Our patient was an 8-month-old Han Chinese baby boy who was referred for heart murmur, recurrent lower respiratory infections, psychomotor retardation, and hypotonia at his initial visit. He was the first child delivered to healthy, non-consanguineous young parents of Han Chinese origin, and was born at 39 weeks’ gestation with a birth weight of 3.1 kg after an uneventful pregnancy. He had no specific family medical history. During the neonatal period, hypotonia and feeding difficulties were noted and recurrent lower respiratory tract infections at 3 months of age (once per month). When he was 8-months old, he presented with heart murmur, failure to thrive, psychomotor retardation (unable to raise his head by himself), and hypotonia. A physical examination showed low weight (only 4 kg) with growth retardation, hypotonia with diminished deep tendon reflexes, bilateral alternating squint, inverted nipples, and hepatomegaly (the lower edge of his liver was located 3 cm below the costal margin at the mid-clavicular line), besides that, we noted a soft (grade 2/6) systolic ejection murmur at the second and the third left intercostal space with a diastolic rumble over his left lower sternum and fixed splitting of S2 was also noted. The rest of the physical examination was unremarkable.
Routine laboratory investigations showed normal urine analysis and fecal analysis, normal complete blood count and blood glucose, and normal blood gas analysis. Immunological examinations showed hypoimmunoglobulinemia (immunoglobulin G (IgG), 3 g/L; control values, 7 to 16 g/L) and low percentage of CD4
T lymphocytes (CD4
T%, 15%; control values, 32 to 51%) in our patient. Biochemical tests revealed his alanine aminotransferase (ALT) was significantly elevated at 450 IU/L (control values, 9 to 50 IU/L) and aspartate aminotransferase (AST) at 329 IU/L (control values, 15 to 40 IU/L), alpha fetal protein (AFP) was markedly elevated at 115.8 ng/ml (control values, ≤ 25 ng/ml), and creatine kinase (CK) levels were mildly elevated at 240 IU/L (control values, 26 to 174 IU/L). An endocrine metabolic workup revealed low levels of insulin-like growth factor 1 in serum ( 55 ng/ml), the rest of endocrine metabolic parameters including insulin, thyroxine, 25-hydroxy vitamin D3 and ammonia, acylcarnitine profile, and lactate were normal. Coagulation parameters showed activated partial thrombin time was prolonged by more than 1.5 times (57.7 seconds; control values, 23 to 35 seconds); antithrombin III was significantly decreased at 34.1% (control values, 85 to 130%). Cranial magnetic resonance imaging (MRI) demonstrated severe atrophy of cerebellar hemispheres with vermis hypoplasia (Fig.
). Chest radiography showed pulmonary blood stasis and increase of lung markings at the frontal position, narrowing of the aortic knob, and enlargement of right atrial at the lateral position; those image features were considered to be caused by ASD (Fig.
). Transthoracic echocardiography revealed normal thickness of interventricular and dilation of the right ventricle. Besides these, a secundum ASD in the middle of the atrial septum (defect size, 8.1 mm) was noted. Color Doppler echocardiography showed a secundum defect with left-to-right shunt in the middle of the atrial septum and the Qp/Qs ratio was 1.6 which meant the blood shunt was moderate (Fig.
). Transabdominal ultrasound showed hepatomegaly (left subcostal oblique diameter, 73.6 mm) with heterogenous echoes, and we considered that it was caused by fatty liver. Urinary ultrasonography showed no abnormal results in bilateral kidneys, ureters, and bladder.
