UNEXPECTED HYPERPARATHYROIDISM IN A PATIENT WITH ACRODYSOSTOSIS

Abstract

Objective:

Acrodysostosis is a rare skeletal dysplasia with one gene mutation associated with pseudohypoparathyroidism. We describe a 15-year-old male patient with genetic acrodysostosis who presented with hyperparathyroidism.

Methods:

Laboratory testing, including genetic testing for acrodysostosis and biochemical evaluation for hypercalcemia, were obtained. For evaluation of the source of hyperparathyroidism, parathyroid imaging including technetium (99mTc) sestamibi (MIBI) scan, ultrasound, and 4-dimensional computed tomography scans were performed.

Results:

The initial calcium level of 11.7 mg/dL (reference range is 8.4 to 10.2 mg/dL), phosphorus of 2.6 mg/dL (reference range is 2.9 to 5.0 mg/dL), and parathyroid hormone (PTH) of 177 pg/mL (reference range is 15 to 65 pg/mL) were suspicious for hyperparathyroidism. Magnesium, albumin, creatinine, and PTH-related peptide levels were normal. His calcium/creatinine ratio was 0.15, calcium/creatinine clearance ratio was 0.008, and the fractional excretion of phosphorus was 34%. Our patient had no symptoms other than long-standing bone pain. Thyroid ultrasound then MIBI scan did not show a parathyroid adenoma or parathyroid gland hyperplasia. Familial hypocalciuric hypercalcemic syndrome was entertained, but without a family history and documented normal calcium levels throughout childhood, it was considered unlikely. On subsequent testing, his calcium and PTH levels increased. Subsequent imaging including repeat thyroid ultrasound, MIBI scan, and computed tomography did not find a definitive cause. Multiple endocrine neoplasia type 1 genetic testing was negative. Without an adenoma seen to remove surgically, we performed a trial of cinacalcet with successful reduction in PTH and normalization of his calcium and phosphorus levels.

Conclusion:

Pseudohypoparathyroidism and hypocalcemia are well reported in acrodysostosis. To the best of our knowledge, this is the first reported case of hypercalcemia caused by hyperparathyroidism in a patient with acrodysostosis.

INTRODUCTION

Acrodysostosis is a rare genetic condition with classic features including severe brachydactyly, facial dysostosis, nasal hypoplasia, developmental delay, and short stature (1,2). This condition has physical similarities and historically was confused with Albright hereditary osteodystrophy, but molecular genetics has shown the conditions have different genetic etiologies, although in a common pathway (3,4). This common pathway is important for G-protein-coupled receptors (GPCRs) and can lead to hormone resistance, usually having resistance to thyroid-stimulating hormone (TSH) and parathyroid hormone (PTH). We describe a case of genetic acrodysostosis with primary hyperparathyroidism, not the expected pseudohypoparathyroidism seen in this condition.

CASE REPORT

Our patient was a 15-year-old male with acrodysostosis with confirmed genetic defect in the gene for cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase 4D, PDE4D. Targeted genetic testing revealed that he was heterozygous for the Y677D variant in the PDE4D gene; prior chromosomal microarray analysis was negative. PDE4D mutation is associated with acrodysostosis type 2. This variant has not been previously reported as a pathologic variant, nor has it been reported in large population cohorts in normal subjects. This particular variant is a non-conservative amino acid substitution and is likely to impact secondary protein structure as this substation in the residues will affect size, charge, polarity, and other properties. This variant was classified as a variant of uncertain significance as there are no other pathogenic variants reported at that particular amino acid residue. In silico analysis using protein and splicing prediction models, as well as evolutionary conservation data predicts this variant is probably damaging to the protein structure function and is most likely pathogenic.

Our endocrine service was consulted for evaluation of new hypercalcemia. Review of his medical history showed normal calcium levels during childhood. Our initial biochemical evaluation showed calcium of 11.7 mg/dL (reference range is 8.4 to 10.2 mg/dL), phosphorus of 2.6 mg/dL (reference range is 2.9 to 5.0 mg/dL), and PTH of 177 pg/mL (reference range is 15 to 65 pg/mL). His magnesium, albumin, creatinine, and PTH-related peptide levels were normal, but his vitamin D level was low at 5.2 ng/mL (reference range is >20 ng/mL).

