Case Report
Pseudohypoparathyroidism: A Diagnosis That Traverses Specialities
Authors:
Cynthia Amrutha Sukumar, Assistant professor, Department of Medicine, Kasturba Medical College, Manipal, India
Sanyam Tomar, Under-graduate, Kasturba Medical College, Manipal, India,
Shipra Rai, Assistant professor, Department of Medicine, Kasturba Medical College, Manipal, India,
Kavitha Saravu, Professor and Unit Chief, Department of Medicine, Kasturba Medical College, Manipal, India; Coordinator, Manipal Center for Infectious Diseases (MAC ID), Manipal Academy of Higher Education, Manipal, India.
Address for Correspondence
Dr. Cynthia Amrutha,
Assistant Professor,
Department of Medicine,
Kasturba Medical College,
Manipal- 576104, Karnataka, India.
E-mail: cynthiaamrutha@gmail.com.
Citation
Sukumar CA, Tomar S, Rai S, Saravu K. Pseudohypoparathyroidism: A Diagnosis That Traverses Specialities. Online J Health Allied Scs.
2020;19(3):12. Available at URL:
https://www.ojhas.org/issue75/2020-3-12.html
Submitted: Sep 4,
2020; Accepted: Nov 25, 2020; Published: Dec 20, 2020 |
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Introduction:
Pseudohypoparathyroidism (PHP) is a diverse group of rare endocrine disorders characterized by resistance to the action of parathyroid hormone (PTH). PHP can be further divided into distinct subtypes: PHP type-1a, PHP type-1b, PHP type-1c, PHP type-2 and pseudopseudohypoparathyroidism (PPHP)].[1]
Genetic defects associated with PHP invariably involve the alpha-subunit of G stimulatory protein (Gsa), which is necessary for the actions of PTH and several other hormones. [2]
PHP-1a is caused by heterozygous inactivating mutations within maternal GNAS allele[3]. This presents as multiple hormone resistance and a group of clinical features including short stature, rounded face, brachydactyly, brachymetacarpia, centripetal obesity, subcutaneous ossifications, termed Albright hereditary osteodystrophy (AHO)[3,4]. The same mutations within the paternal allele lead to pseudo-PHP, with patients having AHO features without evidence of hormone resistance.[5,6]
PHP-1b is characterized by defects in the maternal GNAS imprints. Patients with PHP1-b do not have AHO features and hormone resistance is limited to PTH and TSH. [6]
The aim of our report is highlight the variability in clinical presentation of PHP, the role of biochemical investigations in diagnosis and monitoring of patients.
Case Report
A 26 year old Indian male, presented to the orthopedic department with a pathological fracture of the right humerus and a spontaneous dislocation of the right shoulder joint. Past history revealed development of genu valgum (knock knees) at 14 years of age with history of occasional tetanic contractions at 18 years. Family history indicated similar complaints with patient’s mother and younger sibling. No history of past medical or surgical interventions.
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| Chart 1: Pedigree chart showing affected individuals |
The patient was referred to the department of medicine following a bone scan that suggested a metabolic bone disorder, possibly hyperparathyroidism. Physical examination of the patient revealed short stature, large head, brachydactyly, bulbous fingertips and genu valgum.
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Image 2: Clinical picture showing short stature |
Image 3,4: Radiographs of brachydactyly (left and right) |
Lab investigations showed hypocalcemia with normal phosphate levels, raised PTH and Alkaline phosphatase and low vitamin D levels. A provisional diagnosis of PHP was made. While the patient was started on oral calcium(Tab. Calcimax forte TID) and calcitriol(Rocaltrol 0.25mcg BD) supplementation, genetic consultation was sought. As a definitive diagnosis could only be established using genetic testing, the patient was advised GNAS deletion/duplication analysis, in view of his family history. However, he was unable to afford the genetic test.
| Table 1: Summary of the clinical, biochemical and radiological findings |
Physical examination |
Short stature
Large head
Brachydactyly,
Bulbous fingertips
Genu valgum |
Biochemical investigations |
Serum PTH- 1550
Serum calcium- 8mg/dl
Serum phosphorus-4.6mg/dl
Alkaline phosphatase- 392 IU/ml |
X-rays |
Brachytelephalangy
Osteolytic lesions of the humerus
Thick calvarium of skull |
Bone scan |
Metabolic bone disorder |
Discussion
PHP is a rare genetic disease and its prevalence worldwide has not been accurately estimated. Genetic or epigenetic mutations of the GNAS gene (that encodes the Gsa) lead to loss of function of the Gsa. This impairs signal transmission to adenylate cyclase, preventing cyclic AMP (cAMP) production which is essential for action of PTH and other hormones like thyroid-stimulating hormone, vasopressin, gonadotropins, glucagons, adrenocorticotropin, and growth hormone–releasing hormone.
