Background
H Syndrome (OMIM #612391) is an autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, and induration with numerous systemic manifestations [
1,
2]. Coined in 2008 by Molho-Pessach et al., the syndrome is named for its most common clinical features: hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, low height, hyperglycemia (insulin-dependent diabetes mellitus), and hallux valgus/flexion contractures [
1]. While not always present, the pathognomonic skin findings most often involve the lower limbs, especially the inner thighs, but can appear throughout the body. The histologic correlates to these dermatologic findings include epidermal hyperplasia and increased basal pigmentation, and a dermal infiltrate including histiocytes, lymphocytes, and plasma cells, sometimes accompanied by hemosiderin deposition or calcification. Rosai-Dorfman disease (RDD) and related conditions predisposing to RDD or RDD-like lesions, including H syndrome, are classified as histiocytoses of the R group per a recent revised classification of histiocytoses and related neoplasms by the Histiocyte Society [
3].
The most common features apart from skin findings include flexion contractures of fingers and toes, sensorineural hearing loss, short stature, and hepatosplenomegaly respectively followed by insulin-dependent diabetes mellitus (IDDM), lymphadenopathy, and microcytic anemia. Hypogonadism, azoospermia, and micropenis can also be seen as well as chronic diarrhea, which is often secondary to pancreatic dysfunction. There have been reports of patients with recurrent fever, some of which are accompanied by joint inflammation [
4‐
7]. Laboratory results often reveal chronic elevation of inflammatory markers [
2].
The syndrome is caused by homozygous or compound heterozygous mutations in
SLC29A3, a gene on chromosome 10q22 that encodes the human equilibrative nucleoside transporter 3 (hENT3). This transporter helps with passive sodium-independent transportation of nucleosides and is critical for nucleotide synthesis by salvage pathways [
8]. Multiple missense, nonsense, compound and deletion mutations of
SLC29A3 can lead to H syndrome, partly accounting for its large inter-familial variability. Thus, multiple phenotypically-varying disorders previously thought to be separate entities are now considered one condition; these include pigmented hypertrichosis with IDDM syndrome, familial histiocytosis syndromes (including Faisalbad histiocytosis), dysosteosclerosis, POEMS, and familial rhinosclerema [
2,
9,
10].
To our knowledge, there have been about 90 patients confirmed to have H Syndrome worldwide. Most patients described in the literature have been of Arab descent, with only one noted to be Caucasian. Only a few patients with
SLC29A3 mutations have been identified at North American centers. In this report, we present five pediatric patients recently diagnosed with H Syndrome in three medical centers in the United States. One patient has autoimmune hepatitis with positive serologies, a finding not previously reported in H Syndrome. This patient, along with another, also suffers from polyarthritis; notably, only two cases of arthritis have been reported independent of fever [
11,
12]. These cases illustrate the auto-inflammatory nature of H syndrome while all 5 cases add further information about its clinical phenotype and response to treatment.
Discussion and conclusions
Despite typical clinical findings, all five patients described here were diagnosed with H Syndrome by whole exome sequencing. Presumably, this is due to the relatively recent description of the syndrome and the small number of patients previously identified in the United States. Additionally, patients with identical mutations in SLC29A3 frequently do not have identical phenotypes even when they are siblings, perhaps reducing the clinician’s suspicion for a Mendelian disorder. Patients 2 and 3 demonstrate this aspect of H syndrome, with the proband exhibiting many more characteristics than his sibling.
As shown in Table
1, our patients exhibit many of the manifestations as those reported in the literature, including skin findings, flexion contractures, short stature, hearing loss, and IDDM. When biopsied, our patients’ skin lesions showed dermal and deep subcutaneous inflammation with mostly uninvolved epidermis, as previously described with H Syndrome. The dermatopathologic findings from patient 2 showed findings consistent with previous reports from patients with H syndrome, including mild epidermal hyperplasia with basal pigmentation, albeit relatively mild in this case, rare dermal hemosiderin deposits, and a deep infiltrate including increased plasma cells with perivascular cuffing and histiocytes. While dermal plasma cells in RDD may express IgG4, only weak blush staining was observed in the plasma cells in patient 2, perhaps because of his IgG4 deficiency [
3]. Also, the histiocytic infiltrate in RDD and H syndrome may include larger S-100 positive cells that display emperipolesis, but the histiocytes in this case were not markedly enlarged, did not contain abundant phagocytosed cells, and did not express S-100 protein [
1‐
3,
13].
As might be expected in a report submitted by Pediatric Rheumatologists, there is an increased incidence of arthritis in our patients when compared to the literature. Unfortunately, little is known regarding the histopathology or imaging of the arthritis in this disorder. The sole MRI in this series (Patient 5) did not demonstrate synovitis, even after administration of gadolinium, while ultrasound of Patient 1 demonstrated joint effusions but no synovial thickening.
Some of the manifestations found in our patients have been rarely reported, if ever, in patients with
SLC29A3 mutations. Cardiovascular abnormalities have been described to be a relatively common finding in this disorder, but a bicuspid valve (Patient 2) has not been reported previously. Bicuspid valves, however, may occur in up to 2% of the general population and thus may not be associated with this patient’s
SLC29A3 mutation [
14]. On the other hand, an absent inferior vena cava has been described once before in a patient with H syndrome [
15]. The incidence of absent inferior vena cava is not well defined, however absence or stenosis of the IVC has been estimated to occur in 0.15% to 0.6% of the population and thus this rarer condition could be a manifestation of H syndrome [
16]. Pericarditis (Patient 2) is also a known complication of patients with
SLC29A3 mutations [
2,
4].
