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\begin{document}

\title{Title: A Rare Case of Hermansky-Pudlak Syndrome}



\author[1]{Pushpa Kini}%
\author[1]{Aashna Bhatia}%
\author[1]{Rukmoni Balasubramanian}%
\affil[1]{Kasturba Medical College Manipal}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder
characterised by oculocutaneous albinism, a bleeding diathesis and
platelet storage deficiency. The aim of this paper is to report a case
of a patient with HPS who was followed over a decade. A
2-and-a-half-year-old boy presented with recurrent respiratory tract
infections and%
\end{abstract}%



\sloppy


\emph{Tittle: A Rare Case of Hermansky-Pudlak Syndrome}

\emph{Dr. Pushpa G. Kini, Associate Professor, Department of
Paediatrics, Kasturba Medical College, Manipal Academy of Higher
Education, Manipal}

\emph{Aashna Bhatia, Intern, Kasturba Medical College, Manipal Academy
of Higher Education, Manipal}

\emph{Rukmoni Balasubramanian, Intern, Kasturba Medical College, Manipal
Academy of Higher Education, Manipal}

\emph{Abstract}

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder
characterised by oculocutaneous albinism, a bleeding diathesis and
platelet storage deficiency.

The aim of this paper is to report a case of a patient with HPS who was
followed over a decade. A 2-and-a-half-year-old boy presented with
recurrent respiratory tract infections and global developmental delay.
On examination, he had light golden hair, grey iris with nystagmus,
fundus hypo-pigmented fovea and white macules all over the body. Also
found to have neutropenia without granules on peripheral smear. HPS can
often be a diagnostic dilemma mimicking disorders like Chediak-Higashi
syndrome, in this case diagnosis was made due to characteristic skin and
hair hypopigmentation and ocular findings along with bleeding diathesis.
Our patient was categorised under the HPS2 subtype which has mild
immunodeficiency.

HPS is usually associated with neutropenia and hence pyogenic
infections, the present case however was associated with an advanced
form of pulmonary Tuberculosis- miliary TB and granulomatous TB
lymphadenitis giving rise to the possibility of a T-cell defect.

\emph{Key words: Hermansky-pudlak syndrome, oculocutaneous albinism,
nystagmus, neutropenia, T-cell defect.~}

\emph{Introduction~}

Hermansky-Pudlak syndrome (HPS) is hereditary multi-system disorder
characterized by oculocutaneous albinism, a bleeding diathesis, platelet
storage deficiency. Individuals can also present with pulmonary
fibrosis, granulomatous colitis, and/or immunodeficiency. Ocular
findings include nystagmus, reduced iris pigment, reduced retinal
pigment, foveal hypoplasia with significant reduction in visual acuity
(usually in the range of 20/50 to 20/400), and strabismus. Hair colour
ranges from white to brown; skin colour ranges from white to olive and
is usually at least a shade lighter than that of other family
members.(3) The storage-pool defect arises from the absence of platelet
dense bodies which normally contain adenosine diphosphate (ADP),
adenosine triphosphate (ATP), calcium and serotonin which are necessary
to trigger the secondary aggregation response of platelets(4)

The accumulation of ceroid lipofuscin, an amorphous lipid-protein
complex, is associated with the mentioned findings of pulmonary
fibrosis(5)(6), and granulomatous colitis(7) which can result in
increased morbidity in these individuals. HPS is more prevalent in
Puerto Rico, where HPS type 1 has an estimated prevalence of 1:1800(1)
and most clinical research studies have been conducted there. Worldwide
HPS is rare inherited autosomal recessive disorder, with an estimated
prevalence of only 1:500,000 to 1:1,000,000 in non- Puerto Rican
populations(2), thus making it's presentation in a South-Asian country
such an India extremely rare. In this case report, we discuss a patient
with Hermansky Pudlak Type II who was followed over a decade. This case
is unique because the patient developed disseminated tuberculosis twice
during the course of follow up despite compliance to treatment, implying
a possible T cell defect and hence merits publication.

\emph{Case}

A 2-and-a-half-year-old boy presented with recurrent respiratory tract
infections since 7 months of age, poor weight gain and developmental
delay. Previously was treated for bronchopneumonia and dysentery. Birth
history was normal. Third degree consanguinity was present.~ There was a
sibling death at 2 months of age, possibly due to bronchopneumonia.

\emph{Examination findings}

On examination, the following findings were noted- light golden hair,
grey iris with nystagmus, low set ears, high arched palate, fundus
hypopigmented fovea, hyperextension of joints, genu recurvatum, and
white macules all over the body. Umbilical hernia also present.

