Congenital Chloride Diarrhea

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

CLD is autosomal recessive. It is strongly enriched in populations with founder variants - notably Finland, Poland, Saudi Arabia and Kuwait - where a single ancestral allele accounts for most cases.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:24350656 SUPPORT Human Clinical

"Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by life-long, severe diarrhea with intestinal Cl- malabsorption."

States the mode of inheritance and the defining transport defect.

⚙

Pathophysiology

4

Loss of Apical DRA Chloride/Bicarbonate Exchange

The initiating lesion. DRA (SLC26A3) is a sodium-independent chloride/bicarbonate exchanger expressed at the apical membrane of differentiated ileal and colonic epithelium, where it performs the major chloride-absorbing step of the intestine, taking up luminal chloride in exchange for bicarbonate. Biallelic loss-of-function variants abolish or severely reduce this exchange. Notably, transcript expression can be preserved - the Finnish V317del allele is expressed at normal levels - so the lesion is loss of transport function at the apical membrane rather than loss of the gene product, which is what makes pharmacological rescue of residual protein conceivable.

Colonic epithelial cell CL:0011108

Apical chloride/bicarbonate exchange GO:0015108 ⇓ LOSS OF FUNCTION

Apical plasma membrane GO:0016324

Colon UBERON:0001155

Downstream

Luminal Chloride Retention and Failure of Intestinal Fluid Absorption

Systemic Electrolyte Depletion and Metabolic Alkalosis

Show evidence (2 references)

PMID:8896562 SUPPORT Human Clinical

"A major transport function of the human intestine involves the absorption of chloride in exchange for bicarbonate."

Identifies the physiological transport step whose loss defines this node.

PMID:8896562 SUPPORT Human Clinical

"By mRNA in situ hybridization, we demonstrate that the expression of DRA occurs preferentially in highly differentiated colonic epithelial cells, is unchanged in Finnish CLD patients with delta V317"

Establishes both the cell type in which DRA acts and the point that transcript expression is preserved in the Finnish founder genotype, so the lesion is functional rather than transcriptional.

Luminal Chloride Retention and Failure of Intestinal Fluid Absorption

The rate-limiting step. Chloride that cannot be absorbed accumulates in the ileal and colonic lumen as an osmotically active anion, obligating water retention and abolishing the net fluid absorption that normally occurs across the distal intestine. Because the failed step handles an ion rather than an ingested nutrient, luminal chloride load is set by secretion and diet-salt intake rather than by any single dietary constituent - which is why, unlike the diet-induced congenital diarrheas, the diarrhea cannot be abolished by eliminating a food. Fluid loss begins in fetal life, producing dilated fetal bowel loops and marked polyhydramnios.

Colonic epithelial cell CL:0011108

Intestinal chloride absorption GO:1902476 ↓ DECREASED Intestinal water absorption GO:0006833 ⚠ ABNORMAL

Ileum UBERON:0002116

Downstream

Chloride-Rich Watery Diarrhea and Its Consequences

Show evidence (3 references)

PMID:24350656 SUPPORT Human Clinical

"It results from a reduced activity of the down regulated in adenoma exchanger (DRA), due to mutations in the solute carrier family 26, member 3 (SLC26A3) gene."

Links reduced DRA exchanger activity to the intestinal chloride malabsorption that defines this node.

PMID:35127600 SUPPORT Human Clinical

"The main feature of this condition is a severe chronic osmotic diarrhea that causes a secondary volume contraction"

Describes the luminal osmotic consequence of the transport failure and the volume contraction it produces.

PMID:34988036 SUPPORT Human Clinical

"As early as the prenatal period, importantly, signs similar to those seen in the setting of intestinal obstruction, such as dilated intestinal loops on ultrasound, may be apparent."

Supports the claim that failure of intestinal fluid absorption begins in fetal life, producing dilated bowel loops that mimic obstruction - the reason affected neonates are sometimes taken to laparotomy before the diagnosis is made.

Systemic Electrolyte Depletion and Metabolic Alkalosis

The systemic arm, and the source of the disorder's diagnostic signature. Two processes combine. Stool loss of chloride, sodium and potassium depletes each ion, producing hypochloremia, hyponatremia and hypokalemia. Separately, DRA normally secretes bicarbonate into the lumen in exchange for the chloride it absorbs; when the exchanger fails, that bicarbonate is retained in the body. Retained bicarbonate plus chloride depletion plus volume-contraction-driven secondary hyperaldosteronism produce a hypochloremic, hypokalemic metabolic ALKALOSIS. This is the mirror image of congenital sodium diarrhea, in which failure of sodium/proton exchange causes metabolic ACIDOSIS, and the acid-base direction is what distinguishes the two at the bedside.

