Pseudopseudohypoparathyroidism

Pseudopseudohypoparathyroidism is the Albright hereditary osteodystrophy phenotype without resistance to parathyroid hormone or other hormones. Calcium, phosphate and parathyroid hormone are normal.

It is caused by inactivating variants of the paternal GNAS allele, so it is inherited from the father, and is rare. The same variant inherited from the mother causes pseudohypoparathyroidism type 1A.

Progressive osseous heteroplasia is a related disorder with extensive heterotopic ossification, also from paternal inactivating GNAS variants.

Pathophysiology.

In the proximal renal tubule, the maternal GNAS allele is expressed and the paternal allele is silent. A paternal defect therefore spares tubular function and hormone response, while loss of one allele in other tissues (bone, cartilage, subcutaneous tissue) gives the skeletal phenotype and often low birth weight.

• Short stature, round face, short neck, brachydactyly (short fourth and fifth metacarpals and metatarsals), subcutaneous ossifications and low birth weight.
• Obesity is less marked than in pseudohypoparathyroidism, and learning difficulty is less frequent.

• Normal albumin adjusted calcium, phosphate and parathyroid hormone, with normal thyroid stimulating hormone.
• Hand radiographs show brachydactyly. Imaging of ossifications.
• GNAS sequencing confirms a paternal origin inactivating variant. Inheritance testing in the family.

Differential diagnosis.

• Pseudohypoparathyroidism type 1A (biochemical resistance present).
• Acrodysostosis (PRKAR1A, PDE4D), brachydactyly type E (HOXD13, PTHLH) and Turner syndrome.
• Prader-Willi syndrome and 2q37 deletion.

• No treatment corrects the underlying defect. Manage the skeletal features: orthopaedic or hand surgery for symptomatic ossifications (recurrence is possible), and growth review.
• Weight management and support for developmental needs.
• Genetic counselling is the key step: a variant carried by a mother gives her children pseudohypoparathyroidism type 1A, whereas a variant carried by a father gives them pseudopseudohypoparathyroidism. Test the children of an affected parent.

Monitoring. Calcium, phosphate, parathyroid hormone and thyroid stimulating hormone at diagnosis and yearly in childhood to confirm no resistance has developed.

Referral and escalation. Clinical genetics and paediatric endocrinology.