Poster Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Pseudohypoparathyroidism Type 1b -Exploration of molecular genetics and the role of genetic testing (#108)

Aakansha Zala 1 , Diana Mackay 1 , Sridhar Chitturi 1
  1. Royal Darwin hospital, Darwin, NT, Australia

Pseudohypoparathyroidism (PHP) is a rare metabolic disorder characterised by end-organ resistance to parathyroid hormone (PTH). PHP type 1b (PHP1b) is caused by methylation defects of the GNAS gene. We describe two cases of PHP1b with confirmatory genetic testing. We explore the clinical features of PHP1b and examine the role of genetic testing.

Case 1

A 25-year-old female presented with episodes of muscle spasms and paraesthesia since childhood. Initial tests demonstrated severe hypocalcaemia, hyperphosphatemia and an elevated PTH with normal Vitamin D levels (Table 1). Hand X-rays did not demonstrate Albright hereditary osteodystrophy (AHO) features. CT brain demonstrated widespread calcification of the basal ganglia and bilateral cerebellar calcification. Tests for anterior pituitary were normal.  Genetic testing showed complete loss of methylation of exons A/B, AS and complete gain of methylation at exon NESP, consistent with the diagnosis of PHP1b.

Case 2

A 21-year-old female presented with tonic clonic seizures on a background of carpopedal spasms since childhood, often in the setting of viral illnesses.  Her initial tests demonstrated hypocalcaemia with high-normal phosphate and an elevated PTH (Table 1). MRI brain demonstrated calcification in the caudate, lentiform and dentate nuclei of the cerebellum. Hand X-rays did not demonstrate any AHO features. Genetic testing demonstrated loss of all three maternal GNAS methylation imprints (AS, XL, and A/B) and a gain-of-methylation at NESP, consistent with PHP1b.

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 Introduction

Pseudohypoparathyroidism (PHP) is a group of disorders defined by end organ unresponsiveness to PTH. PTH resistance is characterized by hypocalcaemia, hyperphosphatemia and elevated PTH concentrations. PHP can be divided into three types depending on the molecular characteristics of the disease. PHP types 1a and 1c are characterised by heterozygous inactivating mutations in the maternal GNAS exons 1 through 13. PHP1b is caused by abnormal methylation of the differentially methylated regions (DMRs) in GNAS rather than exons 1-13 in 20q13[1].

Pathophysiology

The alpha subunit of the G protein (Gsα) is coded by exons 1-13 of GNAS gene located on chromosome 20q. The Gsα is coupled to the PTH receptor and mediates downstream regulation of PTH action. Gsα gene is regulated by four upstream DMRs - exon A/B (A/B), GNAS antisense (AS1), extra-large stimulatory G protein (XL), and neuroendocrine secretory protein 55 (NESP), as well as an imprinting control element syntaxin (STX16) [2]. Gsα is expressed in the proximal renal tubules, thyroid, gonads and pituitary gland [2].

Most cases of PHP1b are sporadic, characterised by methylation abnormalities in two or more DMRs of the GNAS gene cluster [1,3,4,5]. The underlying genetic defect of sporadic PHP1b is unknown except where it is caused by paternal uniparental disomy [6]. The rare familial cases of PHP1b are caused by microdeletions in the STX16 or NESP, and are transmitted in maternal autosomal dominant manner [3]. There are no clinical differences between sporadic and familial cases and the extent of methylation defects does not correlate with disease severity [7,8].

 Clinical manifestations

Clinical diagnosis of PHP1b is often difficult and delayed due to the subtle findings. PTH resistance may be absent at birth and develop over time. The most common clinical manifestation are symptoms of hypocalcaemia (45–80%)[9]. Unlike PHP type 1a, there are no clear AHO signs except for mild brachydactyly. Features of hormone resistance are uncommon except for mild thyroid stimulating hormone (TSH) resistance [10].

While chronic hypocalcaemia and associated hyperphosphatemia can result in intracranial deposition of calcium, cognitive issues are rare in PHP1b, unlike with PHP 1a. In both cases presented, there was evidence of radiological calcifications but no neurological manifestations.

Bone development in PHP1b is poorly understood. While studies have demonstrated bone remodelling in PHP1b, data examining whether bone density is normal or reduced has shown conflicting results [11-13]. The prevalence of osteoporosis in these patients is unknown.

Diagnosis

Diagnosis is largely clinical and, due to the subtle findings, can be difficult. Traditionally, to confirm PTH tissue resistance, a PTH infusion test was used with an absent cAMP/phosphaturic response in those with PTH resistance. However, this is no longer recommended in the international guidelines except in research settings [10]. Instead, diagnosis of PHP is based on a series of clinical features including evidence of PTH resistance, early obesity, AHO phenotype, endocrine resistance syndromes (i.e. TSH, growth hormone, gonadotropins) and neurological deficits. Genetic testing can be considered in those who present with PTH resistance with/without the following additional criteria [10]:

 

  • Subcutaneous ossifications that can include deeper ossifications
  • Early-onset (before 2 years of age) obesity associated with TSH resistance or with one of the above
  • AHO alone

Clinical, biochemical and imaging findings of PHP subtypes overlap and does not permit reliable subtype identification. Only genetic testing allows for confirmation of the diagnosis and permits characterization of the subtype of the disease. Correct diagnosis of the subtype allows for a better appreciation of the trajectory of the disease and assists with screening and management. For example, individuals with PHP1a are more likely to have a wider range of hormonal resistance syndromes (including growth hormone and gonadotropins), have a shorter stature with premature epiphyseal fusion and develop more severe neurocognitive/psychosocial issues compared to PHP1b.  As such, early correct diagnosis with genetic testing can guide appropriate, cost effective screening and management with better targeted genetic counselling sessions.

 

Key points:

  1. Pseudohypoparathyroidism Type 1b is marked by methylation defects in the GNAS.
  2. Clinical features suggestive of pseudohypoparathyroidism type 1b include hypocalcaemia, hyperphosphatemia, elevated PTH, early obesity and absence of AHO features (except brachydactyly).
  3. The diagnosis of pseudohypoparathyroidism type 1b is largely clinical but with the aid of genetic testing, early identification of the subtype can be achieved. This allows for a better understanding of the disease trajectory and facilitates more targeted screening/management.

 

 

 

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