Hepatic fibrinogen storage disease: identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen γ-module.

BACKGROUND: Quantitative fibrinogen deficiencies (hypofibrinogenemia and afibrinogenemia) are rare congenital disorders characterized by low/unmeasurable plasma fibrinogen antigen levels. Their genetic basis is invariably represented by mutations within the fibrinogen genes (FGA, FGB and FGG coding for the Aα, Bß and γ chains). Currently, only four mutations (p.Gly284Arg, p.Arg375Trp, delGVYYQ 346-350, p.Thr314Pro), all affecting the fibrinogen γ chain, have been reported to cause fibrinogen storage disease (FSD), a disorder characterized by protein aggregation, endoplasmic reticulum retention and hypofibrinogenemia. OBJECTIVES: To investigate the genetic basis of FSD in two hypofibrinogenemic patients. METHODS: The mutational screening of the fibrinogen genes was performed by direct DNA sequencing. The impact of identified mutations on fibrinogen structure was investigated by in-silico molecular modeling. Liver histology was evaluated by light microscopy, electron microscopy and immunocytochemistry. RESULTS: Here, we describe two hypofibrinogenemic children with persistent abnormal liver function parameters. Direct sequencing of the coding portion of fibrinogen genes disclosed two novel FGG missense variants (p.Asp316Asn, fibrinogen Pisa; p.Gly366Ser, fibrinogen Beograd), both present in the heterozygous state and affecting residues located in the fibrinogen C-terminal γ-module. Liver sections derived from biopsies of the two patients were examined by immunocytochemical analyses, revealing hepatocyte cytoplasmic inclusions immunoreactive to anti-fibrinogen antibodies. CONCLUSIONS: Our work strongly confirms the clustering of mutations causing FSD in the fibrinogen γ chain between residues 284 and 375. Based on an in-depth structural analysis of all FSD-causing mutations and on their resemblance to mutations leading to serpinopathies, we also comment on a possible mechanism explaining fibrinogen polymerization within hepatocytes.

Cholestasis caused by biliary botryoid sarcoma.

A 4-year-old boy with a short history of jaundice and hepatomegaly was studied by endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). A large obstructing choledochal tumour was found at the level of cystic duct insertion and at surgery, a botryoid sarcoma was removed. Subsequent cytotoxic therapy was complicated by persistent dilatation of the extrahepatic bile ducts which necessitated eventual excision. There was no evidence of persistent tumour.

Colorectal polyps: an important cause of rectal bleeding.

Seventy one children with rectal bleeding were examined by total fibreoptic colonoscopy. Large bowel polyps were found in 45; 27 (60%) had solitary rectal polyps. Altogether, 83% of resected polyps were juvenile. No complication of colonoscopic polypectomy occurred. New polyps reoccurred in four (9%) treated children.

Bleeding from duodenal lymphangiectasia.

An 8 year old girl with recurrent upper gastrointestinal bleeding was found to have localised duodenal lymphangiectasia by fibreoptic endoscopy. She did not show physical signs or laboratory evidence of significant enteric protein loss. A low fat diet seemed to prevent further bleeding. Duodenal lymphangiectasia may be associated with gastrointestinal bleeding in children.

Balloon dilatation of cricopharyngeal achalasia.

A 6-month-old male infant with difficulty swallowing, recurrent aspiration pneumonia and failure to thrive was diagnosed with cricopharyngeal achalasia. Normal oral feeding and no further aspirations followed a single catheter balloon dilatation.

Infantile achalasia treated by pneumatic dilatation.

A 4 month old girl with oesophageal achalasia was successfully treated with a single pneumatic dilatation. A subsequent barium swallow showed almost normal oesophageal caliber. During the following eighteen months, vomiting and feeding problems did not recur.

Diarrhoea caused by collagenous colitis.

The first case of collagenous colitis in a child with protracted watery diarrhoea and abdominal pain is reported. Small bowel investigations and the macroscopic appearances were normal, but histological examination of the colon showed collagenous colitis. Steroids temporarily relieved the diarrhoea and induced transient dissolution of the subepithelial collagen band.

Coeliac disease and lymphangiectasia.

Two out of 74 children with coeliac disease demonstrated severe intestinal protein loss. In both children a serial small bowel biopsy specimen showed intestinal lymphangiectasia to be also present. Intestinal lymphangiectasia is another disorder that may be associated with coeliac disease.

Nonoperative treatment of achalasia.

Twelve children with achalasia were treated by the technique of balloon dilatation in the years 1984-1991. Follow-up from 2 to 8 years (mean 3.5 years) showed complete relief of obstruction in 10 patients, while two required esophagomyotomy. Balloon dilatation is effective in the treatment of achalasia.

Coeliac disease and collagenous colitis.

A thirteen and a half year old girl and her father were both investigated because of chronic watery diarrhoea and growth failure or weight loss. Both were diagnosed as having coeliac disease. In the daughter, collagenous colitis was also diagnosed. The father had colonic collagen deposition with inflammatory changes as well. Both improved on gluten-free diets, but colonic collagen deposition persisted.

The role of the accessory pancreatic duct of Santorini in pancreatic drainage in children (with emphasis on choledochal cyst patients).

Pancreatic drainage patterns have been studied by endoscopic retrograde cholangiopancreatography (ERCP) in four children with choledochal cyst (CC). The first two had mild or chemical pancreatitis; the third had a history of recurrent cholangitis and was diagnosed as chronic pancreatitis. The fourth manifested with severe, acute pancreatitis. All children were found to have an impaired flow through the papilla of Vater. In the first three cases, the duct of Santorini (DS) seemed to play an important role in the pancreatic drainage. In the fourth case, however, the duct was found to be absent. ERCP findings in additional eleven children without CC also were reviewed, and in this group the DS did not seem to play any significant role in pancreatic drainage. These results indicate that in children with common bile duct (CBD) anomalies, the DS may relieve the obstruction and ameliorate the pancreatitis.

Recurrent pneumonia caused by diffuse oesophageal spasm.

A 14-month-old severely retarded girl with a history of regurgitation, aspiration, and recurrent pneumonia was found to suffer from diffuse oesophageal spasm. This diagnosis was made by oesophageal cineradiography. This case suggests that diffuse oesophageal spasm is an oesophageal motility disorder that causes respiratory disease in the retarded child.