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To date, around 130 patients have been described in the world literature.

H syndrome becomes clinically apparent mostly during childhood, but cases during infancy and late-onset cases have been reported too. Cutaneous features are the most prevalent. Hyperpigmentation, associated with induration and hypertrichosis, usually appears initially on the medial thighs and shins, but may be more extensive. Sensorineural hearing loss is the second most common manifestation. Additional features include heart anomalies, hepatosplenomegaly, lymphadenopathy, insulin dependent diabetes mellitus, hypogonadism (short stature, gynecomastia, delayed puberty, primary amenorrhea), angiopathy (varicosities, dilated lateral scleral vessels, and facial telangiectasias) and genital masses. Exophthalmos (with normal thyroid function), malabsorption (due to pancreatic exocrine insufficiency), renal anomalies, flexion contractions of interphalangeal joints and hallux valgus (with fixed flexion contractures of the toe), and lytic bone lesions as well as osteosclerosis are also seen. Early-onset recurrent febrile episodes, lateral tibial torsion, and hypertriglyceridemia may be observed. Various hematological abnormalities have been described, including microcytic anemia, myelofibrosis and pure red cell aplasia.

H syndrome is caused by mutations in SLC29A3 (10q22.2) (encoding a nucleoside transporter, hENT3), which result in defective nucleoside transport functions of hENT3. This leads to histiocytic infiltration of numerous organs. There are no clear genotype-phenotype correlations for SLC29A3 mutations. Four allelic disorders have been described: PHID, FHC, FSHML and dysosteosclerosis. However, since H syndrome encompasses the clinical features of the first three allelic disorders, and all share identical mutations in SLC29A3, these disorders are now considered as the same entity.

Diagnosis is suspected by the pathognomonic cutaneous features. If these are lacking, the constellation of additional findings such as hearing loss, fixed flexion contractures of fingers and toes, short stature and hepatosplenomegaly should raise suspicion for H syndrome. Laboratory tests show extremely elevated erythrocyte sedimentation rate, mild microcytic anemia, and elevated liver enzymes. Hypogonadism (hyper- or hypogonadotropic) and azoospremia may be observed. Histopathological examination of involved skin shows a characteristic dermal and subcutaneous interstitial mononuclear infiltrate, composed mainly of small to medium-sized CD68+S100+CD1a- histiocytes (occasionally with emperipolesis) and fibrosis. Diagnosis is confirmed by genetic screening of SLC29A3.

Differential diagnosis includes Torg-Winchester syndrome, hemochromatosis, POEMS syndrome and Rosaï-Dorfman disease.

Prenatal molecular diagnosis is feasible by DNA testing in chorionic villi or amniotic cells.

Transmission is autosomal recessive and genetic counseling should be offered to at-risk couples, informing them of the 25% risk to transmit the causal mutation to their offspring. The clinical picture is highly variable, even within affected families.

Management is mainly supportive. Oral steroids may temporarily improve cutaneous changes in some patients, but are inappropriate for long term use due to side effects. Tocilizumab has been found to be effective in a number of patients. Early screening for sensorineural hearing loss and diabetes mellitus should be performed.

The disease usually runs a variable but progressive course, and early-death has been described.