Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions

Abstract

Context: Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications.

Objective: This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally.

Methods: Forty-four children of affected (n = 7) or unaffected (n = 7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and thyrotropin (TSH) was advised.

Results: The STX16 deletion that causes AD-PHP1B was identified in 25 children. Pretreatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age, and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about 5 years of age. TSH levels showed no consistent rise over time.

Conclusion: Establishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased, thereby establishing the onset of PTH resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered in order to prevent hypocalcemia and associated sequelae.

Keywords: GNAS; STX16; Gs-alpha; PTH; TSH; cAMP; calcium; epigenetics; parent-specific GNAS methylation; phosphate; pseudohypoparathyroidism.

Figure 1.

Schematic presentation of the STX16-GNAS locus. The GNAS complex gives rise to several sense transcripts and 1 antisense transcript. Gsα, which is encoded by exons 1-13, is biallelically expressed in most tissues, except for few tissues that include the proximal renal tubules, where paternal Gsα expression is partially or completely silenced through yet-undefined mechanisms later in life. The promoters for the antisense transcript (AS), for the XL transcript encoding an extra-large form of Gsα and for the A/B transcript are methylated on the maternal allele and are thus transcribed exclusively from the paternal allele. The NESP promoter is methylated on the paternal allele and transcripts are derived only from the maternal allele. NESP, XL, and A/B transcripts have unique first exons that splice onto GNAS exon 2-13. Boxes represent exons and splicing patterns are represented by solid or stippled angled lines. Arrows show the direction of transcription and * indicate sites that undergo methylation on either the maternal (XL, A/B, and AS) or the paternal (NESP) allele. STX16, the gene encoding syntaxin 16, is depicted by a single box although it comprises several exons. Deletions in this gene that lead to loss of methylation at the maternal exon A/B alone (red X) and thus cause AD-PHP1B are represented by the red bracket.

Figure 2.

Laboratory findings before 6 years of age in 4 children with AD-PHP1B due to maternally inherited 3-kb STX16 deletions. Laboratory measurements for PTH (panel A), calcium (panel B), phosphate (panel C), and TSH (panel D) were obtained before treatment with 1,25(OH)₂ vitamin D was started. Relationship between PTH and calcium (panel E), and between PTH and phosphate (panel F). The gray areas represent the normal ranges for each analyte; individual patients are indicated by different symbols and colors.

Figure 3.

First laboratory measurements after identification of a STX16 deletion in untreated AD-PHP1B patients. Measurements of parathyroid hormone (PTH, panel A), calcium (Ca, panel B), phosphate (P, panel C), and thyroid-stimulating hormone (TSH, panel D) for 19 cases with AD-PHP1B due to STX16 deletions. All laboratory measurements were obtained before treatment with calcium and 1,25(OH)₂ vitamin D was initiated. Relationship between PTH and calcium (panel E), and between PTH and phosphate (panel F). The gray areas represent the normal ranges for each analyte; for each patient only the last laboratory measurement before initiation of treatment is shown; individual patients are indicated by different symbols and colors.