Bicarbonate secretion into the intestinal lumen GO:0015701 ↓ DECREASED

Downstream

Chloride-Rich Watery Diarrhea and Its Consequences

Show evidence (1 reference)

PMID:35127600 SUPPORT Human Clinical

"severe chronic osmotic diarrhea that causes a secondary volume contraction with the development of metabolic alkalosis, electrolytes imbalance, failure to thrive, psycho-motor delay and even death"

Names the full systemic consequence set of this node - metabolic alkalosis, electrolyte imbalance, failure to thrive, psychomotor delay and mortality - and attributes it to volume contraction from the diarrhea.

Chloride-Rich Watery Diarrhea and Its Consequences

The clinical output. Lifelong profuse watery diarrhea whose stool chloride concentration exceeds the sum of stool sodium and potassium - the finding that clinches the diagnosis. Untreated, volume contraction and electrolyte depletion cause failure to thrive, psychomotor delay, renal impairment from chronic hypovolemia and hypokalemia, and death. Treated with salt substitution, electrolytes normalise and survival and growth are good, but stool volume remains high, so quality of life is dominated by the number of daily evacuations and by fecal incontinence.

Colon UBERON:0001155

Show evidence (2 references)

PMID:8896562 SUPPORT Human Clinical

"The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content."

States the clinical output and the high stool chloride content that is the diagnostic hallmark of this node.

PMID:35127600 SUPPORT Human Clinical

"The quality of life in CLD patients is negatively influenced by the elevated number of evacuations a day and the fecal incontinence"

Documents the residual disease burden that persists on salt substitution, supporting the distinction between correcting electrolytes and reducing stool volume.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

6

Digestive 1

Chloride-Rich Watery Diarrhea OBLIGATE HP:0002014

Temporal: CHRONIC

Show evidence (1 reference)

PMID:8896562 SUPPORT Human Clinical

"The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content."

Directly states the lifelong, high-chloride diarrhea that defines the disorder, supporting the OBLIGATE frequency band.

Metabolism 1

Hypokalemia HP:0002900

Show evidence (1 reference)

PMID:29654747 SUPPORT Other

"severe diarrhea at birth with concomitant hypochloremic hypokalemic metabolic alkalosis"

Names hypokalemia directly as part of the characteristic biochemical triad of congenital chloride diarrhea. Evidence source is OTHER because this is a review.

Prenatal and Birth 1

Polyhydramnios FREQUENT HP:0001561

Show evidence (2 references)

PMID:34988036 SUPPORT Human Clinical

"In the prenatal period, the symptoms of CCD may include polyhydramnios, preterm labor and abdominal distension."

States the prenatal manifestations of this node - polyhydramnios, preterm labor and abdominal distension - establishing that disease begins in fetal life.

PMID:34988036 SUPPORT Human Clinical

"Polyhydramnios, manifesting due to intrauterine watery diarrhea, as well as pre-term birth, may also be common"

Gives the mechanism (intrauterine watery diarrhea) and the qualifier "common", which supports the FREQUENT band; the hedged "may also be" is why a higher band is not asserted.

Growth 1

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:35127600 SUPPORT Human Clinical

"metabolic alkalosis, electrolytes imbalance, failure to thrive, psycho-motor delay and even death"

Lists failure to thrive among the consequences of the untreated disorder.

Other 2

Metabolic Alkalosis HP:0200114

Show evidence (1 reference)

PMID:35127600 SUPPORT Human Clinical

"secondary volume contraction with the development of metabolic alkalosis, electrolytes imbalance, failure to thrive"

Documents metabolic alkalosis as a characteristic consequence of the volume contraction in this disorder.

Hypochloremia HP:0003113

Show evidence (1 reference)

PMID:24350656 SUPPORT Human Clinical

"life-long, severe diarrhea with intestinal Cl- malabsorption"

Establishes the continuous intestinal chloride malabsorption that depletes body chloride stores and produces hypochloremia.

🧬

Genetic Associations

1

SLC26A3 loss-of-function variants (Causative)

Gene: SLC26A3 hgnc:3018 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:8896562 SUPPORT Human Clinical

"we report segregation of two missense mutations, delta V317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients"

The gene-discovery report identifying the causative DRA/SLC26A3 variants and their segregation in Finnish and Polish patients.

PMID:8896562 SUPPORT Human Clinical

"We conclude that DRA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated."

States the causal conclusion linking the gene to the disease phenotype.

💊

Medical Actions

2

Oral Salt Substitution

Action: Nutritional Support NCIT:C15433

Lifelong oral sodium chloride and potassium chloride substitution is the life-saving mainstay of treatment. It replaces the ions lost in stool, restoring electrolyte balance and preventing metabolic alkalosis, and it transforms the prognosis of a disorder that is otherwise fatal. Its limitation is precise and important: it corrects the systemic consequences without acting on the intestinal transport defect, so stool volume is unchanged and the daily burden of diarrhea persists.

