Discussion
Hermansky-Pudlak syndrome type 2 (HPS-2) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, bleeding diathesis, and neutropenia. Eleven types of HPS associated with mutations in 11 different genes have been recognized, each mutation causing altered biogenesis of lysosomes and lysosome-related organelles and defective intracellular protein trafficking.(8) Molecular genetic testing for mutations in various genes can be used to confirm the diagnosis.
This disorder is found more commonly in individuals from Puerto Rico(9), however, we describe a case presenting in South-Asia which was initially diagnosed at the age of 4 years and eventually followed over the course of 9 years due to multiple complications including miliary TB and TB lymphadenopathy,initially thought to be lymphoma prior to biopsy– a common association with HPS-2 (10).
Hermansky-Pudlak syndrome can often be a diagnostic dilemma as it’s symptoms can be similar to those of other disorders such as Chediak-Higashi syndrome, which was considered. In the present case however, an interesting finding was upper extremity x-rays which demonstrated bullet shaped phalanges; this was more consistent with findings seen in Mucopolysaccharidosis (MPS). HPS was diagnosed due to the characteristic skin and hair hypopigmentation and ocular findings such as a grey iris and nystagmus, bleeding diathesis and neutropenia without granules on peripheral smear. The patient was categorised under the HPS2 subtype which has mild immunodeficiency as seen in this case by recurrent respiratory tract and skin infections along with HPS morphological features.
HPS is usually associated with neutropenia and hence pyogenic infections as demonstrated by a study that showed that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signalling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, Rab32-mediated mTOR signalling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation(11). Another study demonstrated the same via a candidate gene approach and found that canine cyclic neutropenia is the equivalent of the rare human Hermansky Pudlak syndrome type 2 (HPS2), with both diseases resulting from homozygous inactivating mutations of AP3B1, encoding the beta subunit of the adaptor protein 3 (AP3) trafficking complex (12).
The present case, however, was associated with recurrent tuberculosis infection, he was initially treated for miliary tuberculosis shows for 2 years after which he had recurrence of symptoms after 1.5 years despite being treated adequately, giving rise to the possibility of a T-cell defect. This finding has also been demonstrated by a study that reported the occurrence of nodular lymphocyte predominance type Hodgkin lymphoma in two siblings affected by HPS2, by analysing peripheral blood immune cells they found that NK and iNKT cells from HPS2 patients were significantly impaired in their number and function.
By immunohistochemistry, CD8 T-cells from HPS2 NLPHL contained an increased amount of perforin (Prf) + suggesting a defect in the release of this granules-associated protein and peripheral blood immune cell analysis revealed a significant reduction of circulating NKT cells and of CD56brightCD16 Natural Killer (NK) cells subset. In summary suggesting that a combined defect of innate and adaptive effector cells explains susceptibility to infections and lymphoma (10). The vulnerability in the present case maybe due to this defect.
IFN-γ plays a pivotal role in protective immunity against intracellular pathogens, specifically Mycobacterium tuberculosis infection(13). IFN-γ is an important mediator of macrophage activation(14) and humans deficient in either the gene for IFN-γ or the IFN-γ receptor show enhanced susceptibility to mycobacterial infections(15). IFN-γ also has a unique capacity to prime dendritic cells (DCs) for high IL-12 production. HPS2 patients demonstrate a complete defect in IL-12 production by moDCs, and hence likely display impaired T helper 1 polarization likely explaining the impaired immune mechanism in this patient which lead to the susceptibility to recurrent TB infections(16).
Prandini A et all and others studied monocyte derived dendritic cells and plasmacytoid dendritic cells in HPS2 siblings, which found that T-cell costimulatory activity measured by mixed lymphocyte reaction assay was lower in patients with HPS2, suggesting that function and maturation of DCs is abnormal in these patients. It was concluded that AP-3 deficiency resulted in abnormal maturation of monocyte derived DCs and impaired total antigen-presenting cell activity. This impairment of DC activity contributes to susceptibility to bacterial and viral infections, which is well demonstrated in the present case(16)