\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{Title of manuscript : Forme fruste of scleroderma and autoimmune hearing
loss in a young adult with X linked agammaglobulinemia}



\author[1]{Munish Arora}%
\author[1]{Pallavi Nadig}%
\author[1]{Sanchi  Chawla }%
\author[1]{Saniya Sharma}%
\author[1]{Amit Rawat}%
\author[1]{Ramandeep S. Virk}%
\author[1]{Ankur Jindal}%
\affil[1]{Post Graduate Institute of Medical Education and Research}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


Title of manuscript : \emph{Forme fruste of scleroderma} \textbf{and
autoimmune hearing loss in a young adult with X linked
agammaglobulinemia}

Authors-

\begin{enumerate}
\tightlist
\item
  Munish Arora, Allergy Immunology Unit, Advanced Pediatrics Centre,
  Post Graduate Institute of Medical Education and research, Chandigarh,
  India
\item
  Pallavi Nadig, Allergy Immunology Unit, Advanced Pediatrics Centre,
  Post Graduate Institute of Medical Education and research, Chandigarh,
  India
\item
  Sanchi Chawla, Allergy Immunology Unit, Advanced Pediatrics Centre,
  Post Graduate Institute of Medical Education and research, Chandigarh,
  India
\item
  Saniya Sharma, Allergy Immunology Unit, Advanced Pediatrics Centre,
  Post Graduate Institute of Medical Education and research, Chandigarh,
  India
\item
  Amit Rawat, Allergy Immunology Unit, Advanced Pediatrics Centre, Post
  Graduate Institute of Medical Education and research, Chandigarh,
  India
\item
  Ramandeep S. Virk, Department of Otorhinolaryngology, Post Graduate
  Institute of Medical Education and research, Chandigarh, India
\item
  Ankur Kumar Jindal, Allergy Immunology Unit, Advanced Pediatrics
  Centre, Post Graduate Institute of Medical Education and research,
  Chandigarh, India.
\end{enumerate}

\textbf{Correspondence:}

Dr Ankur Kumar Jindal

Assistant Professor, Allergy Immunology Unit,~Department of Pediatrics,

Advanced Pediatrics Centre,

Post Graduate Institute of Medical Education and research,

Chandigarh (India)

E mail id\textbf{:}ankurjindal11@gmail.com; Mobile number: +919592065559

Word count: 766

Number of tables -- Nil

Number of figures- 1

Conflicts of interests: None

Financial support: None

Key words: Agammaglobulinemia, Hearing loss, \emph{Forme fruste of
scleroderma}

To the Editor,

X-linked agammaglobulinemia (XLA) is an antibody deficiency disorder
characterized by recurrent sinopulmonary infections, absent B cells and
immunoglobulins (Ig). It has recently been observed that patients with
XLA have defects in other arms of the immune system and are also
predisposed to develop autoimmune complications and malignancy. With
improvement in care, these patients are now surviving longer and a
spectrum of other complications are being recognized. Arthritis may be
seen in up to 1/3\textsuperscript{rd} of all cases. We report a young
adult with XLA who had inflammatory polyarthritis, skin thickening and
autoimmune sensorineural deafness.

A 24-year-old boy was symptomatic since the age of 3 years with
recurrent episodes of ear discharge and pneumonia. He was evaluated
elsewhere at the age of 10 and was found to have low IgG, IgA and IgM.
He was diagnosed to have hypogammaglobulinemia and was initiated on
immunoglobulin replacement therapy. He started developing pain and
swelling in multiple small and large joints since the age of 13. He was
prescribed naproxen in an another health care facility. At the age of
18, he developed sudden onset sensorineural hearing loss. He was
evaluated elsewhere and was prescribed hearing aids. He was referred to
us for evaluation at the age of 24.

In his family history, his elder sibling died at the age of 25. He had
had history of recurrent infections since early childhood. There was
also history of death of three maternal uncles in early age because of
recurrent infections. However, sibling and maternal uncles were not
evaluated.