With the above clinical results, CDG-1 was considered, and isoelectric focusing of serum transferrin analysis was performed, this analysis showed markedly increased levels of disialotransferrin band and decreased levels of tetrasialotransferrin band, this transferrin pattern was consistent with CDG-1. Enzyme testing of cultured skin fibroblasts for PMM2 activities in our patient demonstrated decreased levels of PMM2 activities (0.4 nmol/min · mg protein; control values, 1.8 to 8.8 nmol/min · mg protein), while the PMM2 activities in his father and mother were both normal (2 and 2.2 nmol/min · mg protein, respectively). The diagnosis of CDG-1a was obvious. Chromosomal microarray analysis was performed and found no chromosomal rearrangement. Whole exon sequencing was performed after his parents gave their informed consent for this genetic analysis and the result showed that our patient was heterozygous for the frameshift mutation and missense mutation in
). The first was 458_462 del TAAGA mutation in exon 6, which was predicted to result in the premature translational termination at amino acid position 153 (I153X), causing the absence of the 93 amino acids of C-terminal domain, and further led to no activity of PMM2 protein derived from this allele. The second was 395 T>C mutation in exon 5, which was predicted to result in the amino acid exchange p.I132T. The p.I132T mutation has been reported to be pathogenic [
]. Furthermore, a cross-species comparison of the PMM2 protein sequence revealed that this isoleucine residue at amino acid position 132 was conserved from protists to primates (Fig.
) and, thus, was likely to be functionally important. Analysis of parental blood samples showed that our patient’s father was heterozygous for the I153X mutation and his mother was heterozygous for the I132T mutation (Fig.
After admission, our patient was treated regularly with general supportive treatment including: liver, heart, and muscle protection; anticoagulant therapy and anti-infective treatment; and intravenously administered immunoglobulin infusion in order to improve immunity. Now, at the age of 3-years old failure to thrive, bilateral alternating squint and inverted nipples still exist, and his weight only increased to 10 kg; the location and feature of existing cardiac souffle remain unchanged, but fixed splitting of S2 disappeared. His hepatomegaly is resolved (the lower edge of his liver was located 1 cm below the costal margin at the mid-clavicular line) and he can raise his head by himself for minutes and speak several single words (two to three words), such as ma-ma or pa-pa. Hypotonia gradually improved but he is still unable to sit or crawl. The infections of his lower respiratory tract became more severe than before and the frequency increased to two to three times per month. Besides that, the symptom of nystagmus emerged which is thought to be related to the aggravation of cerebellar atrophy. Hypoimmunoglobulinemia and low percentage of CD4+ T lymphocytes remained (IgG, 4.7 g/L; CD4+T%, 20%). Liver dysfunction and abnormalities of CK and CK–myocardial band (CK-MB) improved (AST 80 IU/L and AFP 37 ng/ml, CK 100 IU/L and CK-MB 20 IU/L); the levels of antithrombin III slightly increased (45%). A re-examination MRI of his cerebellar revealed atrophy of cerebellar hemispheres still exists and the volume of cerebellar hemispheres was evidently less than the average level of his peers; the absence of cerebellar vermis was noted obviously (Fig. 1c, d). These results may suggest the state of CDG-1a in our patient progresses continually and may develop to the next stage (childhood ataxia-intellectual disability). Re-examination of chest radiography showed narrowing of the aortic knob and enlargement of right atrial had improved slightly compared with his first visit, but pulmonary blood stasis was obviously more aggravated than before (Fig. 2c, d). Re-examination of echocardiography revealed the existing defect had increased and the size increased from 8 to 10 mm; the left-to-right shunt also existed and the Qp/Qs ratio increased from 1.6 to 1.9, which means the blood shunt was more severe than before (Fig. 3c, d). The blood shunt and defect size were all increased, which suggested the exacerbation of ASD. Then, we performed CHD-associated gene sequencing in our patient and his family, which contained mutations in 24 common genes essential to cardiac septation (ACTC1, BRAF, CRELD1, ELN, G6PC3, GATA4, GDF1, GJA1, HRAS, JAG1, KCNJ2, KRAS, MYH6, NKX2-5, NRAS, PTPN11, RAF1, RBM10, SOS1, TBX1, TBX20, TBX5, TLL1, ZFPM2). Mutations in those genes may cause exacerbation of ASD; however, we found that our patient and his parents have no pathogenic mutations in those genes.
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