Novel mutation causing congenital disorder of glycosylation in a child with recurrent anasarca

Discussion

Protein-losing enteropathy is a rare condition not frequently encountered in children. It is considered in an appropriate clinical setting when other causes of protein loss have been ruled out. Underlying aetiology can be broadly classified as primary and secondary. The syndromic association is frequently encountered because of the involvement of the lymphatic system. Secondary causes may have lymphatic duct involvement or loss or change of mucosal integrity because of underlying pathology.

Children with protein-losing enteropathy present with recurrent/chronic diarrhoea, bloating, abdominal pain, ascites, peripheral oedema and failure to thrive. In a study by Wen et al, the most common symptoms were oedema, diarrhoea, ascites and lymphoedema, present in 78%, 62%, 41% and 22%, respectively.1

Along with hypoalbuminaemia, there are hypogammaglobulinaemia and lymphopenia. This predisposes the child to frequent infections, few may also develop opportunistic infections. These patients have protein losses only through the gut, but there is no proteinuria.

Endoscopy findings may vary from diffuse white spots in the duodenum and jejunum to a few scattered spots in the small intestine. Xinias et al had demonstrated oedematous mucosa with exudate and white spots on the duodenal mucosa in 20-month-old and 26-month-old male children, respectively, which showed dilated lymphatics and malformation of intestinal villi seen on biopsy.2

Our patient presented below 1 year of age with atypical episodes of periorbital and pedal oedema, a few of them progressing to anasarca. She never developed ascites nor had recurrent episodes of diarrhoea as seen in protein-losing enteropathy. There was no lymphopenia, hypogammaglobulinaemia or any recurrent episodes of infection. Endoscopy and biopsy showed subtle but inconclusive findings for protein-losing enteropathy. Her proteinuria was also unexplained. Because of these multisystemic inconclusive manifestations, gene sequencing (whole-exome sequencing) was done.

She had a compound heterozygous mutation in the ALG gene (ALG8 chr11:77 825 314G>A; ALG8 chr11:77835081_77835082insACAAAGAGT) suggesting the diagnosis of CDG. This mutation has not been reported earlier. Mutation in the PMM2 gene is the most common mutation of CDG reported.3

The first detected mutation was a heterozygous missense variant (c.671C>T) in exon 6 of the ALG8 gene that results in the amino acid substitution from proline to leucine at codon 224 (p.Pro224Leu) identified. There is a moderate physicochemical difference between proline and leucine. The observed variant is not present in both the 1000 genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging.

The second mutation was a heterozygous nine-base insertion in exon 3 of the ALG8 gene (c.345_353dupACTCTTTGT) that results in an in-frame insertion. This variant results in duplication of leucine at position 116 until valine at position 118 (p.L116_V118dup). The observed variant has a minor allele frequency of 0.0004% in the gnomAD database and is not reported in the 1000 genomes database. This variant is conserved across the species and in-silico prediction of the variant is damaging by Mutation Taster.

CDG is commonly characterised by severe failure to thrive, delayed development, seizures, tone abnormalities, dysmorphic features, eye abnormalities, coagulopathy and pericardial effusion. Kids who have this disorder have a poor prognosis. Our patient did not have seizures, developmental delay or hypotonia. Apart from a broad nasal bridge, no significant dysmorphism was present.

CDG 1H is a severe and very rare form of CDG. The majority of patients have brain involvement, liver pathology, gastrointestinal symptoms, renal tubulopathy, dysmorphism (including brachydactyly), eye involvement (such as cataract) and skin symptoms. Most patients die within 1 year of life.4 Infantile presentation with oedematoascitic syndrome related to severe hypoalbuminaemia resulting from protein-losing enteropathy has been well described.5 Our patient was symptomatic at 8 months of age, with pedal oedema and ascites but did not develop neuromotor retardation, and development parameters remained within normal parameters. This variety of CDG has also been described in a few siblings of affected children with feeding difficulties, ascites, diarrhoea and vomiting6 though they had poor outcomes.

Another case report has described a fatal outcome in an infant who had hypertelorism, low-set and abnormally positioned ears, cryptorchidism, camptodactyly, clubfeet, bilateral thoracic and pulmonary hypoplasia, ventricular septal defects, multiple cystic intrahepatic and extrahepatic bile ducts, cholestasis and diffuse renal microcysts.6 All the above patients did not have any neurological abnormalities.

The CDG 1H variant expressed in our patient is mild, with no neurological involvement, diarrhoea, vomiting and dyselectrolytaemia, who had a novel mutation in her gene ALG8.