Congenital sodium diarrhea (CSD) is a rare congenital diarrhea and enteropathy (CODE) defined by perinatal-onset watery diarrhea with disproportionately high fecal sodium loss, hyponatremia and metabolic ACIDOSIS. With congenital chloride diarrhea it forms the electrolyte-transport-related class of the CODEs - disorders in which the failed apical transport step handles an ion rather than an ingested nutrient, so the diarrhea is independent of feeding and cannot be treated by eliminating any dietary constituent. CSD is genetically heterogeneous but mechanistically convergent. Classic (non-syndromic) CSD is caused by recessive loss-of-function variants in SLC9A3, encoding NHE3, the major sodium/proton exchanger of the intestinal brush border. A second non-syndromic form is caused by dominant ACTIVATING variants in GUCY2C, encoding guanylate cyclase C: excess cyclic GMP both drives CFTR-mediated chloride and water secretion and inhibits NHE3, which is itself a downstream target of GC-C - so the gain-of-function and loss-of-function routes converge on the same failure of NHE3-mediated sodium absorption. A syndromic form is caused by recessive loss-of-function variants in SPINT2, encoding a Kunitz-type serine protease inhibitor, and is distinguished by choanal or anal atresia, hypertelorism and corneal erosions. CSD is the acid-base mirror image of congenital chloride diarrhea: losing the sodium/proton exchanger means protons are retained rather than secreted, giving acidosis where loss of the chloride/bicarbonate exchanger gives alkalosis. Mortality is high in the first years from electrolyte imbalance and the complications of parenteral nutrition, but survivors can adapt to partial or complete enteral nutrition - a natural history distinctly better than that of the structural enteropathies.
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name: Congenital Sodium Diarrhea
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
synonyms:
- CSD
- congenital secretory sodium diarrhea
- diarrhea 8, secretory sodium, congenital
- familial GUCY2C diarrhea syndrome
description: >-
Congenital sodium diarrhea (CSD) is a rare congenital diarrhea and enteropathy
(CODE) defined by perinatal-onset watery diarrhea with disproportionately high
fecal sodium loss, hyponatremia and metabolic ACIDOSIS. With congenital
chloride diarrhea it forms the electrolyte-transport-related class of the CODEs
- disorders in which the failed apical transport step handles an ion rather
than an ingested nutrient, so the diarrhea is independent of feeding and cannot
be treated by eliminating any dietary constituent. CSD is genetically
heterogeneous but mechanistically convergent. Classic (non-syndromic) CSD is
caused by recessive loss-of-function variants in SLC9A3, encoding NHE3, the
major sodium/proton exchanger of the intestinal brush border. A second
non-syndromic form is caused by dominant ACTIVATING variants in GUCY2C,
encoding guanylate cyclase C: excess cyclic GMP both drives CFTR-mediated
chloride and water secretion and inhibits NHE3, which is itself a downstream
target of GC-C - so the gain-of-function and loss-of-function routes converge
on the same failure of NHE3-mediated sodium absorption. A syndromic form is
caused by recessive loss-of-function variants in SPINT2, encoding a Kunitz-type
serine protease inhibitor, and is distinguished by choanal or anal atresia,
hypertelorism and corneal erosions. CSD is the acid-base mirror image of
congenital chloride diarrhea: losing the sodium/proton exchanger means protons
are retained rather than secreted, giving acidosis where loss of the
chloride/bicarbonate exchanger gives alkalosis. Mortality is high in the first
years from electrolyte imbalance and the complications of parenteral nutrition,
but survivors can adapt to partial or complete enteral nutrition - a natural
history distinctly better than that of the structural enteropathies.
disease_term:
preferred_term: congenital sodium diarrhea
term:
id: MONDO:0015170
label: congenital sodium diarrhea
inheritance:
- name: Autosomal recessive inheritance
description: >-
Classic (SLC9A3) and syndromic (SPINT2) CSD are autosomal recessive.
Consanguinity is common in reported kindreds; the original Austrian cohort
traced five affected infants in a circumscribed rural area to a single common
ancestor five generations back.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pedigree analysis of the affected 2 CSD families revealed parental
consanguinity and a common single ancestor 5 generations ago.
explanation: >-
Pedigree evidence for recessive inheritance with a founder effect in a
geographically circumscribed population.
