A 1-year-old boy presents to pediatrics clinic for a well-child visit. He has no complaints. He has a cleft palate and an abnormal facial appearance. He has been riddled with recurrent infections and is followed by cardiology for a ventricular septal defect (VSD). Vital signs are stable, and the patient's physical exam is benign. If this patient's medical history is part of a larger syndrome, what might one also discover that is consistent with the manifestations of this syndrome?

Hypoactive deep tendon reflexes

A 33-year-old woman presents to her primary care provider for a normal check-up. She reports she has been feeling intermittently fatigued over the past 3 months, but she attributes it to her work as a corporate lawyer and balancing family life. She is otherwise healthy and takes no medications. She was adopted and has no information about her biological family. She has 2 children and has been married for 7 years. She drinks 4-5 glasses of wine per week and does not smoke. Her temperature is 99.2°F (37.3°C), blood pressure is 125/65 mmHg, pulse is 78/min, and respirations are 18/min. On exam, she is well-appearing and in no acute distress. A complete blood count is within normal limits. Additional workup is shown below: Serum: Na+: 139 mEq/L Cl-: 99 mEq/L K+: 3.9 mEq/L HCO3-: 23 mEq/L BUN: 18 mg/dL Glucose: 110 mg/dL Creatinine: 1.1 mg/dL Ca2+: 11.1 mg/dL Parathyroid hormone: 700 pg/mL Urine: Na+: 100 mEq/L/24h Ca2+: 100 mg/24h Osmolality: 400 mOsmol/kg H2O Which of the following is the most likely underlying cause of this patient's condition?

Loss-of-function mutation in the calcium-sensing receptor

Over-secretion of parathyroid hormone

Decreased sensitivity to parathyroid hormone

Gain-of-function mutation in the parathyroid hormone receptor gene

Impaired tubular calcium reabsorption

A 52-year-old man comes to the physician because of a 4-month history of fatigue, weakness, constipation, decreased appetite, and intermittent flank pain. He takes ibuprofen for knee and shoulder pain. Physical examination shows mild tenderness bilaterally in the costovertebral areas. His serum calcium concentration is 11.2 mg/dL, phosphorus concentration is 2.5 mg/dL, and N-terminal parathyroid hormone concentration is 830 pg/mL. Which of the following steps in vitamin D metabolism is most likely increased in this patient?

25-hydroxycholecalciferol → 1,25-dihydroxycholecalciferol

Ergocalciferol → 25-hydroxyergocalciferol

7-dehydrocholesterol → cholecalciferol

25-hydroxycholecalciferol → 24,25-dihydroxycholecalciferol

Cholecalciferol → 25-hydroxycholecalciferol

A 20-year-old woman visits the clinic for her annual physical examination. She does not have any complaints during this visit. The past medical history is insignificant. She follows a healthy lifestyle with a balanced diet and moderate exercise schedule. She does not smoke or drink alcohol. She does not take any medications currently. The family history is significant for her grandfather and uncle who had their parathyroid glands removed. The vital signs include: blood pressure:122/88 mm Hg, pulse 88/min, respirations 17/min, and temperature 36.7°C (98.0°F). The physical exam is within normal limits. The lab test results are as follows: Blood Urea Nitrogen 12 mg/dL Serum Creatinine 1.1 mg/dL Serum Glucose (Random) 88 mg/dL Serum chloride 107 mmol/L Serum potassium 4.5 mEq/L Serum sodium 140 mEq/L Serum calcium 14.5 mg/dL Serum albumin 4.4 gm/dL Parathyroid Hormone (PTH) 70 pg/mL (Normal: 10-65 pg/mL) 24-Hr urinary calcium 85 mg/day (Normal: 100–300 mg/day) Which of the following is the next best step in the management of this patient?

Start IV fluids to keep her hydrated

A 28-year-old man comes to the physician for a follow-up examination after a previous visit showed an elevated serum calcium level. He has a history of bipolar disorder. His mother had a parathyroidectomy in her 30s. The patient does not drink alcohol or smoke. Current medications include lithium and a daily multivitamin. His vital signs are within normal limits. Physical examination shows no abnormalities. Laboratory studies show: Serum Sodium 146 mEq/L Potassium 3.7 mEq/L Calcium 11.2 mg/dL Magnesium 2.3 mEq/L PTH 610 pg/mL Albumin 4.2 g/dL 24-hour urine Calcium 23 mg Which of the following is the most likely cause of this patient’s findings?

Abnormal calcium sensing receptors

A 21-year-old male college student is very anxious about having thyroid cancer as he found a lump in his neck a few days ago. He has also had diarrhea and a feeling of warmth on his face for 3 days now. His father and uncle both have been diagnosed with thyroid cancer. The lump is about 1 cm in diameter and is fixed and nontender on palpation. Physical examination is otherwise unremarkable. Ultrasound shows a non-cystic cold nodule that requires fine needle aspiration for diagnosis. Thyroid functions tests are normal, and his calcitonin level is 346 ug/ml. Which of the following genetic mutations would warrant thyroidectomy in this patient?

