis-lymphadenopathy plus syndrome:
Onset and clinical course phenotypic variability
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Histiocytosis-Lymphadenopathy Plus Syndrome

NIH Rare Diseases : 49 Histiocytosis-lymphadenopathy plus syndrome is a group of conditions with overlapping signs and symptoms that affect many parts of the body. This group of disorders includes H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), Faisalabad histiocytosis, and familial Rosai-Dorfman disease (also known as familial sinus histiocytosis with massive lymphadenopathy or FSHML). These conditions were once thought to be distinct disorders; however, because of the overlapping features and shared genetic cause, they are now considered to be part of the same disease spectrum. While some affected individuals have signs and symptoms characteristic of one of these conditions, others have a range of features from two or more of the conditions. The pattern of signs and symptoms can vary, even within the same family. All of the conditions in the spectrum are characterized by histiocytosis, which is an overgrowth of immune systemcells called histiocytes. These cells abnormally accumulate in one or more tissues in the body, which can lead to organ or tissue damage. The lymph nodes are commonly affected, leading to swelling of the lymph nodes (lymphadenopathy). Other areas of cell accumulation can include skin, kidneys, brain and spinal cord (central nervous system), or digestive tract. The spectrum is known as histiocytosis-lymphadenoapthy plus syndrome because the disorders that make up the spectrum can have additional signs and symptoms. H syndrome is named for the collection of symptoms - all starting with the letter H - that are commonly present. These include hyperpigmented skin lesions with excessive hair growth (hypertrichosis) and histiocyte accumulation, enlargement of the liver or liver and spleen (hepatomegaly or hepatosplenomegaly), heart abnormalities, hearing loss, reduced amounts of hormones that direct sexual development (hypogonadism), and short stature (reduced height). In some cases, hyperglycemia/diabetes mellitus may also be present. PHID is characterized by patches of hyperpigmented skin with hypertrichosis and the development of type 1 diabetes during childhood. Faisalabad histiocytosis is characterized by lymphadenopathy and swelling of the eyelids due to the accumulation of histiocytes. Affected individuals may also have joint deformities (contractures) in their fingers or toes, and hearing loss. Familial Rosai-Dorfman disease is characterized by lymphadenopathy, most often in the neck. Histiocytes can also accumulate in other parts of the body. Histiocytosis-lymphadenopathy plus syndrome is caused by mutations in the SLC29A3 gene. The condition is inherited in an autosomal recessive pattern. Treatment is aimed at treating the symptoms present in each individual.    Last updated: 3/28/2016

MalaCards based summary : Histiocytosis-Lymphadenopathy Plus Syndrome, also known as histiocytosis with joint contractures and sensorineural deafness, is related to bare lymphocyte syndrome, type ii and anti-hla hyperimmunization, and has symptoms including fever, recurrent pharyngitis and hepatosplenomegaly. An important gene associated with Histiocytosis-Lymphadenopathy Plus Syndrome is SLC29A3 (Solute Carrier Family 29 Member 3). Affiliated tissues include heart, lymph node and liver.

Genetics Home Reference : 24 Histiocytosis-lymphadenopathy plus syndrome (also known as SLC29A3 spectrum disorder) is a group of conditions with overlapping signs and symptoms that affect many parts of the body. This group of disorders includes H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), Faisalabad histiocytosis, and familial Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy or SHML). These conditions were once thought to be distinct disorders; however, because of the overlapping features and shared genetic cause, they are now considered to be part of the same disease spectrum. While some affected individuals have signs and symptoms characteristic of one of the conditions, others have a range of features from two or more of the conditions. The pattern of signs and symptoms can vary even within the same family.