Mechanism Target:

INHIBITS Systemic Electrolyte Depletion and Metabolic Alkalosis — Replacing chloride, sodium and potassium orally offsets fecal losses and prevents the electrolyte depletion and alkalosis, acting on the systemic arm only and leaving the luminal transport defect untouched.

Show evidence (1 reference)

PMID:35127600 SUPPORT Human Clinical

"Oral salt substitutive therapy is a life-saving therapy: it improves the outcome, leads to electrolytes balance, reduces the risk of developing metabolic alkalosis, but has no effect on symptoms' severity"

States exactly the scope and the limit of this treatment: life-saving and electrolyte-normalising, but without effect on diarrhea severity - which is why it is modelled as acting on the systemic node rather than the central effector.

Oral Sodium Butyrate

Action: Pharmacotherapy NCIT:C15986

Agent: butyrate CHEBI:17968

Oral sodium butyrate is the only therapy that reduces diarrhea severity itself. It acts by two routes: a DRA-independent route in which butyrate uptake stimulates the alternative anion exchanger PAT-1 and the sodium/proton exchangers NHE2 and NHE3 while inhibiting NKCC1, and a DRA-dependent route in which it increases SLC26A3 transcription and translation and reduces DRA mistrafficking and misfolding. Efficacy is genotype-dependent, best in patients with missense and deletion variants - consistent with rescue of residual protein - and some patients experience worsening at the standard 100 mg/kg/day dose. In those patients a step-up schedule from 50 mg/kg/day with weekly 25 mg/kg/day increments has restored responsiveness.

Mechanism Target:

ACTIVATES Loss of Apical DRA Chloride/Bicarbonate Exchange — Butyrate increases SLC26A3 expression and reduces DRA mistrafficking and misfolding, partially restoring the failed apical exchange step, and in parallel stimulates alternative chloride-absorbing transporters.

Show evidence (2 references)

PMID:24350656 SUPPORT Human Clinical

"The effect of butyrate is related in part on a different modulation of the expression of the two main apical membrane Cl- exchangers of epithelial cells, members of the SLC26 anion family."

Attributes butyrate's effect to modulation of the two apical SLC26 chloride exchangers, supporting action on the trigger node.

PMID:24350656 SUPPORT Human Clinical

"The best response was observed in subjects with missense and deletion mutations."

Documents the genotype dependence of the response, consistent with rescue of residual mutant protein rather than replacement of an absent one.

INHIBITS Chloride-Rich Watery Diarrhea and Its Consequences — Clinically, butyrate reduces diarrhea severity, the effect that distinguishes it from salt substitution.

Show evidence (1 reference)

PMID:35127600 SUPPORT Human Clinical

"The step-up therapeutic approach resulted effective in limiting diarrhea severity in all our three previously unresponsive CLD patients."

Reports reduction in diarrhea severity with the step-up butyrate schedule in patients previously unresponsive to standard dosing.

🔬

Diagnosis

2

Stool electrolyte measurement

Measurement of fecal chloride, sodium and potassium is the decisive test: a stool chloride concentration exceeding the sum of stool sodium and potassium establishes the diagnosis. It should be interpreted alongside serum electrolytes and blood gas, which show the characteristic hypochloremic hypokalemic metabolic alkalosis.

Show evidence (1 reference)

PMID:35127600 SUPPORT Human Clinical

"The sure diagnosis of CLD was based on the results of full anamnestic, clinical and laboratory evaluation (including the evaluation of fecal Na+, Cl-, and K+), and the result of the molecular analysis."

States the diagnostic algorithm used at an international reference centre: fecal electrolyte evaluation together with molecular analysis.

SLC26A3 sequencing

Molecular confirmation by SLC26A3 sequencing. Genotype is clinically useful beyond confirmation, because response to butyrate therapy is genotype-dependent.

Show evidence (1 reference)

PMID:24350656 SUPPORT Human Clinical

"We demonstrate a genotype-dependency for butyrate therapeutic efficacy in CLD."

Supports genotyping as therapeutically informative, not merely confirmatory.

🔬

Clinical Trials

1

ACTRN12613000450718 PHASE_II COMPLETED

Single-group open-label interventional study of oral sodium butyrate (100 mg/kg/day) in seven children with congenital chloride diarrhea of differing SLC26A3 genotypes, assessing stool pattern, fecal ion loss and chloride-transporter expression. Registered with ANZCTR and reported in PMID:24350656.

