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\begin{document}

\title{CHRONIC INTESTINAL CONSTIPATION OF ATYPICAL ETIOLOGY IN PRESCHOOL CHILD}



\author[1]{Camila Fachin}%
\author[2]{Carlos Riedi}%
\author[1]{Tarick Salim Ali}%
\author[1]{Milena Conceição}%
\author[1]{Miguel Angelo Agulham}%
\author[1]{Andre Dias}%
\affil[1]{Federal University of Parana}%
\affil[2]{Federal University Parana}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
There is a large spectrum of abnormalities in the CFTR gene that leads
to a partial function of the chloride channel and, thereby, an uncommon
presentation of the disease, the ``CFTR-related diseases''. This report
aims to present a case of a patient with a single gene mutation related
to cystic fibrosis, with an unusual clinical presentation among CFTR
related diseases - chronic intestinal constipation. This patient is not
a cystic fibrosis patient because he does not fulfil the disease's
classic criteria. Furthermore, since the mutation found is not yet
described in the literature, it could be related to CFTR-related
disease.%
\end{abstract}%



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\textbf{KEYWORDS:}

Cystic Fibrosis

CFTR related disease

Chronic constipation

\textbf{ABBREVIATIONS:}

CFTR: Cystic fibrosis transmembrane conductance regulator

G: Guanine

HC: Hospital de Cl\selectlanguage{ngerman}ínicas

Leu: Leucine

Phe: Phenilalanine

T: Tiamine

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{INTRODUCTION:}

Cystic fibrosis is a recessive genetic disease caused by mutation in the
two alleles of the gene CFTR. It can be diagnosed by classic symptoms
and laboratory tests, such as sweat testing or genetic testing for the
identification of CFTR mutations {[}1{]}. When performing the genetic
test, the most frequent mutations for certain ethnic groups are
investigated {[}2{]}. There is a large spectrum of abnormalities in the
CFTR gene that leads to a partial function of the chloride canal and,
thereby, an uncommon presentation of the disease. These presentations do
not fully meet the diagnostic criteria for cystic fibrosis and are
therefore classified as ''CFTR-related diseases'' {[}3{]}. This article
aims to report a case of a patient with a single gene mutation related
to cystic fibrosis, with an unusual clinical presentation among CFTR
related diseases.

\textbf{CASE REPORT:}

A 4-year-old male admitted at the University Hospital with intestinal
constipation since birth, remaining up to 7 days without defecation
followed by abdominal distension and soiling. After the first year of
life, there was a worsening in the clinical scenario with an increase in
the number of days without bowel movements. At another service, the
patient had performed anoplasty and several sessions of anal dilatation.
On physical examination, the abdomen was slightly distended, painless
and without palpable masses. In rectal examination, presence of a large
amount of softened stool. Initially, it was prescribed to the patient:
dietary orientation, rectal enemas with sorbitol and sodium lauryl
sulfate solution and polyethylene glycol orally. After 2 months of
treatment, the patient returns with partial improvement of the
condition, but maintaining soiling and a palpable fecaloma. The patient
was then hospitalized and submitted to rectal enema with lactated ringer
and 12\% glycerin solution. The fecaloma was manually removed under
general anesthesia. Barium enema confirmed megarectum. Surgical rectal
biopsy was performed and no changes were observed in ganglion cells In
addition, anorectal manometry was normal. Due to the persistence of
fecaloma formation, a double-barrel colostomy was performed. Due to the
persistence of fecaloma, even with the colostomy, cystic fibrosis was
investigated. The sweat test was borderline and a therapeutic trial with
acetylcysteine and pancrelipase was initiated; besides performing the
genetic test for cystic fibrosis. The test identified the variation
p.Leu1156Phe G\textgreater{}T, a variant of the CFTR gene of
undetermined meaning.

