Histiocytosis-Lymphadenopathy Plus Syndrome (HLAS)

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Disease Ontology 12 DOID:0111278 OMIM 56 602782 KEGG 36 H00815 MeSH 43 D015618 ICD10 via Orphanet 33 D76.3

Orphanet 58 ORPHA168569 MedGen 41 C1864445 SNOMED-CT via HPO 68 103276001 111522004 122480009 12295008 123526007 123983008 128060009 12856003 134291007 15188001 16294009 17268007 18265008 202271004 203522001 203534009 2109003 230745008 231924000 231925004 234349007 237836003 253366007 253549006 258211005 271607001 276411001 278040002 29271008 29966009 300444006 30288003 30425001 30746006 343087000 34911001 36760000 370999003 386661006 399989005 400003000 403524003 405752007 409712001 414403008 415692008 425558002 441787004 441798003 4754008 48130008 48188009 4830009 49120005 49765009 50177009 52515009 53226007 5468008 54711002 56317004 60657004 60700002 65396000 68591005 700339006 70142008 71325002 73211009 77957000 80281008 80515008 8074002 815008 8186001 86094006 86765009 86854008 89155008 9014002 95828007 more UMLS 71 C1864445

Genetics Home Reference : ²⁵ 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. SLC29A3 A feature common to the disorders in this spectrum is histiocytosis, which is the overgrowth of immune system cells called histiocytes. The cells abnormally accumulate in one or more tissues in the body, which can lead to organ or tissue damage. The buildup often occurs in the lymph nodes, leading to swelling of the lymph nodes (lymphadenopathy). Other areas of cell accumulation can include the skin, kidneys, brain and spinal cord (central nervous system), or digestive tract. This spectrum is known as histiocytosis-lymphadenopathy plus syndrome because the disorders that make up the spectrum can have additional signs and symptoms. A characteristic feature of H syndrome is abnormal patches of skin (lesions), typically on the lower body. These lesions are unusually dark (hyperpigmented) and have excessive hair growth (hypertrichosis). In addition, histiocytes accumulate at the site of the skin lesions. Other features of H syndrome include enlargement of the liver (hepatomegaly), heart abnormalities, hearing loss, reduced amounts of hormones that direct sexual development (hypogonadism), and short stature. Like H syndrome, PHID causes patches of hyperpigmented skin with hypertrichosis. PHID is also characterized by the development of type 1 diabetes (also known as insulin-dependent diabetes mellitus), which usually begins in childhood. Type 1 diabetes occurs when the body does not produce enough of the hormone insulin, leading to dysregulation of blood sugar levels. Faisalabad histiocytosis typically causes lymphadenopathy and swelling of the eyelids due to accumulation of histiocytes. Affected individuals can also have joint deformities called contractures in their fingers or toes and hearing loss. The most common feature of familial Rosai-Dorfman disease is lymphadenopathy, usually affecting lymph nodes in the neck. Histiocytes can also accumulate in other parts of the body.

MalaCards based summary : Histiocytosis-Lymphadenopathy Plus Syndrome, also known as histiocytosis with joint contractures and sensorineural deafness, is related to hydrops fetalis, nonimmune and alpha-thalassemia, and has symptoms including fever An important gene associated with Histiocytosis-Lymphadenopathy Plus Syndrome is SLC29A3 (Solute Carrier Family 29 Member 3), and among its related pathways/superpathways are Binding and Uptake of Ligands by Scavenger Receptors and Malaria. The drugs Immunologic Factors and Vaccines have been mentioned in the context of this disorder. Affiliated tissues include heart, lymph node and liver, and related phenotypes are delayed puberty and decreased testicular size

Disease Ontology : ¹² A syndrome characterized by histiocytosis, hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, and reduced height that has material basis in homozygous or compound heterozygous mutation in SLC29A3 on 10q22.1. This syndrome comprises features from 4 histiocytic disorders that were previously considered distinct: Faisalabad histiocytosis, sinus histiocytosis with massive lymphadenopathy, H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome.

NIH Rare Diseases : ⁵² 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 system cells 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.

OMIM : ⁵⁶ 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)

KEGG : ³⁶ The H syndrome is an autosomal-recessive condition characterized by the association of cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, sensorineural hearing loss, hypogonadism, short stature, and hyperglycemia. Anomalies such as hallux valgus and fixed flexion contractures of the toe and finger joints are additional clinical fiindings.

UniProtKB/Swiss-Prot : ⁷³ 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.

Wikipedia : ⁷⁴ H syndrome, also known as Histiocytosis-lymphadenopathy plus syndrome or PHID, is a rare genetic... more...

Clinical features from OMIM:

602782

#	Description	GenomeRNAi Source Accession	Score	Top Affiliating Genes
1	Decreased shRNA abundance (Z-score < -2)	GR00366-A-181	9.1	HBA2 SLC29A3
2	Decreased shRNA abundance (Z-score < -2)	GR00366-A-184	9.1	SLC29A3
3	Decreased shRNA abundance (Z-score < -2)	GR00366-A-213	9.1	SLC29A3
4	Decreased shRNA abundance (Z-score < -2)	GR00366-A-48	9.1	HBA2
5	Decreased shRNA abundance (Z-score < -2)	GR00366-A-72	9.1	HBA2

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