Target Phenotypes: Chloride-rich watery diarrhea HP:0002014

Show evidence (2 references)

ICTRP:ACTRN12613000450718 SUPPORT Other

"| Register | ANZCTR |"

WHO ICTRP registration record establishing the trial's identity and primary registry. The trial has no ClinicalTrials.gov NCT identifier, so it is keyed on its ANZCTR/ICTRP identifier.

ICTRP:ACTRN12613000450718 SUPPORT Other

"| Recruitment status | Completed |"

Registry record of the recruitment status supporting the COMPLETED value.

{ }

Source YAML

click to show

name: Congenital Chloride Diarrhea
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
synonyms:
- CLD
- CCD
- congenital chloridorrhea
- Darrow-Gamble disease
- congenital secretory chloride diarrhea 1
description: >-
  Congenital chloride diarrhea (CLD) is a rare autosomal recessive congenital
  diarrhea caused by biallelic loss-of-function variants in SLC26A3, which
  encodes the apical sodium-independent chloride/bicarbonate exchanger DRA
  ("down-regulated in adenoma") of the ileal and colonic epithelium. It is the
  prototype of the electrolyte-transport-related class of congenital diarrheas
  and enteropathies, a class kept separate in the current nosology from the
  diet-induced (osmotic) congenital diarrheas: here the transport step that fails
  handles an ion rather than an ingested nutrient, so the diarrhea is entirely
  independent of what the infant is fed and cannot be treated by dietary
  elimination. Loss of DRA abolishes intestinal chloride absorption, so chloride
  is retained in the lumen and carries water with it, while the coupled
  bicarbonate secretion that DRA normally performs also fails. The result is a
  distinctive and diagnostically decisive biochemical signature: profuse watery
  stool with a chloride concentration exceeding the sum of sodium and potassium,
  together with hypochloremia, hyponatremia, hypokalemia and metabolic ALKALOSIS
  - the opposite acid-base derangement to the metabolic acidosis of congenital
  sodium diarrhea, its mirror-image disorder. Disease begins in utero: failure to
  absorb intestinal fluid causes fetal bowel dilatation and marked polyhydramnios,
  frequently with premature birth, and the neonate can be mistaken for having
  intestinal obstruction because the watery stool is passed as apparent urine.
  Lifelong oral salt substitution (sodium chloride and potassium chloride) is
  life-saving and normalises electrolytes, but does not reduce stool volume; oral
  sodium butyrate can reduce diarrhea severity in a genotype-dependent manner.
disease_term:
  preferred_term: congenital chloride diarrhea
  term:
    id: MONDO:0008964
    label: congenital secretory chloride diarrhea 1
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    CLD is autosomal recessive. It is strongly enriched in populations with
    founder variants - notably Finland, Poland, Saudi Arabia and Kuwait - where
    a single ancestral allele accounts for most cases.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24350656
    reference_title: "Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital chloride diarrhea (CLD) is an autosomal recessive disorder
      characterized by life-long, severe diarrhea with intestinal
      Cl- malabsorption.
    explanation: >-
      States the mode of inheritance and the defining transport defect.
genetic:
- name: SLC26A3 loss-of-function variants
  gene_term:
    preferred_term: SLC26A3
    term:
      id: hgnc:3018
      label: SLC26A3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Biallelic SLC26A3 variants reduce or abolish DRA chloride/bicarbonate
    exchange. The originally reported alleles were two missense variants
    (V317del and H124L) and a frameshift (344delT); the V317 deletion is the
    Finnish founder allele, supported by the population history of Finland.
    Genotype matters therapeutically as well as diagnostically: response to oral
    butyrate is genotype-dependent, best in patients carrying missense and
    deletion variants, consistent with butyrate acting partly by rescuing
    mistrafficking or misfolding of a residual protein rather than by replacing
    an absent one.
  evidence:
  - reference: PMID:8896562
    reference_title: "Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report segregation of two missense mutations, delta V317 and H124L, and
      one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD
      patients
    explanation: >-
      The gene-discovery report identifying the causative DRA/SLC26A3 variants
      and their segregation in Finnish and Polish patients.
  - reference: PMID:8896562
    reference_title: "Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that DRA is an intestinal anion transport molecule that causes
      chloride diarrhoea when mutated.
    explanation: >-
      States the causal conclusion linking the gene to the disease phenotype.
pathophysiology:
- name: Loss of Apical DRA Chloride/Bicarbonate Exchange
  conforms_to: "electrolyte_transport_related_diarrhea#Loss of an Apical Intestinal Electrolyte Transport Step"
  description: >-
    The initiating lesion. DRA (SLC26A3) is a sodium-independent
    chloride/bicarbonate exchanger expressed at the apical membrane of
    differentiated ileal and colonic epithelium, where it performs the major
    chloride-absorbing step of the intestine, taking up luminal chloride in
    exchange for bicarbonate. Biallelic loss-of-function variants abolish or
    severely reduce this exchange. Notably, transcript expression can be
