Congenital chloride diarrhea (CCD, also congenital chloridorrhea or Darrow Gamble syndrome) is a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

due to an autosomal recessive mutation on

chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total D ...

. The mutation is in downregulated-in-adenoma (DRA), a gene that encodes a

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

of intestinal cells. The protein belongs to the solute carrier 26 family of

membrane transport protein A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembra ...

s. More than 20 mutations in the gene are known to date. A

rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discov ...

, CCD occurs in all parts of the world but is more common in some populations with genetic founder effects, most notably in

Finland Finland ( fi, Suomi ; sv, Finland ), officially the Republic of Finland (; ), is a Nordic country in Northern Europe. It shares land borders with Sweden to the northwest, Norway to the north, and Russia to the east, with the Gulf of B ...

Symptoms and signs

Chronic diarrhoea starting from early neonatal period. Failure to thrive is usually accompanying diarrhea.

Pathophysiology

CCD causes persistent secretory diarrhea. In a

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

, it leads to polyhydramnios and

premature birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...

. Immediately after birth, it leads to

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

, hypoelectrolytemia,

hyperbilirubinemia Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

abdominal distention Abdominal distension occurs when substances, such as air (gas) or fluid, accumulate in the abdomen causing its expansion. It is typically a symptom of an underlying disease or dysfunction in the body, rather than an illness in its own right. Pe ...

, and

failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

Diagnosis

CCD may be detectable on

prenatal ultrasound Obstetric ultrasonography, or prenatal ultrasound, is the use of medical ultrasonography in pregnancy, in which sound waves are used to create real-time visual images of the developing embryo or fetus in the uterus (womb). The procedure is a stan ...

. After birth, signs in affected babies typically are abdominal distension, visible peristalsis, and watery stools persistent from birth that show chloride loss of more than 90 mmol/L. An important feature in this

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

that helps in the diagnosis, is that it is the only type of diarrhea that causes

metabolic alkalosis Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct res ...

rather than

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...

Treatment

Available treatments address the symptoms of CCD, not the underlying defect. Early diagnosis and aggressive salt replacement therapy result in normal growth and development, and generally good outcomes. Replacement of

NaCl Sodium chloride , commonly known as salt (although sea salt also contains other chemical salts), is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. With molar masses of 22.99 and 35.45 g/ ...

and

KCl Potassium chloride (KCl, or potassium salt) is a metal halide Salt (chemistry), salt composed of potassium and chlorine. It is odorless and has a white or colorless vitreous lustre, vitreous crystal appearance. The solid dissolves readily in wa ...

has been shown to be effective in children.

History

Observations leading to the characterization of the SLC26 family were based on research on rare human diseases. Three rare recessive diseases in humans have been shown to be caused by genes of this family.

Diastrophic dysplasia Diastrophic dysplasia is an autosomal recessive dysplasia which affects cartilage and bone development. ("Diastrophism" is a general word referring to a twisting.) Diastrophic dysplasia is due to mutations in the ''SLC26A2'' gene. Affected indivi ...

, congenital chloride diarrhea, and

Pendred syndrome Pendred syndrome is a genetic disorder leading to congenital bilateral (both sides) sensorineural hearing loss and goitre with euthyroid or mild hypothyroidism (decreased thyroid gland function). There is no specific treatment, other than suppo ...

are caused by the highly related genes

SLC26A2 The sulfate transporter is a solute carrier family protein that in humans is encoded by the ''SLC26A2'' gene. SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A de ...

(first called DTDST), SLC26A3 (first called CLD or DRA), and

SLC26A4 Pendrin is an anion exchange protein that in humans is encoded by the ''SLC26A4'' gene (solute carrier family 26, member 4). Pendrin was initially identified as a sodium-independent chloride-iodide exchanger with subsequent studies showing that i ...

(first called PDS), respectively. Two of these diseases, diastrophic dysplasia and congenital chloride diarrhea, are

Finnish heritage disease A Finnish heritage disease is a genetic disease or disorder that is significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Sweden ( Meänmaa) and Russia ( Karelia and Ingria). There are 36 rare diseases regar ...

References

External links

{{Medical resources , ICD10 = P78.3 , ICD9 = , ICDO = , OMIM = 214700 , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = C536210 , GeneReviewsNBK = , GeneReviewsName = , Orphanet = 53689 Diarrhea Rare diseases