\emph{Investigations}

Peripheral smear showed neutropenia without granules. Lowest absolute
neutrophil count was 51cells/\selectlanguage{greek}μ\selectlanguage{english}L. X-ray of the wrist showed bullet shaped
phalanges as shown in Figure A (interestingly a finding seen in patients
of mucopolysaccharidoses). X-ray of the nasopharynx showed 80\% adenoids
and X ray lateral spine showed kyphosis.

\emph{Course of the illness and treatment~}

Chediak Higashi syndrome was considered in view of overlapping symptoms
of oculocutaneous albinism and neutropenia, hence Vitamin C was given
and there was gradual catch up in gross motor milestones, with normal
speech and mentation. TSH was raised and hence started on daily thyroid
replacement therapy in view of primary hypothyroidism.

He continued to remain neutropenic and had multiple episodes of upper
respiratory tract infections.

At 4 years of age he presented with fever and respiratory distress. ANC
was 151cells/\selectlanguage{greek}μ\selectlanguage{english}L and X-ray showed bilateral diffuse non homogenous
opacities suggestive of miliary tuberculosis as seen in Figure B.
Patient was started on anti-tubercular treatment - pyrazinamide,
rifampicin and isoniazid, which was continued for 2 years and compliance
was good.

At follow up diagnosis was revised to be Hermansky-Pudlak syndrome due
characteristic skin and hair hypopigmentation with ocular findings and
neutropenia with absence of characteristic cytoplasmic granules in
neutrophils on peripheral smear along with bleeding diathesis.

At 8 years of age patient presented with multiple firm submandibular,
upper deep cervical and submental lymph nodes. FNAC of the cervical
lymph nodes showed granulomatous lymphadenitis suggestive of
TB---started on anti-tubercular treatment - pyrazinamide, ethambutol,
isoniazid and rifampicin. After few months there was increase in size of
the swellings, as Hermansky-Pudlak Type 2 is a high-risk condition for
lymphoma a LN biopsy was done which showed caseating granulomatous
lymphadenitis. Ciprofloxacin was added along with ATT.

ATT given for 18 months, and lymph nodes regressed.

At 10 years of age patient was admitted with Dengue fever, serology was
positive for NS1 Dengue. He had hepatosplenomegaly and petechiae over
lower limbs and hands, treated with supportive measures. ANC at this
time was 70 cells/ \selectlanguage{greek}μ\selectlanguage{english}L.

At 12 years the patient was admitted with adenotonsillitis with
membranous patch over left tonsil. Lateral X ray neck showed adenoid
hypertrophy. Patient underwent adenotonsillectomy with bilateral grommet
insertion.

\emph{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 CD56\textsuperscript{bright}CD16\textsuperscript{-}~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-\selectlanguage{greek}γ \selectlanguage{english}plays a pivotal role in protective immunity against intracellular
pathogens, specifically Mycobacterium tuberculosis infection(13). IFN-\selectlanguage{greek}γ
\selectlanguage{english}is an important mediator of macrophage activation(14) and humans
deficient in either the gene for IFN-\selectlanguage{greek}γ \selectlanguage{english}or the IFN-\selectlanguage{greek}γ \selectlanguage{english}receptor show
enhanced susceptibility to mycobacterial infections(15). IFN-\selectlanguage{greek}γ \selectlanguage{english}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)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\emph{Figure B: Chest X-Ray of the patient suggestive of miliary
tuberculosis}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& \emph{Hermansky-Pudlak Syndrome} & \emph{Chediak-Higashi Syndrome
(CHS)}\tabularnewline
\midrule
\endhead
Oculocutaneous albinism & Present & Present\tabularnewline
Cytoplasmic granules in platelets and neutrophils & \emph{Always absent}
& \emph{Characteristic finding}\tabularnewline
Intellectual disability/ Neurological findings & May or may not be
present & Present in all\tabularnewline
Hepatosplenomegaly & May or may not be present & Maybe
present\tabularnewline
Hemophagocytic lympohistiocytosis & May or may not be present & Also
called the accelerated phase of CHS- develops in 85\% of
patients\tabularnewline
\bottomrule
\end{longtable}

*Declaration statement for conflict of interest: The authors have no
conflict of interest to declare. There is no financial interest to
report.

*Consent statement: Written informed consent was obtained from the
patient to publish this report in accordance with the journal's patient
consent policy.

\emph{References}

1. Santiago Borrero PJ, Rodr\selectlanguage{ngerman}íguez-Pérez Y, Renta JY, Izquierdo NJ, del
Fierro L, Muñoz D, et al. Genetic Testing for Oculocutaneous Albinism
Type 1 and 2 and Hermansky--Pudlak Syndrome Type 1 and 3 Mutations in
Puerto Rico. Journal of Investigative Dermatology. 2006
Jan;126(1):85--90.