OMIM : 53 The histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC described an autosomal recessive disease involving joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes (summary by Morgan et al., 2010). SHML, or familial Rosai-Dorfman disease, was described as a rare cause of lymph node enlargement in children, consisting of chronic massive enlargement of cervical lymph nodes frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal sites were involved in approximately 25% of patients, including salivary glands, orbit, eyelid, spleen, and testes. The involvement of retropharyngeal lymphoid tissue sometimes caused snoring and sleep apnea (summary by Kismet et al., 2005). H syndrome was characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss was also found in about half of patients, and many had short stature. PHID was characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome, with hepatosplenomegaly occurring in about half of patients (Cliffe et al., 2009). Bolze et al. (2012) noted that mutations in the SLC29A3 gene (612373) had been implicated in H syndrome, PHID, FHC, and SHML, and that some patients presented a combination of features from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' Bolze et al. (2012) suggested that the histologic features of the lesions seemed to be the most uniform phenotype in these patients. In addition, the immunophenotype of infiltrating cells in H syndrome patients was shown to be the same as that seen in patients with the familial form of Rosai-Dorfman disease, further supporting the relationship between these disorders (Avitan-Hersh et al., 2011; Colmenero et al., 2012). (602782)

UniProtKB/Swiss-Prot : 71 Histiocytosis-lymphadenopathy plus syndrome: A syndrome characterized by the combination of features from 2 or more of four histiocytic disorders, originally thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC features include joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes. SHML causes lymph node enlargement in children frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. H syndrome is characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss is found in about half of patients. PHID is characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome.

Related Diseases for Histiocytosis-Lymphadenopathy Plus Syndrome

Diseases related to Histiocytosis-Lymphadenopathy Plus Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 47)
# Related Disease Score Top Affiliating Genes
1 bare lymphocyte syndrome, type ii 12.1
2 anti-hla hyperimmunization 11.9
3 bare lymphocyte syndrome, type i 11.9
4 hla modifier 11.9
5 t-cell subgroups, non-hla-linked 11.9
6 immunodeficiency, partial combined, with absence of hla determinants and beta-2-microglobulin from lymphocytes 11.9
7 immunodeficiency by defective expression of hla class 1 11.9
8 graft-versus-host disease 11.5
9 celiac disease 1 11.2
10 severe cutaneous adverse reaction 11.2
11 pemphigus vulgaris 11.2
12 diabetes mellitus, ketosis-prone 11.2
13 fetal and neonatal alloimmune thrombocytopenia 11.2
14 hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 10.9
15 narcolepsy 1 10.8
16 goodpasture syndrome 10.8
17 adult-onset immunodeficiency with anti-interferon-gamma autoantibodies 10.8
18 epilepsy occipital calcifications 10.8
19 systemic onset juvenile idiopathic arthritis 10.8
20 dysosteosclerosis 10.8
21 vacterl association with hydrocephaly, x-linked 10.8
22 rheumatoid arthritis 10.8
23 blood group, i system 10.5
24 alzheimer disease 10.4
25 arthritis 10.4
26 leukemia 10.3
27 influenza 10.3
28 haemophilus influenzae 10.3
29 hepatitis 10.3
30 otitis media 10.0
31 lymphadenitis 9.9
32 aging 9.8
33 alpha/beta t-cell lymphopenia with gamma/delta t-cell expansion, severe cytomegalovirus infection, and autoimmunity 9.8
34 diabetes mellitus 9.8
35 sickle cell disease 9.8
36 histiocytosis 9.5
37 rosai-dorfman disease 9.5
38 fibrosis of extraocular muscles, congenital, 1 9.4
39 dowling-degos disease 1 9.4
40 muckle-wells syndrome 9.4
41 alopecia universalis congenita 9.4
42 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 9.4
43 alopecia 9.4
44 sensorineural hearing loss 9.4
45 hypertrichosis 9.4
46 retroperitoneal fibrosis 9.4
47 wells syndrome 9.4

Graphical network of the top 20 diseases related to Histiocytosis-Lymphadenopathy Plus Syndrome:



Diseases related to Histiocytosis-Lymphadenopathy Plus Syndrome

Symptoms & Phenotypes for Histiocytosis-Lymphadenopathy Plus Syndrome

Symptoms via clinical synopsis from OMIM:

