Molecular and clinical studies of intestinal malrotation

Sammanfattning: Intestinal malrotation (IM) can present as a potentially life-threatening condition with midgut volvulus and need of immediate surgery, but also as a chronic condition with longlasting symptoms. It is a well-known neonatal condition but it is not as well “explored” up to adulthood. Familial cases and chromosomal aberrations have been described, as well as genetic syndromes associated with intestinal malrotation, but the molecular cause is not known. The aim of study I and II was to describe symptoms, management and outcomes of IM throughout all age groups by scrutinizing medical records and through interviews. In study III and IV the aim was to study the molecular background of IM. In study I, 39 adult patients, 15-67 years old, were included. 31 (79%) underwent a Ladd’s procedure and among them 12 (31%) as an emergency procedure. A triple contrast CT scan confirmed the diagnosis and many patients, who often had symptoms for several years were relived of symptoms after Ladd’s procedure, even though six needed re-do surgery because of recurrence. In study II, 138 children were included based on strict inclusion criteria, 1-15 years old. 125 (91%) had Ladd’s procedure and only one had recurrence needing re-do surgery. The major findings were that the most common diagnostic symptom up to 5 years of age was vomiting, while abdominal pain was a more relevant symptom in older children and adults. Complications were mainly detected among extremely premature children, with an overall mortality of 50%, and also among children who had severely affected circulation. Four children had a chronic intestinal failure, two because of midgut volvulus and 14 patients (11%) had adhesive bowel obstruction. In study III, by using array CGH we detected six different copy number variants (CNVs) in five patients of the 47 DNA samples that were analyzed. Five were found in patients with other malformations or developmental delay and one in a patient with isolated IM had a variant of unknown significance in the GALNT14 gene. In study IV, we performed whole genome sequencing (WGS) in ten children with severe isolated IM, and found two maternally inherited allelic mutations in the TTC7A gene in a boy with isolated IM. Further studies showed that the mother also had a rotational abnormality. The rare autosomal recessively inherited TTC7A deficiency disorder causes multiple intestinal atresia and immunodeficiency, but also IM in some case reports. In conclusion, the results of this thesis show that IM should be regarded as a malformation affecting all age groups, and midgut volvulus can occur in all ages. The symptoms vary with age and calls for an active strategy for diagnosis and treatment. Extreme prematurity as well as midgut volvulus with severely affected circulation, increase the risk for shortterm complications after surgery. We recommend genetic screening for CNVs in cases with IM and other associated malformations or a neurodevelopmental disorder and the TTC7A gene needs to be further studied in larger groups of cases with IM.