\textbf{DISCUSSION:}

The diagnostic criteria for cystic fibrosis suggest that there must be
both the characteristic clinical phenotype of the disease and also a
documented dysfunction of the CFTR protein {[}1{]}. The patient of this
report cannot be considered a cystic fibrosis patient because he does
not have the classic clinical features of the disease, the sweat
chloride test has shown indeterminate values and he doesn't present two
known genes or gene variant that causes the disease.

The CFTR-related diseases are those that have association with CFTR gene
dysfunction, but do not fulfil the diagnostic criteria for the disease
{[}4{]}. This new classification is related to the advances in genetic
testing that guide the diagnosis criteria for cystic fibrosis and this
new group of diseases. In fact, it is still difficult to distinguish
those two entities {[}3{]}, and as new discoveries are made, new
classifications systems will be adopted.

Three clinical entities have strong support in the literature, being
defined as CFTR-related diseases: bilateral congenital absence of the
vas deferens with CFTR dysfunction, recurrent acute pancreatitis or
chronic pancreatitis with CFTR dysfunction, and disseminated
bronchiectasis with CFTR dysfunction {[}3{]}. In addition to these
presentations, other phenotypes were observed associated with mutations
in the CFTR gene, such as sinusitis and bronchopulmonary allergic
aspergillosis {[}2{]}. Many of the patients with these phenotypes will
never progress to a phenotype of frank cystic fibrosis and, therefore,
their follow-up may be done differently from that usually done in
patients with cystic fibrosis {[}3{]}.

The patient reported has a p.Leu1156Phe G\textgreater{}T alteration, in
which is observed a guanine to thymine change at nucleotide 3599 in exon
18, which would lead to a replacement of leucine by phenylalanine in the
protein sequence at residue 1156 (L1156F) {[}5{]}. Although this change
is localized in the CFTR gene, it still represents an undetermined
meaning mutation {[}5{]}. Given the presentation of the reported
patient, oligosymptomatic cystic fibrosis with only chronic
constipation, indeterminate sweat chloride test and a genetic alteration
in the CFTR coding area, without the characterization of frank cystic
fibrosis, it is believed that the mutation found, not yet described in
the literature, could be related and could be classified as a
CFTR-related disease. For more accurate diagnosis, in addition to the
sweat test and mutation investigation in the CFTR gene, measurements of
nasal potential difference {[}2{]} {[}3{]} and intestinal current
measurement {[}3{]} should be performed.

\textbf{REFERENCES:}

Rosenstein BJ, Cutting GR, Boat TF, Cantin A, Dorkin HL, Durie P,
FitzSimmons S, Knowles MR, Saiman L, Tullis E: The diagnosis of cystic
fibrosis: a consensus statement. J Pediatr 1998, 132:589-595.

Peadar G Noone; Michael R Knowles: Review `CFTR-opathies': disease
phenotypes associated with cystic fibrosis transmembrane regulator gene
mutations. Respiratory Research Vol 2 No 6. Available online
http://respiratory-research.com/content/ 2/6/328.

C. Bombieri et al. Recommendations for the classification of diseases as
CFTRrelated disorders. Journal of Cystic Fibrosis Volume 10 Suppl 2
(2011) S86--S102

Molecular Genetics Laboratory, Hospital for Sick Children. Cystic
Fibrosis and CFTR- Related Disorders. OMG1620P/02. Available from: URL:

\emph{https://www.sickkids.ca/PDFs/Paediatric\%20Laboratory\%20Medicine/info-sheets/}

\emph{56255-CF\_OMG1620P\_02.pdf}

Cystic Fibrosis Mutation Database. Mutation Details for
c.3468G\textgreater{}T. Available from: URL:
http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1640\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1-Barium-enema-showing-dilated-rectum-and-sigmoid/Figure-1-Barium-enema-showing-dilated-rectum-and-sigmoid}

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\includegraphics[width=0.70\columnwidth]{figures/Figure-2--Intraoperative-period-double-barrel-colostomy/Figure-2--Intraoperative-period-double-barrel-colostomy}

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