    preserved - the Finnish V317del allele is expressed at normal levels - so the
    lesion is loss of transport function at the apical membrane rather than loss
    of the gene product, which is what makes pharmacological rescue of residual
    protein conceivable.
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Colonic epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  molecular_functions:
  - preferred_term: Apical chloride/bicarbonate exchange
    term:
      id: GO:0015108
      label: chloride transmembrane transporter activity
    modifier: LOSS_OF_FUNCTION
  cellular_components:
  - preferred_term: Apical plasma membrane
    term:
      id: GO:0016324
      label: apical plasma membrane
  locations:
  - preferred_term: Colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:8896562
    reference_title: "Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A major transport function of the human intestine involves the absorption
      of chloride in exchange for bicarbonate.
    explanation: >-
      Identifies the physiological transport step whose loss defines this node.
  - reference: PMID:8896562
    reference_title: "Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By mRNA in situ hybridization, we demonstrate that the expression of DRA
      occurs preferentially in highly differentiated colonic epithelial cells, is
      unchanged in Finnish CLD patients with delta V317
    explanation: >-
      Establishes both the cell type in which DRA acts and the point that
      transcript expression is preserved in the Finnish founder genotype, so the
      lesion is functional rather than transcriptional.
  downstream:
  - target: Luminal Chloride Retention and Failure of Intestinal Fluid Absorption
    causal_link_type: DIRECT
  - target: Systemic Electrolyte Depletion and Metabolic Alkalosis
    causal_link_type: DIRECT
- name: Luminal Chloride Retention and Failure of Intestinal Fluid Absorption
  conforms_to: "electrolyte_transport_related_diarrhea#Luminal Electrolyte Retention and Failure of Net Ion Absorption"
  description: >-
    The rate-limiting step. Chloride that cannot be absorbed accumulates in the
    ileal and colonic lumen as an osmotically active anion, obligating water
    retention and abolishing the net fluid absorption that normally occurs across
    the distal intestine. Because the failed step handles an ion rather than an
    ingested nutrient, luminal chloride load is set by secretion and diet-salt
    intake rather than by any single dietary constituent - which is why, unlike
    the diet-induced congenital diarrheas, the diarrhea cannot be abolished by
    eliminating a food. Fluid loss begins in fetal life, producing dilated fetal
    bowel loops and marked polyhydramnios.
  role: central_effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Colonic epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  biological_processes:
  - preferred_term: Intestinal chloride absorption
    term:
      id: GO:1902476
      label: chloride transmembrane transport
    modifier: DECREASED
  - preferred_term: Intestinal water absorption
    term:
      id: GO:0006833
      label: water transport
    modifier: ABNORMAL
  locations:
  - preferred_term: Ileum
    term:
      id: UBERON:0002116
      label: ileum
  evidence:
  - reference: PMID:24350656
    reference_title: "Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It results from a reduced activity of the down regulated in adenoma
      exchanger (DRA), due to mutations in the solute carrier family 26, member 3
      (SLC26A3) gene.
    explanation: >-
      Links reduced DRA exchanger activity to the intestinal chloride
      malabsorption that defines this node.
  - reference: PMID:35127600
    reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main feature of this condition is a severe chronic osmotic diarrhea
      that causes a secondary volume contraction
    explanation: >-
      Describes the luminal osmotic consequence of the transport failure and the
      volume contraction it produces.
  - reference: PMID:34988036
    reference_title: "Prenatal and Postnatal Manifestations of Congenital Chloride Diarrhea Due to a Heterozygote Variant of the SLC26A3 Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As early as the prenatal period, importantly, signs similar to those seen
      in the setting of intestinal obstruction, such as dilated intestinal loops
      on ultrasound, may be apparent.
    explanation: >-
      Supports the claim that failure of intestinal fluid absorption begins in
      fetal life, producing dilated bowel loops that mimic obstruction - the
      reason affected neonates are sometimes taken to laparotomy before the
      diagnosis is made.
  downstream:
  - target: Chloride-Rich Watery Diarrhea and Its Consequences
    causal_link_type: DIRECT
- name: Systemic Electrolyte Depletion and Metabolic Alkalosis
  conforms_to: "electrolyte_transport_related_diarrhea#Ion-Specific Systemic Depletion and Acid-Base Derangement"
  description: >-
    The systemic arm, and the source of the disorder's diagnostic signature. Two
    processes combine. Stool loss of chloride, sodium and potassium depletes each
    ion, producing hypochloremia, hyponatremia and hypokalemia. Separately, DRA
    normally secretes bicarbonate into the lumen in exchange for the chloride it
    absorbs; when the exchanger fails, that bicarbonate is retained in the body.
