Avishay Lahad

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects

Somech and colleagues identify two new mutations in STN1 that causes Coats plus syndrome and telomere abnormalities in human, recapitulated in a zebra fish model.

Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort

Background:Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients.Methods:Retrospective study comprising all 52 patients (aged 2–26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts.Results:Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (−1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients.Conclusion:Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.

Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report.

Objective: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. Methods: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. Results: Fifty-three patients, 27 (49%) boys, age 14.6 ± 5.2 years (range 5.9–26.1 years), were included. Twenty-three patients (43.4%), age 9.9 ± 5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 ± 73.8 IU/L, aspartate aminotransferase 70 ± 50 IU/L, alkaline phosphatase 331 ± 134 IU/L, and gamma glutamyl transferase 114.7 ± 8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. Conclusions: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

Exome sequencing as a differential diagnosis tool: resolving mild trichohepatoenteric syndrome

To the Editor: Whole-exome sequencing is an indispensable tool for deciphering the genetic underpinnings of rare Mendelian disorders. However, the use of this methodology as a routine clinical diagnostics tool is only beginning to emerge (1, 2). We report the genetic resolution of a mild case of congenital diarrhea by whole-exome sequencing, with implications to the utility of routine use of such analysis. Patient 12.1 (Fig. 1a), 4-year-old girl in a Middle-Eastern Arab consanguineous family with no gastrointestinal history, developed persistent secretory diarrhea at 18 days of age, which did not improve upon cessation of feedings, nor under a trial of Galactomin 19 formula (for suspicion of glucose–galactose malabsorption), and has been completely dependent on total parenteral nutrition (TPN) ever since. She had minor dysmorphic features but no obvious developmental delay (Fig. 1b). Despite mild elevation of liver transaminases, abdominal ultrasounds suggested no major hepatic phenotype. Duodenal biopsies excluded tufting enteropathy and microvillous inclusion disease. Brain magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) and metabolic screens including urine reducing substances, blood and urine amino acid profiles, blood homocysteine levels and lipid profile, were normal. There were no presentations of cardiac, cutaneous, platelet or immune deficiency phenotypes as immunoglobulin levels were normal and patient responded well to vaccinations (Table S1, Supporting Information). Sweat test and genetic testing excluded cystic fibrosis. Exome sequencing of the patient (Appendix S1) revealed 590 rare homozygous variants. These were prioritized using VarElect within GeneCards (3), showing five gastrointestinally related candidate genes (Table S2). The strongest phenotype implication was for TTC37, a known gene for trichohepatoenteric syndrome [THES (MIM 222470)], harboring a homozygous damaging missense mutation in an evolutionary conserved residue (c.2282 A>G; p.Leu761Pro), with zero frequency in controls, that withstood validation (Fig. 1a,c). Microscopic examination of the patient’s hair showed hair shafts of varying sizes, some discontinuous with areas of thinning and breaks (trichorhexis nodosa, Fig. 1d). Thus, these results provide convincing support for identifying the patient as afflicted with THES. THES is a rare form of congenital diarrhea with an estimated frequency of 1 in 450,000 births. This heterogeneous disorder has a widely varying spectrum of phenotypes while most prevalent clinical features include secretory diarrhea, hair abnormalities and facial dysmorphism. Liver dysfunction is associated in about half of the patients and varies in severity (4, 5). In retrospect, our patient appears to have a rather mild form of THES. While presenting certain facial dysmorphism and minor hair phenotypes, she showed none of the reported hepatic symptoms and had no immune deficiency. Further, none of the less frequent THES symptoms were observed, including cardiac, cutaneous and platelet abnormalities (4). The hair abnormalities observed prior to the microscopic examination were minor and could have occurred because of severe malnutrition caused by the diarrhea. Such mild clinical presentation accounts for the fact that THES was not suspected in the present case. Hartley et al. identified nine recessively inherited mutations in TTC37 in families of variable ethnic origins (6). Some of these were also found in another study that analyzed TTC37 in 12 THES patients from 11 different families (7). The TTC37 homozygous missense mutation we found is extremely rare in the general population (<6× 10−5), and not previously reported. This is potentially related to the unusual syndromic disposition, somewhat different from the previously described patients, and perhaps also to the uncommon ethnogeograpy – causing THES in Middle-Eastern Arabs not previously reported (6, 7). The definitive molecular diagnosis will allow pre-natal testing and genetic counseling to the family for future pregnancies. It could also focus on essential medical evaluation preventing unnecessary invasive examinations and can potentially allow new therapeutic approaches if such arise in the future (6). In summary, our findings illustrate that whole-exome sequencing may be successfully used for undiagnosed patients with atypical or mild presentation of a known disorder, with particular relevance to the emerging era of routine clinical DNA sequencing.

Current therapy of pediatric Crohn’s disease

Inflammatory bowel diseases (IBD), including Crohns disease (CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate, antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor (TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy - induction and maintenance of remission while improving the patients growth and overall well-being.