Pseudohypoparathyroidism

Pseudohypoparathyroidism is resistance to parathyroid hormone, causing hypocalcaemia, hyperphosphataemia and raised parathyroid hormone with normal kidney function.

Type 1A is caused by inactivating variants of the maternal GNAS allele and combines parathyroid hormone resistance with Albright hereditary osteodystrophy and resistance to other hormones. Type 1B is due to loss of methylation at the GNAS locus and mainly gives resistance to parathyroid hormone and thyroid stimulating hormone. Types 1C and 2 are rare.

It is rare, about 1 in 150,000 people, and is usually diagnosed in childhood.

Pathophysiology.

The stimulatory G protein alpha subunit couples receptors to adenylyl cyclase. In proximal renal tubules the maternal allele is the only one expressed, so a maternal defect abolishes the parathyroid hormone response and phosphaturia, while calcium reabsorption in the distal tubule is preserved.

The same loss causes resistance to thyroid stimulating hormone, gonadotrophins and growth hormone releasing hormone.

• Hypocalcaemia: paraesthesia, muscle cramps, tetany, seizures, prolonged QT, cataracts and basal ganglia calcification.
• Albright hereditary osteodystrophy (type 1A): short stature, round face, obesity, brachydactyly (short fourth and fifth metacarpals), subcutaneous ossifications and learning difficulty.
• Hypothyroidism, hypogonadism and growth hormone deficiency may be present.

Red flags.

• Seizure, tetany or laryngospasm.
• Prolonged QT or arrhythmia.

• Low adjusted calcium (ionised calcium if unsure), raised phosphate, raised parathyroid hormone, normal creatinine, normal magnesium and normal 25-hydroxyvitamin D.
• Thyroid stimulating hormone with free thyroxine, prolactin, LH, FSH, IGF-1 and glucose.
• Hand radiographs for brachydactyly, and head CT for basal ganglia calcification.
• GNAS sequencing and methylation analysis confirm subtype. Test for gene dosage and family members.
• ECG for the QT interval.

Differential diagnosis.

• Hypoparathyroidism (parathyroid hormone low or inappropriately normal).
• Vitamin D deficiency or resistance, magnesium depletion and kidney disease.
• Pseudopseudohypoparathyroidism, acrodysostosis and brachydactyly type E.

• Acute symptomatic hypocalcaemia: 10 mL of 10% calcium gluconate (2.25 mmol) intravenously over 10 minutes with ECG monitoring, repeated if needed, then an infusion of 0.9% sodium chloride or 5% glucose with calcium gluconate 100 mL of 10% in 1 litre at 50 to 100 mL/h titrated to calcium. Correct magnesium.
• Maintenance: calcium carbonate 1 to 2 g elemental calcium daily in divided doses with meals, plus calcitriol 0.5 to 1 microgram daily (range 0.25 to 2 micrograms). Aim for calcium in the low normal range and parathyroid hormone in the upper normal range.
• Urinary calcium is low in this condition, so hypercalciuria occurs less than in other forms. Keep phosphate controlled with diet and a calcium based binder if needed.
• Levothyroxine for thyroid stimulating hormone resistance (about 1.6 micrograms/kg daily; start 25 to 50 micrograms in older adults or heart disease). Replace sex steroids and growth hormone as needed. Weight control from early childhood.
• Surgical removal of painful ossifications is not routine because of recurrence.

Special groups. Children: growth, obesity and neurodevelopment need paediatric review. Pregnancy: calcitriol requirements change, so check calcium monthly. Genetic counselling: inheritance from a mother gives type 1A, from a father gives pseudopseudohypoparathyroidism.

Monitoring. Calcium, phosphate, parathyroid hormone, creatinine and urinary calcium every 3 to 6 months, thyroid function yearly, renal ultrasound yearly for nephrocalcinosis.

Referral and escalation. Endocrinology and clinical genetics; paediatric endocrinology for children; emergency admission for severe hypocalcaemia.