Variants in SLC29A3
are known to cause pigmented hypertrichosis with insulin-dependent diabetes (PHID) and H syndrome (skin hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism and low height) (7
), with the addition of two related conditions, Faisalabad histiocytosis and sinus histiocytosis with massive lymphadenopathy. All four disorders were recently suggested to be aggregated under the term histiocytosis–lymphadenopathy plus syndrome [see OMIM (Online Mendelian Inheritance in Man) no. 602782 and references therein]. There is some clinical overlap between PHID and H syndrome, and in some families both conditions manifest (9
). Furthermore, there is phenotypic variability as mildly affected individuals have also been described (10
). Table shows the overlap between PHID, H syndrome and DSS. Although PHID and H syndrome do not manifest osteopetrosis, affected individuals can have camptodactyly, clinodactyly, short stature and hallux valgus. In one family where one child was diagnosed with H syndrome and another more severely affected child was diagnosed with PHID and brachydactyly, a skeletal survey in the latter was noted only to show osteopenia in the metacarpals and metatarsals (9
Comparison of clinical features among different SLC29A3-related conditions
One of the mutations we identified (p.Thr449Arg) has previously been shown to impair nucleoside transport (11
). Also, in the homozygous state, like in subject 2, the variant caused PHID. Furthermore, one of the heterozygous mutations in subject 1 (p.Arg386Gln) causes H syndrome when homozygous in a Syrian family (12
). The reasons for the pleiotropism and variability of SLC29A3-related diseases are not known; however, modifier genes could possibly be involved. We queried the list of rare and novel variant changes in genes known to be important for osteoclastogenesis and osteoclast function, using Uniprot (13
) and Genedistiller (14
), but we did not identify such likely candidates apart from the CLCN7
missense variant of unknown significance previously published for subject 1 and her father (1
). Good coverage was obtained for known osteopetrosis genes in both subjects and no other notable variants were identified. Future investigation of additional DSS patients will allow the assessment of the role of known osteopetrosis genes or other modifier genes in the presentation of DSS. SLC29A3
encodes a nucleoside transporter localized in lysosomes and is highly expressed in some white blood cells such as histiocytes and macrophages. Mice deficient in SLC29A3 have significant lysosomal dysfunction in macrophages (15
); proper lysosomal function is also crucial for osteoclasts. We propose that SLC29A3 could be important for osteoclast differentiation and activity.
In summary, we describe two unrelated children with DSS associated with autosomal recessive inheritance of variants in SLC29A3. While we have unraveled a single locus for this disease that has potential genetic heterogeneity, investigation of future cases will be critical to better understand the pathophysiology of DSS. The importance of SLC29A3 for lysosomes, its expression in osteoclasts and the reduced number of osteoclasts both in vivo and in vitro in our patients suggest that this protein may impact osteoclast differentiation and function.