Gastrointestinal Defects And Immunodeficiency Syndrome

A number sign (#) is used with this entry because of evidence that gastrointestinal defects and immunodeficiency syndrome (GIDID) is caused by homozygous or compound heterozygous mutation in the TTC7A gene (609332) on chromosome 2p21.

Description

Gastrointestinal defects and immunodeficiency syndrome (GIDID) is characterized by multiple intestinal atresia, in which atresia occurs at various levels throughout the small and large intestines. Surgical outcomes are poor, and the condition is usually fatal within the first month of life. Some patients exhibit inflammatory bowel disease (IBD), with or without intestinal atresia, and in some cases, the intestinal features are associated with either mild or severe combined immunodeficiency (Samuels et al., 2013; Avitzur et al., 2014; Lemoine et al., 2014).

Clinical Features

Multiple intestinal atresia is likely separate from duodenal atresia (223400) and jejunal atresia (243600) because of the wide distribution of involvement, from stomach to anus (Guttman et al., 1973). Dallaire and Perreault (1974) reported 5 French Canadian patients with multiple intestinal atresia in 3 sibships with common ancestry. Two of the 3 sibships had demonstrably consanguineous parents. Intraluminal calcifications were demonstrable radiographically.

Blackburn et al. (1983) reported a male with multiple intestinal atresia whose older sib and a paternal uncle had died as neonates with similar anomalies.

Kao et al. (1983) reported 2 affected black sibs; Arnal-Monreal et al. (1983) reported 2 affected Spanish sibs; and Puri et al. (1985) reported 3 affected Irish sibs.

Shen-Schwarz and Fitko (1990) reviewed 18 cases from the literature and reported an isolated case in an infant with imperforate anus.

Moreno et al. (1990) reported a family in which 3 brothers had multiple intestinal atresia in combination with severe combined immunodeficiency (SCID; see 601457). All 3 died in the first months of life. Since both are known to be autosomal recessive disorders, it is possible that this represents an instance of genetic linkage of intestinal atresia with an autosomal recessive form of SCID. Deficiency of adenosine deaminase was excluded. Bigorgne et al. (2014) reported 6 patients from 6 unrelated pedigrees with multiple intestinal atresia with combined immunodeficiency, including the younger sister of the patients reported by Moreno et al. (1990). She was born with a prepyloric diaphragm defect, 'micro-small' intestine, microcolon, and colic atresia. At 7 months of age, she developed SCID. A thymus could not be visualized on chest x-ray at age 20 months. She died at age 2.5 years of sepsis. Bigorgne et al. (2014) also reported a male born in France, whose parents came from geographically close villages in Sri Lanka, who was diagnosed prenatally with intestinal atresia. He later displayed rapidly progressive, generalized, profound SCID. At age 4 years, he developed progressive skin abnormalities with mild pachyderma on both hands and feet. He was still alive at age 8.

Gungor et al. (1995) reported 2 affected children, the offspring of consanguineous Turkish parents. Most reported cases have been either prematurely born or small for gestational age. Polyhydramnios can be detected prenatally in some cases. Plain radiographs of the abdomen demonstrated calcified areas, which were found to be intraluminal during surgery. In some of the patients, the intraluminal material is described as a pasty milky substance. Calcification of intraluminal meconium is probably secondary to intestinal stasis. The calcific collections may permit prenatal detection of the disorder by ultrasonography (McHugh and Daneman, 1991). Low level of disaccharidase in the amniotic fluid at 15-19 weeks of gestation is another diagnostic test (Morin et al., 1980).

Bilodeau et al. (2004) reviewed 16 cases of multiple intestinal atresia, 11 female and 5 male, occurring over 30 years in the Quebec area, including 4 probands from Saguenay-Lac-St-Jean. Five patients presented with intrauterine growth retardation. Other associated anomalies included malrotation in 3 patients, common bile duct dilation in 2, and omphalocele, ventricular septal defect, and congenital cystic adenomatoid malformation in 1 patient each. Two patients had IgM immunodeficiency. Intestinal atresia was strongly suspected prenatally in 6 of 13 patients who had prenatal ultrasound scans, based on the presence of polyhydramnios, calcifications, and/or bowel distention. Laparotomy was performed on all patients, and all had multiple areas of type I and/or type II atresia from the foregut to the hindgut. Despite an attempt at curative surgery in 11 patients, none regained bowel function; all patients eventually died, with a mean survival time of 50 days. Pathologic examination of the resected bowel revealed sieve-like luminae in 10 of 15 patients. Other frequent findings included mucous membrane ulceration and granulation tissue, each noted in 3 cases.

