Apoptotic enteropathy, gluten intolerance, and IBD-like inflammation associated with lipotoxicity in DGAT1 deficiency-related diarrhea: a case report of a 17-year-old patient and literature review.

We present a long-term follow-up in a 17-year-old girl with DGAT1-related diarrhea, an autosomal recessive disorder characterized by impaired triglyceride absorption. Neonatal presentation included severe congenital diarrhea, protein-losing enteropathy, and failure to thrive requiring total parenteral nutrition. Duodenal biopsies revealed apoptotic enteropathy and acute inflammation with the presence of macrophages and Touton giant cells, related to the intake of fat. She was able to switch to enteral nutrition on a fat-free diet. However, at age 10, she developed gluten-induced enteropathy and then IBD-like inflammation 5 years later. Immunohistochemistry was able to confirm the diagnosis, while DGAT1 sequencing remained inconclusive. This highlights the role of histopathology and immunohistochemistry, despite the increasing importance of genetic analysis in the diagnostic work-up. This report also illustrates that parenteral nutrition weaning is possible in DGAT1-related diarrhea, but gut barrier dysfunction might increase the risk of autoimmune intestinal disease.

Lymphedema complicated by protein-losing enteropathy with a 22q13.3 deletion and the potential role of CELSR1: A case report.

INTRODUCTION: 22q13.3 deletion syndrome is a well-known syndrome characterized by typical clinical findings including neonatal hypotonia, absent or severely delayed speech, intellectual disability, and other various features, and detection of a heterozygous deletion of chromosome 22q13.3 with the involvement of at least part of SHANK3. It is reported that 10% to 29% of patients with 22q13.3 deletion syndrome present lymphedema. Protein-losing enteropathy (PLE) has never been reported in 22q13.3 deletion syndrome. PATIENT CONCERNS: The patient presented to our institution for refractory hypoalbuminemia and chronic lymphedema in both legs. DIAGNOSIS: The patient manifested intellectual disability, absent speech, tooth grinding, dysmorphic face, and abnormal hands and toenails. Copy-number variation sequencing confirmed the maternal deletion in 22q13.31-q13.33 (chr22:46285592-51244566, hg19). The patient was genetically diagnosed with 22q13.3 deletion syndrome. INTERVENTIONS: Low-fat diets and medium-chain triglycerides supplements were prescribed. The patient was recommended to wear compression garments and elevate legs. OUTCOMES: The symptom of diarrhea was resolved, but hypoalbuminemia persisted. Lower extremities lymphedema was gradually becoming severe. CONCLUSIONS: Primary lymphedema and PLE can occur simultaneously in a patient with 22q13.3 deletion syndrome. The 2 phenotypes could share the same genetic etiology of congenital lymphatic abnormalities. CELSR1 deletion may play a role in lymphatic dysplasia. The case also provides additional proof of the pathogenic effect of CELSR1 on hereditary lymphedema.

Lymphocyte Immune Response and T Cell Differentiation in Fontan Patients with protein-losing enteropathy.

BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation. There is increasing discussion about whether lymphatic dysregulation is involved as pathomechanism of PLE. This investigation focuses on the interplay between alteration of lymphatic cells and immunologic pathway alterations. METHODS: Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients (n = 10 Fontan patients with PLE, n = 30 Fontan patients without PLE, and n = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway analysis was performed to identify significantly enriched pathways. To determine lymphocyte populations and subtypes multiparameter flow cytometry was used. RESULTS: miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed networks of which four of the ten largest were associated with immunologic processes. This finding is supported by significant T cell deficiency with decreased CD4+ count (p = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ (p < 0.0001) and CD8+ (p = 0.0002) T cell differentiation toward effector and terminal differentiated T cells in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly increased frequencies of CD4+ CD25+ CD127- regulatory T cells (Treg) in Fontan patients with PLE (p = 0.0011). CONCLUSION: PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency, significant alterations of T cell differentiation, and increased Treg frequency reflecting an immune status of chronic inflammation and shortened protection against pathogens and autoimmunity. These cellular alterations seemed to be dysregulated by several miRNA controlled immunological pathways.

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

An initial genome-wide investigation of protein-losing enteropathy in Gordon setters: Exploratory observations.

