The long-term outcome following thoraco-amniotic shunting for congenital lung malformations.

AIM OF THE STUDY: Insertion of a thoraco amniotic shunt (TAS) during fetal life is a therapeutic option where there is a high risk of death secondary to large congenital lung malformations (CLM). The aim of this study is to present our center's long-term experience. METHODS: Retrospective single center review of the period (Jan 2000-Dec 2020). We included all fetuses that underwent TAS insertion for CLM with detailed analysis of those live newborns managed in our center. Data are quoted as median (range). MAIN RESULTS: Thirty one fetuses underwent 37 TAS insertions at a 25 (20-30) weeks gestational age. This was successful on 1st attempt in 30 (97%) fetuses. In 6 cases a 2nd shunt was required at 6.5 (2-10) weeks following the 1st insertion. Twenty-eight survived to be born. Sixteen (9 male) infants were delivered in our center at 39 (36-41) weeks gestational age and birth weight of 3.1 (2.6-4.2) kg. All infants underwent surgery at 2 (0-535) days (emergency surgery, n = 9; expedited n = 4; elective surgery, n = 3). Final histopathology findings were CPAM Type 1 (n = 14, n.b. associated with mucinous adenocarcinoma, n = 1), CPAM Type 2 (n = 1) and an extralobar sequestration (n = 1). Postoperative stay was 16 (1-70) days with survival in 15/16 (94%). One infant died at 1 day of life secondary to a combination of pulmonary hypoplasia and hypertension. Median follow up period was 10.7 (0.4-20.4) years. Nine (60%) children developed a degree of chest wall deformity though none have required surgical intervention. Clinically, 14/15 (93%) have otherwise normal lung function without limitations of activity, sporting or otherwise. One child has a modest exercise limitation (FVC - 70% predicted). CONCLUSIONS: TAS insertion is associated with high perinatal survival and should be considered in fetuses at risk of hydrops secondary to large cystic lung malformation. Their long term outcome is excellent although most have a mild degree of chest wall deformity.

Neonatal congenital pulmonary airway malformation associated with mucinous adenocarcinoma and KRAS mutations.

AIM OF THE STUDY: Congenital pulmonary airway malformation (CPAM) has an estimated prevalence in Europe of 1.06/10,000 live births with most being detected using maternal ultrasound screening. Malignant transformation is a possible complication though its prevalence is unknown and previous reports have usually been in older children. We reviewed our experience to identify those CPAM cases associated with malignancy. METHODS: Single centre retrospective review of all surgically treated children with antenatally-detected CPAM, with detailed review of cases associated with malignancy. MAIN RESULTS: 210 infants and children underwent resectional surgery for CPAM during the period 1994-2020, with 43(20.5%) undergoing surgery during the neonatal period. Of these, 3 infants, all males, had undergone surgical resection for respiratory distress (at 3, 4 and 8 days of life) with subsequent histological confirmation as Stocker type 1 CPAM with clear foci of mucinous adenocarcinoma. Subsequent genetic analysis showed somatic KRAS (Kirsten Rat Sarcoma Viral Oncogene) mutations in all three cases. No adjuvant treatment was required, and all are asymptomatic and disease-free at most recent follow-up (8 months, 2 and 6 years) CONCLUSIONS: This series highlights a clear association between type 1 CPAM and mucinous adenocarcinoma with KRAS point mutations, suggesting that the process of carcinogenesis has the potential to start in utero. This underlines the importance of discussing the risk of malignancy in prenatal and postnatal counselling.

Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.