A 33-year-old woman comes to the office for evaluation of hypercalcemia. She was recently seen in the emergency department for uncomplicated appendicitis and was found to have a serum calcium level of 10.7 mg/dL. The patient underwent a laparoscopic appendectomy and was released the following day. Prior to this, she had not seen a physician in over 7 years. She now feels well and has no other medical problems. The patient has had 2 uneventful pregnancies and her menstrual periods are normal. She is divorced and currently not sexually active. She does not use tobacco, alcohol, or illicit drugs. Her mother has had "a high calcium level for a long time," but the patient does not know if she received any specific treatment. Blood pressure is 123/68 mm Hg and pulse is 87/min with regular rhythm. BMI is 22 kg/m². Physical examination is normal with well-healing abdominal wounds. Laboratory results are as follows: Which of the following is the most appropriate next step in management of this patient?

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Explanation: 11ec2b69_bebf_487c_8f63_911658f586ca_MD0005_00 This patient has mild, asymptomatic hypercalcemia. In light of a high-normal parathyroid hormone (PTH) level and low urinary calcium excretion, this is consistent with familial hypocalciuric hypercalcemia (FHH). FHH is an autosomal dominant disorder caused by mutations of the calcium-sensing receptor (CaSR) that lead to decreased sensitivity to calcium. Normally, high-normal calcium levels suppress PTH secretion, but in FHH, higher calcium concentrations are required to suppress PTH release. Concurrently, the defective CaSR causes increased reabsorption of calcium in renal tubules. higher calcium concentrations The most common cause of hypercalcemia with an elevated PTH is primary hyperparathyroidism (PHPT). PHPT must be differentiated from FHH as FHH follows a benign course, whereas untreated PHPT can lead to osteoporosis, nephrolithiasis, and chronic kidney disease. FHH can be distinguished from PHPT by assessment of urinary calcium excretion. FHH is associated with low urinary calcium levels (typically <100 mg/24 hours). Although PHPT causes increased reabsorption of calcium, net excretion is increased (often >300 mg/24 hours) due to accelerated bone turnover. Urine calcium excretion can be more precisely assessed using the urine calcium/creatinine clearance ratio (UCCR): UCCR is usually <0.01 in FHH compared to >0.02 in PHPT. If UCCR is low, the diagnosis of FHH is confirmed by testing for CaSR mutations. (Choice A) Mutations in the RET proto-oncogene are the most common cause of the multiple endocrine neoplasia (MEN) types 2A and 2B, which are also typically autosomal dominant. MEN 2A is associated with PHPT due to parathyroid hyperplasia, but urinary calcium excretion would be increased. (Choice B) Excess secretion of PTH-related peptide causes humoral hypercalcemia of malignancy, characterized by severe (eg, >14 mg/dL) hypercalcemia and suppressed PTH. (Choices C and E) Parathyroidectomy is indicated for patients with PHPT who have symptomatic hypercalcemia or additional complications (eg, osteoporosis, chronic kidney disease). Ultrasound of the neck is often used to localize a parathyroid adenoma in preparation for surgery. Parathyroidectomy is not indicated for FHH. Educational objective: Familial hypocalciuric hypercalcemia (FHH) is a benign autosomal dominant disorder characterized by mild hypercalcemia with a normal or mildly elevated parathyroid hormone level. FHH can be distinguished from primary hyperparathyroidism (PHPT) by urinary calcium excretion, which will be low in FHH and elevated in PHPT. References: Differentiating familial hypocalciuric hypercalcemia from primary hyperparathyroidism. (http://www.ncbi.nlm.nih.gov/pubmed/23425644) Familial hypocalciuric hypercalcemia: a review. (http://www.ncbi.nlm.nih.gov/pubmed/21986511)

A 33-Year-Old Woman Comes to the Office for Evaluation of Hypercalcemia