TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib).
Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications.
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, University Hospital of Pisa, Pisa, Italy.
Angelo
A
Molinaro
Dov
D
Tiosano
Rieko
R
Takatani
Dionisios
D
Chrysis
William
W
Russell
Nikolas
N
Koscielniak
Marie-Laure
ML
Kottler
Patrizia
P
Agretti
Giuseppina
G
De Marco
Petteri
P
Ahtiainen
Marta
M
Christov
Outi
O
Mäkitie
Massimo
M
Tonacchera
Harald
H
Jüppner
D000328:Adult; D002675:Child, Preschool; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D044127:Epigenesis, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011547:Pseudohypoparathyroidism / Q000097:blood* / Q000235:genetics; D051438:Syntaxin 16 / Q000235:genetics; D013972:Thyrotropin / Q000097:blood*; D055815:Young Adult
C496118:STX16 protein, human; D051438:Syntaxin 16; D013972:Thyrotropin
EPIGENETICS; GNAS; HYPOTHYROIDISM; PSEUDOHYPOPARATHYROIDISM; PTH