Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report
Thyroid Research volume 16, Article number: 10 (2023)
Thyrotoxic periodic paralysis (TPP) is a rare condition characterized by muscle paralysis, thyrotoxicosis, and hypokalemia. It presents with paralysis of both proximal and distal musculature in upper and lower limbs and may affect respiratory musculature and the cardiac conduction system. Early diagnosis is essential, as the condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias.
A 19-year-old Caucasian man was admitted acutely with paralysis in upper and lower limbs and tachycardia. Over several months, he had experienced anxiousness, sweating more than usual, had daily palpitations, shortness of breath on exertion, and loose stools, and had lost 21 kg over the last year. Initial blood gas showed very low potassium of 1.4 mM, and blood tests showed decreased Thyroid-stimulating hormone (TSH) < 0.01 × 10− 3 IU/L, elevated free thyroxine (fT4) of 63.5 pM (reference interval (RI): 12.0–22.0 pM), and elevated total triiodothyronine (T3) of 8.2 nM (RI: 1.0–2.6 nM). He was diagnosed with TPP and treated with liquid oral potassium chloride (30 mmol every 30 minutes) and propylthiouracil (initial dose of 400 mg followed by 200 mg three times daily). TSH-receptor antibodies (TRAB) and thyroid-peroxidase antibodies (TPO-ab) were highly elevated. Thyroid ultrasound showed a normal-sized gland and color Doppler sonography showed increased vascularity throughout the gland, compatible with Graves’ disease. He was discharged on day 4 with a normal potassium level and followed in the outpatient clinic where he received standard care for Graves’ disease. Genetic testing using whole-genome sequencing found no genetic variants in genes previously associated with TPP.
TPP is very rare in Caucasians but more often affects young men in East Asian populations. The case presents a Caucasian man with TPP where genetic testing of CACNA1S, KCNJ18, SCN4A, KCNJ2, KCNE3, and ABCC8 shows no pathogenic variants in genes previously associated with TPP.
Thyrotoxic periodic paralysis (TPP) is a rare condition characterized by muscle paralysis, thyrotoxicosis, and hypokalemia. It presents with paralysis of both proximal and distal musculature in upper and lower limbs and may affect respiratory musculature and the cardiac conduction system. The condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias. Most often the aetiology of thyrotoxicosis is Graves’ disease and there is a strong male preponderance, even though most people with Graves’ disease are women. High thyroid and beta-adrenergic activity can stimulate Na-K adenosine triphosphatase (ATPase) activity because thyroid hormones increase the number and sensitivity of beta receptors, which leads to increased catecholamine-mediated potassium uptake. This may explain why stress may precipitate episodes of TPP. Carbohydrate intake leading to hyperinsulinemia (which leads to muscle uptake of potassium) and an influx of potassium after exercise-related potassium release from muscles have been reported as precipitating episodes of TPP. Because the trans-membrane transport of potassium is changed in TPP, researchers have looked for genetically determined channelopathies involved in potassium transport in TPP patients. Until now several have been found .
Here, we present a case of a 19-year-old Caucasian man who was admitted acutely around 5 am with paralysis in upper and lower limbs, with lower limbs most severely affected, and no other comorbidities. He had woken up in the night with spasms of the lower limbs, unable to get out of bed and unable to stand. He had experienced two similar episodes within the last year with remission of symptoms the following morning. He did not consult his general practitioner, thinking he had just slept on his arms and legs.
During the last year, he had lost 21 kg, from a weight of 82 kg (body mass index (BMI) 27.7 kg/m2) to 61 kg (BMI 20.6 kg/m2), a reduction of 26%. He had been intermittently anxious, sweating more than usual, had daily palpitations, shortness of breath on exertion, and loose stools. He had irritable/dry eyes and slight irritation when moving his eyes. There was no prior steroid intake, no heavy alcohol use, and no history of diabetes or hypertension. The history revealed no prior factors or events to happen before the admission. His family history was unremarkable. None of his five siblings or parents had experienced similar symptoms and none had a history of thyroid illness, hypokalemia, or hypertension.
On examination in the emergency department, he was unable to stand. Muscle strength was reduced in the upper (Medical Research Council scale for muscle strength (MRC) 3/5) and lower limbs (MRC 2/5), and he was just able to lift his arms. He had no respiratory distress. Deep tendon reflexes were reduced in upper limbs and absent in lower limbs. Cranial nerve examination was normal, and there was no sensory loss. The thyroid gland was not enlarged or tender. Eyes were normal with no redness, swelling, or exophthalmos.