53
Metabolic Features:
fever

Abdomen Spleen:
splenomegaly

Growth Height:
short stature

Skeletal Feet:
hallux valgus
contractures of toes

Head And Neck Ears:
hearing loss, sensorineural

Abdomen Pancreas:
diabetes mellitus, insulin-dependent
pancreatic exocrine deficiency
pancreatomegaly (rare)
pancreatic hypoplasia, mild (rare)

Head And Neck Nose:
nasal mass due to histiocytosis

Head And Neck Neck:
cervical lymphadenopathy

Skeletal:
intrauterine fractures of long bones and clavicles

Muscle Soft Tissue:
retroperitoneal fibrosis (rare)

Immunology:
hyperglobulinemia, polyclonal (in some patients)
lymphadenopathy, generalized (in some patients)

Skeletal Hands:
clinodactyly
camptodactyly
contractures of fingers

Abdomen Liver:
hepatomegaly

Endocrine Features:
hypergonadotropic hypogonadism
growth hormone deficiency
hypogonadotropic hypogonadism (rare)
diabetes mellitus, insulin-dependent

Head And Neck Eyes:
episcleritis
exophthalmos
histiocytic deposits in eyelids
eyelid infiltrates
orbital mass due to histiocytosis

Cardiovascular Heart:
atrial septal defect (rare)
ventricular septal defect (rare)
septal thickening (rare)
mitral valve prolapse (rare)
cardiomegaly (rare)
more
Head And Neck Face:
submandibular lymphadenopathy

Head And Neck Mouth:
retropharyngeal lymphadenopathy

Abdomen External Features:
inguinal lymphadenopathy, bilateral, extending across suprapubic area

Skeletal Limbs:
contractures of elbows

Hematology:
nonclonal myeloproliferation

Laboratory Abnormalities:
elevated inflammatory markers


Clinical features from OMIM:

602782

Human phenotypes related to Histiocytosis-Lymphadenopathy Plus Syndrome:

31 (show top 50) (show all 65)
# Description HPO Frequency HPO Source Accession
1 fever 31 HP:0001945
2 recurrent pharyngitis 31 occasional (7.5%) HP:0100776
3 hepatosplenomegaly 31 frequent (33%) HP:0001433
4 clinodactyly 31 HP:0030084
5 hydrocephalus 31 occasional (7.5%) HP:0000238
6 diabetes mellitus 31 occasional (7.5%) HP:0000819
7 hyperreflexia 31 occasional (7.5%) HP:0001347
8 gingival overgrowth 31 occasional (7.5%) HP:0000212
9 hearing impairment 31 frequent (33%) HP:0000365
10 splenomegaly 31 HP:0001744
11 hepatomegaly 31 HP:0002240
12 delayed skeletal maturation 31 occasional (7.5%) HP:0002750
13 pes planus 31 occasional (7.5%) HP:0001763
14 malabsorption 31 occasional (7.5%) HP:0002024
15 sensorineural hearing impairment 31 HP:0000407
16 short stature 31 frequent (33%) HP:0004322
17 ichthyosis 31 occasional (7.5%) HP:0008064
18 delayed puberty 31 hallmark (90%) HP:0000823
19 intellectual disability, mild 31 occasional (7.5%) HP:0001256
20 cardiomegaly 31 occasional (7.5%) HP:0001640
21 full cheeks 31 occasional (7.5%) HP:0000293
22 hypertriglyceridemia 31 occasional (7.5%) HP:0002155
23 hernia 31 occasional (7.5%) HP:0100790
24 alopecia 31 occasional (7.5%) HP:0001596
25 atrial septal defect 31 occasional (7.5%) HP:0001631
26 microcytic anemia 31 occasional (7.5%) HP:0001935
27 hypogonadism 31 occasional (7.5%) HP:0000135
28 hypergonadotropic hypogonadism 31 HP:0000815
29 decreased testicular size 31 hallmark (90%) HP:0008734
30 mitral valve prolapse 31 occasional (7.5%) HP:0001634
31 ventricular septal defect 31 occasional (7.5%) HP:0001629
32 varicose veins 31 occasional (7.5%) HP:0002619
33 azoospermia 31 occasional (7.5%) HP:0000027
34 recurrent fractures 31 occasional (7.5%) HP:0002757
35 hallux valgus 31 occasional (7.5%) HP:0001822
36 gynecomastia 31 occasional (7.5%) HP:0000771
37 proptosis 31 occasional (7.5%) HP:0000520
38 osteolysis 31 occasional (7.5%) HP:0002797
39 cleft upper lip 31 occasional (7.5%) HP:0000204
40 abnormality of cardiovascular system physiology 31 occasional (7.5%) HP:0011025
41 lymphadenopathy 31 frequent (33%) HP:0002716
42 enlarged kidney 31 occasional (7.5%) HP:0000105
43 bronchiectasis 31 occasional (7.5%) HP:0002110
44 micropenis 31 occasional (7.5%) HP:0000054
45 episcleritis 31 HP:0100534
46 hyperpigmentation of the skin 31 hallmark (90%) HP:0000953
47 lipodystrophy 31 occasional (7.5%) HP:0009125
48 histiocytosis 31 hallmark (90%) HP:0100727
49 episodic fever 31 occasional (7.5%) HP:0001954
50 camptodactyly 31 frequent (33%) HP:0012385