The objective of this preliminary study was to identify genomic regions that may predispose Gordon setters from the United Kingdom to familial protein-losing enteropathy (PLE) at a young age. A total of 106 related Gordon setters was used, including 6 affected dogs from an affected litter, 6 case controls from the same litter, 10 related/affected dogs, and 84 related/unaffected dogs. Genomic DNA was collected from each Gordon setter and extracted from buccal mucosal swabs. Genotyping of affected and unaffected dogs was carried out using the Canine Illumina HD SNP array and data generated were analyzed with PLINK software, using fixation index (Fst) and runs of homozygosity (ROH) methods. Pairwise Fst analyses between the affected and unaffected Gordon setter dogs identified various regions of differentiation on chromosomes 10, 18, 21, and 23 that contained several important genes. These regions revealed 5 candidate genes, including RARB, TTC7A, SOCS5, PIGF, and RHOD, that are associated with human inflammatory bowel disease (IBD) and could potentially be associated with PLE in Gordon setters. Run of homozygosity (ROH) analyses revealed additional unique regions on chromosomes 15 and 17. These regions contained genes SYT1, UCN, and FNDC that could also be potential candidates for PLE in Gordon setters. The biological functions of the identified genes provided initial insights into the pathophysiology of PLE. Further large-scale studies are warranted to investigate the possible causality of these genomic regions and any possible genetic markers that could be used in predicting susceptibility to PLE syndrome.

L'objectif de cette étude préliminaire était d'identifier les régions génomiques susceptibles de prédisposer les chiens Gordon setter du Royaume-Uni à l'entéropathie familiale de perte de protéines (PLE) à un jeune âge. Un total de 106 Gordon setter apparentés a été utilisé, dont six chiens affectés d'une portée affectée, six cas témoins de la même portée, 10 chiens apparentés/affectés et 84 chiens apparentés/non affectés. L'ADN génomique a été obtenu à partir de chaque Gordon setter et extrait des écouvillons de la muqueuse buccale. Le génotypage des chiens affectés et non affectés a été effectué à l'aide de la matrice SNP Canine Illumina HD et les données générées ont été analysées avec le logiciel PLINK, en utilisant des méthodes d'indice de fixation (Fst) et d'homozygotie (ROH). Des analyses Fst par paires entre les chiens Gordon setter affectés et non affectés ont identifié diverses régions de différenciation sur les chromosomes 10, 18, 21 et 23 qui contenaient plusieurs gènes importants. Ces régions ont révélé cinq gènes candidats, dont RARB, TTC7A, SOCS5, PIGF et RHOD, qui sont associés à la maladie inflammatoire de l'intestin (IBD) humaine et pourraient potentiellement être associés à la PLE chez les Gordon setter. Les analyses d'homozygotie (ROH) ont révélé des régions uniques supplémentaires sur les chromosomes 15 et 17. Ces régions contenaient les gènes SYT1, UCN et FNDC qui pourraient également être des candidats potentiels pour la PLE chez les Gordon setter. Les fonctions biologiques des gènes identifiés ont fourni un aperçu initial de la physiopathologie de la PLE. D'autres études à grande échelle sont nécessaires pour étudier la causalité possible de ces régions génomiques et tous les marqueurs génétiques possibles qui pourraient être utilisés pour prédire la sensibilité au syndrome PLE.(Traduit par Docteur Serge Messier).

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C>T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE.

Glycomacropeptide Ameliorates Indomethacin-Induced Enteropathy in Rats by Modifying Intestinal Inflammation and Oxidative Stress.

Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is considered a serious and increasing clinical problem without available treatment. Glycomacropeptide (GMP) is a 64-amino acid peptide derived from milk κ-casein with numerous biological activities. The aim of this study was to investigate the protective effect of GMP on NSAID enteropathy in rats. Enteropathy was induced by seven days oral indomethacin administration. Rats were orally GMP treated from seven days previous and during the establishment of the enteropathy model. Changes in metabolism, hematological and biochemical blood alterations, intestinal inflammation and oxidative damage were analyzed. Integrity barrier markers, macroscopic intestinal damage and survival rate were also evaluated. GMP treatment prevented anorexia and weight loss in animals. Furthermore, prophylaxis with GMP ameliorated the decline in hemoglobin, hematocrit, albumin and total protein levels. The treatment had no therapeutic efficacy on the decrease of occludin and mucin (MUC)-2 expression in intestinal tissue. However, GMP markedly decreased neutrophil infiltration, and CXCL1, interleukin-1ß and inducible nitric oxide synthase expression. Nitric oxide production and lipid hydroperoxide level in the small intestine were also diminished. These beneficial effects were mirrored by preventing ulcer development and increasing animal survival. These results suggest that GMP may protect against NSAID enteropathy through anti-inflammatory and antioxidant properties.

A PTPN11 mutation in a woman with Noonan syndrome and protein-losing enteropathy.