On examination, he was cachectic with shiny skin over fingers and lower
limbs. The skin was noted to be thickened. There were deformities (swan
neck and boutonniere deformities) on multiple joints of fingers and toes
(Figure 1). Knee joints were swollen along with restriction of
movements. He had multiple contractures leading to restriction of
movements of knee joints, ankle joints and elbow joints. Respiratory,
cardiovascular and nervous system examination was unremarkable.
Laboratory examination showed normal inflammatory parameters such as
C-reactive protein and erythrocyte sedimentation rate. Rheumatoid factor
was negative. Immunoglobulin profile of the patient revealed normal
serum IgG (914) low serum IgA (\textless{}26 mg/dl) and IgM
(\textless{}18mg/dl). Flow cytometry revealed markedly reduced
proportion of B cells (\textless{}1\%) with normal proportion of T cells
and NK cells. T cell immunophenotyping showed that activated T cells
(CD3+HLADR+) were increased in the patient as compared to
control(46.91\% VS 10.50\%) and follicular helper T cells (CD45RA+
CXCR5+) were decreased in number (1.42\% VS 7.11\%).

Nail fold capillaroscopy showed no capillary dropout or haemorrhages.
Skin biopsy revealed changes of fibrosis. Ultrasound knee joints
revealed synovial hypertrophy along with minimal effusion.

Whole exome sequencing revealed hemizygous missense variation in exon 15
of the BTK gene (chrX:g.101356060G\textgreater{}C) that resulted in the
amino acid substitution of glycine for arginine at codon 554. This
variant has previously been reported in patients affected with XLA.

He was diagnosed to have XLA with polyarthritis presenting as\emph{forme
fruste of scleroderma} . He was continued on monthly intravenous
immunoglobulin replacement (400mg/kg) and cotrimoxazole prophylaxis. For
arthritis, he was advised naproxen and physiotherapy. He also underwent
cochlear implant on follow up and is currently doing well.

Patients with XLA usually present with recurrent sino-pulmonary and
gastrointestinal infections, while autoimmune features are infrequent as
compared to patients with common variable
immunodeficiency\textsuperscript{1}. Index patient presented with
features of both recurrent infections as well as autoimmunity. He had
features of deforming inflammatory arthritis (\emph{forme fruste of
scleroderma} ) along with autoimmune sensorineural hearing loss (SNHL).

Previously published reports have suggested that juvenile chronic
arthritis in males may be the initial clinical presentation of
XLA.\textsuperscript{2} Index case had previously been diagnosed to have
hypogammaglobulinemia and he developed arthritis while he was on
immunoglobulin replacement therapy. When he presented to us, he had
already developed a chronic deforming arthritis that resembled the
clinical presentation of \emph{forme fruste of scleroderma.}

Even though scleroderma has rarely been reported in patients with
XLA\textsuperscript{3.} Index patient likely had \emph{forme fruste of
scleroderma} as other clinical features of scleroderma were not seen.

Index patient also had features of autoimmune SNHL as hearing loss
developed acutely. Several authors have reported SNHL in patients with
agammaglobulinemia and have proposed following
mechanisms\textsuperscript{4,5}: Impaired clearance of apoptotic cells;
diminished B cell tolerance as Bruton tyrosine kinase (Btk) is essential
for B cell tolerance (Absence of Btk leads to inappropriate continuous
receptor editing by B cells. This enables B cells to overcome
Btk-responsible maturation defects and escape to the periphery); and
compromised regulatory T cell function.

To conclude, we report a young adult with XLA who presented with unusual
constellation of autoimmune manifestations.

Acknowledgements: None

Author contributions: All authors contributed to the study conception
and design. All authors read and approved the final manuscript\emph{.}

\textbf{References :}

\begin{enumerate}
\tightlist
\item
  Shillitoe BMJ, Gennery AR. An update on X-Linked agammaglobulinaemia:
  Clinical manifestations and management.~Curr Opin Allergy Clin
  Immunol~2019; 19(6):571--7.
\item
  Fu JL, Shyur SD, Lin HY, Lai YC. X-linked agammaglobulinemia
  presenting as juvenile chronic arthritis: report of one case. Acta
  Paediatr. 1999; 40(4): 280-3.
\item
  Pamuk ON, Pamuk GE, Turgut B, Cakir N. Scleroderma in a patient with
  X-linked agammaglobulinaemia. Scand J Rheumatol. 2004; 33(1) :59-60.
\item
  Berlucchi, Marco \& Soresina, Annarosa \& Redaelli de Zinis, Luca \&
  Valetti et al. Sensorineural Hearing Loss in Primary Antibody
  Deficiency Disorders. The Journal of pediatrics.2008;153. 293-6.
\item
  Richter D, Conley ME, Rohrer J, Myers LA et al . A contiguous deletion
  syndrome of X-linked agammaglobulinemia and sensorineural deafness.
  Pediatr Allergy Immunol. 2001(4);12(2):107-11. Figure legend: Figure1:
  Shiny thickened skin with deformities in small joints of hands in the
  index patient
\end{enumerate}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

