A homozygous PTH mutation causes a novel form of autosomal recessive hypoparathyroidism that can be misdiagnosed as pseudohypoparathyroidism

Presentation Number: OR43-1
Date of Presentation: June 18th, 2013

Sihoon Lee*1, Michael Mannstadt2, So Young Park3, Young Sil Eom4, Ashok Khatri5, Thomas Dean5, Thomas J Gardella5 and Harald W Jueppner6
1Gachon University School of Medicine, Incheon, Korea, Republic of (South), 2Harvard/MGH, Boston, MA, 3Cheil General Hospital, Kwandong University College of Medicine, Seoul, Korea, Republic of (South), 4Gachon University Gil Medicial Center, Incheon, Korea, Republic of (South), 5Massachusetts General Hospital, Boston, MA, 6Massachusetts General Hospital and Harvard Medical School, Boston, MA


Background: Only four different PTH mutations have been described thus far as a cause of isolated hypoparathyroidism (IHP) (1-6). These mutations are either heterozygous or homozygous nucleotide changes affecting only those PTH exons encoding the PrePro portion of the hormone and the resulting amino acid changes impair PTH synthesis or secretion.

Patients and Methods: We identified a family in which three siblings presented with severe hypocalcemia and hyperphosphatemia. The male index case (55 yo) was first evaluated at the age of 12 years because of transient muscle cramps and sudden loss of consciousness; calcium 4.6 mg/dl, phosphate 8.2 mg/dl, PTH undetectable. While other family members had normal biochemistries, his two sisters had severe, asymptomatic hypocalcemia (7.1 and 6.5 mg/dl, respectively) with elevated serum phosphorus levels (4.8 and 6.2 mg/dl, respectively). PTH levels were measured with two different assays, intact (iPTH) and biointact PTH (biPTH); both assays (Immutopics) use the same anti-PTH antibody for capture, but different antibodies for detection. DNA from the proband and his immediate family, including the two affected sisters underwent nucleotide sequence analysis of candidate genes, including CASR, GCMB, and PreProPTH. COS-7 cells were transfected with plasmids encoding wild-type (WT) or mutant PTH, and PTH levels were measured in conditioned medium.

Results: The two affected sisters, who were naive to treatment with calcium or vitamin D analogs when tested at age 50 and 47 years, respectively, revealed PTH levels of 8 and 5 pg/ml, respectively, when measured by iPTH assay, and 1455 and 679 pg/ml, respectively, when measured by biPTH assay, thus raising ambiguities regarding the underlying diagnosis, namely IHP or pseudohypoparathyroidism (PHP). However, nucleotide sequence analysis of PreProPTH revealed that all three patients are carriers of the same homozygous missense mutation in exon 3, thus establishing the diagnosis of hypoparathyroidism; the proband’s mother, brother, and his two children were heterozygous carriers. The identified mutation alters the secreted PTH such that it is detected predominantly by the biPTH assay that uses a detection antibody directed against the first few amino acid residues of the secreted peptide. In fact, analysis of conditioned medium from COS-7 cells expressing either WT or mutant PTH revealed high levels of PTH when measured with the biPTH assay, but much lower levels when measured with the iPTH assay.

Conclusion: Unlike a previously reported PTH mutation in a patient with a parathyroid adenoma (7), the mutation identified in our kindred appears to impairs PTH bioactivity, but not secretion. However, the location of the mutation prevented detection by the antibody used in the iPTH assay, and it thus may be necessary to evaluate hypocalcemic patients with different assays.


Disclosure: MM: Advisory Group Member, NPS. HWJ: Speaker, Amgen, Speaker, Genzyme Corporation, Speaker, Roche Diagnostics, Speaker, Pfizer, Inc., Consultant, Immutopics, Intl.. Nothing to Disclose: SL, SYP, YSE, AK, TD, TJG