BACKGROUND: Noonan syndrome is an autosomal dominant, variably expressed multisystem disorder characterized by specific facial and cardiac defects, delayed growth, ectodermal abnormalities, and lymphatic dysplasias. Lymphedema and chylous pleural effusions are common in Noonan syndrome, but protein-losing enteropathy (PLE) has only rarely been described in the condition and little is known about its genetic associations. CASE PRESENTATION: We report the case of a 30-year-old Chinese woman who developed severe recurrent edema and hypoproteinemia. Gastroduodenoscopy showed a "snowflake" appearance of lymphangiectasia in the duodenum, and CT reconstruction of the small intestine showed segmental thickening of the intestinal wall with localized stenosis. Whole exome sequencing revealed that the patient harbored a pathogenic variant of PTPN11 (c.A922G p.N308D), which was unfortunately inherited by her 2.5-year-old daughter who had short stature and atrial septal defect but no hypoproteinemia. CONCLUSIONS: This case of Noonan syndrome with PLE was associated with a PTPN11 mutation. A comprehensive review of PLE in Noonan syndrome revealed that PLE often presents late in this context but there is no clear genotype-phenotype correlation. Genetic evaluation with next-generation sequencing can be useful for securing the diagnosis and planning early intervention and management.

Clonality testing as complementary tool in the assessment of different patient groups with canine chronic enteropathy.

Differentiation between canine chronic enteropathy (CCE) and intestinal lymphoma is a diagnostic challenge as histopathology might fail to yield unequivocal results. Detection of clonal rearrangements of the T-cell-receptor gamma (TCRG) chain and IG heavy chain (IGH) V-J genes offer a useful solution. In this retrospective study, histopathology samples of 35 CCE patients and 7 healthy Beagle dogs underwent clonality testing. Patients suffered either from inflammatory bowel disease (IBD), food responsive diarrhea (FRD) or protein loosing enteropathy secondary to IBD (PLE/IBD). Healthy Beagles served as controls (CO). Canine IBD activity index (CIBDAI) and histopathological WSAVA-grading differed significantly (p<0.001) between groups. CIBDAI improved significantly after appropriate therapy (p < 0.0001). Intestinal biopsies of all CO showed polyclonal patterns for B- and T-cell primers. All samples from CCE patients showed polyclonal patterns for the B-cell primers. Targeting TCRG, 4 patients showed a monoclonal or oligoclonal pattern of the lymphocytic infiltrates in the duodenum and/or colon. Clinical improvement was observed in all dogs. Although a small cell lymphoma cannot be excluded in view of the short follow up duration, a false positive result, in the sense of a canonical rearrangement or unspecific amplification due to a antigenic stimulation in a non-neoplastic inflammatory process is possible.

Novel PLVAP Mutation in Protein Losing Enteropathy.

Introduction: A genetic cause of the protein-losing enteropathy (PLE) disease Diarrhea 10 (DIAR10) are mutations in the recently described PLVAP (plasmalemma vesicle protein). Case report: An infant with fatal PLE had a novel homozygous frameshift mutation (c.339dupT; p.Ala114Cysfs*9) leading to a premature stop codon in exon 1 of the PLVAP (NM_031310) gene detected by Whole Exome Sequencing (WES). Conclusion: The frameshift mutation (PLVAP; c.339dupT; p.Ala114Cysfs*9) we have described in our patient has not been previously reported. This is the fifth case reported with a mutation in PLVAP associated with PLE and DIAR10.

Phenotype and Genotype of a Cohort of Chinese Children with Early-Onset Protein-Losing Enteropathy.

OBJECTIVES: To examine the phenotypes and perform next-generation sequencing in children with early-onset protein-losing enteropathy. STUDY DESIGN: We performed a retrospective review of 27 children with early-onset protein-losing enteropathy. Patients were characterized on clinical, immunologic, and systemic involvements. Targeted gene panel sequencing and whole-exome sequencing were performed in 9 patients. RESULTS: In 27 patients (55.6% male), median age of disease onset was 173 days, and 59.3% had onset of disease before 1 year of age. Initial gastrointestinal symptoms included diarrhea (74.1%), vomiting (33.3%), and abdominal distention (48.1%). All patients had hypoalbuminemia, with an average serum albumin concentration of 20.2 ± 5.4 g/L. Hypogammaglobulinemia was identified in 72% of the patients. Upper endoscopy showed typical presentation of intestinal lymphangiectasia (n = 13). Patients frequently received intravenous albumin and immunoglobulin infusions as well as parenteral nutrition. Next-generation sequencing in 9 patients with available DNA showed 1 patient had compound heterozygous CCBE1 mutations and 2 had novel homozygous DGAT1 mutations. Monogenic diseases were identified in 3 of 9 patients who underwent genetic sequencing. Three subjects (11.1%) died, of whom 2 had homozygous DGAT1 mutations. No significant correlation was found between age of symptom onset, serum albumin, serum IgG, lymphocyte count, CD4+ cells, and mortality. CONCLUSIONS: Monogenic diseases may be observed in children with early-onset protein-losing enteropathy, and genetic evaluation with next-generation sequencing should be considered.

