Fetal goiter is an extremely rare complication of pregnancy. Its incidence is 1 in 40,000 deliveries. Antithyroid maternal therapy is responsible for 10-15% of fetal congenital hypothyroidism and can be considered as the most frequent underlying cause for this condition. The frequency of fetal goiter that is associated with fetal hypothyroidism and normal maternal thyroid function, as in our case, is even less frequent. Fetal goiter is associated with increased rate of perinatal complications and long-term morbidity, due to peripartum complications including labor dystocia due to its mass effect, as well as neonatal airway obstruction that may lead to hypoxic-ischemic brain injury and death. We present, in this study, a case report of late antenatal fetal goiter in an euthyroid woman and a literature review of the diagnosis and treatment of these cases.

Ataxia telangiectasia (AT) is a genetic condition caused by mutations involving ATM (Ataxia Telangiectasia Mutated). This gene is responsible for the expression of a DNA double stranded break repair kinase, the ATM protein kinase. The syndrome encompasses combined immunodeficiency and various degrees of neurological abnormalities and increased risk of malignancy. Typically, patients present early in life with delay in neurological milestones, but very infrequently, with life threatening infections typical of a profound T cell deficiency. It would therefore be unexpected to identify this condition immediately after birth using T cell receptor excision circle (TREC)-based newborn screening (NBS) for SCID. We sought to evaluate the frequency of AT detected by NBS, and to assess immunity as well as the genetic aberrations associated with this early presentation. Here, we describe the clinical, laboratory, and genetic features of patients diagnosed with AT through the Ontario NBS program for SCID, and followed in our center since its inception in 2013. Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic. All of our patients had compound heterozygous mutations involving the FRAP-ATM-TRRAP (FAT) domain of the ATM gene, which appears critical for kinase activity and is highly sensitive to mutagenesis. Our patients presented with profound lymphopenia involving both B and T cells. The ratio of naïve/memory CD45+RA/RO T cells population was variable. T cell repertoire showed decreased T cell diversity. Two out of four patients had decreased specific antibody response to vaccination and hypogammaglobulinemia requiring IVIG replacement. In two patients, profound decreased responses to phytohemagglutinin stimulation was observed. In the other two patients, the initial robust response declined with time. In summary, the rate of detection of AT through NBS had been surprisingly high at our center. One case was identified per year, while the total rate for SCID has been five new cases per year. This early detection may allow for better prospective evaluation of AT shortly after birth, and may assist in formulating early and more effective interventions both for the neurological as well as the immune abnormalities in this syndrome.

In conclusion, we have reported a syndromic patient with combined immune deficiency and a homozygous MAN2B2 variant p.Asp38Asn associated with abnormalities of glycosylation and lysosomal involvement that were reversed in vitro upon lentivirus-mediated transfer of wild-type MAN2B2. We propose MAN2B2 biallelic p.Asp38Asn as a novel pathogenic variant leading to combined immune deficiency, abnormal glycosylation, and lysosomal involvement. Patients have normal transferrin isoelectric focusing profiles, and mild glycosylation changes by electrospray-ionization quadrupole time-of-flight in blood. At the age of 5 years, the patient received hematopoietic stem cell transplantation from her phenotypically HLA-matched father after reduced-intensity conditioning with fludarabine, busulfan, and rabbit antithymocyte globulin. Six months after hematopoietic stem cell transplantation, improvement in Tcell count and function, and in immunoglobulin production (with independence from intravenous immunoglobulins), was observed (Table E1), and stabilization of the disease was achieved, with resolution of infections. Our findings imply MAN2B2 deficiency as a novel CDG. On the basis of our data, we recommend screening for putative pathogenic variants in the MAN2B2 gene in pediatric patients presenting with combined immune deficiency and severe growth delay with intellectual or developmental disability.