Pseudohypoparathyroidism with normocalcemia: a rare case report from Nepal

Abstract

Introduction:

Pseudohypoparathyroidism (PHP), a rare genetic disorder is characterized by features of hypoparathyroidism due to tissue resistance to effect of parathyroid hormone (PTH).

Case presentation:

A 1-year-old girl, the first child of healthy non-consanguineous parents with no family history of similar conditions or skeletal deformities, presented with small bumps on her leg, wrist, and periumbilical region for 6 months. Lab results revealed high serum phosphate, low vitamin D, normal calcium, and elevated PTH levels. Genetic testing identified a missense mutation in the GNAS gene, confirming a diagnosis of Albright osteodystrophy syndrome/progressive osseous heteroplasia. She was treated with vitamin D supplements and is on regular follow-up. The unusual case in this case is absence of family history and delayed clinical diagnosis.

Discussion:

PTH regulates calcium and phosphate levels by increasing blood calcium, reducing phosphate, and promoting the production of 1,25-dihydroxy-vitamin D (calcitriol). In pseudo-hypoparathyroidism (PHP), resistance to PTH in bones and kidneys leads to low calcium, high phosphate, and compensatory hyperparathyroidism. PHP often presents with hypocalcemia and hyperphosphatemia, but normocalcemia can occur due to effective compensatory mechanisms. A hallmark of Albright hereditary osteodystrophy, subcutaneous ossifications, can signal PHP. PHP type IA, linked to GNAS mutations, can present with elevated TSH at birth. Early diagnosis requires careful monitoring of calcium, phosphorus, PTH levels, and genetic testing. Management includes calcium and calcitriol supplementation with regular follow-up.

Conclusion:

This case highlights the importance of diagnosing PHP, even in normocalcemic patients, when clinical signs like subcutaneous ossifications are present.

Introduction

Pseudo-hypoparathyroidism is a rare genetic disorder characterized by resistance to parathyroid hormone at cellular level resulting in hyperphosphatemia and hypocalcemia^[1,2]. It is considered to be inherited as a sex-linked dominant trait diagnosed generally at the age of 5–10 years. It has prevalence of 3.4 million per million^[1]. It can present with clinical features like tetany, muscle cramps, and sometimes, distinct physical characteristics like short stature or round face^[2]. In this case report, we describe a 1-year-old female child who presented with multiple small subcutaneous nodules in leg, wrist, and periumbilical areas with normocalcemia who was later diagnosed with Albright hereditary osteodystrophy.

HIGHLIGHTS

• Pseudohypoparathyroidism (PHP), a rare genetic disorder can very rarely present with normocalcemia, low vitamin D level, and hyperphosphatemia.

• It is crucial to diagnose PHP even in normocalcemic patients with features of subcutaneous ossifications.

Case presentation

A 1-year-old female presented with a medical history of multiple small bumps/growth under the skin of leg, wrist and on periumbilical areas for 6 months of age which was insidious in onset, nonprogressive, non-painful, and not associated with discharge. There were no other gastrointestinal or urinary symptoms. She was the first offspring of two phenotypically healthy non-consanguineous parents with no obvious skeletal deformities and with no similar family history. She was born after a full-term pregnancy after spontaneous conception but was underweight at birth with no antenatal complications of pregnancy. On the third day of life, she was diagnosed with jaundice for which phototherapy was done. On further investigation, TSH was found to be 13 mIU/L for which 24 mcg thyronorm was started. Regular follow-up was done and thyroid function test came out to be normal at 1 year of age, so thyronorm was stopped. She was exclusively breastfed till 6 months of age and had adequate sun exposure. On examination, there were multiple swellings under the skin of the leg, wrist and on the periumbilical area which were slightly mobile, hard in consistency, and not associated with any discharge. She is developmentally appropriate for her age.

Laboratory testing showed markedly elevated parathyroid hormone (110.9 pg/ml), high serum phosphate 5.6 mg/dl, low vitamin D (26.7 ng/ml), and normal calcium level (1.21 mmol/L). Other values are as shown in the Table 1. X-rays of the limbs reveal no brachydactyly. Genomic DNA from the patient was extracted from whole blood leukocytes. Then DNA samples were analyzed for sequencing of the GNAS gene which came to be normal with no pathogenic mutation so, it was concluded to be sporadic cause. Genetic testing of the patient showed a mutation in GNAS gene of missense variant with heterozygous zygosity which showed the diagnosis of Albright osteodystrophy syndrome/progressive osseous heteroplasia.

Table 1.

Result of initial blood tests

	Value	Reference range
Calcium (mmol/L)	2.5	2.1–2.6
Ionized calcium (mg/dl)	4.9	4.5–5.5
Phosphorus (mg/dl)	5.6	2.5–4.8
Parathyroid hormone (pg/ml)	110.9	15.0–68.3
24-hour urine calcium (mmol/24 hr)	0.4	2.5–7.5
24-hour urine creatinine (µmol/24 hr)	8460	8840–13 260
Alkaline phosphatase (U/L)	207	<500
Creatinine (µmol/L)	43
Vitamin D (ng/ml)	26.7	30–50
TSH (µIU/ml)	3.28	0.3–4.5
Free triiodothyronine (fT3) pmol/L	5.57	2.4–6.0
Free thyroxine (T4) pmol/L	13.12	9.0–19.0

She is under vitamin D supplementation and thyronorm is stopped as TSH came out to be normal this time. Currently, calcification is decreasing in size on the leg but calcification in other areas is of the same size and the patient is in follow-up with endocrinologist every 6 months in Kathmandu, Nepal. She has received all the vaccines as per the immunization protocol of Nepal till date.