On admission, his vital signs were the following: Heart rate 120 bpm, blood pressure 104/45 mmHg, respiratory rate 16/min., temperature 36.6 °C, and oxygen saturation 99%. Electrocardiography (ECG) showed atrial flutter with varying 1:2 and 1:3 block (Fig. 1, panel A).
Initial blood gas showed potassium of 1.4 mM and slight metabolic acidosis with pH 7.34 and bicarbonate of 21 mM but was otherwise unremarkable. The initial venous lab values (Table 1) confirmed severe hypokalemia with potassium of 1.4 mM, normal sodium of 139 mM, normal magnesium, leukocytes and neutrophils elevated at 18.4 × 109/L and 16.0 × 109/L respectively, but with normal C-reactive protein (CRP) < 3 mg/L. Thyroid-stimulating hormone (TSH) was < 0.01 × 10− 3 IU/L, free thyroxine (fT4) and total triiodothyronine (T3) were elevated at 63.5 pM (reference interval (RI): 12.0–22.0 pM) and 8.2 nM (RI: 1.0–2.6 nM), respectively. TSH-receptor antibodies (TRAB) and thyroid-peroxidase antibodies (TPO-ab) were highly elevated. Alkaline phosphatase was elevated.
Treatment was initiated in the emergency room with 30 mmol liquid oral potassium chloride. He was transferred to the Intensive Care Unit for ECG monitoring and treated with oral propranolol 10 mg every 2 hours and 30 mmol liquid oral potassium chloride every 30 minutes. Two hours after admission, potassium was normalized, potassium supplements were stopped, and he had regained power in both upper and lower limbs. The ECG changed to sinus rhythm with a frequency of 100–120 bpm (Fig. 1, panel B). He developed rebound hyperkalemia with a peak value of 6.9 mM 4 h after admission which normalized without treatment over 8 h. Propylthiouracil was started with an initial dose of 400 mg followed by 200 mg three times daily. Intravenous hydrocortisone was initially given at 100 mg every 8 h until a small suspicion of adrenal insufficiency based on a low systolic blood pressure and potentially precipitated by hyperthyroidism could be ruled out. Hydrocortisone was stopped the next day. He was discharged on day 4 with a normal potassium level and continued propylthiouracil 200 mg three times daily and propranolol 10 mg four times daily. Thyroid ultrasound showed a normally sized gland and color Doppler sonography showed increased vascularity throughout the gland, compatible with Graves’ disease. He was followed in the outpatient clinic, changed from propylthiouracil to thiamazole, and received standard care for Graves’ disease. Since TPP was suspected genetic testing was performed using whole genome sequencing (WGS) of DNA isolated from peripheral blood. An in silico panel of genes previously associated with thyrotoxic periodic paralysis was applied, including CACNA1S (NM_000069.3), KCNJ18 (NM_001194958.2), SCN4A (NM_000334.4), KCNJ2 (NM_000891.3), KCNE3 (NM_005472.4), and ABCC8 (NM_000352.6). Coding regions (+/− 20 bp of adjacent intronic regions) were analyzed for non-polymorphic single nucleotide variants as well as copy number variants. No genetic variants were identified within these regions and thus a genetic cause of the symptoms could not be established. Additionally, WGS showed as expected that the patient was of European descent.
Discussion and conclusions
The aetiologies of hypokalemic periodic paralysis (HPP) can be divided into thyrotoxic periodic paralysis (TPP), hypernatremic hypokalemic paralysis (HHP), familial periodic paralysis (FPP) and idiopathic/sporadic periodic paralysis (SPP). Patients with SPP do not have hyperthyroidism, hypernatremia, or a family history of HPP. Among Caucasians, most cases of HPP are due to FPP, whereas in an Asian population most cases of HPP are due to TPP . TPP is very rare in Caucasians.
We investigated the genetic predispositions for TPP previously documented in the literature, encompassing six different genes. Pathogenic variants in the SCN4A gene (sodium voltage-gated channel alpha subunit 4) and the CACNA1S gene (calcium voltage-gated channel subunit alpha1 S) can cause HPP. Pathogenic variants in CACNA1S cause up to 70%, and SCN4A pathogenic variants about 10% of all cases of HPP. HPP caused by SCN4A or CACNA1S variant are inherited in an autosomal dominant pattern .
