In a recent significant achievement, a five-year-old boy suffering from an ultra-rare genetic disorder has been successfully treated with a targeted therapy at Madhukar Rainbow Children’s Hospital in Delhi. The boy diagnosed with CHAPLE syndrome had severe protein loss through the intestine, leading to persistent diarrhea, abdominal symptoms, swelling, recurrent infections, nutritional deficiencies, and dangerously low blood protein levels.
In conversation with THE WEEK, Dr Rohan Grotra, Consultant - Pediatric Gastroenterology and Hepatology at Madhukar Rainbow Children’s Hospital, spoke about the extremely rare disorder and the challenges involved in detecting it.
Interview excerpts:
1. What is CHAPLE syndrome?
CHAPLE syndrome, short for CD55 deficiency with hyperactivation of complement, angiopathic thrombosis and proteinlosing enteropathy- is an inherited disorder in whch an abnormal activation of the body's complemet immune system causes damage to the intestional and lymphatic systems.
2. Why do some patients present with severe, life-threatening protein-losing enteropathy and thrombosis early in childhood, while others experience a milder course?
It depends on the severity of mutations. Certain mutations cause severe deficiencynif enzymes which causes a serious clinical course duting early childhood, while mutational variants with mild deficiency have a milder course which manifests later.
2. How rare is CHAPLE syndrome, and how many known cases were reported in India?
CHAPLE syndrome is an exceptionally rare genetic disorder, with fewer than 100 patients estimated to have been diagnosed worldwide. The draft does not provide a confirmed number of reported cases in India.
3. What makes this disorder so challenging to manage? Having treated a case previously, could you briefly explain the main difficulties you faced during diagnosis and treatment?
CHAPLE syndrome is particularly challenging to manage because it can initially resemble other causes of intestinal protein loss. In the reported case, the child had severe and persistent protein-losing enteropathy, with significant loss of essential proteins and immunoglobulins. Despite conventional supportive treatment, the underlying disease continued to pose a major clinical challenge.
Detailed evaluation, including genetic testing, was essential to identify the disease-causing abnormality in the CD55 gene and confirm the diagnosis. Traditionally, treatment has focused on managing the consequences of protein loss through albumin and immunoglobulin replacement, nutritional support, infection management and control of gastrointestinal symptoms. The availability of targeted complement inhibition offers an opportunity to address the underlying disease mechanism rather than relying solely on supportive care.
4. How did this current case differ from your first? Were the challenges similar, or did unique complications arise?
Current case was similar to presentation to the 1st one, however, this time we were aware of the clinical course and availability of targetted therapy. We stopped the unecessary drugs and quickly procured the targetted therapy from USA.
5. Given how rare CHAPLE syndrome is, what common conditions is it most frequently misdiagnosed as?
CHAPLE syndrome may initially be mistaken for more common causes of protein-losing enteropathy because of the similarity in clinical presentation. However, the draft does not identify specific conditions that it is most frequently misdiagnosed as.
6. What specific clinical triggers or lab results should prompt a gastroenterologist or immunologist to order genetic testing for CD55 deficiency?
Genetic testing should be considered in children with unexplained or refractory protein-losing enteropathy, particularly when accompanied by persistent hypoalbuminaemia, gastrointestinal symptoms, oedema, growth failure or hypogammaglobulinaemia. These findings should raise suspicion of an underlying rare genetic or immune-mediated disorder.
In the reported case, detailed genetic evaluation identified a disease-causing abnormality in the CD55 gene, confirming CHAPLE syndrome. The draft does not specify additional laboratory thresholds or individual test results that should be used to determine when genetic testing is indicated.
7. How successful is the treatment, and what is life like in the long term for those receiving it?
In the reported case, treatment with pozelimab produced a marked clinical and biochemical response, including improvement in protein levels and the manifestations of protein-losing enteropathy. This response enabled the treating team to move away from repeated supportive replacement therapies towards disease-specific treatment.
Pozelimab works by blocking the terminal complement protein C5, thereby suppressing the uncontrolled complement activation responsible for much of the disease process. Published clinical experience has also demonstrated substantial improvement in symptoms and quality of life among children with CHAPLE syndrome following treatment.
