“Knuckle, Knuckle, Dimple, Dimple” Sharma S, MD; Min Z, MD; Singh S, BA; Rivera-Ramirez L, MD; Williams R, MD, FACP Department of Medicine, Harbor Hospital, Baltimore, MD Pseudohypoparathyroidism (PHP) refers to a group of inherited disorders that exhibit various clinical findings typical of hypoparathyroidism that are often associated with skeletal and developmental abnormalities. Unlike true hypoparathyroidism in which there is hypocalcemia due to parathyroid hormone (PTH) deficiency, in pseudohypoparathyroidism, hypocalcemia is present in the setting of high parathyroid hormone levels but a deficient target organ response to the PTH. This is a report of a patient who presented with asymptomatic hypocalcemia and was later found to have pseudohypoparathyroidism. INTRODUCTION A 22 year-old Caucasian male presented to the Endocrine clinic after being referred by his primary care provider for asymptomatic hypocalcemia. He reported feeling fatigued and having cold intolerance, but he denied any recent changes in his appetite or weight. CHIEF COMPLAINT AND HISTORY OF PRESENT ILLNESS Hypothyroidism – on thyroxine replacement PAST MEDICAL/SURGICAL HISTORY ALLERGIES No known drug allergies SOCIAL HISTORY Non-smoker and denies alcohol use and drug abuse FAMILY HISTORY Mother – Pseudopseudohypoparathyroidism (PPHP) MEDICATION Levothyroxine 137 mcg once daily LABORATORY INVESTIGATIONS 9.8 14 42 362 136 4.3 98 0.9 Ca2+ – 8.1 mg/dL(8.4-10.2) Albumin – 4 g/dL (3.5-5) PO4-– 5 mg/dL (2.5-4.5) iPTH – 496 pg/dL (12-65) 25-OH Vit D – 34 ng/mL DISCUSSION Pseudohypoparathyroidism (PHP) can present in a multitude of ways, including asymptomatic hypocalcemia, neonatal hypothyroidism, hypogonadism. There are various forms of PHP, namely type I (subdivided into type Ia and Ib) and type II as shown in the table below. The PHP-I is the most common and transmitted in an autosomal dominant fashion and is due to mutations in the GNAS1 gene mapped to chromosome 20q13. This gene codes for the stimulatory alpha-subunit of the trimeric Gs protein that connects G-protein coupled receptors of various hormones (TSH, LH, FSH, PTH) with their intracellular signaling cascades. Mutations in this gene lead to a decreased sensitivity of renal tissues normally responsive to PTH which causes hypocalcemia and hyperphosphatemia; decreased response to TSH leads to primary hypothyroidism. These metabolic disturbances can be associated with a combination of clinical findings including short stature, obesity, shortened fourth and fifth metacarpal bones due to premature closure of the epiphyses, and a round face, known as Albright’s hereditary osteodystrophy (AHO). AHO phenotype presents in PHP-Ia and PPHP which are traced through multiple kindreds, and have an inheritance pattern consistent with paternal gene imprinting – only females, not males, can transmit the full disease with hypocalcemia. The paternal GNAS1 gene is imprinted (silenced) in the renal cortex, and metabolic findings of PHP become present only in patients who inherit a mutated allele from their mothers. The patient’s mother has phenotype of AHO without biochemical abnormalities, consistent with PPHP (as shown in Fig.2) and is likely inherited the gene from the patient’s grandfather. However, it appears that our patient inherited a mutated maternal allele for GNAS1 which explains his combination of metabolic abnormalities and AHO phenotype (PHP -Ia). PHYSICAL EXAM DIAGNOSIS AND TREATMENT Temp 36°C; BP – 120/65 mmHg; HR – 74/min Height – 5 feet ; Weight- 75 kg; BMI – 29 General examination showed a short stature with a round face Cardiovascular and respiratory examinations are normal. His fourth and fifth metacarpal bones were shortened bilaterally (arrows), demonstrating typical “Knuckle, Knuckle, Dimple, Dimple” appearance (Circles)(Fig. 1). Figure .1: Patient’s hands -Pseudohypoparathyriodism (PHP) Figure 2. Patient’s mother’s hands – pseudopseudohypoparathyroidism(PPHP) DISCUSSION Diagnosis of pseudohypoparathyroidism was made. He was treated with oral Vitamin D and calcium. After 2-3months of therapy, his serum calcium, phosphate and iPTH levels were normalized. CONCLUSION PHP is a rare hereditary disorder and may present with biochemical findings of primary hypothyroidism, hypocalcemia, hyperphosphatemia and elevated PTH levels. Physical manifestations of AHO further help us lead to the diagnosis of PHP-Ia. 85 27 REFERENCES: 1. Harrison’s Principles of Internal Medicine, 17th Ed (2008): Diseases of Parathyroid Gland 2. Goldman: Cecil Medicine, 23rd Ed (2007); Endocrinology and Metabolism 3. The Australasian Genetic Resource Book 2007: Genetic Imprinting fact sheet