Pseudohypoparathyroidism type Ia (PHP Ia) is a rare hereditary syndrome, and patients with early PHP Ia are generally not diagnosed based on the presentation of cutaneous nodules as the main clinical feature. Here, we describe a Chinese boy with PHP Ia in whom the main clinical feature was cutaneous nodules, and the patient exhibited a novel GNAS mutation.

A 5-year-old boy presented with a 5-year history of cutaneous nodules scattered over his entire body. The patient had a short stature, round face, short neck, and slightly flattened nose; he also had multiple hard papules and cutaneous nodules scattered over his entire body. The patient had a significantly elevated parathyroid hormone level. His serum calcium level was reduced, while his serum phosphorus level was increased and his serum thyroid-stimulating hormone level was elevated. Skin biopsy showed osteoma cutis in subcutaneous tissue. Sanger sequencing revealed a frameshift mutation, c.399delT (p.Ser133Argfs*2) in exon 5 of the GNAS gene. The patient was diagnosed with PHP Ia and subclinical hypothyroidism. He was given 1,25-dihydroxyvitamin D, calcium carbonate, and synthetic L-thyroxine. After 3 months of treatment, the patient’s parathyroid hormone level decreased, and his serum calcium and serum phosphorus levels were normal. Moreover, his thyroid-stimulating hormone level decreased.

These findings can help dermatologists to diagnose PHP Ia in patients with cutaneous nodules as the main early clinical feature.

Pseudohypoparathyroidism (PHP) is a rare, sporadic or familial disorder characterized by an elevated plasma level of parathyroid hormone (PTH) caused by resistance to PTH action in target tissues[1,2]. PHP was first reported in 1942 by Albright et al[3] and classified into PHP type I (PHP I) and PHP type II (PHP II) according to the renal response to exogenous PTH administration. PHP I is divided into subtypes Ia, Ib, and Ic. Patients with PHP Ia display hypocalcemia, hyper-phosphatemia, PTH resistance, and variable developmental abnormalities [e.g., Albright’s hereditary osteodystrophy (AHO)]. PHP Ia is caused by inactivating mutations of the guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene, which encodes the alpha subunit of the stimulatory heterotrimeric G protein (Gsα)[4].

Patients with PHP Ia generally seek medical attention due to epileptic seizures, and both the misdiagnosis and missed diagnosis rates are extremely high. Here, we describe a patient with PHP Ia who presented with multiple cutaneous nodules as the main clinical feature; this patient did not experience epileptic seizures and exhibited a novel GNAS mutation.

The proband was diagnosed with PHP Ia by the presence of hormone resistance, cutaneous ossification, obesity, and AHO phenotype, and maternal inheritance of the GNAS mutation. This proband had elevated TSH levels and normal T3 and T4 levels, so a diagnosis of subclinical hypothyroidism was made. Therefore, the final diagnosis of the patient was PHP Ia combined with subclinical hypothyroidism.

The patient was given 1,25-dihydroxyvitamin D at a dose of 0.25 μg once daily and calcium carbonate at a dose of 300 mg once daily; he was instructed to avoid dairy, soy, and other high-phosphorus food products. Because the patient’s subclinical hypothyroidism led to concerns regarding his neurologic development, he was also administered synthetic L-thyroxine at a dose of 12.5 μg once daily.

After 3 mo of treatment, the patient’s PTH level decreased to 184.10 ng/L (normal range, 15-65 ng/L) with serum calcium and phosphorus levels of 2.24 (normal range, 2.20-2.65 mmol/L) and 2.05 mmol/L (normal range, 1.29-2.26 mmol/L), respectively; his TSH level decreased to 8.12 mIU/L (normal range, 0.35-4.94 mIU/L).

PHP is a rare autosomal dominant inherited disorder that is associated with an exon mutation in the maternal allele of the GNAS gene. The GNAS gene is located on chromosome 20q13, which consists of 13 exons and 12 introns. The product of the GNAS gene is Gsα, which is an important component of the cAMP/protein kinase. PTH mainly couples with Gsα through the PTH receptor to form a complex that activates adenylate cyclase and promotes the generation of cAMP, thereby regulating the cell response. GNAS is a complex imprinted gene encoding Gsα that exhibit exclusively maternal or paternal expression[5]. Maternal allele of the GNAS gene is the only source of Gsα in the kidney (the paternal allele is normally silenced in this tissue). In PHP Ia, mutations in the maternal GNAS allele result in a marked reduction of Gsα levels, leading to failure to elicit an appropriate increment in urinary cAMP and phosphate excretion following exogenous PTH infusion and PTH resistance[6]. Because the target organs (i.e., the kidney and bone) do not respond to PTH, hypocalcemia feedback stimulates excessive parathyroid secretion of PTH.