Chen et al. (2013) studied 8 unrelated patients with multiple intestinal atresia from families of various ethnic origins, including Arabic, Serbian, Bosnian, French Canadian, mixed European, and Italian. Profound CD8+ T-cell lymphopenia was observed in all 7 patients tested. Severe hypogammaglobulinemia was a common feature, and all patients had recurrent and severe infections. Chen et al. (2013) noted that in contrast to typical SCID cases, these patients had fewer viral infections and a higher frequency of bloodstream infections caused by intestinal microbes, and suggested that this might reflect abnormalities of the gut barrier in patients with multiple congenital atresia. Postmortem analysis of the thymus from 1 patient showed severe lymphoid depletion and vague corticomedullary demarcation with preservation of Hassell corpuscles; severe lymphoid depletion affecting both T and B cells was also demonstrated in peripheral lymph nodes from 2 patients. Chen et al. (2013) designated the phenotype in these patients 'combined immunodeficiency with multiple intestinal atresias (CID-MIA).'

Avitzur et al. (2014) reported 5 infants from 3 families who had severe IBD, associated with immunodeficiency in 2 families and with jejunal atresia in 1 family. Three patients died in the first year of life and another at 19 months; 1 patient was alive and partially treated with total parenteral nutrition (TPN). Pathologic analysis of patient intestinal specimens from all 3 families showed similar features, including loss of intestinal architecture, focal scarring, and severe inflammation with increased enterocyte apoptosis as well as areas where surface epithelium was detached. Avitzur et al. (2014) designated the disorder in these families as a very early-onset inflammatory bowel disease (VEOIBD).

Lemoine et al. (2014) described 13 affected members of a large consanguineous kindred who had enteropathy associated with T-cell, B-cell, and natural killer cell combined immunodeficiency. All patients exhibited signs of IBD within the first days or months of life, with recurrent severe diarrhea that was sometimes bloody. The severity of gastrointestinal manifestations gradually decreased with age; the 9 patients who required parenteral nutrition were able to discontinue it by 5 years of age, although the enteropathy was fatal in 1 case. Endoscopy showed severe inflammation, with an erythematous stomach and multiple areas of ulcerative lesions in the sigmoid; immunohistopathologic analysis revealed major lesions in the antrum and colon in all patients, whereas the small intestine was relatively unaffected. The changes observed in the fundus and antrum were similar in all patients analyzed at different ages, and included disorganized epithelial architecture with tufting, loss of apical mucin, abnormal pseudostratified cell organization with glandular distortion, and epithelial apoptosis. Colon lesions were severe and widespread, with epithelial dedifferentiation and little remaining mucus-secreting tissue; glandular necrosis, cell apoptosis, and crypt abscesses in multiple sites were also observed. There was an inflammatory infiltrate of mononuclear cells and a high eosinophil count in the lamina propria of both the gastric and colonic areas. Five patients in this family also had with transient alopecia from the age of 2 to 4 years, and 4 had onychopathy; 4 patients developed signs of autoimmune disease in the second decade of life, including autoimmune hepatitis, hemolytic anemia, thyroiditis, psoriasis, and type I diabetes. Of 13 affected individuals, 8 were alive at the time of the report, with the 3 oldest being 14, 28, and 50 years of age. Lemoine et al. (2014) also studied a 2-year-old boy from an unrelated family who had a similar but milder phenotype, with protracted neonatal bloody diarrhea and recurrent anal abscesses. He received partial enteral nutrition for 10 months, and had recurrent respiratory tract infections associated with hypogammaglobulinemia. He also had sparse hair, including absent eyebrows. Lemoine et al. (2014) designated the condition in the 2 families 'enteropathy-lymphocytopenia-alopecia (ELA).'

Neves et al. (2018) reported a 5-year-old girl who presented with type 1 ileal atresia (ileocecal membrane) at 2 months of age. At 5 months she developed bloody diarrhea, and colon biospy showed inflammatory pseudopolyps, caliciform cell depletion, and glandular distortion/atrophy. Examination showed dysmorphic features including prominent forehead and hypertelorism as well as enamel dysplasia. At 20 months she developed self-limited but recurrent elevations of liver enzymes, and biopsy showed mild fibrosis and interface hepatitis. She also experienced episodes of leukocytosis and thrombocytosis unrelated to infections, and immunologic evaluation revealed severe symptomatic hypogammaglobulinemia, associated with recurrent respiratory infections and absent serologic response to vaccines. Subcutaneous immunoglobulin replacement resulted in dramatic improvement, with fewer infections, no more episodes of leukocytosis, and improvement in colonic inflammation. At age 5 years, she had been asymptomatic for 12 months and was at the 50th centile for height, weight, and head circumference, with normal neurologic development.