2. Nazir HF, AL Sukaiti N, Khater D, Elbeshlawy I, Hassanein N.
Hermansky-Pudlak Syndrome: Spectrum in Oman. J Pediatr Hematol Oncol.
2023 Apr;45(3):e389--94.

3. Introne WJ, Huizing M, Malicdan MC V, O'Brien KJ, Gahl WA.
Hermansky-Pudlak Syndrome. GeneReviews .

4. Bagheri A, Abdollahi A. Hermansky-pudlak syndrome; a case report. J
Ophthalmic Vis Res. 2010 Oct;5(4):269--72.

5. Harmon KR, Witkop CJ, White JG, King RA, Peterson M, Moore D, et al.
Pathogenesis of pulmonary fibrosis: platelet-derived growth factor
precedes structural alterations in the Hermansky-Pudlak syndrome. J Lab
Clin Med. 1994 Apr;123(4):617--27.

6. Garay SM, Gardella JE, Fazzini EP, Goldring RM. Hermansky-Pudlak
syndrome. Pulmonary manifestations of a ceroid storage disorder. Am J
Med. 1979 May;66(5):737--47.

7. Schinella RA, Greco MA, Cobert BL, Denmark LW, Cox RP.
Hermansky-Pudlak syndrome with granulomatous colitis. Ann Intern Med.
1980 Jan;92(1):20--3.

8. Summers CG, Hand JL. Hermansky-Pudlak syndrome. Post TedW, editor.
UpToDate, Waltham, MA;

9. Pierson DM, Ionescu D, Qing G, Yonan AM, Parkinson K, Colby TC, et
al. Pulmonary Fibrosis in Hermansky-Pudlak Syndrome. Respiration.
2006;73(3):382--95.

10. Lorenzi L, Tabellini G, Vermi W, Moratto D, Porta F, Notarangelo LD,
et al. Occurrence of Nodular Lymphocyte-Predominant Hodgkin Lymphoma in
Hermansky-Pudlak Type 2 Syndrome Is Associated to Natural Killer and
Natural Killer T Cell Defects. PLoS One. 2013 Nov 26;8(11):e80131.

11. Cavounidis A, Pandey S, Capitani M, Friedrich M, Cross A, Gartner L,
et al. Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial
immunity and inflammation due to dysregulated immunometabolism. Mucosal
Immunol. 2022 Nov;15(6):1431--46.

12. Berliner N, Horwitz M, Loughran TP. Congenital and Acquired
Neutropenia. Hematology. 2004 Jan 1;2004(1):63--79.

13. Lalvani A, Millington KA. T Cells and Tuberculosis: Beyond
Interferon\selectlanguage{english}-\selectlanguage{greek}γ. \selectlanguage{english}J Infect Dis. 2008 Apr;197(7):941--3.

14. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An
essential role for interferon gamma in resistance to Mycobacterium
tuberculosis infection. Journal of Experimental Medicine. 1993 Dec
1;178(6):2249--54.

15. Ottenhoff THM, Kumararatne D, Casanova JL. Novel human
immunodeficiencies reveal the essential role of type-1 cytokines in
immunity to intracellular bacteria. Immunol Today. 1998
Nov;19(11):491--4.

16. Prandini A, Salvi V, Colombo F, Moratto D, Lorenzi L, Vermi W, et
al. Impairment of dendritic cell functions in patients with adaptor
protein-3 complex deficiency. Blood. 2016 Jun 30;127(26):3382--6.

17. Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM,
et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak
syndrome type II. Blood. 2006 Jul 1;108(1):81--7.

18. Lucchini G, Marsh R, Gilmour K, Worth A, Nademi Z, Rao A, et al.
Treatment dilemmas in asymptomatic children with primary hemophagocytic
lymphohistiocytosis. Blood. 2018 Nov 8;132(19):2088--96.

19. Trottestam H, Horne A, Aric\selectlanguage{ngerman}ò M, Egeler RM, Filipovich AH, Gadner H,
et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis:
long-term results of the HLH-94 treatment protocol. Blood. 2011 Oct
27;118(17):4577--84.

20. Dell'Acqua F, Saettini F, Castelli I, Badolato R, Notarangelo LD,
Rizzari C. Hermansky-Pudlak syndrome type II and lethal hemophagocytic
lymphohistiocytosis: Case description and review of the literature. J
Allergy Clin Immunol Pract. 2019 Sep;7(7):2476-2478.e5.

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