Diagnosis and Management of Congenital Hypothyroidism Associated with Pseudohypoparathyroidism

Abstract

Hypothyroidism is a particular condition observed in pseudohypoparathyroidism (PHP), a rare disorder characterized by parathyroid (PTH) resistance leading to hypocalcemia and hyperphosphatemia associated with a GNAS (guanine nucleotide-binding protein α-subunit) mutation (PHP1A) or epimutation (PHP1B). To determine the presence of hypothyroidism at birth we conducted a retrospective study in our cohort of patients presenting with either PHP1A (n = 116) or PHP1B (n = 99). We also investigated patients presenting at birth with congenital hypothyroidism (CH) and a eutopic thyroid gland for phosphocalcium abnormalities suggesting PTH resistance and PHP. Our study reveals CH as the earliest diagnostic clue for PHP1A, but not for PHP1B. We estimated the frequency of CH at birth to be between 8 and 34% in patients presenting with PHP1A. The elevation of phosphatemia and PTH concentration precedes hypocalcemia in PHP1A. Conversely, the frequency of PHP1A in patients presenting CH is dramatically low. This may be due to the low prevalence of PHP1A which remains unknown. Conclusions: Subclinical and overt hypothyroidism can occur in PHP1A patients at birth many years before PTH resistance becomes clinically apparent. Although such cases appear to be rare, some pediatric patients with unexplained CH are likely to benefit from measuring calcium, phosphorus, and PTH for extended periods of time.

Pseudohypoparathyroidism

“…An elevated TSH is often detected by neonatal screening and may be an initial feature of the disease, 8,51,[60][61][62][63] which may be misdiagnosed as congenital hypothyroidism associated with a small thyroid gland. 64 Thirty percent to 80% of these patients may have subtle subcutaneous ossifications as early as in infancy that are not as severe as in POH. 65,66 PTH resistance, the hallmark of this disease, is usually not present at birth; it develops over time and hypocalcemia is present in most patients by the age of 7 to 8 years.…”

Central Precocious Puberty in a Boy with Pseudohypoparathyroidism Type 1A due to a Novel GNAS Variant, with Congenital Hypothyroidism as the First Manifestation

“…Unlike resistance to TSH, PTH resistance, the hallmark of PHP1A, usually manifests after the first few years of life due to gradual silencing of paternal Gsa in the renal proximal tubule ( 4 ). As a result, the diagnosis of PHP1A is often delayed, especially in patients with non-specific features such as obesity or short stature ( 2 , 4 , 5 , 6 , 7 ). Childhood obesity was proposed as an early clinical sign of PHP1A as it might develop in very early life and could even be recognized before any other endocrine disturbances ( 2 , 5 ).…”

“…TSH resistance has frequently been described as the presenting feature of PHP1A with diverse severity, from isolated hyperthyrotropinemia to overt hypothyroidism, and might present at birth as congenital hypothyroidism or later during infancy and childhood ( 2 , 3 ). The diagnosis of PHP1A was reported to often be delayed in patients presenting with isolated TSH resistance, until other manifestations became apparent ( 4 , 5 , 6 , 7 ).…”

Genetics and Epigenetics of Bone Remodeling and Metabolic Bone Diseases

“…Mutations on GNAS, NESP55, and STX16 genes are associated with pseudohypoparathyroidism (PHP), a rare disease inherited in an autosomal dominant pattern. PHP is marked by parathyroid (PTH) resistance, hypocalcemia, and hyperphosphatemia caused by a GNAS (guanine nucleotide-binding protein-subunit) mutation (PHP1A) or epimutation (PHP1B) [210].…”