Mild progressive osseous heteroplasia overlap syndrome with PTH and TSH resistance appearing during adolescence and not early childhood

Abstract

Purpose: Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS-inactivating mutations are classified as "inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2." This study reports a case of mild POH overlap syndrome to improve understanding of genotype-phenotype correlations.

Methods: A 13-year and 6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies.

Results: He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation.

Conclusion: We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

Keywords: Deep ectopic ossification; POH overlap syndrome; PTH/TSH resistance; Sporadic GNAS mutation.