H syndrome D76.3

The name H syndrome was proposed in 2008 by Israeli dermatologists V. Molho-Pessach and collaborators.

The term "histiocytosis-lymphadenopathy plus syndrome" , also known as H syndrome, refers to a very rare congenital form of systemic histiocytosis with the main eponymous features of hyperpigmentation, hypertrichosis, hepatosplenomegaly, cardiac abnormalities, hearing loss, hypogonadism, and occasionally hyperglycemia (H syndrome).

The term "histiocytosis-lymphadenopathy-plus syndrome" is used to group together disease entities that have been published under different names but differ only in degree. They are evaluated as partial manifestations of the histiocytosis-lymphadenopathy-plus syndrome.:

• PHID (Pigmented hypertrichosis with insulin-dependent diabetes mellitus). PHID syndrome is characterized by hyperpigmented patches of skin with hypertrichosis and the development of type 1 diabetes in childhood.
• Faisalabad histiocytosis: lymphadenopathy and swelling of the eyelids due to histiocytic infiltration; affected individuals may also have digital joint deformities and hearing loss.
• Familial sinus histiocytosis with massive lymphadenopathy (FSHML).

Histiocytosis lymphadenopathy plus syndrome is caused by mutations in the SLC29A3 gene. The disease is inherited in an autosomal recessive manner.

All diseases that belong to the spectrum of histiocytosis are characterized by a pronounced histiocytic lymphadenopathy. Furthermore, histiocytic infiltration of other organs occurs, which can lead to various organ or tissue damage. Affected organs are: skin (scleroderma-like iniltrate with hypertrichosis), kidneys, brain, digestive tract and CNS. Furthermore, growth disorders, deafness, hypergammaglobulinemia, hyperglycemia, musculoskeletal abnormalities, etc. are found (see casuistics).

Familial Rosai-Dorfman syndrome is characterized by lymphadenopathy, most commonly in the neck. Histiocytes may also accumulate in other parts of the body. It is considered by most authors to be an independent clinical picture.

Moynihan et al (1998) observed what appeared to be a new form of histiocytosis associated with joint contractures and sensorineural deafness in a highly consanguineous family from Pakistan, which they termed "Faisalabad histiocytosis." The index patient presented at 3 years of age with gummy swellings of her eyelids. Bioptically, the lesions showed histiocytes with increased numbers of plasma cells and eosinophils. Furthermore, the patient showed systemic symptoms with failure to thrive and generalized lymphadenopathy. No enlargement of liver or spleen. At 15 years of age, she developed symptoms of dyspnea and stridor, and was found to have fever, lymphadenopathy, proptosis, an increased erythrocyte sedimentation rate, and hypergammaglobulinemia. Radiation therapy to the larynx and trachea and systemic administration of cyclophosphamide and prednisolone resulted in marked improvement. Ovarian insufficiency was later diagnosed. Another affected family member was born with foot deformities and was deaf by the age of 5 years. At age 13, swelling around the eyes appeared, and later he developed progressive deformities of the hands. At age 50, he developed swelling in the neck that required surgical intervention. At age 58, he was completely deaf, had a wide and thickened nose, thick ears, a soft swelling under the left eye, flexion deformities in all fingers, and severely deformed feet.

Kismet et al (2005) reported 3 Turkish brothers with sinus histiocytosis and massive lymphadenopathy (SHML). The proband was an 8-year-old boy who presented at 2 years of age with fever, bilateral cervical and submandibular lymph node enlargement, and hepatomegaly. Lab: Leukocytosis, elevated erythrocyte sedimentation rate (ESR), elevated immunoglobulins (mainly IgG). Histopathology of a resected neck lymph node: massive histiocytic infiltration; he also suffered from severe sensorineural hearing loss. At the age of 8 years, interferon therapy resulted in regression of the cervical lymph nodes. Two younger brothers were also affected, one with massive bilateral cervical and submandibular lymphadenopathy and fever, and the other with an orbital histiocytic mass and sensorineural hearing loss.

