Int J Clin Exp Med 2018;11(4):4295-4300 www.ijcem.com /ISSN:1940-5901/IJCEM0062264 Case Report Spinal stenosis associated with PHP-Ia: a case report and literature review Dongmei Wang1*, Yingying Chen2*, Minghui Zheng3, Yafang Hu1 Departments of 1Neurology, 3Spine Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China; 2Department of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guang- dong, China. *Equal contributors. Received July 25, 2017; Accepted February 6, 2018; Epub April 15, 2018; Published April 30, 2018 Abstract: Pseudohypoparathyroidism type Ia (PHP-Ia) is an extremely rare hereditary disorder. We report the case of a 33-year-old male with PHP-Ia and typical Albright hereditary osteodystrophy phenotype, with complaints of paraparesis due to extensive cervical spinal stenosis. The spinal stenosis was caused by diffused ossification of the posterior longitudinal ligament and multilevel intervertebral disc herniation. It is a rare but important manifestation of PHP-Ia that is being increasingly reported. This report aimed to highlight the relationship between spinal stenosis and PHP-Ia through extensive literature review and recommends that all patients with evident neurological symp- toms due to spondylopathy should be screened for serum calcium, phosphate and PTH level to rule out PHP. More- over, early diagnosis and timely corrections of hypocalcemia, hyperphosphatemia and elevated PTH level as well as effective body weight control are important to prevent rare neurological complications in patients with PHP-Ia. Keywords: Pseudohypoparathyroidism type Ia, spinal stenosis, albright hereditary osteodystrophy, GNAS gene Introduction ter and anti-thyroid antibodies are usually ab- sent [8]. Pseudohypoparathyroidism (PHP), an extreme- ly rare hereditary disorder, is characterized by Herein, we present the case of a Chinese man deficient target tissue response to parathyroid with typical AHO phenotype and delayed diag- hormone (PTH) action, which results in hypocal- nosis of PHP-Ia, complaining of paraparesis due cemia and hyperphosphatemia despite elevat- to extensive cervical spinal stenosis. ed plasma PTH levels [1]. Thus, the main neuro- Case report logical manifestations of PHP are tetany and pseudoseizures due to hypocalcemia [2]. Pa- A 33-year-old male was referred to the spine tients with PHP usually display typical charac- surgery department of our hospital in October teristics, namely Albright hereditary osteodys- 2015. He complained of progressive stiffness, trophy (AHO) [3], which includes short stature, numbness of the chest, abdomen and bilateral round face, early onset obesity, ectopic intra- lower limbs as well as bilateral hip pain for membranous calcifications, brachydactyly, dif- four months. He also suffered from progressive fuse osteopenia and mental retardation. Dental motor and sensation dysfunction of bilateral abnormalities include enamel hypoplasia, de- lower limbs for two months, which led to walk- layed eruption and impacted teeth [4]. Spinal ing disability and confined him to a wheelchair. stenosis is rarely observed among PHP pa- Additionally, he suffered from episodic spasms tients. According to its different pathogenesis of bilateral lower limbs for about two months and phenotype, PHP is classified as PHP-Ia, and dizziness for three days. PHP-Ib, PHP-Ic and PHP-II [5], among which PHP-Ia is the most common type [6]. Patients Physical examination on admission revealed with PHP-Ia usually develop resistance towards that his height was 160 cm and his weight other hormones, such as thyroid-stimulating was 66.5 kg [body mass index (BMI): 25.9 kg/ hormone (TSH), gonadotropins and growth hor- m2]. He had brachydactyly of all extremities mone-releasing hormone (GHRH) [7], while goi- and restricted movement of cervical spine. The Spinal stenosis associated with PHP-Ia Figure 1. Cervical MRI, CT and X-ray of the pelvis and right lower limb. T1 and T2 weighted sagittal cervical MRI scan confirmed remarkable cervical stenosis with signal changes of the cervical spinal cord (A and B). Spine CT recon- structions showed evident cervical spinal stenosis due to diffused ossification of the posterior longitudinal ligament and multilevel intervertebral disc herniation (C). X ray of the pelvis and right lower limb indicated degeneration of the bilateral hip joints, diffused muscle ossification, and osteoporosis of pelvis and right limb (D-F). muscle tone of bilateral lower limbs was re- (RR: 0.81-1.45 mmol/L) and low potassium markably increased and the muscle power of level of 3.08 mmol/L (RR: 3.50-5.30 mmol/L). bilateral lower limbs was slightly impaired (level Thyroid function test showed a serum TSH 4/5), without muscle atrophy. Hoffmann and level of 9.396 