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Autosomal-recessive congenital sodium diarrhea (CSD) is characterized by
perinatal onset of a persistent watery diarrhea with nonproportionally high
fecal sodium excretion.
explanation: >-
States the recessive inheritance and the defining clinical and biochemical
features of the disorder.
- name: Autosomal dominant inheritance
description: >-
The GUCY2C-associated form is autosomal dominant and results from activating
(gain-of-function) rather than loss-of-function variants, so it does not
follow the recessive pattern of the other two forms. It was delineated in a
32-member Norwegian family. Applies to the GUCY2C-activating subtype only.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:22436048
reference_title: "Familial diarrhea syndrome caused by an activating GUCY2C mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Familial diarrhea disorders are, in most cases, severe and caused by
recessive mutations. We describe the cause of a novel dominant disease in
32 members of a Norwegian family.
explanation: >-
Establishes the dominant inheritance of the GUCY2C form and explicitly
contrasts it with the recessive majority of familial diarrheas.
genetic:
- name: SLC9A3 loss-of-function variants
gene_term:
preferred_term: SLC9A3
term:
id: hgnc:11073
label: SLC9A3
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: Classic non-syndromic CSD
features: >-
Recessive missense, splicing, truncating and whole-gene-deletion variants in
SLC9A3 (including one instance of uniparental disomy) cause classic
non-syndromic CSD. All reported variants lie in the NHE3 N-terminal transport
domain and all missense variants fall in putative membrane-spanning domains.
Functional testing in NHE-null fibroblasts showed reduced basal surface
expression and/or loss of basal transport function, with acute regulation
preserved - so the defect is in constitutive NHE3 activity rather than in its
regulation.
evidence:
- reference: PMID:26358773
reference_title: "Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SLC9A3 missense, splicing and truncation mutations, including an instance
of uniparental disomy, and whole-gene deletion were identified in nine
patients from eight families with CSD.
explanation: >-
The gene-discovery report identifying SLC9A3 as a cause of CSD and
describing the variant spectrum.
- reference: PMID:26358773
reference_title: "Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SLC9A3 missense mutations compromised NHE3 activity by reducing basal
surface expression and/or loss of basal transport function of NHE3
molecules, whereas acute regulation was normal.
explanation: >-
Functional characterization localizing the defect to constitutive NHE3
surface expression and transport rather than to acute regulation. Evidence
source is IN_VITRO because activity was assayed in NHE-null fibroblasts.
- name: GUCY2C activating variants
gene_term:
preferred_term: GUCY2C
term:
id: hgnc:4688
label: GUCY2C
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: GUCY2C-activating form
features: >-
A heterozygous missense variant (c.2519G>T) in GUCY2C, encoding guanylate
cyclase C, causes a dominant familial diarrhea syndrome that presents as
non-syndromic CSD. The variant is activating, not inactivating: ligand
exposure produces markedly increased cyclic GMP. Affected individuals have
increased susceptibility to inflammatory bowel disease, small-bowel
obstruction and esophagitis, an inflammatory dimension absent from the other
forms.
evidence:
- reference: PMID:22436048
reference_title: "Familial diarrhea syndrome caused by an activating GUCY2C mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a heterozygous missense mutation (c.2519GāT) in GUCY2C in all
affected family members and observed no other rare variants in the exons of
genes in the candidate region.
explanation: >-
Identifies the causative heterozygous GUCY2C variant and its segregation
with disease.
- reference: PMID:22436048
reference_title: "Familial diarrhea syndrome caused by an activating GUCY2C mutation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Exposure of the mutant receptor to its ligands resulted in markedly
increased production of cyclic guanosine monophosphate (cGMP).
explanation: >-
Demonstrates that the variant is activating, the point that distinguishes
this form mechanistically from the loss-of-function forms. Evidence source
is IN_VITRO because cGMP production was measured in transfected HEK293T
cells.