The patient first presented with a pathological fracture raising suspicion of an underlying metabolic bone disorder. Low serum calcium and normal serum phosphorus despite very high PTH levels made hyperparathyroidism an unlikely diagnosis. Due to target organ resistance to PTH, hypocalcemia along with high PTH levels is characteristic of PHP, making it the provisional diagnosis.
Of the several subtypes of PHP, patients with PHP-1a and PHP-1c present with resistance to multiple hormones, along with features of AHO. However, this patient displayed neither multiple hormonal resistance nor all the classical AHO features, therefore making PHP-1a and PHP-1c unlikely diagnoses. Patients with PHP-1b do not show typical features of AHO and usually exhibit hormone resistance in tissues where Gsa is derived from maternal allele only, like renal proximal tubules.[6]
Recently, several independent studies have shown patients with hormone resistance and mild AHO like features in whom coding Gsa mutations were excluded but GNAS imprinting defects were confirmed, indicating an overlap between molecular and clinical features of PHP-1a and PHP-1b.[3][7][8] Consequently, PHP classification fails to differentiate all patients with different clinical and molecular findings and therefore, in this case, it is crucial for the patient to undergo genetic testing to establish final diagnosis. Presently, a new classification is being established by the EuroPHP network, based on molecular pathology.[9,10]
The treatment plan for this patient was based on the clinical diagnosis of PHP. The patient was started on oral calcium and calcitriol to correct hypocalcemia and bring down PTH levels. Regular monitoring was done using the same parameters showing improvements in serum calcium but PTH levels continued to rise. On doubling the dose of oral calcium and calcitriol ,PTH levels decreased from 1709 to 1175pg/mL. The patient was asked to come back every month for regular serum calcium, serum phosphate, Vitamin D and PTH monitoring. This allowed for therapeutic adjustments to be made till calcium-phosphate homeostasis was attained.
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Chart 2: Graph showing the PTH trend from admission to last follow-up |
Conclusion
As pseudohypoparathyroidism is a rare condition, a complete biochemical investigation is essential in diagnosis due to variable presentations of PHP. The final diagnosis can only be made through costly gene testing which is not feasible in the present scenario. Although treatment is fairly symptomatic and cost effective once diagnosis is made, insufficient funds halt further investigations at the molecular level. Hence, it is imperative to use high clinical suspicion in patients with the typical biochemical abnormalities of PHP to effectively diagnose this condition.
References
- Mantovani G, Bastepe M, Monk D et al. Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients. Hormone Research in Paediatrics. 2020;93(3):182-96.
- Wimeau JL, Balavoine AS, Ladsous M, Velayoudom-Cephise FL, Vlaeminck-Guillem V. Multihormonal resistance to parathyroid hormone, thyroid stimulating hormone, and other hormonal and neurosensory stimuli in patients with pseudohypoparathyroidism. Journal of Pediatric Endocrinology and Metabolism. 2006;19(Supplement):653-62.
- Mantovani G, Elli FM, Spada A. GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification? Hormone and Metabolic Research. 2012 Sep;44(10):716-23.
- Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, Steele G, Smallwood PM, Levine MA. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. New England Journal of Medicine. 1990 May 17;322(20):1412-9.
- Elli FM, deSanctis L, Ceoloni B, Barbieri AM, Bordogna P, Beck-Peccoz P, Spada A, Mantovani G. Pseudohypoparathyroidism Type Ia and Pseudo-Pseudohypoparathyroidism: The Growing Spectrum of GNAS Inactivating Mutations. Human Mutation. 2013 Mar 1;34(3):411-6.
- Bastepe M. The GNAS locus and pseudohypoparathyroidism. InGenomic imprinting 2008 (pp. 27-40). Springer, New York, NY.
- Mantovani G, de Sanctis L, Barbieri AM et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients. The Journal of Clinical Endocrinology & Metabolism. 2010 Feb 1;95(2):651-8.
- de Nanclares GP, Fernández-Rebollo E, Santin I et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s hereditary osteodystrophy. The Journal of Clinical Endocrinology & Metabolism. 2007 Jun 1;92(6):2370-3.
- Turan S. Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder. Journal of Clinical Research in Pediatric Endocrinology. 2017 Dec;9(Suppl 2):58.
- Pereda A, Garin I, de Nanclares GP. What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis. BMC Medical Genetics. 2018 Dec;19(1):32.
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