Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant syndrome of developmental delay, cortical vision loss with optic nerve atrophy, epilepsy, and autism spectrum disorder. Due to its many overlapping features with congenital disorders of glycosylation (CDG), the differential diagnosis between these disorders may be difficult and relies on molecular genetic testing. We report on a 31-year-old female initially diagnosed with ALG6-CDG based on glycosylation abnormalities on transferrin isoelectrofocusing and targeted genetic testing, and later diagnosed with BBSOAS by whole-exome sequencing (WES). Functional studies on cultured fibroblasts including Western blotting and RT-qPCR, as well as mass spectrometry of glycosylated transferrin and MALDI-TOF glycan analysis in serum, demonstrated normal glycosylation in this patient. In this report, we extend the phenotype of BBSOAS with ataxia and protein-losing enteropathy. This case is illustrative of the utility of whole exome sequencing in the diagnostic odyssey, and the potential pitfalls of relying on focused genetic testing results for diagnosis of conditions with complex overlapping phenotypes.     

Pathological and immunohistological findings and genetic aberrations of intestinal enteropathy-associated T cell lymphoma in Japan

Takeshita M, Nakamura S, Kikuma K, Nakayama Y, Nimura S, Yao T, Urabe S, Ogawara S, Yonemasu H, Matsushita Y, Karube K & Iwashita A
(2011) Histopathology 58 , 395–407
Pathological and immunohistological findings and genetic aberrations of intestinal enteropathy‐associated T cell lymphoma in Japan Aims: To elucidate the clinicopathological findings of primary intestinal enteropathy‐associated T cell lymphoma (EATL) in Japan, a non‐endemic area for coeliac disease. Methods and results: Of the 24 cases, four (17%) had large‐cell lymphoma (type I), and the remaining 20 (83%) had medium‐sized lymphoma (type II). Lymphoma cells of the three type I cases were CD56‐positive. Only one (4%) case showed typical CD56‐ and CD8‐negative and CD30‐positive type I EATL. In type II EATL, lymphoma cells of the 16 (80%) and 11 (55%) cases were positive for CD56 and CD8, respectively. Intramucosal tumour spreading and adjacent enteropathy‐like lesions were detected in 15 (71%) and 16 (76%) of 21 cases, with a severe increase of intraepithelial lymphocytes (IELs) in 12 (57%). IELs of enteropathy‐like lesions in five (24%) cases expressed T‐bet, with no cases of CD30‐positive IELs. Characteristic findings from comparative genomic hybridization of 15 cases indicated gains of 8q2 (47%), Xp (53%) and Xq (73%), but no gain of 9q3. Regarding, human leucocyte antigen (HLA) status, six cases examined did not express the DQB1*02 allele. Conclusions: Japanese EATL exhibited different histology, cytogenetic findings and HLA status from those of typical type I EATL. The rare incidence of coeliac disease may influence the tumour cell characteristics of EATL and IELs.     

Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies — Novel tool for diagnostics and patient follow-up

Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes.     

Systemic lupus erythematosus: A case report with unusual manifestations and favourable outcome after plasmapheresis

We report a case of systemic lupus erythematosus (SLE) in a 15-year-old girl with severe neurological disease, platelet function disorder and pulmonary haemorrhage, which remitted after plasmapheresis. The patient developed protein-losing enteropathy shrinking lung, and acute pancreatitis with pseudocyst formation. These infrequent complication of SLE are discussed.     

Lymphatics in the Alimentary Tract of Children in Health and Disease: Study on Mucosal Biopsies Using the Monoclonal Antibody D2-40

Primary intestinal lymphangiectasia and intestinal lymphatic hypoplasia are 2 causes of protein-losing enteropathy in children and share many common clinical features. For the diagnosis of lymphatic hypoplasia on endoscopic biopsies of the intestine, i.e., based on a negative finding in a small specimen, a very sensitive and specific method for identifying lymphatics is essential. In the present study, lymphatic vessels were labelled using D2-40 immunostaining in mucosal biopsy specimens of the alimentary tract of children in whom no histologic abnormality was noted and of those who had different relatively common pediatric conditions, including inflammatory and neoplastic diseases. Using this method, lymphatic vessels were well visualized even in young infants and not destroyed by diseases. The presence of the muscularis mucosae in specimens was important for adequate assessment. In the duodenum and esophagus, lymphatics were observed in every single section; in the stomach, ileum, and colon, they were less regular and several sections were sometimes required. The extreme sensitivity of this method for demonstrating lymphatic vessels in the duodenum makes it ideal for the histologic diagnosis of intestinal lymphatic hypoplasia. In 4 patients who were considered to have this diagnosis based on clinical features, full-thickness intestinal biopsies and electron microscopy, D2-40 immunostaining confirmed the absence or marked paucity of lymphatics.     

AN IN VITRO MODEL FOR GLUTEN ENTEROPATHY

Fetal rat jejunum can be grown in culture and normal villi are seen to develop in vitro. The addition of an extract of wheat gliadin inhibited mucosal maturation and caused epithelial and mesenchymal damage. This model may be useful for the study of gluten enteropathy.     

Transient hypoproteinemia and hypoprothrombinemia in an infant

A 7 months old infant with transient hypoproteinemia and hypoprothrombinemia is described. The hypoproteinemia is attributed to protein losing enteropathy, and transient Menetrier's disease is suggested as a possible cause for the protein loss. Assuming that this baby was not vitamin K deficient, and knowing that the molecular weight of prothrombin is lower than that of albumin, the hypoprothrombinemia might be due to prothrombin loss into the gut together with albumin.     

A simple screening method for detecting gastrointestinal protein loss in intestinal lymphangiectasia

A ten month old female Turkish child with chylous ascites, diarrhea, steatorrhea, peripheral edema and hypoproteinemia was investigated for protein losing enteropathy which probably dated from the first weeks of life. Gastrointestinal protein loss appeared to be due to abnormalities of the intestinal lymphatics. In order to detect a localized lymphoenteric fistula, lymphangiography was tried but failed due to hypoplasia of peripheral lymphatics. However, three hours after intradermal injection of Patent Blue, the dye appeared in the stools of the patient, suggesting intestinal protein loss via a lympho-enteric fistula.This observation may provide the basis for a diagnostic test for gastro-intestinal protein loss in patients with intestinal lymphangiectasia.