The SLC29A3 gene encodes the human equilibrative nucleoside transporter, hENT3, a mitochondrial and a lysosomal nucleoside transporter which mediates intracellular salvage of hydrophilic nucleosides (4). The loss of hENT3 has been associated with clinical spectrum disorders of SLC29A3 gene defects, also known as Histiocytosis-lymphadenopathy plus syndrome comprising features of 4 histiocytic disorders sharing overlapping clinical manifestations previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML) or Familial Rosai Dorfman disease (RDD), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID) (3) (5) (6). The first condition to be associated with recessive mutations in the SLC29A3 gene was the H syndrome (7). To our knowledge, almost 100 patients worldwide have been confirmed to have H syndrome (8). Patients with this syndrome were mostly described in families of Arab origin from consanguineous parents (8) (9). H syndrome clinical presentation is variable in its spectrum and degree of severity. It is characterized by major clinical findings of cutaneous hyperpigmentation, with hypertrichosis and concomitant diverse systemic manifestations that include hearing loss, flexion contractures/ hallux valgus, short stature, hypogonadism, hepatosplenomegaly, cardiomyopathy, and potential hyperglycemia (10) (8). The common clinical manifestations of H syndrome, and the hallmarks for the diagnosis, are large hyperpigmented and hypertrichotic skin lesions, which are symmetrically involving the lower part of the body typically in the medial areas of the thighs, camptodactyly, sensorineural hearing loss and short stature (11) (12). As in our case, cutaneous hyperpigmentation was the hallmark of H syndrome, and it was described in all four patients. Other features such as genital masses, hallux valgus, hepatomegaly and splenomegaly, gynecomastia, pericardial effusion, exophthalmos, dilated lateral scleral vessels and facial telangiectasia, are present in less than 30% of patients (13). Recently, several novel features have been recognized including premature graying of the hair, bilateral optic disc swelling, hypospadias, retroperitoneal fibrosis, Raynaud's phenomenon and generalized lipoatrophy (14) (10) (15) (16). As shown in Table I, our patients exhibit several manifestations including cutaneous pigmentation, flexion contractures, and hearing loss. Although short stature was reported in mostly H syndrome reports, our four patients have a normal height (8). H syndrome clinical presentation can also vary within the same family (17), as illustrated by the intrafamilial phenotypic variability in our 4 related patients.
Standardized histopathological skin lesions criteria proposed by Doviner et al, consist of the presence of hyperpigmentation of basal layer; widespread fibrosis of dermis and mononuclear cell infiltrates consisting mainly of monocyte-derived cells (small CD68+ histiocytes and CD34+ FXIIIa+ dendrocytes), and plasma cells (18). H syndrome histological findings in our cases showed an inflammatory dermal infiltrate rich in plasma cells (CD138+). This atypical histological presentation is increasingly described in the literature (10).
Based on the above clinical and histological descriptions, the diagnosis of H syndrome should be strongly suspected and confirmed by the molecular study. In contrast with H syndrome, the Familial RDD phenotype was only twice associated with mutations in the SLC29A3 gene (3). The first case was identified by Morgan et al in 3 Turkish brothers previously studied by Kismet et al with features of cervical, lymphadenopathy, short stature, hepatomegaly sensorineural deafness and orbital mass (3) (19). Jonard et al reported in a 17-year-old Moroccan girl with overlapping features of Familial RDD and H syndrome presenting with only a progressive sensorineural hearing impairment and a single cervical node (20). Herein, we report an additional Familial RDD case in 54-year-old Tunisian women with a prominent cutaneous feature not previously described. Our patient is the first case of Familial RDD with clinical features of cutaneous RDD including erythematous nodular plaques on the face. Interestingly, cutaneous lesions, found in our patient, are similar to those described in the sporadic form of RDD. Deafness and lymphadenopathy were observed in our patient which is in line with those reported by Morgan et al and Jonard et al (3) (20). Following our observation, cutaneous pigmentation and flexion contractures have not been reported in Familial RDD patients. However, sensorineural hearing loss is present in both Familial RDD and H syndrome (3) (20). Histologically, the hallmark of Familial RDD is emperipolesis which is typically absent in H syndrome (3). As seen in our cases, mutations in SLC29A3 have been found to cause a wide variety of phenotypes. To our knowledge, more than 22 pathogenic or likely pathogenic variants have been identified in the SLC29A3 gene (4) (Table II). The 2 most common mutations reported in H syndrome are c.1309G>A; [p.Gly437Arg] and c.1279G>A; [p.Gly427Ser] (8). Nine out of 25 reported mutations were found in the 6th exon of the gene highlighting the effectiveness of initial screening of this coding region for mutation’s detection in SLC29A3 (5) (17).