We started him on vitamin D₂ at 2,000 IU daily as well as a multivitamin containing 400 IU of vitamin D. After 6 months, his vitamin D level normalized and his labs remained consistent with hyperparathyroidism. He did not have any abdominal pain, constipation, nephrolithiasis, or changes in mental status, but he did have bone pain. Evaluation for the etiology of his hyperparathyroidism included a neck ultrasound, which was normal and then a technetium (99mTc) sestamibi (MIBI) scan, which did not suggest a parathyroid adenoma nor parathyroid gland hyperplasia.

Upon normalization of his vitamin D level, we evaluated for the possibility of familial hypocalciuric hypercalcemia (FHH) with a urinary calcium/creatinine ratio of 0.15 (ratios >0.2 indicate hypercalciuria), calcium/creatinine clearance ratio of 0.008 (which is low and can be seen in FHH), and fractional excretion of phosphorus at 34% (reference range is <20%, increased fractional excretion of phosphorous is consistent with phosphorus wasting seen in hyperparathyroidism). PTH levels can be slightly elevated in FHH, but our patient’s PTH was over 2.7 times the upper reference range.

Calcium and PTH levels continued to remain elevated over the next 12 months. Imaging studies were repeated including ultrasounds, MIBI scans, and 4-dimensional computed tomography of the parathyroid glands and continued to not reveal any definitive cause. Genetic testing for multiple endocrine neoplasia 1 was performed as parathyroid hyperplasia can be missed on imaging and was negative. Without an adenoma seen to remove surgically and levels remaining elevated, we performed a trial of cinacalcet with successful reduction in PTH and normalization of his calcium and phosphorus levels.

Cinacalcet (Sensipar) is a calcium mimetic that causes activation of the calcium-sensing receptor and leads to a decrease in PTH secretion (1). We started the patient at 30 mg daily with improvement of his calcium, phosphorus, and PTH levels. Subsequently, his dose was increased, but compliance has been a concern (Table 1).

Table 1.

Blood Chemistry Before and After Cinacalcet Commencement in January of 2018

	May 2012	Sep 2015	Mar 2016	Nov 2016	Apr 2017	Oct 2017	Feb 2018	Mar 2018	Oct 2018	Jan 2019	Dec 2019
Calcium (mg/dL)	10.0	11.7	12.2	12.4	12.1	11.9	10.3	10.2	11.9	11.2	10.6
Phosphorus (mg/dL)	–	2.6	2.8	2.5	2.3	2.6	2.5	2.4	2.1	2.0	2.9
Albumin (mg/dL)	4.5	4.3	–	–	4.6	4.6	–	–	–	–	4.5
Parathyroid hormone (pg/mL)	–	177	121	173	192	136	165	118	177	177	97
Vitamin D (ng/mL)	–	5.2	21.6	12.7	33.4	21.1	20.5	–	–	32.1	22.4

DISCUSSION

Acrodysostosis was first described in 1967, also known as Arkless-Graham syndrome or Maroteaux-Malamut syndrome (2,3). Incidence is unknown but there are less than 80 cases of acrodysostosis reported in the literature (4). The classic description includes severe brachydactyly, facial dysostosis, and nasal hypoplasia. Developmental delay and short stature are common as well (5). Before molecular genetics elucidated a different etiology, acrodysostosis was believed to be part of Albright hereditary osteodystrophy as there is significant overlap in the phenotypic appearances of acrodysostosis, psuedohypoparathyroidism type 1a, and pseudopseudohypoparathyroidism. The cause of this phenotypic confusion is due to the common pathway important to these conditions, the GPCR-G-protein alpha subunit-cAMP cAMP-protein kinase A signaling pathway. Patients with Albright hereditary osteodystrophy and acrodysostosis can have hormone resistance because of this defect. TSH and PTH resistance are seen in these conditions because the TSH and PTH receptors are GPCRs. Defects of any of step along the GPCR-G-protein alpha subunit-cAMP-protein kinase A signaling pathway can lead to hormone resistance.