- name: SPINT2 loss-of-function variants
gene_term:
preferred_term: SPINT2
term:
id: hgnc:11247
label: SPINT2
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: Syndromic CSD
features: >-
Homozygous or compound heterozygous SPINT2 variants, encoding a Kunitz-type
serine protease inhibitor, cause the syndromic form. Reported alleles include
a recurrent c.593-1G>A splice variant plus p.Y163C, c.1A>T, c.337+2T>C and
c.553+2T>A. They act by loss of protein synthesis or by failure to inhibit
the serine protease trypsin, so the proposed mechanism is excess serine
protease activity in affected tissues. Genotype-phenotype separation is
clean: SPINT2 variants were found in all syndromic patients and in none of
the classic-CSD patients. SPINT2 variants also cause a syndromic form of
congenital tufting enteropathy, so the same gene reaches two CODE classes.
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The same mutation and four distinct, homozygous or compound heterozygous
mutations (p.Y163C, c.1A-->T, c.337+2T-->C, c.553+2T-->A) were identified
in all syndromic patients. No SPINT2 mutations were found in
classic-CSD patients.
explanation: >-
Establishes SPINT2 as the syndromic-form gene and documents the clean
genotype-phenotype separation from classic CSD.
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SPINT2 mutations were associated with loss of protein synthesis or failure
to inhibit the serine protease trypsin in vitro.
explanation: >-
Characterizes the two molecular consequences of the SPINT2 variants,
supporting the excess-protease mechanism proposed for this form.
pathophysiology:
- name: Constitutive Guanylate Cyclase C Activation
description: >-
The upstream lesion of the GUCY2C arm only. A dominant activating variant in
guanylate cyclase C raises cyclic GMP on ligand exposure. Excess cGMP acts in
two directions: it hyperactivates CFTR, driving chloride and water secretion,
and it inhibits NHE3, which is itself a downstream target of GC-C. This node
is therefore placed upstream of the NHE3 lesion rather than beside it - the
two are sequential in the GUCY2C arm, not alternative entry points at the
same level. Conformers entering through SLC9A3 do not pass through this node.
role: trigger
biological_scale: MOLECULAR
cell_types:
- preferred_term: Small-intestinal enterocyte
term:
id: CL:0000584
label: enterocyte
molecular_functions:
- preferred_term: Guanylate cyclase C activity
term:
id: GO:0004383
label: guanylate cyclase activity
modifier: GAIN_OF_FUNCTION
biological_processes:
- preferred_term: Cyclic GMP production
term:
id: GO:0006182
label: cGMP biosynthetic process
modifier: INCREASED
locations:
- preferred_term: Small intestine
term:
id: UBERON:0002108
label: small intestine
evidence:
- reference: PMID:22436048
reference_title: "Familial diarrhea syndrome caused by an activating GUCY2C mutation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Exposure of the mutant receptor to its ligands resulted in markedly
increased production of cyclic guanosine monophosphate (cGMP).
explanation: >-
Demonstrates the gain-of-function that defines this node - markedly
increased cGMP from the mutant receptor. Evidence source is IN_VITRO
because cGMP was measured in transfected HEK293T cells.
- reference: PMID:22436048
reference_title: "Familial diarrhea syndrome caused by an activating GUCY2C mutation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This may cause hyperactivation of the cystic fibrosis transmembrane
regulator (CFTR), leading to increased chloride and water secretion from
the enterocytes, and may thus explain the chronic diarrhea in the affected
family members.
explanation: >-
Gives the parallel secretory arm of this node. The authors hedge it as a
proposed explanation, which is why the edge leaving this node is typed as
having known intermediates rather than as direct.
downstream:
- target: Loss of NHE3-Mediated Apical Sodium/Proton Exchange
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Loss of NHE3-Mediated Apical Sodium/Proton Exchange
conforms_to: "electrolyte_transport_related_diarrhea#Loss of an Apical Intestinal Electrolyte Transport Step"
description: >-
The convergence point of every genetic form, and the node that carries the
transport lesion itself. NHE3 is the major sodium/proton exchanger of the
intestinal brush border. It is lost by two distinct routes that meet here
rather than being alternatives at the same level: in classic CSD, recessive
SLC9A3 variants directly reduce its surface expression or transport function
while leaving acute regulation intact; in the GUCY2C form, excess cyclic GMP
from the upstream activating variant inhibits it, NHE3 being a downstream
target of GC-C. The syndromic SPINT2 form is proposed to act through excess
serine protease activity in the affected epithelium, a route that is less
well resolved at the transport level and is not modelled as a separate node
here.