    Retained bicarbonate plus chloride depletion plus volume-contraction-driven
    secondary hyperaldosteronism produce a hypochloremic, hypokalemic metabolic
    ALKALOSIS. This is the mirror image of congenital sodium diarrhea, in which
    failure of sodium/proton exchange causes metabolic ACIDOSIS, and the acid-base
    direction is what distinguishes the two at the bedside.
  role: effector
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: Bicarbonate secretion into the intestinal lumen
    term:
      id: GO:0015701
      label: bicarbonate transport
    modifier: DECREASED
  evidence:
  - reference: PMID:35127600
    reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe chronic osmotic diarrhea that causes a secondary volume contraction
      with the development of metabolic alkalosis, electrolytes imbalance,
      failure to thrive, psycho-motor delay and even death
    explanation: >-
      Names the full systemic consequence set of this node - metabolic alkalosis,
      electrolyte imbalance, failure to thrive, psychomotor delay and mortality -
      and attributes it to volume contraction from the diarrhea.
  downstream:
  - target: Chloride-Rich Watery Diarrhea and Its Consequences
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Chloride-Rich Watery Diarrhea and Its Consequences
  conforms_to: "electrolyte_transport_related_diarrhea#Electrolyte Crisis, Growth Failure and Long-Term Morbidity"
  description: >-
    The clinical output. Lifelong profuse watery diarrhea whose stool chloride
    concentration exceeds the sum of stool sodium and potassium - the finding that
    clinches the diagnosis. Untreated, volume contraction and electrolyte
    depletion cause failure to thrive, psychomotor delay, renal impairment from
    chronic hypovolemia and hypokalemia, and death. Treated with salt
    substitution, electrolytes normalise and survival and growth are good, but
    stool volume remains high, so quality of life is dominated by the number of
    daily evacuations and by fecal incontinence.
  role: consequence
  biological_scale: ORGANISM
  locations:
  - preferred_term: Colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:8896562
    reference_title: "Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea
      with a high chloride content.
    explanation: >-
      States the clinical output and the high stool chloride content that is the
      diagnostic hallmark of this node.
  - reference: PMID:35127600
    reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The quality of life in CLD patients is negatively influenced by the
      elevated number of evacuations a day and the fecal incontinence
    explanation: >-
      Documents the residual disease burden that persists on salt substitution,
      supporting the distinction between correcting electrolytes and reducing
      stool volume.
phenotypes:
- name: Chloride-Rich Watery Diarrhea
  category: Gastrointestinal
  description: >-
    Lifelong profuse watery diarrhea with a stool chloride concentration
    exceeding the sum of stool sodium and potassium. In the neonate the stool is
    so watery that it may be mistaken for urine, delaying recognition.
  phenotype_term:
    preferred_term: Chloride-rich watery diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  frequency: OBLIGATE
  evidence:
  - reference: PMID:8896562
    reference_title: "Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea
      with a high chloride content.
    explanation: >-
      Directly states the lifelong, high-chloride diarrhea that defines the
      disorder, supporting the OBLIGATE frequency band.
- name: Metabolic Alkalosis
  category: Metabolic
  description: >-
    Hypochloremic, hypokalemic metabolic alkalosis from stool chloride loss,
    retained bicarbonate and volume-contraction-driven secondary
    hyperaldosteronism. The alkalotic direction distinguishes CLD from congenital
    sodium diarrhea, which causes metabolic acidosis.
  phenotype_term:
    preferred_term: Metabolic alkalosis
    term:
      id: HP:0200114
      label: Metabolic alkalosis
  evidence:
  - reference: PMID:35127600
    reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      secondary volume contraction with the development of metabolic alkalosis,
      electrolytes imbalance, failure to thrive
    explanation: >-
      Documents metabolic alkalosis as a characteristic consequence of the volume
      contraction in this disorder.
- name: Hypochloremia
  category: Metabolic
  description: >-
    Low serum chloride from continuous fecal chloride loss; corrected by oral
    chloride salt substitution.
  phenotype_term:
    preferred_term: Hypochloremia
    term:
      id: HP:0003113
      label: Hypochloremia
  evidence:
  - reference: PMID:24350656
    reference_title: "Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      life-long, severe diarrhea with intestinal Cl- malabsorption
    explanation: >-
      Establishes the continuous intestinal chloride malabsorption that depletes
      body chloride stores and produces hypochloremia.
- name: Hypokalemia
  category: Metabolic
  description: >-
    Low serum potassium from fecal potassium loss compounded by secondary
    hyperaldosteronism; contributes to the metabolic alkalosis and, if chronic,
    to renal impairment.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:29654747
    reference_title: "Advances in Evaluation of Chronic Diarrhea in Infants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      severe diarrhea at birth with concomitant hypochloremic hypokalemic