Two different genetic and phenotypic syndromes of acrodysostosis are now identified (6,7). Acrodysostosis type 1 involves the gene for type 1 regulatory subunit of cAMP-dependent protein kinase alpha (PRKAR1A) while acrodysostosis type 2 involves the gene for cAMP-specific phosphodiesterase 4D (PDE4D). The existence of GPCR hormone resistance is typical of the type 1 syndrome. Patients with the PDE4D defects of type 2 are less likely to have hormone resistance (8).

The dysostosis characterizing acrodysostosis is similar in patients affected by both types. Typical clinical features comprise a facial dysostosis (broad face, widely spaced eyes, maxillonasal hypoplasia) associated with a peripheral dysostosis characterized by small broad hands and feet with stubby digits. Included is an image of our patient, showing pronounced mid-face hypoplasia as well as a hand radiograph showing small, broad hands with brachydactyly, epiphyseal/metaphyseal dysplasia, and absent growth centers with cone-shaped epiphyses (Fig. 1 and 2).

Fig. 1.

Facial features of dysostosis and nasal hypoplasia.

Fig. 2.

Hand X-ray of our patient with acrodysostosis at 3 years of age. Brachydactyly, epiphyseal/metaphyseal dysplasia, and absence of growth centers with cone-shaped epiphyses and epiphyseal stippling are seen.

Primary hyperparathyroidism is characterized by hypercalcemia with inappropriately elevated PTH. In primary hyperparathyroidism, one or more of the parathyroid glands is overactive and causes overproduction of PTH. This increased PTH acts on bone to increase serum calcium levels and the kidney to increase resorption of calcium and increasing 1-alpha hydroxylase activity. This leads to increased 1,25-dihydoxyvitamin D, increasing intestinal absorption of calcium. The overall effect of PTH is increased serum calcium levels and decreased phosphorus levels. Classic symptoms of hyperparathyroidism can include kidney stones, bone pain, abdominal pain, and fatigue. Laboratory testing for primary hyperparathyroidism will show hypercalcemia, elevated PTH, and hypophosphatemia. The most common cause is a single parathyroid adenoma, followed by parathyroid gland hyperplasia. Primary hyperthyroidism may be part of a larger genetic syndrome as well.

FHH is an autosomal dominant condition caused by an inactivating mutation in the calcium-sensing receptor gene called CaSR. It is characterized by lifelong mild and typically asymptomatic hypercalcemia. The inactivating mutation of the CaSR gene in FHH renders the receptor less sensitive to calcium, requiring higher than normal serum calcium concentration to reduce PTH production. In the kidney, this defect leads to an increase in tubular calcium and magnesium reabsorption. The urinary calcium excretion in FHH is generally in the low-normal to reduced range. The fractional excretion of calcium (calcium/creatinine clearance ratio) is often <0.01 in patients with FHH, indicating that more than 99% of the filtered calcium has been reabsorbed, despite the presence of hypercalcemia. This can be used to improve the discrimination of FHH from primary hyperparathyroidism. Although this is typical for FHH, the fractional excretion of calcium may also be low in patients with primary hyperparathyroidism, whose values often range between 0.01 and 0.05. The diagnosis of FHH, and particularly its distinction from primary hyperparathyroidism, is primarily based upon the family history, laboratory findings, and genetic testing (9).

We did pursue genetic testing to rule out FHH, but the patient’s insurance plan denied our request. Even without genetic testing, FHH is very unlikely secondary to normal calcium levels throughout childhood, no family history of FHH or hypercalcemia, fractional excretion of phosphorous consistent with hyperparathyroidism, the degree of elevation of our patient’s PTH, and the low likelihood to have 2 different rare genetic conditions. Hypercalcemia not associated with hyperparathyroidism has been reported in 1 patient with acrodysostosis (10), but this is the first reported case of hypercalcemia caused by hyperparathyroidism in acrodysostosis that we are aware of.

CONCLUSION

Pseudohypoparathyroidism and hypocalcemia are well reported in acrodysostosis. To the best of our knowledge, this is the first reported case of hypercalcemia caused by primary hyperparathyroidism in a patient with acrodysostosis.

Abbreviations

cAMP

cyclic adenosine monophosphate

FHH

familial hypocalciuric hypercalcemia

GPCR

G-protein-coupled receptor

MIBI

technetium (99mTc) sestamibi

PTH

parathyroid hormone

TSH

thyroid-stimulating hormone