No abstract

The physiology and regulation of bone minerals in the fetus and the newborn is significantly different from children and adults. The bone minerals calcium, phosphate and magnesium are all maintained at higher concentrations in utero to achieve adequate bone accretion. This is an integral component of normal fetal development which facilitates safe neonatal transition to post-natal life. When deciphering the cause of bone mineral disorders in newborns, the potential differential diagnosis list is broad and complex, including several extremely rare conditions. Also, significant discoveries including new embryological molecular genetic transcription factors, the role of active placental mineral transport, and hormone regulation factors have changed the understanding of calcium and phosphate homeostasis in the fetus and the newborn. This article will guide clinicians through an updated review of calcium and phosphate physiology, then review specific conditions pertinent to successful neonatal care. Furthermore, with the advancement of increasingly rapid molecular genetic testing, genomics will continue to play a greater role in this area of fetal diagnostics and prognostication.

An 8-month-old boy was brought to a metropolitan emergency department (ED) with a 2-month history of progressive lethargy, feeding difficulties, weight loss of 760 g, inability to sit unsupported and irritability. He was breast fed, with the addition of solids at 5 months. For this presentation, he had been reviewed at same metropolitan ED and twice by a general practitioner, with reassurance from doctors that the symptoms were attributable to a viral illness with associated gingivostomatitis. His past medical history and family history were unremarkable, and he was not reported to be taking any medications.On examination, he was pale, lethargic and irritable, with a weight of 7.05 kg (3rd centile), length 69.5 cm (37th centile) and head circumference 43.5 cm (20th centile). General vital signs were unremarkable. He had sunken eyes, dry lips and tongue, cool peripheries, generalised hypotonia and was unable to hold his head upright or sit unassisted. Spontaneous movements were symmetrical but weak. Deep tendon reflexes were intact. His oral cavity demonstrated multiple small white gingival lesions. With this exception, ear, nose and throat; cardiorespiratory; and abdominal examinations were normal.Investigations revealed extreme hypercalcaemia 5.3 mmol/L (normal range (NR) 1.9-2.7), phosphate 1.42 mmol/L

Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes. Case This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation. Management She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures. Conclusion This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A -related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.

BackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.