The clinical manifestations of PHP Ia include signs of hypoparathyroidism, characterized by calcium and phosphorus metabolism disorders[7-9]. Some patients also demonstrate a typical AHO phenotype, including short stature, obesity, round face, short neck, short and coarse fingers/toes, and ectopic ossification. The molecular mechanisms of GNAS-related heterotopic ossification have not been fully elucidated. It might involve aberrant differentiation of mesenchymal progenitor cells in the dermis or subcutaneous fat. Researchers have reported that activation of Hedgehog signaling causes GNAS-related heterotopic ossification. In PHP Ia with mutations in GNAS, Hedgehog signaling is activated in progenitor cells, which leads to heterotopic ossification and inhibition of formation of adipocytes[10,11]. Heterotopic calcification or ossification is extremely common in patients with AHO, which mainly occurs in the subcutaneous tissue and brain parenchyma; the most common manifestation is calcification of the brain basal ganglia. Seizures can also be caused by brain parenchymal calcification and hypocalcemia. Thyroid hormone, growth hormone, and gonadotropin are mediated by Gsα; therefore, patients with a GNAS mutation may present with resistance to other hormones, including TSH, growth hormone, and gonadotropin-releasing hormone. Therefore, patients with PHP Ia may exhibit hypothyroidism and hypogonadism. The patient in this case had an elevated TSH level and normal triiodothyronine and thyroxine levels; thus, a diagnosis of subclinical hypothyroidism was made.

PHP Ia needs to be distinguished from PHP Ib, PTH Ic, and pseudo-PHP. PHP type Ib is a rare genomic disease that is typically sporadic; a minority of patients demonstrate autosomal dominant inheritance. PHP Ib is associated with abnormal epigenetic regulation of the GNAS gene due to the loss of GNAS promoter methylation; the GNAS gene coding sequence is unaltered. In addition to PTH resistance, the clinical manifestations of PHP Ib typically include resistance to many other hormones. PHP Ib is generally not accompanied by AHO characteristics, but some patients may exhibit short fingers and toes. Patients with PTH Ic exhibit AHO characteristics and resistance to multiple hormones, but have normal Gsα activity; thus far, the molecular and genetic mechanisms of PTH Ic remain unknown. Pseudo-PHP is a syndrome caused by a mutation of the paternal allele of the GNAS gene; affected patients exhibit AHO characteristics, as well as normal serum calcium and normal serum phosphorus, but lack PTH resistance.

There have been previous reports of patients with PHP Ia in whom the diagnosis was confirmed by genetic analysis. PHP Ia cases with GNAS mutations previously described are reviewed[12-33] and summarized in Table 1. For example, two Korean patients with PHP Ia were confirmed to have a nonsense mutation of c.94A>T (p.Lys32X) and a known frameshift mutation of c.344_345insT (p.V117RfsX23) in the GNAS gene[24]. Another study of patients with PHP Ia revealed two novel mutations: A c.569_570del mutation (p.Tyr190CysfsX19) and a splicing mutation (c.659+1G>A) in the GNAS gene[25]. A Turkish boy was reported to have PHP type Ia (GNAS gene mutation, IVS4+5G>C); his mother had pseudo-PHP[33]. Here, we describe a 5-year-old boy with PHP Ia who had the c.399delT (p.Ser133Argfs*2) mutation in the GNAS gene; his mother carried the same mutation. Notably, the C.399delT mutation of exon 5 in the GNAS gene is a frameshift mutation; this frameshift mutation causes AGT→AGG, resulting in an Arg to Ser amino acid variant. The second codon after this mutation site (c.399delT) becomes the stop codon (TGA), which induces early termination of translation and leads to a truncated protein associated with partial PTH resistance. We searched for this mutation in published online databases including Exome Aggregation Consortium, genome Aggregation Database, ClinVar database, and Human Gene Mutation Database; there was no information about the site in these databases. Therefore, we concluded that the c.399delT mutation in the GNAS gene is novel.

PHP Ia is a rare genetic disease with an extremely high rate of missed diagnosis. The findings in this report can help dermatologists to recognize and accurately diagnose PHP Ia in patients with cutaneous nodules as the main early clinical feature. If necessary, genetic testing should be conducted to confirm the diagnosis.