Introduction

Congenital disorders of glycosylation (CDG) are a group of disorders caused by defects in proteins or lipid glycosylation. Over 100 types of CDG have been reported thus far [1, 2], but the clinical suspicion for each subtype is difficult to determine. Isoelectric focusing of transferrin or apolipoprotein C-III has been used to analyze glycosylation patterns. However, not all types can be detected by these assays.

CDG is usually characterized by severe multisystemic abnormalities in affected patients. Curative treatment is not available in most cases, but definitive diagnosis is still important to determine the need for palliative care for the patient and future reproductive counseling for the parents. Herein, we report a patient who was eventually diagnosed with an extremely rare CDG type, mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb), using targeted exome sequencing. Our patient came from the third family reported with this subtype. Of note, despite its extreme rarity, the affected patients from the three families shared similar dysmorphic features and systemic abnormalities that may facilitate the diagnostic process for this type.

Case description

The patient was the second child born at 37 weeks of gestation from non-consanguineous Korean parents. The first child died at age seven months due to unexplained liver failure.

On prenatal ultrasonography, polyhydramnios, cardiomegaly, hepatomegaly, and hydrocele were found. Soon after birth, he was hypotonic with generalized edema and hepatomegaly. He had dysmorphic facial features with a narrow forehead, hirsutism, light-colored hair, short palpebral fissure, hypertelorism, long eyelashes, a broad nose, retrognathia, and a high-arched palate (Fig. 1a). His fingers overlapped, second over third and fifth over fourth (Fig. 1b). His mother recalled a similar facial appearance of his dead sibling. He showed recurrent apnea and oxygen supplementation via nasal cannula with aminophylline was continuously required. Hepatosplenomegaly with progressive cholestasis and thrombocytopenia was also noted. In addition, thyroid hormone was given due to hypothyroidism with a low thyroixine-binding globulin level. Serum immunoglobulin G was normal, but IgA and IgM were decreased for the age of the patient. He had no seizure events, but suffered from a recurrent syndrome of inappropriate antidiuretic hormone secretion, which was recovered by volume restriction.

Fig. 1
figure 1

Pictures of the patient’s face (a) and hand (b) at 3 months of age. Note the dysmorphic features with microcephaly, narrow forehead, hirsutism, long eyelashes, hypertelorism, retrognathia, and clenched overlapped fingers

Full size image

His karyotype was 46, XY and his mitochondrial DNA in peripheral leukocytes had a normal sequence with no large deletions. Array comparative genomic hybridization results were normal.

At four months of age, he expired due to multiple organ failure.

Materials and methods

Written informed consent was obtained for exome sequencing from all parents and the study was approved by the local ethics committee. Exome sequencing was performed at one month of age using genomic DNA extracted from peripheral blood leukocytes. Exomes were captured using the TruSight One Panel (Illumina Inc., San Diego, CA, USA), which enriches a 12-Mb region spanning 4813 genes. Sequencing was performed on the NextSeq platform (Illumina Inc.). Sequence reads were aligned to the reference genome, hg19, using Burrow-Wheeler Aligner (version 0.7.12, MEM algorithm) [3]. Candidate variants were confirmed by Sanger sequencing using custom-designed primers.

Results

The following two variants in the MOGS gene, encoding mannosyl-oligosaccharide glucosidase, were considered as candidate variants: c.2405 C > T (p,Thr802Ile) and c.1603C > T (p.Arg535*) of exon 4 (NM_006302.2). Genetic analysis showed that the parents were heterozygous for one of the each mutated alleles.

To confirm CDG, transferrin plasma levels were measured by isoelectric focusing (IEF), as previously described [4]. Trisialotransferrin was elevated, but monosialotransferrin and asialotransferin were not (Fig. 2). Based on the above results, the patient was diagnosed with MOGS-CDG.

Fig. 2
figure 2

Isoelectric focusing of transferrin showing an abnormal trisialotransferrin pattern. Patient, sample 3; Normal control, sample 1, 2, 4; PMM2-CDG, sample 5; COG2-CDG, sample 6

Full size image

Discussion

Including the case described here, only four patients from three unrelated families have been reported with MOGS-CDG [5, 6]. The first reported patient died at 74 days [5], but two other siblings were reported to be alive at 6 and 11 years [6].

CDG should be included in the differential diagnosis for any congenital condition exhibiting multisystemic manifestations [7, 8]. Despite being an extremely rare CDG type, there are some recognizable clinical features in MOGS-CDG. The two patients, including our case, for whom detailed clinical information was available, showed common dysmorphic features. These include a short palpebral fissure, long eyelashes, a broad nose, retrognathia, hirsutism, and clenched overlapped fingers (Table 1). The presence of other shared manifestations, including generalized edema, apnea, and hypogammaglobulinemia, will help diagnose this subtype.

Table 1 Clinical characteristics of patients reported to have MOGS-CDG
Full size table

Currently, IEF is the first step in screening for CDG [4]. However, transferrin polymorphisms can confuse the interpretation of results [9] and a normal IEF pattern may also be observed in some patients [5, 8]. In our case, elevated trisialotransferrin was consistent with type 2 CDG [10]. In a previous case (patient 1, Table 1), IEF was normal and the diagnosis of MOGS-CDG was made by urinary oligosaccharide identification using thin layer chromatography and glucosidase I activity measurement in cultured skin fibroblasts and genetic testing [5]. The two siblings of the other case were diagnosed by urine chromatography analysis, mass spectrometry, and genetic testing [6].

Thyroid-binding globulin is decreased and hypogammaglobulinemia is observed in all MOG-CDG cases [11, 12]. Hypogammaglobulinemia results from the shortened half-life of immunoglobulins due to a glycosylation defect. However, two patients (case 2 and 3) who survived for several years, paradoxically did not have a serious infection to enveloped viruses despite hypogammaglobulinemia [6]. In MOGS-CDG, viral replication and cellular entry is thought to be impaired due to a glycosylation defects in human viral receptors and the viral envelope.

The clinical course of a patient with MOGS-CDG is expected to be grave, considering the very short life-span of the two patients including our case [5]. The longer survival observed in the other siblings [6] are associated with the reciprocal mitotic recombination between compound heterozygous alleles, which causes reversion to a wild-type allele in somatic cells. The survival or growth advantage of these cells with the wild-type allele ameliorates the phenotype of the siblings [13].

With rapid advances in human genome studies, multi-gene testing using next-generation sequencing techniques may help the genetic diagnosis of CDG. Although each subtype is extremely rare, CDG is now gaining recognition as an important group of diverse diseases affecting pan-ethnic populations. As more cases are identified, the clinical characteristics of each subtype will be delineated as MOGS-CDG described here.