role: trigger
biological_scale: MOLECULAR
cell_types:
- preferred_term: Small-intestinal enterocyte
term:
id: CL:0000584
label: enterocyte
molecular_functions:
- preferred_term: Brush-border sodium/proton exchange (NHE3)
term:
id: GO:0015385
label: sodium:proton antiporter activity
modifier: LOSS_OF_FUNCTION
cellular_components:
- preferred_term: Enterocyte brush border
term:
id: GO:0005903
label: brush border
locations:
- preferred_term: Small intestine
term:
id: UBERON:0002108
label: small intestine
evidence:
- reference: PMID:26358773
reference_title: "Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major
intestinal brush-border Na(+)/H(+) exchanger.
explanation: >-
Identifies the transporter whose loss defines the classic arm of this
trigger and establishes it as the major brush-border sodium/proton
exchanger.
- reference: PMID:26358773
reference_title: "Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study identifies recessive mutations in NHE3, a downstream target of
GC-C, as a cause of CSD
explanation: >-
States the relationship that makes this a single convergent node rather
than two unrelated mechanisms: NHE3 is a downstream target of guanylate
cyclase C, so activating GC-C and inactivating NHE3 act on the same axis.
downstream:
- target: Failure of Net Intestinal Sodium Absorption
causal_link_type: DIRECT
- name: Failure of Net Intestinal Sodium Absorption
conforms_to: "electrolyte_transport_related_diarrhea#Luminal Electrolyte Retention and Failure of Net Ion Absorption"
description: >-
The rate-limiting step. NHE3-mediated electroneutral sodium absorption is the
principal route by which the small intestine and colon reclaim luminal
sodium, and it is the driving force for the water absorption that follows it.
When that step fails - whether the exchanger is absent, non-functional, or
inhibited by excess cGMP - sodium is retained in the lumen at concentrations
far above what the remaining absorptive routes can clear, and in the GUCY2C
form active chloride secretion adds to the luminal ion load. This is the
disorder-agnostic convergence point of all three genetic forms and the reason
fecal sodium is disproportionately high, which is the diagnostic signature.
role: central_effector
biological_scale: TISSUE
cell_types:
- preferred_term: Small-intestinal enterocyte
term:
id: CL:0000584
label: enterocyte
biological_processes:
- preferred_term: Intestinal sodium absorption
term:
id: GO:0035725
label: sodium ion transmembrane transport
modifier: DECREASED
- preferred_term: Intestinal absorption
term:
id: GO:0050892
label: intestinal absorption
modifier: DECREASED
locations:
- preferred_term: Intestine
term:
id: UBERON:0000160
label: intestine
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Defective jejunal brush-border Na(+)/H(+) exchange has been reported in
three sporadic patients
explanation: >-
Documents defective brush-border sodium/proton exchange measured directly
in patient jejunum, the functional defect this node represents.
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Congenital sodium diarrhea (CSD) is caused by defective sodium/proton
exchange
explanation: >-
States the transport lesion underlying the disorder. Note that this
paper's own negative conclusion - that CSD is unrelated to the known NHE
genes including NHE3 - was later overturned by PMID:26358773, which
identified recessive SLC9A3/NHE3 variants; only the sodium/proton-exchange
defect claim is cited here.
downstream:
- target: Luminal Sodium Retention and Obligated Water Loss
causal_link_type: DIRECT
- target: Systemic Sodium Depletion and Metabolic Acidosis
causal_link_type: DIRECT
- name: Luminal Sodium Retention and Obligated Water Loss
conforms_to: "electrolyte_transport_related_diarrhea#Obligated Water Loss and Feeding-Independent Watery Diarrhea"
description: >-
Sodium retained in the lumen is osmotically active and obligates water,
producing the high-volume watery stool. Because the retained solute is an ion
the body itself secretes and recycles rather than an ingested nutrient, stool
output does not fall when feeds are withheld and no dietary elimination
abolishes it - the practical feature that separates this class from the
diet-induced congenital diarrheas at the bedside. Diarrhea begins
perinatally and, as in congenital chloride diarrhea, intrauterine fluid loss
can present as polyhydramnios.