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype.

BACKGROUND: Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency. OBJECTIVE: To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years. METHODS: Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function. RESULTS: We identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein's transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected. CONCLUSIONS: Biallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP's importance in EC barrier function in the gut.

Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency.

BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy.

BACKGROUND: Protein-losing enteropathy (PLE) is characterised by gastrointestinal protein leakage due to loss of mucosal integrity or lymphatic abnormalities. PLE can manifest as congenital diarrhoea and should be differentiated from other congenital diarrhoeal disorders. Primary PLEs are genetically heterogeneous and the underlying genetic defects are currently emerging. OBJECTIVES: We report an infant with fatal PLE for whom we aimed to uncover the underlying pathogenic mutation. METHODS: We performed whole exome sequencing (WES) for the index patient. Variants were classified based on the American College of Medical Genetics and Genomics guidelines. WES results and our detailed clinical description of the patient were compared with the literature. RESULTS: We discovered a novel homozygous stop mutation (c.988C>T, p.Q330*) in the Plasmalemma Vesicle-Associated Protein (PLVAP) gene in a newborn with fatal PLE, facial dysmorphism, and renal, ocular and cardiac anomalies. The Q330* mutation is predicted to result in complete loss of PLVAP protein expression leading to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE. Recently, another single homozygous stop mutation in PLVAP causing lethal PLE in an infant was reported. CONCLUSIONS: Our findings validate PLVAP mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.

Somatic PTPN11 Mutation in a Child With Neuroblastoma and Protein Losing Enteropathy.

Neuroblastoma and protein losing enteropathy (PLE) are diagnoses commonly seen by oncologists and gastroenterologists, respectively. The concurrence of these 2 entities is rare, and not well explained. We describe the sixth case of PLE in a child with neuroblastoma, and the first for which genetic information is available. Tumor DNA had a mutation in the PTPN11 gene, which has been described in neuroblastoma, and in Noonan syndrome-a diagnosis in which neuroblastoma and PLE independently have been reported. Constitutional DNA was normal. Genetic studies in future patients will be needed to support the link between neuroblastoma and PLE.

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Protein-losing enteropathy in a patient with familial adenomatous polyposis and advanced colon cancer.

A 29-year-old female visited a hospital because of increasingly severe lower leg edema. She was diagnosed as having multiple polyps in the stomach and colon by gastroscopy and sigmoidoscopy as well as multiple liver tumors by abdominal CT. She was referred to our hospital for further examination. Total colonoscopy revealed a type 2 tumor in the transverse colon and more than 200 polyps distributed throughout the colorectum. Biopsies of the tumor and polyps showed histological characteristics of adenocarcinoma and tubulovillous adenoma, respectively. Thus, she was diagnosed as having metastatic colon cancer derived from familial adenomatous polyposis (FAP). Laboratory tests showed a marked hypoalbuminemia of 1.1 g/dl. The fecal alpha-1 anti-trypsin test showed abnormal clearance (62.1 ml/day), and scintigraphy using 99mTc-human serum albumin revealed protein loss in the whole colon. Multiple ligation probe amplification analysis of the APC gene identified a germline duplication of exons 11-13. Direct sequencing of the reverse transcription PCR products of APC mRNA revealed a deletion of 25 base pairs and a tandem duplication of exons 11-13. This case was considered to be protein-losing enteropathy resulting from numerous colonic tubulovillous adenomas and advanced colon cancer in a FAP patient with unusual mutational events in APC.

Protein-losing enteropathy with intestinal lymphangiectasia in skeletal dysplasia with Lys650Met mutation.

Protein-losing enteropathy is a primary or secondary manifestation of a group of conditions, and etiologies which are broadly divisible into those with mucosal injury on the basis of inflammatory and ulcerative conditions, mucosal injury without erosions or ulcerations, and lymphatic abnormalities. We describe the first case of protein-losing enteropathy in a pediatric patient, with severe skeletal dysplasia consistent with thanatophoric dysplasia type I and DNA analysis that revealed a c.1949A>T (p.Lys650Met) in exon 15 of the FGFR3 gene. She presented with protein-losing enteropathy in her 6th month. Post-mortem examination revealed lymphangiectasia in the small intestine. To our knowledge, this is the first report of intestinal lymphangiectasia as a complication of skeletal dysplasia resulting in severe protein-losing enteropathy. © 2016 Wiley Periodicals, Inc.