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)