Inheritance

The transmission pattern of multiple intestinal atresia in several reported families (e.g., Dallaire and Perreault, 1974, Puri et al. (1985), and Gungor et al., 1995) was consistent with autosomal recessive inheritance.

Population Genetics

Shen-Schwarz and Fitko (1990) noted that the patients reported by Guttman et al. (1973), Dallaire and Perreault (1974), Martin et al. (1976), Daneman and Martin (1979), and Skoll et al. (1987) were all French Canadian, suggesting an increased frequency in this ethnic group.

Mapping

In a large consanguineous kindred with enteropathy and combined immunodeficiency, Lemoine et al. (2014) performed genomewide homozygosity mapping with a SNP array that revealed a common 4-Mb region on chromosome 2p21-p16.3.

Molecular Genetics

Samuels et al. (2013) sequenced the exomes of 3 French Canadian probands with multiple intestinal atresia and identified only 1 homozygous variant shared by all 3 patients, a 4-bp deletion in the TTC7A gene (609332.0001), which was confirmed by Sanger sequencing and segregated with disease in each family. Sanger sequencing in 4 more affected French Canadian families revealed homozygosity for the 4-bp deletion in 1 proband; in 2 families in which DNA was unavailable from the deceased affected individuals, the parents were heterozygous for the deletion. In another French Canadian family, 2 affected sibs, 1 of whom exhibited severe immunodeficiency characterized by recurrent infections associated with hypogammaglobulinemia and profound T-cell lymphopenia, were compound heterozygous for the 4-bp deletion and a missense mutation (L832P; 609332.0002) in the TTC7A gene. Samuels et al. (2013) concluded that TTC7A was the likely causal gene for multiple intestinal atresia.

In 8 unrelated patients of varying ethnic origins who had combined immunodeficiency and multiple intestinal atresia, Chen et al. (2013) identified homozygous or compound heterozygous mutations in the TTC7A gene (see, e.g., 609332.0001, 609332.0002, 609332.0008-609332.0010). All of the mutations were not found or were rare in the 1000 Genomes Project and Exome Sequencing Project (ESP65400) databases, and were located at highly conserved regions of the gene.

Bigorgne et al. (2014) reported 6 patients from 6 unrelated pedigrees with multiple intestinal atresia and combined immunodeficiency who had mutations in the TTC7A gene (see, e.g., 609332.0003-609332.0007). Using gut organoids from 2 of these patients, Bigorgne et al. (2014) found that a lack of TTC7A led to disorganized and pseudostratified cell structures, low numbers of villi, and high levels of apoptosis. The authors found that TTC7A plays a critical role in apicobasal polarization of epithelial cells by regulating the RhoA (165390) signaling pathway.

In 5 infants from 3 families with apoptotic enterocolitis, variably associated with immunodeficiency and/or intestinal atresia, Avitzur et al. (2014) identified homozygosity or compound heterozygosity for mutations in the TTC7A gene (609332.0011-609332.0015). The authors noted that all reported TTC7A-deficient patients either died in infancy due to progressive bowel disease or failed allogeneic hematopoietic stem cell transplantation, or survived with short gut and total parenteral nutrition.

In a large consanguineous kindred with enteropathy and combined immunodeficiency mapping to chromosome 2p21-p16.3, Lemoine et al. (2014) sequenced the candidate gene TTC7A and identified homozygosity for a previously reported missense mutation (E71K; 609332.0014), which segregated with disease in the family. In addition, an affected 2-year-old boy from an unrelated family was compound heterozygous for a 1-bp deletion and a missense mutation in TTC7A.

In a 5-year-old girl with enteropathy, hepatic abnormalities, and isolated hypogammaglobulinemia, who was negative for mutation in the TTC37 (614589) and SKIV2L (600478) genes, Neves et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the TTC7A gene (A863T, 609332.0016 and S539L, 609332.0017). Her unaffected parents were each heterozygous for 1 of the mutations, both of which were rare in the gnomAD database.

Genotype/Phenotype Correlations

Neves et al. (2018) stated that 52 patients with GIDID had been reported worldwide, and noted that there appeared to be a severe form, with multiple intestinal atresia and combined immunodeficiency, resulting in premature death, and a milder form, with predominant features of very early-onset IBD, less severe immunologic involvement, and hair abnormalities. The authors suggested that the milder phenotype was associated with missense mutations that were likely hypomorphic, whereas the severe phenotype was associated with null mutations.

History

Mishalany and Der Kaloustian (1971) described multiple-level intestinal atresia in 2 sons of distantly related parents.