role: effector
biological_scale: TISSUE
biological_processes:
- preferred_term: Transepithelial water movement into the lumen
term:
id: GO:0006833
label: water transport
modifier: INCREASED
locations:
- preferred_term: Intestine
term:
id: UBERON:0000160
label: intestine
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
perinatal onset of a persistent watery diarrhea with nonproportionally high
fecal sodium excretion
explanation: >-
States the output of this node - persistent watery stool carrying
disproportionate sodium - and its perinatal onset.
downstream:
- target: Electrolyte Crisis, Growth Failure and Later Enteral Adaptation
causal_link_type: DIRECT
- name: Systemic Sodium Depletion and Metabolic Acidosis
conforms_to: "electrolyte_transport_related_diarrhea#Ion-Specific Systemic Depletion and Acid-Base Derangement"
description: >-
The systemic arm, and the acid-base mirror image of congenital chloride
diarrhea. NHE3 exports a proton into the lumen for every sodium it absorbs;
when the exchanger fails, that proton is retained in the body while sodium is
lost in stool. The result is hyponatremia with metabolic ACIDOSIS - the
opposite derangement to the hypochloremic metabolic ALKALOSIS produced when
the chloride/bicarbonate exchanger DRA fails in congenital chloride diarrhea.
Urinary sodium is low-to-normal, confirming that the loss is enteric rather
than renal, which is the discriminating measurement.
role: effector
biological_scale: ORGANISM
biological_processes:
- preferred_term: Systemic acid-base regulation
term:
id: GO:0006885
label: regulation of pH
modifier: ABNORMAL
evidence:
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of CSD in 4 of 5 patients was based on daily fecal sodium
excretion between 98 and 190 mmol/L, hyponatremia, metabolic acidosis, and
low-to-normal urinary sodium concentrations.
explanation: >-
Gives the complete biochemical signature of this node with quantitative
fecal sodium values, including the low-to-normal urinary sodium that
localizes the loss to the gut.
downstream:
- target: Electrolyte Crisis, Growth Failure and Later Enteral Adaptation
causal_link_type: DIRECT
- name: Electrolyte Crisis, Growth Failure and Later Enteral Adaptation
conforms_to: "electrolyte_transport_related_diarrhea#Electrolyte Crisis, Growth Failure and Long-Term Morbidity"
description: >-
The clinical output. Mortality risk is high in the first years of life, from
immediate electrolyte imbalance and from the complications of long-term
parenteral nutrition. The natural history then diverges from that of the
structural enteropathies in a clinically important way: survivors can
eventually adapt to partial or complete enteral nutrition, so parenteral
dependence is not necessarily lifelong and transplantation is not the
expected endpoint. Management is supportive - aggressive sodium and fluid
replacement with correction of acidosis - since no therapy addresses the
transport defect itself.
role: consequence
biological_scale: ORGANISM
locations:
- preferred_term: Intestine
term:
id: UBERON:0000160
label: intestine
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients from both groups have a high risk of mortality due to immediate
electrolyte imbalances and complications from long-term parenteral
nutrition in the first years of life, but survivors can eventually adapt to
partial or complete enteral nutrition.
explanation: >-
States both halves of this node: the early mortality risk and the enteral
adaptation achievable by survivors, which distinguishes the prognosis of
CSD from that of the enterocyte-structural enteropathies.
has_subtypes:
- name: Classic non-syndromic CSD
display_name: Classic (non-syndromic) congenital sodium diarrhea, SLC9A3-related
description: >-
Recessive SLC9A3/NHE3 loss of function. Isolated intestinal disease with no
atresias or facial features. Presented in seven families in the cohort that
delineated the syndromic/classic split.
- name: Syndromic CSD
display_name: Syndromic congenital sodium diarrhea, SPINT2-related
description: >-
Recessive SPINT2 loss of function. Intestinal disease plus choanal or anal
atresia, hypertelorism and corneal erosions. Occurred in ten families in the
delineating cohort. SPINT2 also causes a syndromic form of congenital
tufting enteropathy.