      metabolic alkalosis
    explanation: >-
      Names hypokalemia directly as part of the characteristic biochemical triad
      of congenital chloride diarrhea. Evidence source is OTHER because this is a
      review.
- name: Polyhydramnios
  category: Prenatal
  description: >-
    Marked polyhydramnios with dilated fetal bowel loops, caused by failure of
    fetal intestinal fluid absorption. It is often the first sign of the disorder
    and is frequently associated with premature birth.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  frequency: FREQUENT
  evidence:
  - reference: PMID:34988036
    reference_title: "Prenatal and Postnatal Manifestations of Congenital Chloride Diarrhea Due to a Heterozygote Variant of the SLC26A3 Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the prenatal period, the symptoms of CCD may include polyhydramnios,
      preterm labor and abdominal distension.
    explanation: >-
      States the prenatal manifestations of this node - polyhydramnios, preterm
      labor and abdominal distension - establishing that disease begins in fetal
      life.
  - reference: PMID:34988036
    reference_title: "Prenatal and Postnatal Manifestations of Congenital Chloride Diarrhea Due to a Heterozygote Variant of the SLC26A3 Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Polyhydramnios, manifesting due to intrauterine watery diarrhea, as well as
      pre-term birth, may also be common
    explanation: >-
      Gives the mechanism (intrauterine watery diarrhea) and the qualifier
      "common", which supports the FREQUENT band; the hedged "may also be" is
      why a higher band is not asserted.
- name: Failure to Thrive
  category: Growth
  description: >-
    Growth failure from chronic volume and electrolyte depletion in untreated or
    inadequately substituted patients; growth is generally good once salt
    substitution is established.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35127600
    reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      metabolic alkalosis, electrolytes imbalance, failure to thrive, psycho-motor
      delay and even death
    explanation: >-
      Lists failure to thrive among the consequences of the untreated disorder.
diagnosis:
- name: Stool electrolyte measurement
  description: >-
    Measurement of fecal chloride, sodium and potassium is the decisive test: a
    stool chloride concentration exceeding the sum of stool sodium and potassium
    establishes the diagnosis. It should be interpreted alongside serum
    electrolytes and blood gas, which show the characteristic hypochloremic
    hypokalemic metabolic alkalosis.
  evidence:
  - reference: PMID:35127600
    reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sure diagnosis of CLD was based on the results of full anamnestic,
      clinical and laboratory evaluation (including the evaluation of fecal Na+,
      Cl-, and K+), and the result of the molecular analysis.
    explanation: >-
      States the diagnostic algorithm used at an international reference centre:
      fecal electrolyte evaluation together with molecular analysis.
- name: SLC26A3 sequencing
  description: >-
    Molecular confirmation by SLC26A3 sequencing. Genotype is clinically useful
    beyond confirmation, because response to butyrate therapy is
    genotype-dependent.
  evidence:
  - reference: PMID:24350656
    reference_title: "Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate a genotype-dependency for butyrate therapeutic efficacy in
      CLD.
    explanation: >-
      Supports genotyping as therapeutically informative, not merely
      confirmatory.
treatments:
- name: Oral Salt Substitution
  description: >-
    Lifelong oral sodium chloride and potassium chloride substitution is the
    life-saving mainstay of treatment. It replaces the ions lost in stool,
    restoring electrolyte balance and preventing metabolic alkalosis, and it
    transforms the prognosis of a disorder that is otherwise fatal. Its
    limitation is precise and important: it corrects the systemic consequences
    without acting on the intestinal transport defect, so stool volume is
    unchanged and the daily burden of diarrhea persists.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Systemic Electrolyte Depletion and Metabolic Alkalosis
    treatment_effect: INHIBITS
    description: >-
      Replacing chloride, sodium and potassium orally offsets fecal losses and
      prevents the electrolyte depletion and alkalosis, acting on the systemic
      arm only and leaving the luminal transport defect untouched.
    evidence:
    - reference: PMID:35127600
      reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Oral salt substitutive therapy is a life-saving therapy: it improves the
        outcome, leads to electrolytes balance, reduces the risk of developing
        metabolic alkalosis, but has no effect on symptoms' severity
      explanation: >-
        States exactly the scope and the limit of this treatment: life-saving and
        electrolyte-normalising, but without effect on diarrhea severity - which
        is why it is modelled as acting on the systemic node rather than the
        central effector.
- name: Oral Sodium Butyrate
  description: >-
    Oral sodium butyrate is the only therapy that reduces diarrhea severity
    itself. It acts by two routes: a DRA-independent route in which butyrate
    uptake stimulates the alternative anion exchanger PAT-1 and the sodium/proton