UMLS symptoms related to Histiocytosis-Lymphadenopathy Plus Syndrome:


fever

Drugs & Therapeutics for Histiocytosis-Lymphadenopathy Plus Syndrome

Search Clinical Trials , NIH Clinical Center for Histiocytosis-Lymphadenopathy Plus Syndrome

Cochrane evidence based reviews: histiocytosis, sinus

Genetic Tests for Histiocytosis-Lymphadenopathy Plus Syndrome

Genetic tests related to Histiocytosis-Lymphadenopathy Plus Syndrome:

# Genetic test Affiliating Genes
1 Histiocytosis-Lymphadenopathy Plus Syndrome 28 SLC29A3

Anatomical Context for Histiocytosis-Lymphadenopathy Plus Syndrome

MalaCards organs/tissues related to Histiocytosis-Lymphadenopathy Plus Syndrome:

38
Heart, Lymph Node, Liver, Spleen, Skin, Kidney, Salivary Gland

Publications for Histiocytosis-Lymphadenopathy Plus Syndrome

Articles related to Histiocytosis-Lymphadenopathy Plus Syndrome:

# Title Authors Year
1
An Egyptian family with H syndrome due to a novel mutation in SLC29A3 illustrating overlapping features with pigmented hypertrichotic dermatosis with insulin-dependent diabetes and Faisalabad histiocytosis. ( 22989030 )
2013
2
SLC29A3 mutation in a patient with syndromic diabetes with features of pigmented hypertrichotic dermatosis with insulin-dependent diabetes, H syndrome and Faisalabad histiocytosis. ( 23623699 )
2013
3
Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. ( 20140240 )
2010
4
Faisalabad histiocytosis mimics Rosai-Dorfman disease: brothers with lymphadenopathy, intrauterine fractures, short stature, and sensorineural deafness. ( 16155931 )
2006

Variations for Histiocytosis-Lymphadenopathy Plus Syndrome

UniProtKB/Swiss-Prot genetic disease variations for Histiocytosis-Lymphadenopathy Plus Syndrome:

71
# Symbol AA change Variation ID SNP ID
1 SLC29A3 p.Gly427Ser VAR_057884 rs121912583
2 SLC29A3 p.Gly437Arg VAR_057885 rs121912584
3 SLC29A3 p.Met116Arg VAR_067801 rs267607057
4 SLC29A3 p.Arg134Cys VAR_067802
5 SLC29A3 p.Ser184Arg VAR_067804 rs1023257012Histiocytosis-lymphadenopathy
6 SLC29A3 p.Arg363Gln VAR_067806 rs387907066
7 SLC29A3 p.Arg363Trp VAR_067807 rs387907067
8 SLC29A3 p.Thr449Arg VAR_067809 rs267607058