- name: GUCY2C-activating form
display_name: Familial GUCY2C diarrhea syndrome (dominant, activating)
description: >-
Dominant activating GUCY2C variant raising cyclic GMP. Milder, early-onset
chronic diarrhea with increased susceptibility to inflammatory bowel disease,
small-bowel obstruction and esophagitis. Paradoxically associated with
prolonged rather than accelerated gut transit.
genes:
- preferred_term: GUCY2C
term:
id: hgnc:4688
label: GUCY2C
evidence:
- reference: PMID:28957388
reference_title: "Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Despite having diarrhea, the FGDS patients have prolonged transit time
through the gut compared to HC, particularly in colon.
explanation: >-
Supports the paradoxical motility phenotype asserted for this subtype -
diarrhea with prolonged rather than accelerated transit, most marked in
the colon - which distinguishes it from the other CSD forms.
phenotypes:
- name: Watery Diarrhea with High Fecal Sodium
category: Gastrointestinal
description: >-
Persistent watery diarrhea of perinatal onset carrying disproportionately
high fecal sodium - between 98 and 190 mmol/L in the original cohort. It does
not remit on withholding feeds.
phenotype_term:
preferred_term: Watery diarrhea with high fecal sodium
term:
id: HP:0002014
label: Diarrhea
temporality: CHRONIC
frequency: OBLIGATE
evidence:
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
daily fecal sodium excretion between 98 and 190 mmol/L
explanation: >-
Quantifies the fecal sodium loss that defines the disorder.
- name: Metabolic Acidosis
category: Metabolic
description: >-
Metabolic acidosis from retention of protons that NHE3 would normally export
into the lumen. This is the acid-base feature that distinguishes CSD from
congenital chloride diarrhea, which causes metabolic alkalosis.
phenotype_term:
preferred_term: Metabolic acidosis
term:
id: HP:0001942
label: Metabolic acidosis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hyponatremia, metabolic acidosis, and low-to-normal urinary sodium
concentrations
explanation: >-
Documents metabolic acidosis as part of the diagnostic biochemical triad.
The VERY_FREQUENT band is a derived count: 4 of 5 patients in the cohort,
i.e. 80%, the floor of the band. The cohort is a small sample of this
entry's own population rather than a broader or narrower entity, so the
band is scope-matched, but n=5 is thin and a larger series could move it.
- name: Hyponatremia
category: Metabolic
description: >-
Low serum sodium from continuous enteric sodium loss, with low-to-normal
urinary sodium confirming the loss is not renal.
phenotype_term:
preferred_term: Hyponatremia
term:
id: HP:0002902
label: Hyponatremia
frequency: VERY_FREQUENT
evidence:
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hyponatremia, metabolic acidosis, and low-to-normal urinary sodium
concentrations
explanation: >-
Documents hyponatremia with low-to-normal urinary sodium in the diagnostic
cohort. As for metabolic acidosis above, the VERY_FREQUENT band is the
derived 4-of-5 count from this cohort; hyponatremia is also named in the
disease definition, so the band is not resting on the count alone.
- name: Choanal Atresia
category: Craniofacial
description: >-
Choanal atresia occurs in the SPINT2-associated syndromic form and is one of
the features that separates it from classic CSD.
phenotype_term:
preferred_term: Choanal atresia
term:
id: HP:0000453
label: Choanal atresia
subtype: Syndromic CSD
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSD associated with choanal or anal atresia, hypertelorism, and corneal
erosions--i.e., a syndromic form of CSD
explanation: >-
Defines the syndromic form by this feature set, supporting the subtype
assignment.
- name: Anal Atresia
category: Gastrointestinal
description: >-
Anal atresia occurs as an alternative to choanal atresia in the syndromic
form.
phenotype_term:
preferred_term: Anal atresia
term:
id: HP:0002023
label: Anal atresia
subtype: Syndromic CSD
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSD associated with choanal or anal atresia, hypertelorism, and corneal
erosions--i.e., a syndromic form of CSD
explanation: >-
Names anal atresia among the defining features of the syndromic form.
- name: Hypertelorism
category: Craniofacial
description: >-
Increased interocular distance, part of the facial phenotype of the
SPINT2-associated syndromic form.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
subtype: Syndromic CSD
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSD associated with choanal or anal atresia, hypertelorism, and corneal
erosions--i.e., a syndromic form of CSD
explanation: >-
Names hypertelorism among the defining features of the syndromic form.