mIU/L (0.55-4.78 mIU/L) and Babinski signs were positive on both sides, and serum free T4 level of 1.17 ng/dl (0.89-1.76 the deep tendon reflex of left lower limb was ng/dl). Based on the clinical features and labo- hyperactive with knee clonus. ratory tests, the diagnosis of PHP was made. Three-dimensional reconstruction of the com- Genetic test revealed a heterozygous frame- puted tomography (CT) images revealed evi- shift mutation in the causative gene of PHP-Ia, dent cervical spinal stenosis due to diffused guanine nucleotide-binding protein alpha (GN- ossification of the posterior longitudinal liga- AS) gene that simulates activity of the polypep- ment and multilevel intervertebral disc hernia- tide 1, NM_080425.2, c.2277dupC, p.Val76- tion. A magnetic resonance imaging (MRI) of 0Argfs*23. Sanger sequencing confirmed the the brain and entire spine indicated marked de novo mutation (Figure 2). The genetic test cervical stenosis due to intervertebral disc was performed by BGI (Shenzhen, China) with herniation within C2/3, C3/4, C4/5, C5/6 and next-generation sequencing coupled with DNA C6/7. Moreover, signal changes of the cervical target-capture array on Illumina HiSeq2000 spinal cord were noted. The X-ray of the chest, platform. The genetic test further confirmed pelvis and bilateral lower limbs showed degen- the diagnosis of PHP-Ia. eration of bilateral hip joints, diffused muscle ossification, and osteoporosis of pelvis and Given the diagnosis of PHP-Ia, the patient was right lower limb (Figure 1). Additionally, the started on oral calcium supplement and thyrox- patient had decreased bone mineral density ine replacement. In order to alleviate his neuro- (BMD), with the lowest BMD Z-score of -2.0. logical symptoms, the patient underwent a pos- terior decompression and laminoplasty. After The laboratory examination revealed consider- the surgery, his symptoms including motor and ably high iPTH of 214.4 pg/ml [reference range sensation disturbance of bilateral lower limbs (RR): 12-72 pg/ml], decreased serum calcium were significantly relieved. One-month post- level of 2.04 mmol/L (RR: 2.20-2.65 mmol/L), operation, the patient walked to our clinic with high serum phosphate level of 1.49 mmol/L the help of a walker. He was referred to the oral 4296 Int J Clin Exp Med 2018;11(4):4295-4300 Spinal stenosis associated with PHP-Ia Figure 2. Sanger sequencing confirmed the de novo mutation, NM_080425.2, c.2277dupC, p.Val760Argfs*23. and maxillofacial surgery department of our nized complication of PHP [7]. To our knowl- hospital in 2017 to extract multiple impacted edge, there are 14 reported cases of spinal teeth. stenosis associated with PHP-Ia (Table 1). As seen in Table 1, eight of the 14 reported pa- Discussion tients were male and almost all the patients had cervical and/or thoracic spinal stenosis. PHP-Ia is an autosomal dominant disease Several mechanisms of spinal stenosis as- caused by heterozygous mutations within the sociated with PHP-Ia have been described. Ch- GNAS gene [2], which can be diagnosed by ronic hypocalcemia and hyperphosphatemia genetic test. Mapped to the chromosome 20- due to untreated hypoparathyroidism may ca- q13, the GNAS gene consists of 13 exons [9] use extraskeletal ossifications, excessive bone s>/. GNAS gene mutation with c.348_349insC formation in the vertebral canal and multiple mutation was the first identified mutation [10]. herniated intervertebral disc (HIVD) [6], leading So far more than 100 mutations of PHP-Ia to paravertebral ligament ossification and hy- have been identified in all exons except exon 3, pertrophic laminae, which are the most com- while exon 5 and exon 7 are two hot-spots [5]. mon causes of spinal stenosis in patients with Among these mutations, small insertions, dele- PHP-Ia [7]. Congenital short pedicles second- tions and amino-acid substitutions predomi- ary to premature closure of the physes is nate [11], causing deficiency of functional Gαs also an important factor leading to spinal ste- protein, an intermediary coupling protein that nosis [16]. Besides, central obesity of PHP-Ia stimulates adenylyl cyclase. Maternal muta- patients may result in reactive bone formation tions involving GNAS exons that encode Gαs and ossifications of paravertebral ligament by lead to PHP-Ia, while the same or similar muta- increasing inflammation and by direct bioc- tions on the paternal allele lead to pseudop- hemical effects on the spine [17], which play an seudohypoparathyroidism (PPHP) [12]. The mu- important role in spinal stenosis. Our patient tation observed in our patient, c.2277dupC, p. had severe cervical spinal stenosis due to both Val760Argfs*23, caused a frameshift after the ossification of the posterior longitudinal liga- 760 amino