Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Hypophosphataemia in the newborn: a peculiar cause (#44)

Emily Papadimos 1 2 , David Coman 2 3 , Louise S Conwell 1 2 , Jim McGill 2 3 , Kalliope Demetriou 2 3 , Anita Inwood 2 3 , Mark Harris 1 2
  1. Department of Endocrinology and Diabetes, Queensland Children's Hospital, South Brisbane, QLD, Australia
  2. School of Clinical Medicine, Faculty of Medicine, The University of Queensland, Brisbane, QLD
  3. Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD, Australia

Mucolipidosis Type II (MLII, or I-cell disease) is an autosomal recessive lysosomal storage disorder caused by deficiency of enzyme N-acetylglucosamine-1-phosphotransferase (G1cNAc-PT), encoded by GNPTAB(1). The early radiographic phenotype may mimic hyperparathyroidism and rickets, which appears to evolve into osteodystrophy over the first 4 months of life(1). Hyperparathyroidism has been reported but the mechanism is unclear(2-6). We describe the biochemical trajectory of two neonatal cases of MLII.

Case one. First child of non-consanguineous parents induced at 38+2 weeks due to asymmetrical intra-uterine growth restriction. Birth weight was 2.240kg (<1%), length 49cm (30%) and head circumference 32.5cm (5%). He was noted to have coarse facial features, hypertrophic gums, bell-shaped chest, mild splenomegaly, and thyrombocytopenia and vacuolated lymphocytes on full blood count. He had acute hepatic synthetic dysfunction and conjugated hyperbilirubinaemia within the first 24 hours of life. Skeletal radiographs showed severe diffuse osteopenia with ill-defined, irregular ossification of the proximal humeri and femoral metaphyses, in addition to extensive “periosteal cloaking” of the long bones, with no metaphyseal cupping, splaying or fraying. Urine oligosaccharide and plasma lysosomal enzyme assays were diagnostic of Mucolipidosis Type II, which was genetically confirmed (pathogenic compound heterozygous variants in GNPTAB gene).

Case two. Male born at 37+6 weeks to non-consanguineous Pakistani parents with two healthy older children. A late antenatal ultrasound was suspicious for skeletal dysplasia with FISH for Trisomy 13, 18 and 21, CGH-microarray and FGFR3 gene negative on amniotic fluid analysis. His birth weight was 2740g (10%), length 44cm (<1%) and head circumference 32cm (2%). Dysmorphic features included a large anterior fontanelle, long bone bowing, severe bilateral talipes and gingival hypertrophy. He had a distal hypospadias and developed a unilateral inguinal hernia and left ventricular dysfunction. Skeletal radiographs showed generalised osteopaenia, with bowing and ‘periosteal cloaking’ of long bones, as well as early ossification/stippling at elbows. The diagnosis of MLII was made on urine oligosaccharide and plasma lysosomal enzyme assays.

Both patients showed evidence of secondary hyperparathyroidism in the first week of life: increased parathyroid hormone (PTH), alkaline phosphatase (ALP) and 1,25-dihydroxyvitamin D, with decreased phosphate and normal serum calcium. Spot urinary calcium/creatinine ratio was 0.3mol/mol and 0.5mol/mol respectively. Case 1 did not have vitamin D metabolites measured. Case 2 had normal 25-hydroxyvitamin D 88nmol/L (50-150) and elevated 1,25-vitamin D 1000pmol/L (48-190).

Case 1 commenced phosphate supplementation and by six weeks, phosphate had normalised, but PTH and ALP remained elevated; PTH 16pmol/L (1-7) and ALP 2120U/L (120-650). 25-hydroxyvitamin D was 41nmol/L and he commenced cholecalciferol. Unfortunately, he suffered aspiration pneumonia and died from respiratory failure at four months.

Initially, Case 2 did not receive any supplementation but by twelve weeks had worsening hypophosphataemia 0.88mmol/L (1.45-2.5), increasing PTH 114pmol/L (1-7) and ALP 4830U/L (120-650), and commenced cholecalciferol in the setting of 25-hydroxyvitamin D deficiency 14nmol/L (50-150). Within one month, there was a marked reduction in PTH 35pmol/L (1-7) and ALP 2430U/L (120-650), normalisation of both phosphate 1.38mmo/L (1.45-2.5) and 25-hydroxyvitamin D 106nmol/L (50-150) and elevation in 1,25-vitamin D 1356pmol/L (48-190).

These cases support existing literature describing hyperparathyroidism in newborns with MLII(2-6), which does not seem to be driven by postnatal hypocalcaemia. The underlying mechanism is unknown but theories include abnormalities in calcium-sensing receptor signaling(4), or a defect in PTHrp dependent active placental calcium transport, resulting in fetal hypocalcaemia and secondary hyperparathyroidism(1, 3, 5, 6). Additionally, both cases developed 25-hydroxyvitamin D deficiency, suggesting the need for vigilant monitoring in early life, and may have therapeutic implications. Recognition of secondary hyperparathyroidism as an early feature of MLII may contribute to timely diagnosis.

Key Points:

  1. Mucolipidosis Type II should be considered in the differential diagnosis of neonatal hyperparathyroidism.
  2. The radiological features of Mucolipidosis Type II evolve over time, with early changes described as similar to hyperparathyroidism or rickets.
  3. 25-hydroxyvitamin D deficiency occurred in both cases, suggesting the need for vigilant surveillance in early life.
  4. The underlying mechanism of hyperparathyroidism in Mucolipidosis Type II is unknown but may relate to abnormalities in calcium-sensing receptor signaling or defects in trans-placental calcium transport.
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