ClinVar genetic disease variations for Histiocytosis-Lymphadenopathy Plus Syndrome:

6 (show all 15)
# Gene Variation Type Significance SNP ID Assembly Location
1 SLC29A3 SLC29A3, IVS2, G-A, +1 single nucleotide variant Pathogenic
2 SLC29A3 NM_018344.5(SLC29A3): c.308_309delTT (p.Phe103Terfs) deletion Pathogenic rs796052139 GRCh38 Chromosome 10, 71344216: 71344217
3 SLC29A3 NM_018344.5(SLC29A3): c.1088G> A (p.Arg363Gln) single nucleotide variant Pathogenic rs387907066 GRCh37 Chromosome 10, 73122025: 73122025
4 SLC29A3 SLC29A3, 1-BP DEL, 243A deletion Pathogenic
5 SLC29A3 NM_018344.5(SLC29A3): c.1157G> A (p.Arg386Gln) single nucleotide variant Pathogenic rs397515429 GRCh37 Chromosome 10, 73122094: 73122094
6 SLC29A3 NM_018344.5(SLC29A3): c.607T> C (p.Ser203Pro) single nucleotide variant Pathogenic rs397514626 GRCh37 Chromosome 10, 73111542: 73111542
7 SLC29A3 NM_018344.5(SLC29A3): c.1228C> T (p.Gln410Ter) single nucleotide variant Pathogenic rs587780462 GRCh38 Chromosome 10, 71362408: 71362408
8 SLC29A3 NM_018344.5(SLC29A3): c.300+1G> A single nucleotide variant Pathogenic rs587780463 GRCh38 Chromosome 10, 71323055: 71323055
9 SLC29A3 NM_018344.5(SLC29A3): c.1279G> A (p.Gly427Ser) single nucleotide variant Pathogenic rs121912583 GRCh37 Chromosome 10, 73122216: 73122216
10 SLC29A3 NM_018344.5(SLC29A3): c.1330G> T (p.Glu444Ter) single nucleotide variant Pathogenic rs267607056 GRCh37 Chromosome 10, 73122267: 73122267
11 SLC29A3 NM_018344.5(SLC29A3): c.1309G> A (p.Gly437Arg) single nucleotide variant Pathogenic rs121912584 GRCh37 Chromosome 10, 73122246: 73122246
12 SLC29A3 NM_018344.5(SLC29A3): c.1045delC (p.Leu349Serfs) deletion Pathogenic rs869025176 GRCh37 Chromosome 10, 73121982: 73121982
13 SLC29A3 NM_018344.5(SLC29A3): c.940delT (p.Tyr314Thrfs) deletion Pathogenic rs869025177 GRCh37 Chromosome 10, 73121877: 73121877
14 SLC29A3 NM_018344.5(SLC29A3): c.347T> G (p.Met116Arg) single nucleotide variant Pathogenic rs267607057 GRCh37 Chromosome 10, 73104012: 73104012
15 SLC29A3 NM_018344.5(SLC29A3): c.1346C> G (p.Thr449Arg) single nucleotide variant Pathogenic rs267607058 GRCh37 Chromosome 10, 73122283: 73122283

Expression for Histiocytosis-Lymphadenopathy Plus Syndrome

Search GEO for disease gene expression data for Histiocytosis-Lymphadenopathy Plus Syndrome.

Pathways for Histiocytosis-Lymphadenopathy Plus Syndrome

GO Terms for Histiocytosis-Lymphadenopathy Plus Syndrome

Sources for Histiocytosis-Lymphadenopathy Plus Syndrome

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10 dbSNP
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58 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
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67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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