A male neonate weighing 2,020 g was given birth to by a 33-year-old Chinese mother (gravida 2, para 2) via cesarean section. The parents are non-consanguineous. During the first 5 weeks of pregnancy, the mother was treated with progesterone, and dydrogesterone until week 13 of gestation due to the signs of abortion. At week 24 of pregnancy, edema developed at the mother's lower limbs and gradually aggravated to anasarca at the end of the pregnancy. The mother was diagnosed with gestational diabetes at week 25 of gestation and her blood sugar levels fluctuated within a normal range through diet control. By 36 weeks, an ultrasound showed oligohydramnios and a normal heart silhouette, increased cardiothoracic ratio, and a small lung volume, indicating pulmonary hypoplasia (Figure 1). The family history was unremarkable.
Labor was induced considering the oligohydramnios and a 3-h premature rupture of the fetal membrane at week 36. The placenta was grayish red and the focal purple red. No abnormalities were found in the umbilical cord. The Apgar scores of this neonate at 1 min and 5 min were 5 and 7, respectively. Ten minutes after birth, the neonate was admitted to the neonatal intensive care unit (NICU) for ventilation support due to tachypnea.
A physical examination on admission showed a weak response, weak crying, hoarseness, respiratory distress, positive signs of triple concave and anasarca. The neonate had many special clinical phenotypes (Figure 2). The facial features included dysmorphic hypertelorism, down-slanting eyes, an eye movement disorder, ectropion, hypophasis, thickening of the helix, constriction of the auricular rim, curl of the auricle and auricle cartilage, a flat nasal bridge, small nostrils, and everted lips. Ichthyotic and collodion skin covered the entire body with a shiny, red and tight appearance and was very friable, much like a layer of gelatinous film. The skin on the hands, feet, groin and scrotum was peeling extensively, and red tender skin was exposed. The breath sounds were clear, and no rales were heard during the auscultation of both lungs. A continuous machinery rumbling murmur was heard at the upper left sternal edge. A 3/6 pansystolic murmur was heard all over the precordium but clearest at the left sternal edge. The abdomen was markedly distensible. The liver was 5 and 6 cm under the right costal margin and under processus xiphoideus, respectively. The spleen was 6 cm below the left costal margin. Both organs had an extremely firm, stone-like texture when palpated. The neonate was immobile unless upon stimuli, accompanied by flexion contractures at the elbow and knee joint, hypertonia, akinesia. Myoclonic movements were noted soon after birth. Myoclonic seizures manifested through limb jitters that lasted about 10 s before alleviation. The bilateral testis did not descend to the scrotum. The neonate had small microcaulia. Primitive reflexes were not elicited.
At birth, the CBC indicated a platelet count of 19,000/mm3, WBC 11,880/mm3, and hemoglobin at 143 g/L. At 2 d of age, the CBC indicated the platelet count at 8,000/mm3, WBC 13,170/mm3, and hemoglobin at 165 g/L.
A liver function test noted hypoproteinemia (TP 53.1 g/L, ALB 26.9 g/L); elevated enzymes (AST 123.4 U/L); and cholestasis (TBILI/ DBILI 43/28 mumol/L, TBA 25 mumol/L, gamma-GT 183U/L, ALP 249 U/L), LDH 326 U/L at birth. The peak values of TBILI 89 U/L, DBILI 69 U/L, TBA 37 mumol/L, gamma-GT 773 U/L, ALP 296 U/L, LDH 1055 U/L.
The initial coagulation test showed the following: PT of 25.7 s, APTT of 40.4 s, TT of 26.4 s, INR of 2.08, FIB 0.79 g/L.
The neonate underwent a bone marrow puncture at 5 d of age because he had no response to intravenous platelet and gamma globulin treatment. Bone marrow aspiration indicated proliferous granulocytic cells and erythroid cells. The ratio of lymphocytes was high. Three megakaryocytes were found in the whole smear. No Gaucher cells were found.
The pathology of the placenta, fetal membrane and umbilical cord showed chronic inflammation with placental villi denatured necrotic calcification focus and umbilical cord arteriovenous congestion and focal hemorrhage.
