Syndromic diarrhea (ORPHA:84064)
A rare gastroenterologic disease manifesting as intractable diarrhea in the first month of life with failure to thrive and associated with facial dysmorphism, hair abnormalities, and, in some cases, immune disorders and intrauterine growth restriction.
Epidemiology
Syndromic diarrhea (SD/THE) prevalence is <1/1,000,000. More than 100 cases have been reported worldwide.
Clinical description
Severe, persistent and intractable diarrhea most often starts within the first month after birth (at latest 6 months) and is accompanied by severe malabsorption resulting in early and relentless protein-energy malnutrition and failure to thrive. SD children in most reported cases (>70%) were below the 10th percentile of birth weight and nearly half were born preterm suffering from intrauterine growth restriction. Patients present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hair is woolly, easily removable and in some cases sparse and poorly pigmented; further analysis reveals trichorrhexis nodosa, pili torti, trichothiodystrophy and aniso- and poikilotrichosis. Liver disease, with extensive fibrosis or cirrhosis and siderosis, affects about half of the patients, and hepatomegaly may be observed. Patients are prone to frequent infections and may fail to produce antibodies upon vaccination or present low immunoglobulin levels. Skin abnormalities including café au lait spots, xerosis and rubbery skin are seen in half of the reported cases and are more prevalent with time. Cardiac abnormalities have been reported in a few cases and mild intellectual deficiency in half of patients.
Etiology
Autosomal recessive mutations in SKIV2L (40% of cases) and TTC37 (60% of cases) lead to SD/THE. These genes encode proteins that form the Ski complex, a group of proteins responsible for the 3'-5' degradation of aberrant mRNA. Many different mutations have been identified and are spread along the genes. How Ski complex defects lead to the observed phenotype has yet to be elucidated and no genotype/phenotype correlation has been established to date.
Diagnostic methods
Diagnosis is suggested by clinical features. Small intestine biopsy shows non-specific villous atrophy with variable mononuclear cell infiltration of the lamina propria, but no specific histological abnormalities involving the epithelium. Genetic testing confirms these observations.
Differential diagnosis
Differential diagnoses include all causes of chronic diarrhea, copper and iron deficiencies due to malnutrition, intestinal epithelial dysplasia, and microvillus inclusion disease.
Antenatal diagnosis
Antenatal diagnosis should be offered to the parents of an affected child once the molecular defect has been characterized.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Intractable diarrhea requires parenteral nutrition during a variable period of time ranging from a few months to over a decade. In some cases, the association of enteral with parenteral nutrition can be indicated. Immunoglobulin supplementation may be necessary and antibody production after vaccination should be monitored. Finally, some children can present with a severe liver disease, independent of parenteral nutrition, but which could be worsened by it. In cases of severe liver disease, the only therapeutic option is a liver graft.
Prognosis
Prognosis is poor with a mortality rate of up to 50%. The main complications are severe liver disease and infections. Some patients are rapidly weaned off parenteral nutrition but others remain under parenteral dependence for more than 10 years. Most of the children achieve a small final stature and half manifest mild intellectual deficit.

                            Last update: 
                            November 2019


                            - Expert reviewer(s): 
                            Pr Catherine BADENS  - Dr Alexandre FABRE