Down expression of the Ras protooncogene

Activating mutation of the BRAF gene

Parathyroid disorders for USMLE Step 1: High-Yield Pathology Lessons

Parathyroid Physiology - Calcium's Command Center

Primary function: Regulate serum calcium via Parathyroid Hormone (PTH).
PTH actions:
- Bone: ↑ Ca²⁺ & PO₄³⁻ resorption.
- Kidney: ↑ Ca²⁺ reabsorption, ↓ PO₄³⁻ reabsorption.
- Gut (indirectly): ↑ Vitamin D (calcitriol) activation → ↑ Ca²⁺ absorption.
📌 Mnemonic: PTH = Phosphate Trashing Hormone.

Parathyroid Hormone and Calcitonin in Calcium Homeostasis

⭐ PTH stimulates the enzyme 1-alpha-hydroxylase in the proximal convoluted tubules of the kidney, converting calcidiol to the active form, calcitriol (1,25-dihydroxyvitamin D).

Hyperparathyroidism - Calcium Overload Chaos

Primary: Unregulated PTH secretion, most often from a parathyroid adenoma (>80%).
- Labs: ↑ PTH, ↑ Ca²⁺, ↓ PO₄³⁻, ↑ urinary cAMP, ↑ alkaline phosphatase.
- Clinical: 📌 "Stones, bones, groans, psychiatric overtones."
  - Stones: Recurrent calcium nephrolithiasis.
  - Bones: Osteitis fibrosa cystica ("brown tumors").
  - Groans: Constipation, pancreatitis, peptic ulcers.
  - Psychiatric: Fatigue, depression, confusion.
Secondary: Compensatory PTH secretion from chronic hypocalcemia.
- Cause: Chronic kidney disease is the most common cause (↓ 1,25-dihydroxyvitamin D, ↑ PO₄³⁻).
- Labs: ↑ PTH, but ↓ or normal Ca²⁺.
Tertiary: Autonomous PTH secretion following long-standing secondary hyperparathyroidism. Labs show ↑ PTH and ↑ Ca²⁺.

Osteitis Fibrosa Cystica Progression

⭐ Differentiate primary hyperparathyroidism from Familial Hypocalciuric Hypercalcemia (FHH), which presents with low urinary calcium excretion due to a CASR gene mutation.

Hypoparathyroidism - The Calcium Crash

Etiology: Most commonly iatrogenic (post-thyroidectomy). Also, autoimmune disease, DiGeorge syndrome (22q11 deletion), severe hypomagnesemia.
Pathophysiology: ↓PTH leads to ↓Ca²⁺ and ↑PO₄³⁻.
- ↓Renal Ca²⁺ reabsorption & ↓bone resorption.
- ↓1α-hydroxylase activity → ↓calcitriol → ↓GI Ca²⁺ absorption.
Clinical: Neuromuscular excitability from hypocalcemia.
- Tetany: Chvostek's sign (facial tap), Trousseau's sign (carpal spasm with BP cuff).
- Paresthesias (perioral, digital), seizures.
- ECG: Prolonged QT interval.
Labs: ↓Ca²⁺, ↑PO₄³⁻, ↓PTH.

⭐ Trousseau's sign (carpopedal spasm induced by ischemia) is more specific for hypocalcemia than Chvostek's sign.

Trousseau's Sign: Clinical Demonstration & Causes

📌 CATS: Convulsions, Arrhythmias, Tetany, Spasms/Stridor.

PTH Pretenders - Mimics & Variants

Familial Hypocalciuric Hypercalcemia (FHH):
- Autosomal dominant defect in the Ca²⁺-sensing receptor (CASR) gene.
- Results in asymptomatic hypercalcemia, normal or mildly ↑PTH, and low urine calcium excretion.
- Benign; parathyroidectomy is not indicated.

⭐ Differentiate FHH from primary hyperparathyroidism via the calcium/creatinine clearance ratio (CCCR). A ratio <0.01 strongly suggests FHH.

Pseudohypoparathyroidism (PHP):
- End-organ resistance to PTH → hypocalcemia, hyperphosphatemia, despite ↑PTH levels.
- Type 1a: Maternal GNAS1 mutation. Associated with Albright's Hereditary Osteodystrophy (AHO) phenotype: short stature, obesity, shortened 4th/5th metacarpals.
Pseudopseudohypoparathyroidism (PPHP):
- Paternal GNAS1 mutation. Patient has the AHO phenotype but with normal biochemistry (Ca²⁺, PO₄³⁻, PTH).

High‑Yield Points - ⚡ Biggest Takeaways

Primary hyperparathyroidism, most often from a parathyroid adenoma, causes symptomatic hypercalcemia ("stones, bones, groans").

Secondary hyperparathyroidism is a physiologic response to hypocalcemia, typically from chronic kidney disease.

Tertiary hyperparathyroidism is autonomous PTH secretion after chronic secondary disease, causing marked hypercalcemia.

Hypoparathyroidism, commonly post-thyroidectomy, presents with hypocalcemic tetany (Chvostek/Trousseau signs).

Pseudohypoparathyroidism involves end-organ PTH resistance, leading to hypocalcemia despite high PTH.

Familial Hypocalciuric Hypercalcemia (FHH) causes asymptomatic hypercalcemia with low urine calcium.

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