Discussion

Pseudohypoparathyroidism (PHP) is a rare genetic disorder marked by the clinical features of hypoparathyroidism, often accompanied by unique skeletal and developmental abnormalities^[1]. PTH regulates calcium and phosphate levels by increasing blood calcium, reducing phosphate, and encouraging production of 1, 25-dihydroxy-vitamin D (calcitriol). It facilitates calcium release from bones, promotes bone breakdown, and enhances renal calcium reabsorption^[2]. Additionally, PTH and calcitriol work together to boost calcium and phosphate absorption in the intestine. In PHP, resistance in the bones and kidneys to PTH leads to low calcium and high phosphate, triggering compensatory hyperparathyroidism as the glands increase PTH production^[3]. PHP typically presents with hypocalcemia and hyperphosphatemia. Despite the typical biochemical abnormality seen in PHP, this patient exhibited normocalcemia. Normocalcemia, if seen is rare, particularly in those with milder disease or due to effective compensatory mechanisms maintaining calcium levels^[4]. This case illustrates the importance of considering PHP even in normocalcemic patient when characteristic physical findings such as subcutaneous calcifications are present. Subcutaneous ossification, a hallmark of Albright hereditary osteodystrophy (AHO) is often the first presenting sign in infants with PHP^[5]. These calcified nodules result from ectopic bone formation and are a key clinical clue. Despite normocalcemia in this case, the elevated PTH level and clinical features point toward PHP type IA. The likelihood of PHP type IA could be elevated in patients who have both elevated TSH levels and a normally positioned thyroid gland. Therefore, detailed physical examinations and monitoring of calcium, phosphorus, and PTH levels are important, particularly for those with a slight TSH elevation and a normal thyroid gland during their initial consultation^[6].

The early manifestation of TSH resistance can be indicative of PHP type IA, but due to its uncommon nature, it is often wrongly diagnosed as primary hypothyroidism, leading to a lack of physical examination in those with congenital hypothyroidism^[7,8]. While PTH levels tend to increase with age, elevated TSH may be detected at birth, resulting in many diagnoses during newborn screening. A large study revealed that TSH resistance was present in all young infants with PHP. Additionally, newborn screening for high TSH can diagnose up to 30% of PHP type IA cases at birth^[9]. If primary hypothyroidism is presumed and nodules are overlooked, patients might experience neuromuscular symptoms or potentially life-threatening hypocalcemia complications^[10]. Generally, elevated PTH levels result in hypocalcemia, and PHP type IA is usually diagnosed when severe hypocalcemic symptoms such as seizures, paresthesia, and tetany appear, especially as calcium demand grows in childhood^[10]. This makes it hard to detect at a young age. Due to mutation of the PTH1r gene, there can be resistance to PTH and PTHrP which may later present in the form of Blomstrand Lethal Chondroplasia, Endochromatosis, Eiken syndrome, and Primary failure of tooth eruption^[11]. This report, along with a review of the literature, underscores the necessity of thorough physical examinations for congenital hypothyroidism. To prevent missing a PHP diagnosis, active lesion biopsies, GNAS (Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide) gene sequencing, and serial checks of calcium and PTH levels are recommended for patients being treated^[6,10]. After genetic testing, in our case, GNAS mutation was recognized to be heterozygous, autosomal dominant, and of missense variant indicating toward Albright osteodystrophy syndrome^[3]. Efforts have been made to diagnose PHP early by looking at indicators such as low birth weight for gestational age, early onset of obesity, cognitive challenges, delays in development, and temporary hypothyroidism^[10]. Yet, these signs are often subtle in infants, and in 30% of PHP type IA cases, cognitive development progresses normally. Low birth weight and inadequate subsequent weight gain were contributing indicators in our patient.

The management of PHP in a normocalcemic infant is largely conservative with a focus on regular monitoring, family education, and managing any evolving symptoms or complications^[12]. Since these infants might remain normocalcemic for a significant period, proactive follow-up and early detection of changes in their condition are crucial for timely intervention^[6]. Recent studies show that along with calcium and vitamin D, calcilytics, PTH analogs, and orally active small molecules of PTH1R agonist can join the treatment lineup^[13]. In our case, supplementation entails calcium and calcitriol with an aim of maintaining normocalcemia and control over dairy products to counteract hyperphosphatemia. Close monitoring of growth with an option of Growth Hormone (GH) supplementation and evaluation for ongoing physical signs of AHO may be crucial.

Conclusion

This case emphasizes the need to consider PHP, even in normocalcemic patients, when clinical signs such as subcutaneous ossifications are present. Early recognition and diagnosis, particularly of PHP type IA, are essential to prevent complications. Genetic testing and regular monitoring of calcium, phosphate, and PTH levels play a crucial role in managing these patients. Conservative treatment with calcium and calcitriol, alongside close follow-up, can help maintain normocalcemia and prevent further complications, ensuring better long-term outcomes.

Ethical approval

Ethical approval is not required for case report in our institution (Institutional Review Committee, Institute of Medicine, Maharajgunj, Nepal).

Consent

Written informed consent was obtained from the patient’s parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

No funding was received for the study.

Author contributions

D.A., S.A., S.R.D., K.P., P.P., B.B., and R.S. wrote the original manuscript, reviewed, and edited the original manuscript. J.A. reviewed and edited the original manuscript. S.A. is the senior author and manuscript reviewer.

Conflicts of interest disclosure

The authors have no conflict of interest to declare.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Subodh Adhikari.

Provenance and peer review

Not commissioned, externally peer reviewed.

Data availability statement

All available data are within the manuscript itself.