Background Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. Objective We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families. Methods We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A ( TTC7A ) on 3 additional patients with CID-MIA. Results Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA. Conclusions We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.

/pdf/whole-exome-sequencing-identifies-tetratricopeptide-repeat-3v6xlhou0f.pdf

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias

Background Congenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype. A genetic basis for MIA is likely. We had previously ascertained a cohort of patients of French-Canadian origin, most of whom were deceased as infants or in utero. The goal of the study was to identify the molecular basis for the disease in the patients of this cohort. Methods We performed whole exome sequencing on samples from five patients of four families. Validation of mutations and familial segregation was performed using standard Sanger sequencing in these and three additional families with deceased cases. Exon skipping was assessed by reverse transcription-PCR and Sanger sequencing. Results Five patients from four different families were each homozygous for a four base intronic deletion in the gene TTC7A , immediately adjacent to a consensus GT splice donor site. The deletion was demonstrated to have deleterious effects on splicing causing the skipping of the attendant upstream coding exon, thereby leading to a predicted severe protein truncation. Parents were heterozygous carriers of the deletion in these families and in two additional families segregating affected cases. In a seventh family, an affected case was compound heterozygous for the same 4bp deletion and a second missense mutation p.L823P, also predicted as pathogenic. No other sequenced genes possessed deleterious variants explanatory for all patients in the cohort. Neither mutation was seen in a large set of control chromosomes. Conclusions Based on our genetic results, TTC7A is the likely causal gene for MIA.

https://jmg.bmj.com/content/jmedgenet/50/5/324.full.pdf

Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia

The increasing incidence of pediatric inflammatory bowel disease, coupled with the efficiency of whole-exome sequencing, has led to the identification of tetratricopeptide repeat domain 7A (TTC7A) as a steward of intestinal health. TTC7A deficiency is an autosomal-recessively inherited disease. In the 5 years since the original description, more than 50 patients with more than 20 distinct disease-causing TTC7A mutations have been identified. Patients show heterogenous intestinal and immunologic disease manifestations, including but not limited to multiple intestinal atresias, very early onset inflammatory bowel disease, loss of intestinal architecture, apoptotic enterocolitis, combined immunodeficiency, and various extraintestinal features related to the skin and/or hair. The focus of this review is to highlight trends in patient phenotypes and to consolidate functional data related to the role of TTC7A in maintaining intestinal homeostasis. TTC7A deficiency is fatal in approximately two thirds of patients, and, as more patients continue to be discovered, elucidating the comprehensive role of TTC7A could show druggable targets that may benefit the growing cohort of individuals suffering from inflammatory bowel disease.

TTC7A: Steward of Intestinal Health.

Postoperative chylothorax occurs due to trauma to lymphatic vessels and can occur after any thoracic procedure. This study reviewed recent literature to evaluate the management and outcomes of surgical chylothorax in neonates. PubMed database was searched for articles in English, Portuguese and Spanish from 2000 to 2016. Data were collected for surgery, chylothorax management, complications, mortality and length of hospital stay (LOS). Twenty studies offered 107 neonates: congenital diaphragmatic hernia (CDH) (n = 76, 71%), cardiac malformations (n = 25, 23.4%), esophageal atresia (n = 5, 4.7%) and CDH + extralobar sequestration (n = 1, 0.9%). Medium-chain triglycerides (MCT) was the initial treatment in 52 neonates (48.6%), prednisolone + MCT in one (0.9%), total parenteral nutrition in 51 patients (47.7%), and three patients (2.8%) did not require any treatment. Octreotide and somatostatin were used as second or third line treatment in 25 neonates (23.4%), and 15 neonates (14%) underwent 17 surgeries, including thoracic duct ligation (TDL) (n = 9); pleurodesis (n = 3) (2 patients required TDL); TDL + pleurodesis (n = 2), and TDL + placement of hemostat (n = 1). Complications due to the chylothorax were reported in 27 neonates (25.2%): hypoalbuminemia + hyponatremia (n = 18), hypoalbuminemia (n = 4), hypoalbuminemia with cutaneous flushing as colateral effect of somatostatin (n = 1), loose stool after somatostatin use (n = 1), pneumonia (n = 1), congestive heart failure + hypernatremia (n = 1), and hyponatremia (n = 1). There were 21 deaths (19.6%) and median LOS was 53.4 days (30–93.1 days). Conservative management is appropriate as initial treatment for neonatal postsurgical chylothorax. Octreotide and somatostatin are safe in neonates and surgical approach should be considered in prolonged leaks.

Surgical chylothorax in neonates: management and outcomes

Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort.

Hereditary multiple intestinal atresia (HMIA), a presumed autosomal recessive disorder, is an unusual and rare form of recurrent intestinal atresia which can be associated with severe combined immunodeficiency (SCID). The combination of HMIA and SCID is invariably lethal. The authors describe this fatal association in two siblings. The parents are consanguineous and have three other normal healthy children. Both index cases had abnormal antenatal ultrasounds and were symptomatic after birth. The final diagnosis of HMIA with SCID was confirmed in both siblings. They were never able to receive enteral feeds, remained totally dependent on parenteral nutrition, had repeated episodes of sepsis and died after a very difficult neonatal intensive care course. In this article we have reviewed the clinical course and outcome of both cases. The existing literature on multiple intestinal atresia, HMIA and HMIA with immunodeficiency is also reviewed.

/pdf/hereditary-multiple-intestinal-atresia-hmia-with-severe-1ylnso60yt.pdf

Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years

Chylothorax, a known complication of surgery for Congenital Diaphragmatic hernia, can sometimes be resistant to treat. Octeriotide (Somatostatin analogue) can be useful in this situation. However, the dose and schedule of Octeriotide therapy in neonates is not well established. We report two cases of resistant chylothorax following surgery for congenital diaphragmatic hernia which were successfully managed by using an escalating infusion of octeriotide. The literature on the subject is also reviewed.

Use of octeriotide in the management of neonatal chylothorax secondary to repair of congenital diaphragmatic hernia: a report of two cases and review of literature.

Ibrahim El Sayed Bassiouny

Papers

Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years

Use of octeriotide in the management of neonatal chylothorax secondary to repair of congenital diaphragmatic hernia: a report of two cases and review of literature.