- name: Recurrent Corneal Erosions
category: Ophthalmological
description: >-
Corneal erosions in the syndromic form, overlapping the ophthalmological
phenotype seen in SPINT2-associated congenital tufting enteropathy.
phenotype_term:
preferred_term: Recurrent corneal erosions
term:
id: HP:0000495
label: Recurrent corneal erosions
subtype: Syndromic CSD
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSD associated with choanal or anal atresia, hypertelorism, and corneal
erosions--i.e., a syndromic form of CSD
explanation: >-
Names corneal erosions among the defining features of the syndromic form.
diagnosis:
- name: Fecal and urinary sodium measurement
description: >-
Measurement of fecal sodium with paired serum electrolytes, blood gas and
urinary sodium is the diagnostic core. The pattern is high fecal sodium with
hyponatremia, metabolic acidosis and low-to-normal urinary sodium; the last
of these localizes the loss to the gut rather than the kidney.
evidence:
- reference: PMID:11113072
reference_title: "Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of CSD in 4 of 5 patients was based on daily fecal sodium
excretion between 98 and 190 mmol/L, hyponatremia, metabolic acidosis, and
low-to-normal urinary sodium concentrations.
explanation: >-
States the diagnostic criteria actually used to establish CSD in a
published cohort.
- name: SLC9A3, GUCY2C and SPINT2 sequencing
description: >-
Molecular confirmation. The presence or absence of atresias, hypertelorism
and corneal erosions directs testing: syndromic features point to SPINT2,
isolated intestinal disease to SLC9A3, and a dominant family history with
inflammatory complications to GUCY2C.
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No SPINT2 mutations were found in classic-CSD patients.
explanation: >-
Supports using the syndromic/classic clinical split to direct molecular
testing, since the genotype-phenotype separation is complete in the
delineating cohort.
treatments:
- name: Sodium and Fluid Replacement
description: >-
Supportive management is the only available treatment: aggressive replacement
of sodium and water with correction of the metabolic acidosis, delivered
parenterally in infancy. Nothing addresses the underlying transport defect.
Because survivors can adapt to partial or complete enteral nutrition, the
goal is to carry the child through the high-mortality early years rather than
to plan for lifelong parenteral support.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Nutritional Support
term:
id: NCIT:C15433
label: Nutritional Support
target_mechanisms:
- target: Systemic Sodium Depletion and Metabolic Acidosis
treatment_effect: INHIBITS
description: >-
Replacing sodium and water and correcting acidosis offsets the systemic
consequences of enteric loss. It acts only on the systemic arm and leaves
luminal sodium retention and stool volume unchanged.
evidence:
- reference: PMID:19185281
reference_title: "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients from both groups have a high risk of mortality due to immediate
electrolyte imbalances and complications from long-term parenteral
nutrition in the first years of life
explanation: >-
Establishes electrolyte imbalance as the immediate threat to life that
replacement therapy addresses, and records the competing risk from the
parenteral route itself.
notes: >-
CSD and congenital chloride diarrhea together form the
electrolyte-transport-related class of the congenital diarrheas and
enteropathies (PMID:29654747), and are curated as conformers of the
electrolyte_transport_related_diarrhea module. Neither conforms to
diet_induced_osmotic_diarrhea: the failed step handles an ion rather than an
ingested nutrient, the diarrhea persists during bowel rest, and no dietary
elimination abolishes it. The two are acid-base mirror images, which is the
most useful bedside discriminator - alkalosis in chloride diarrhea, acidosis
here.
Curation caution on PMID:11113072: that paper's title asserts CSD is unrelated
to the known sodium/proton exchanger genes, and it specifically excluded NHE3.
That negative conclusion was overturned in 2015 by PMID:26358773, which
identified recessive SLC9A3/NHE3 variants as a cause. The 2000 paper is cited
here only for its inheritance, phenotype and biochemistry findings, which
stand; it must not be cited for the claim that NHE3 is not involved.
The GUCY2C form is curated here as a subtype rather than a separate entry
because Janecke et al. classify it as a non-syndromic form of CSD, but it is
atypical on three counts - dominant rather than recessive, gain- rather than
loss-of-function, and accompanied by inflammatory bowel disease susceptibility.
A future split into its own entry (familial GUCY2C diarrhea syndrome) would be
defensible if its inflammatory arm is curated in depth.