At birth, an echocardiography revealed (1) normal size of the atrium and ventricular chamber, normal thickness of the ventricular wall, normal structure of the valve; (2) normal connection and inner diameter of the aorta and pulmonary artery; (3) LVEF 62%; (4) CDFI: a patent ductus arteriosus with continuous left-to-right shunt signal between the root of the left pulmonary artery and the initial segment of the descending aorta, a beam width of 1.5 mm; ventricular septal defect with small left-to-right shunt signal in the middle segment of the ventricular septum during systole, a beam width of 1.2 mm, Vmax 3.0 m/ s, PGmax 37 mmHg measured by CW; a moderate reflux signal at the atrial side of the tricuspid orifice during systole, Vmax 3.3 m/ s, Pgmax 44 mmHg, moderate tricuspid regurgitation measured by CW, the pulmonary artery systolic pressure of 54 mmHg estimated by the degree of tricuspid regurgitation.
An abdominal ultrasound showed palpable hepatosplenomegaly and cholestasis. A genital ultrasound revealed that the bilateral testis had hydrocele. At 2 d of age, lung computed tomography indicated a lack of air in the lungs (Figure 3A), and a brain computed tomography revealed multiple hemorrhagic lesions in the left frontal, temporal and parietal lobes (Figure 3B). At 9 d of age, a craniocerebral MRI disclosed a small hemorrhagic lesion in the left parietal lobe accompanied with a widening of part of the external space. At 14 d of age, the neonate developed frequent tonic seizures and an electroencephalogram showed sharp waves, spike waves, and outburst suppressions. The sleep cycle was not observed. At 16 d of age, no hemorrhagic lesions were found in the craniocerebral MRI.
At 19 d of age, an echocardiography demonstrated LVEF 63%, VSD with small left-to-right shunt signal and a pulmonary artery systolic pressure of 47 mmHg. At 35 d of age, an echocardiography demonstrated LVEF 60%, VSD and a pulmonary artery systolic pressure of 38 mmHg.
Cytogenetic evaluation revealed 46 XY. No copy number variation associated with clinical symptoms was detected in the whole genome copy number variation analysis.
We correlated all the aforementioned manifestations with a possible metabolic disease. At 44 d of age, the leukocyte enzyme assay for beta-glucocerebrosidase revealed an activity of 0.00 nmol/h/mg (control range: 10-25 nmol/h/mg), explicitly supporting the diagnosis of PLGD. Testing of the mother and father revealed serum beta-glucocerebrosidase enzymatic activities of 13.3 and 17.8 nmol/h/mg, respectively. Urinary screening for metabolic disorders by GCMC was negative.
The proband's GBA sequencing analysis demonstrated two heterozygous mutations, Gly234Glu (c.701G>A; p.G234E) in exon 7and His413Pro (c.1238A>C; p.H413P) in exon 10 (Figure 4).
Following admission to the NICU, the patient was given non-invasive respiratory support. Without sucking and swallowing, he was always kept fed through a gastric tube. With refractory thrombocytopenia, he was treated with 2 days of an intravenous infusion of gamma globulin (1 g/kg/d) and intermittent multiple transfusion of platelets; the platelet count fluctuated between 22,000 and 68,000/mm3. After treatment with intravenous infusion of vitamin K, ethamsylate and cryoprecipitate, anomaly coagulation parameters were improved. Levetiracetam, and phenobarbital were administrated orally to control the severe myoclonus, but the symptoms were poorly controlled. At 44 d of age, with the confirmation of PLGD diagnosis, the treatment was discontinued upon the parent's request. The patient was then discharged and taken home.
During the follow-up period, the patient kept gastric tube feeding, had no increase in physique, and gradually developed a pale face, obstinate hiccups, progressive neurological deterioration, hepatosplenomegaly, abdominal varicose veins, systemic edema (especially in the lower limbs and scrotum). He was supplied with humidified oxygen via a face mask, adequate caloric intake was ensured and excessive salt intake was avoided. He was also given dihydrochlorothiazide, spironolactone, and lanatoside C. However, respiratory failure, hepatic failure, and renal failure gradually occurred. The patient died at the age of 73 days.