Abstract
Background: Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by end-organ resistance to PTH. Most subtypes are caused by pathogenic variants or epigenetic alterations in GNAS, which encodes the alpha subunit of the G protein regulating end-organ response to PTH. PHP type 1B (PHP1B) is caused by methylation defects in GNAS and presents with isolated renal PTH resistance. Clinical Case: A 29-year-old gentleman presented with intermittent muscle spasms, perioral and digital paresthesias, fatigue, and anxiety. Family history was notable for similar symptoms in his sister and nephew. Physical examination revealed normal stature, non-dysmorphic facies, and no soft tissue ossifications or skeletal anomalies. Chvostek sign was positive. Laboratory studies showed total calcium 6.0 mg/dL (n 8.6–10.0 mg/dL), phosphorus 6.8 mg/dL (n 2.5–3.5 mg/dL), creatinine 0.8 mg/dL (n 0.8–1.3 mg/dL), albumin 5.0 (n 3.5–5.0 mg/dL), PTH 231 pg/mL (n 15–65 pg/mL), total 25-hydroxyvitamin D 19 mg/mL (n 20–50 ng/mL), and 1,25-dihydroxyvitamin D 45 pg/mL (n 18–64 pg/mL). Additional endocrine testing showed TSH 6.4 mIU/L (n 0.3–4.2 mIU/L), free T4 1.1 ng/dL (n 0.9–1.7 ng/dL), and TPO antibody <0.3 IU/mL (n <9.0 IU/mL). Renal ultrasound was normal. CT head showed diffuse intracranial calcifications. He was diagnosed with PHP1B and started on calcitriol, cholecalciferol, and calcium carbonate. He declined genetic testing. Repeat laboratory studies were improved with total calcium 8.5 mg/dL, phosphorus 3.9 mg/dL, total 25-hydroxyvitamin D 49 mg/mL, PTH 124 pg/mL, and 24-hour urinary calcium 269 mg (n <250 mg). Conclusion: International consensus guidelines for the diagnosis and management of PHP and related disorders were recently published by Mantovani et al. in 2018. Proposed clinical and biochemical major criteria include PTH resistance, ectopic ossifications, early-onset obesity, TSH resistance, and Albright hereditary osteodystrophy (AHO; round facies, short stature, brachydactyly, developmental delay). Unlike PHP type 1A, PHP1B often presents later in life and features of AHO are usually absent, so diagnosis requires a high degree of clinical suspicion. It is recommended that patients with suspected PHP have molecular confirmation with sequencing, methylation, and/or copy number variant analysis of GNAS. Routine monitoring of calcium, phosphorus, and PTH levels and treatment with active vitamin D analogues with or without calcium supplements are advised to maintain normal calcium and phosphorus and PTH <2 times the upper limit of normal. Other recommendations include renal imaging for nephrocalcinosis, eye exam for cataracts, CT head imaging (in patients with neurological findings) for calcifications, regular dental care, and management of comorbid endocrinopathies. A multidisciplinary approach is needed in this complex, heterogeneous group of disorders.
First International Consensus on the diagnosis and management of fibromuscular dysplasia