We observed a number of immunologic abnormalities and immune-mediated manifestations in our patients. Hypergammaglobulinemia is frequently described in patients with H syndrome, presumably as a manifestation of systemic inflammation, but selective subclass deficiency of IgG2 and IgG4 (Patient 2) is a novel finding and may or may not be a characteristic of H Syndrome. One other case report documented a low number of B memory cells, as in Patient 2, but the clinical significance of this finding is not clear [
17].
Generally speaking, autoantibody formation does not seem to be characteristic of H syndrome, although one patient in the literature was originally diagnosed to have systemic lupus erythematosus on the basis of positive anti-double-stranded DNA antibodies [
17]. IDDM is clearly associated with H syndrome, although in contrast to Patient 3, most of the patients have not had autoantibodies detected [
18]. Serum anti-endomysial antibody is a relatively specific test for celiac disease and its presence has not been described before in patients with
SLC29A3 mutations. The occurrence of autoantibodies associated with IDDM and celiac disease in Patient 3 may reflect the patient’s genetic predisposition to developing these disorders separate from her
SLC29A3 mutations, since IDDM and celiac disease share a common genetic predisposition [
19]. While hepatomegaly has been previously described in H syndrome, autoimmune hepatitis with or without autoantibodies (Patient 1) has not been described in H syndrome, but rather lymphocytic infiltration of the liver portal spaces [
1]. Arthralgias and polyarticular arthritis (Patient 1 and 2) have also been described previously. It is not clear if the contracture deformities of fingers and toes found in many patients are a manifestation of synovitis or another pathologic process [
2,
18].
Short stature is a very frequent finding in H syndrome. Previous reports have implicated decreased growth hormone production following stimulation and low IGF-1 levels [
1]. Inflammation in Systemic Juvenile Idiopathic Arthritis is also associated with short stature and low IgF-1 levels; successful control of the inflammation with tocilizumab in Systemic Juvenile Idiopathic Arthritis is followed by an increase in growth velocity and IGF-1 [
20]. Such an increase in growth velocity was seen in Patient 2 after initiation of tocilizumab therapy, although he was also receiving growth hormone treatment at the time. The cause of short stature in H syndrome may be due in part to the effect of systemic inflammation on the growth hormone/IGF-1 axis.
Given the complexity of H Syndrome, there is a lack of consensus regarding its treatment. Despite recognition of the inflammatory nature of H syndrome, treatment has been largely unsuccessful [
2,
17]. Per previous reports, patients tend to respond poorly to agents directed against IL-1 or TNF-alpha such as anakinra, canakinumab and adalimumab, and colchicine or NSAIDs provide only partial relief [
2,
4]. Our experience, and that of others, indicates that systemic corticosteroids have a beneficial effect on the underlying inflammation, but they are not a good long-term treatment, particularly since inflammation returns as the dose is reduced [
21]. Our experience suggests that there may also be a role for methotrexate (Patients 1, 4 and 5), either alone or in combination with other medications. In this report, Patient 2 and 5 had a striking response to treatment with tocilizumab, a humanized monoclonal antibody directed against the IL-6 receptor, including reduction in hyperpigmentation and subcutaneous fibrosis, acceleration of growth velocity, and improvement in inflammatory indices, scrotal induration, and microcytic anemia. In contrast, Mistry et al. recently reported a patient with
SLC29A3 mutations who did not have clinical improvement with tocilizumab, despite normalization of the patient’s CRP [
17].
With further research into the pathophysiology of H syndrome, more directed therapy will hopefully become available. There is some thought that macrophage dysfunction in patients with H Syndrome leads to a compromised immune response and elevated systemic inflammation. Hsu et al. found macrophage-dominated histiocytosis and lysosomal disturbances within macrophages present in an ENT3 null mouse model [
22].
Genetic research is also expanding what we know about H Syndrome. By 2013, 21 different disease-causing mutations in SLC29A3 had been described [
2]. The c.1087 > T (p.R363W) mutation in patient 1 has been described twice before in patients of Hispanic background, both with H syndrome. Similar to patient 1, both of these patients are homozygous for this mutation [
23,
24]. The c.347 T > G (p.M116R) mutation in patients 1 and 2 was reported once before in a Caucasian American patient with Pigmented Hypertrophic Dermatosis with IDDM [
25]. This patient was homozygous for the mutation and had parents who were fourth cousins. The other mutation in patients 2 and 3, c.610 + 1G > C, encodes a probable pathogenic splice site mutation and has not been reported before. Patients 4 and 5 are heterozygous for the c.1309G > A (p.G437R) mutation, one of the most common mutations found in patients of Arab descent [
26]. The other mutation in patients 4 and 5 results in a splice site mutation at c.300 due to a G > C substitution, which has been recently described in a Moroccan patient [
27]. Of interest, a different mutation at this same site (c.300 G > A) has been reported in patients of Pakistani descent with Faisalbad histiocytosis [
28].
H syndrome, which seems to be more common among persons of Arab descent, has been described worldwide and should be included in the differential diagnosis of patients with short stature and systemic inflammation, particularly when accompanied by the characteristic cutaneous findings [
2]. This disorder should be included among autoinflammatory syndromes, although autoimmune manifestations sometimes occur. Treatment of systemic inflammation with IL-6 blockade appears to be a promising therapeutic option in patients with H syndrome as it reduces systemic inflammation, but may not control all of the clinical manifestations. Additional treatments to consider are combination therapy with biologics and other immune suppressants. Better identification and understanding of the pathophysiology of this rare disorder may help devise earlier diagnosis and better treatment strategies.