Hamadah and Banka (2006) described well-demarcated, nontender, hyperpigmented indurations on the inner surfaces of both thighs extending to the pubic area and knees with mild hypertrichosis over the thigh plaques in a 13-year-old girl and her 11-year-old brother who were from a first cousin. The lesions were slowly progressive over 2 to 5 years. The girl had mild swelling of the labia and the boy had diffuse pigmentation and induration of the scrotum with a swollen and retracted penis. Both had marked induration and atrophy of the lateral buttocks. Lab: elevated ESR, antinuclear antibodies. Skin biopsy of both siblings was similar and showed plasma cell panniculitis with an intense plasma cell and lymphocyte infiltrate and fibrosis mainly in the lower dermis and adipose tissues. A muscle biopsy in the boy was unremarkable.

Rossbach et al (2006) described two brothers born to parents of Palestinian origin with double first relationship who had lymphadenopathy, lymph node histology, and polyclonal hypergammaglobulinemia suggestive of Rosai-Dorfman disease (RDD) but also showed features reminiscent of the autosomal recessive syndrome known as Faisalabad histiocytosis, including intrauterine fractures, short stature, and sensorineural hearing impairment. The proband was born with intrauterine fractures of both humeri, the right femur, and the left fibula, as well as blue sclerae and low-set, posteriorly rotated ears. At 14 months of age, a CT scan of the brain revealed ventriculomegaly with communicating hydrocephalus due to developmental delay and generalized hypotonia. A lymph node biopsy showed capsular fibrosis of the nodes and chronic inflammation with enlargement of the sinuses resulting in architectural distortion and partial effacement of the follicles and germinal centers. Lab: elevated IgG and IgA levels.

At the age of 16, he was short statured, had severe sensorineural hearing loss, double coiled hair pattern, frontal hump, hypertelorism, pectus carinatum, and hyperpigmentation of the lower extremities. He had cervical, submandibular, and, most importantly, bilateral inguinal lymphadenopathy. A younger brother of the proband was also born with intrauterine fractures; skin fibroblast studies were normal. In the postnatal period, complications included patent ductus arteriosus, a small atrial septal defect, aspiration pneumonia, and polycythemia. At the age of 9 years, he was short statured and had marked anemia, reticulocytopenia, and mild splenomegaly. The bone marrow showed a nonclonal myeloproliferative process with a large number of cells of the monocytic and histiocytic series.

Prendiville et al (2007) reported four unrelated boys, three with insulin-dependent diabetes, who had progressive development of pigmented hypertrichotic skin on the inner thighs with variable involvement of the genitals, trunk, and limbs. Three of the boys had blood-related parents. Two boys had episcleritis and orbital proptosis with similar facial features and musculoskeletal abnormalities such as clinodactyly, flat feet, and short stature. Hepatosplenomegaly was present in 3 of the boys. Laboratory markers of inflammation were elevated: ESR, C-reactive protein, IgA. Biopsies from the skin and orbit showed a chronic inflammatory cell infiltrate consisting of polyclonal lymphocytes, histiocytes, and plasma cells.

Molho-Pessach et al (2008) reported 10 patients (9 males and 1 female) from 6 unrelated blood Arab families from a small region near Jerusalem who had progressive skin thickening, hyperpigmentation, and hypertrichosis that began on the inner thigh and spread to the mid and lower parts of the body, with conspicuous sparing of the knees and buttocks. Seven of the 10 patients had splenomegaly or hepatosplenomegaly; 5 had short stature; 5 had cardiac abnormalities, including atrial and ventricular septal defects, mitral valve prolapse, and cardiomegaly; 5 had hearing loss; 6 had dilated lateral scleral vessels; and 4 had exophthalmos. Several of the male patients had subcutaneous solid masses within a massively swollen scrotum with apparent micropenis, and 3 had gynecomastia. Laboratory examination of 4 patients revealed grossly elevated ESR levels, normal glucose levels; furthermore, growth hormone deficiency, hypergonadotropic hypogonadism, with azoospermia in 3 patients. Histopathologic examination of the skin showed hyperpigmentation of the basal layer with acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous adipose tissue. Molho-Pessach et al (2008) termed this constellation of symptoms the "H syndrome," for hyperpigmentation, hypertrichosis, hepatosplenomegaly, cardiac abnormalities, hearing loss, hypogonadism, short stature, and occasionally hyperglycemia.

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