    exchangers NHE2 and NHE3 while inhibiting NKCC1, and a DRA-dependent route in
    which it increases SLC26A3 transcription and translation and reduces DRA
    mistrafficking and misfolding. Efficacy is genotype-dependent, best in
    patients with missense and deletion variants - consistent with rescue of
    residual protein - and some patients experience worsening at the standard
    100 mg/kg/day dose. In those patients a step-up schedule from 50 mg/kg/day
    with weekly 25 mg/kg/day increments has restored responsiveness.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: butyrate
      term:
        id: CHEBI:17968
        label: butyrate
  target_mechanisms:
  - target: Loss of Apical DRA Chloride/Bicarbonate Exchange
    treatment_effect: ACTIVATES
    description: >-
      Butyrate increases SLC26A3 expression and reduces DRA mistrafficking and
      misfolding, partially restoring the failed apical exchange step, and in
      parallel stimulates alternative chloride-absorbing transporters.
    evidence:
    - reference: PMID:24350656
      reference_title: "Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The effect of butyrate is related in part on a different modulation of
        the expression of the two main apical membrane Cl- exchangers of
        epithelial cells, members of the SLC26 anion family.
      explanation: >-
        Attributes butyrate's effect to modulation of the two apical SLC26
        chloride exchangers, supporting action on the trigger node.
    - reference: PMID:24350656
      reference_title: "Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The best response was observed in subjects with missense and deletion
        mutations.
      explanation: >-
        Documents the genotype dependence of the response, consistent with rescue
        of residual mutant protein rather than replacement of an absent one.
  - target: Chloride-Rich Watery Diarrhea and Its Consequences
    treatment_effect: INHIBITS
    description: >-
      Clinically, butyrate reduces diarrhea severity, the effect that
      distinguishes it from salt substitution.
    evidence:
    - reference: PMID:35127600
      reference_title: "Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The step-up therapeutic approach resulted effective in limiting diarrhea
        severity in all our three previously unresponsive CLD patients.
      explanation: >-
        Reports reduction in diarrhea severity with the step-up butyrate
        schedule in patients previously unresponsive to standard dosing.
clinical_trials:
- name: ACTRN12613000450718
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Single-group open-label interventional study of oral sodium butyrate
    (100 mg/kg/day) in seven children with congenital chloride diarrhea of
    differing SLC26A3 genotypes, assessing stool pattern, fecal ion loss and
    chloride-transporter expression. Registered with ANZCTR and reported in
    PMID:24350656.
  target_phenotypes:
  - preferred_term: Chloride-rich watery diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: ICTRP:ACTRN12613000450718
    reference_title: "Butyrate as therapy for congenital chloride diarrhea"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Register | ANZCTR |"
    explanation: >-
      WHO ICTRP registration record establishing the trial's identity and
      primary registry. The trial has no ClinicalTrials.gov NCT identifier, so
      it is keyed on its ANZCTR/ICTRP identifier.
  - reference: ICTRP:ACTRN12613000450718
    reference_title: "Butyrate as therapy for congenital chloride diarrhea"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Recruitment status | Completed |"
    explanation: >-
      Registry record of the recruitment status supporting the COMPLETED value.
notes: >-
  CLD is the prototype of the electrolyte-transport-related class of congenital
  diarrheas and enteropathies. It deliberately does NOT conform to the
  diet_induced_osmotic_diarrhea module. Although the retained luminal chloride is
  osmotically active and older literature calls the diarrhea "osmotic", the
  module models substrate-specific failure to handle an ingested NUTRIENT, whose
  defining feature is remission on dietary elimination of that nutrient; here the
  failed step handles an ion, the diarrhea is independent of feeding, and no
  dietary elimination abolishes it. The current CODE nosology (PMID:29654747)
  separates these two classes for exactly this reason and gives congenital
  chloride diarrhea as its example of the electrolyte-transport class. Note that
  the same source also cautions that the older "secretory" label is imprecise
  here, since the primary lesion is loss of chloride ABSORPTION rather than
  active anion secretion - which is why the MONDO label "congenital secretory
  chloride diarrhoea 1" is retained as the disease_term but the entry text
  describes the mechanism as absorptive failure. The mirror-image disorder is
  congenital sodium diarrhea (SLC9A3/GUCY2C), where loss of sodium/proton
  exchange produces metabolic acidosis instead of alkalosis. Both are curated as
  conformers of the electrolyte_transport_related_diarrhea module, which factors
  out the shared chain and treats the opposite acid-base directions as a
  predicted consequence of which transporter's coupling partner is lost.

Congenital Chloride Diarrhea

Ask OpenScientist

OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Clinical Trials

Source YAML