Hypocalcaemia and hypoparathyroidism — formative SAQs

SAQ 1 (10)

A 10-day-old infant born at term to a mother with poorly controlled type 1 diabetes presents with a generalised tonic-clonic seizure. The seizure self-terminates after two minutes. Blood glucose is normal. Ionised calcium is 0.7 mmol/L, total calcium 1.6 mmol/L (albumin 35 g/L), phosphate 3.2 mmol/L, and PTH 1.5 pmol/L (low). Magnesium is 0.45 mmol/L. The infant has a soft cardiac murmur and a cleft palate. [8][9]

1. Define hypocalcaemia, classify this case by PTH and timing, and state the most likely underlying diagnosis and the pathophysiological basis. (3) [8][9]
2. Give the emergency management including the drug, dose, route, and the critical safety rule for administration. (4) [1][3]
3. Outline the confirmatory investigation, the role of magnesium, and the long-term management plan. (3) [3][7]

Model answer

Definition and classification. Hypocalcaemia is a total calcium below 2.1 mmol/L or ionised below 1.1 mmol/L (this infant's ionised of 0.7 confirms it; the total of 1.6 is also low even before albumin correction). This is late neonatal hypocalcaemia (day 10) with a low PTH (1.5 pmol/L) and high phosphate (3.2 mmol/L) — the biochemical signature of hypoparathyroidism. The combination of late neonatal hypocalcaemia, low PTH, high phosphate, a cardiac murmur, and cleft palate points to 22q11.2 deletion syndrome (DiGeorge). In DiGeorge, the third and fourth pharyngeal pouches fail to develop, so the parathyroid glands and thymus are hypoplastic or absent, producing hypoparathyroidism and immune deficiency alongside the conotruncal cardiac defects and palatal abnormalities. [8][9]

Emergency management. The infant is seizing from symptomatic hypocalcaemia. Give intravenous 10% calcium gluconate at 0.5 mL per kilogram (maximum 20 mL) over 5 to 10 minutes with continuous cardiac monitoring. The critical safety rule is to give it slowly: rapid intravenous calcium causes bradycardia, arrhythmia, and can arrest the heart in systole. Calcium gluconate is used (not calcium chloride) for peripheral access because it is less vesicant if extravasation occurs. After the bolus, transition to a continuous infusion or oral calcium and calcitriol once the infant is stable. [1][3]

Investigation, magnesium, and long-term plan. Confirm the diagnosis with 22q11.2 deletion testing (FISH or chromosomal microarray), a cardiac echo (to define the conotruncal anatomy), and an immune panel (T-cell subsets, given thymic hypoplasia). The magnesium is low (0.45 mmol/L) and must be replaced, because severe hypomagnesaemia both suppresses PTH secretion and causes PTH resistance — the hypocalcaemia will not correct fully until magnesium is restored. Long-term management is oral elemental calcium (30 to 75 mg/kg/day) and calcitriol (20 to 60 ng/kg/day), because native vitamin D cannot be activated without PTH. Target a calcium just below normal to avoid hypercalciuria and nephrocalcinosis. A coordinated endocrine, cardiac, immunology, and developmental team is required, with a MedicAlert identifier and a sick-day plan. [3][7]

SAQ 2 (10)

A 9-year-old girl is referred for short stature, round face, and short fourth metacarpals. Her serum calcium is 1.7 mmol/L, phosphate 2.4 mmol/L (high), PTH 28 pmol/L (markedly elevated), and 25-hydroxyvitamin D 62 nmol/L (normal). She has subcutaneous ossifications on her forearms. Her mother has a similar body habitus but normal biochemistry. [4]

1. What is the diagnosis, what is the pathophysiological basis, and how does the family history fit? (3) [4]
2. Explain how you distinguish this condition from hypoparathyroidism and from vitamin D deficiency using the biochemistry. (4) [3][4]
3. Describe the long-term management, the treatment target, and the surveillance plan. (3) [1][7]

Model answer

Diagnosis and pathophysiology. This is pseudohypoparathyroidism type 1a (Albright hereditary osteodystrophy). The child has the classic phenotype (short stature, round face, brachydactyly with short fourth metacarpals, subcutaneous ossifications) and the biochemical signature of hypocalcaemia with a markedly elevated PTH (28 pmol/L) and high phosphate. The pathophysiology is end-organ resistance to PTH: a mutation in the GNAS gene encoding the Gs-alpha stimulatory protein means the PTH receptor cannot generate the cAMP second messenger, so the kidney and bone cannot respond to PTH despite it being present in abundance. The mother has the phenotype but normal biochemistry — this is pseudo-pseudohypoparathyroidism, because GNAS is imprinted and the phenotype depends on the parental origin of the mutation (maternal inheritance produces full biochemical resistance; paternal inheritance produces the skeletal phenotype only). [4]

Biochemical distinction. The three conditions are separated by PTH and 25-hydroxyvitamin D. Hypoparathyroidism has low calcium, high phosphate, and a low PTH — the gland is failing. Pseudohypoparathyroidism has low calcium, high phosphate, and a high PTH — the gland works but the target organs resist. Vitamin D deficiency has low or low-normal calcium, low phosphate (because PTH drives phosphaturia), a high PTH, and a low 25-hydroxyvitamin D. This child has a high PTH with high phosphate and a normal 25-hydroxyvitamin D (62 nmol/L), which excludes both true hypoparathyroidism and vitamin D deficiency and confirms end-organ resistance. [3][4]

Long-term management. Management is oral elemental calcium (30 to 75 mg/kg/day) and calcitriol (20 to 60 ng/kg/day) — the same as for hypoparathyroidism, because the goal is to correct the hypocalcaemia rather than supply PTH (the body is already making excess PTH it cannot use). The treatment target is a calcium just below normal, not high-normal, because the unprotected kidney develops hypercalciuria, nephrocalcinosis, and nephrolithiasis when calcium is driven too high. Surveillance includes serial calcium, phosphate, renal function, and the urinary calcium-to-creatinine ratio to detect hypercalciuria before it damages the kidney. The Mantovani consensus guides subtype classification, genetic counselling (maternal GNAS inheritance), and surveillance for the associated endocrine and developmental features. A MedicAlert identifier, a sick-day plan, and structured transition to adult endocrinology complete the plan. [1][7]