We report a missense homozygous mutation in exon 6 c.1088G>A, [p.Arg363Gln] changing Arginine to Glutamine which is found in a highly evolutionarily conserved position in the protein between the 8th and the 9th Transmembrane domains of the transport. This same mutation was for the first time reported by Molho Pessach et al in a 13-year-old Spanish boy and a 20-year-old Arab man with H syndrome (21). The second patient was an 11-month-old boy from a consanguineous Tunisian family who presented with early-onset, recurrent episodes of fever, hyperpigmentation with hypertrichosis, dysmorphic features, hepatosplenomegaly and pericardial effusion (22). In addition, Korbi et al identified in a Tunisian patient, with a severe phenotype of H syndrome, a compound heterozygosity for the Arg363Gln and a splice site mutation c.300+1G>C in intron 2 of the SLC29A3 gene (23). Jaouadi et al described a 23-year-old Tunisian man, with an Arg363Gln mutation in a homozygous state, presented with hyperpigmentation and hypertrichosis, inguinal and scrotal swelling and retracted penis (24). As shown in our study, the Arg363Gln mutation seems to be the most frequent mutation among Tunisian patients with H syndrome. The medical history of our family highlights a wide phenotypic variability characterizing H syndrome, in terms of organ involvement and disease severity and confirms that patients carrying the same mutation in the SLC29A3 gene may display different symptoms.
It is well-known that SLC29A3 spectrum disorder is characterized by a poor phenotype-genotype correlation, thus a given mutation may be responsible for different phenotypes (13) (5) (4). For instance, the most common mutation, Gly437Arg mutation has been identified in patients with H syndrome, FHC, PHID or Familial RDD (3). Although the phenotypes of Familial RDD and H syndrome are distinguished by a minimal clinical overlap, both may be associated with identical mutations of c.307delTT, c.1309G>A and c.1088G>A in SLC29A3 (3) (20) (8).
In the current study, we identified two different phenotypes (Familial RDD/ H syndrome) sharing the same c.1088G>A mutation in a single extended family. Our observation supports the idea of poor phenotype-genotype correlation in the SLC29A3 mutations. As indicated in Table III, it now seems that phenotypic heterogeneity is a common finding in SLC29A3 disorders. In addition to our report, Spiegel et al reported in an Israeli Moslem Arab family, a 28-year-old PHID woman, her 5-year-old nephew had features consistent with H syndrome, and her 23-year-old sister had a more severe phenotype combining features of both syndromes (6). In this context, Al-Haggar et al reported an 8-years Egyptian female who had overlapping features of H syndrome and PHID (17). Jesus et al reported a Moroccan girl born to consanguineous parents who presented with cumulative features of PHID, H syndrome, FHC and Familial RDD in whom a homozygous splice site mutation (c.300+1G>C) in the SLC29A3 gene was identified (25).
In 2 Pakistani brothers originally reported by Moynihan et al, Morgan et al. identified a homozygous splice site mutation (c.300+1G>A) of the SLC29A3 gene (3) (26). Additionally to the variable phenotypes between FHC and H syndrome, this mutation has also been found in patients diagnosed with H syndrome (8). The present study emphasizes the previously reported intra-familial clinical heterogeneity among Tunisian patients with overlapping features of SLC29A3 disorders (Familial RDD/H syndrome) even in patients who share the same SLC29A3 mutation. This suggests the implication of other genetic and/or epigenetic regulatory factors, that can influence the clinical expression of this observed variation (4) (3) (5).