The KCNJ18 gene (potassium inwardly rectifying channel subfamily J member 18) encodes the inwardly rectifying potassium channel, Kir2.6. The locus is regulated by thyroid hormone, and variants in KCNJ18 have been associated with TPP [4, 7, 10, 15]. A major haplotype of KCNJ18 in East Asian populations is significantly associated with susceptibility to TPP, and this haplotype is much more common in East Asian than Caucasian populations .
The KCNJ2 gene (potassium inwardly rectifying channel subfamily J Member 2) encodes the inwardly rectifying potassium channel, Kir2.1. Variants in the KCNJ2 gene have been found to be significantly associated with TPP . In a single study, a missense variant in the KCNE3 gene (potassium voltage-gated channel subfamily E regulatory subunit 3) has been found to be associated with TPP . Finally, a single study from 2014 found that a genetic variant of the ABCC8 gene (subunit of the beta-cell ATP-sensitive potassium channel) which controls insulin secretion after feeding, was associated with susceptibility to TPP .
Using WGS followed by in silico panel analysis of coding regions we found no pathogenic variants in any of the above-mentioned genes in our patient. Hence, we did not find a genetic predisposition to TPP in this Caucasian man. The absence of a genetic predisposition in our patient is further supported by the fact that none of his five siblings or parents had ever experienced similar symptoms and none had a history of thyroid illness, hypokalemia, or hypertension.
TPP in Caucasians, although very rare, have been documented in earlier case reports, most recently in [1, 2, 8, 9, 13, 16]. Only in one case report by Rasheed et al. , a 27-year-old Irish man with TPP showed no genetic predisposition in CACNA1S, SCN4A and KCNJ18. Genetic analyses of KCNJ2, KCNE3 and ABCC8 was not done.
In the present case, treatment of hypokalaemia was done with liquid oral potassium chloride, 30 mmol every 30 minutes, which in a few hours led to rebound hyperkalaemia. In retrospect, the dose of potassium was too high. In some treatment protocols, the dose is advised to be at 30 mmol every 2 h with a maximum of 90 mmol in the first 24 hours of treatment.
In conclusion, we report the case of a young Caucasian man with TPP, without pathogenic variants in six genes previously reported to predispose to TPP, and without any relevant family history. Hence, we found no genetic explanation for why our patient developed TPP, suggesting that acquired environmental triggers or yet unidentified gene variants may play a role as co-factors in TPP pathogenesis. Having performed WGS we are able to reanalyze the sequencing data in the future, as new knowledge of predisposing genes appears. This may further the understanding of the genetic background of the rare occurrence of TPP in Caucasians.
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Thyrotoxic periodic paralysis (TPP)
Whole genome sequencing
Bao YK, Ganesan VC, Rapp R, Bao SS. Bilateral lower extremity paralysis in a Caucasian male presenting to the emergency department. Case Rep Emerg Med. 2018;2018:1–3. https://doi.org/10.1155/2018/5740509.
Bilha S, Mitu O, Teodoriu L, Haba C, Preda C. Thyrotoxic periodic paralysis—a misleading challenge in the emergency department. Diagnostics. 2020;10:316. https://doi.org/10.3390/diagnostics10050316.
Cannon SC. Further evidence for shared genetic susceptibility in both sporadic and Thyrotoxic periodic paralysis. J Neurol Sci. 2020;412:116794. https://doi.org/10.1016/j.jns.2020.116794.
Cheng C-J, Lin S-H, Lo Y-F, Yang S-S, Hsu Y-J, Cannon SC, et al. Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. J Biol Chem. 2011;286:27425–35. https://doi.org/10.1074/jbc.M111.249656.
Dias Da Silva MR, Cerutti JM, Arnaldi LAT, Maciel RMB. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J Clin Endocrinol Metab. 2002;87:4881–4. https://doi.org/10.1210/jc.2002-020698.
Fialho D, Griggs RC, Matthews E. Periodic paralysis. In: Handbook of clinical neurology: Elsevier; 2018. p. 505–20. https://doi.org/10.1016/B978-0-444-64076-5.00032-6.
Gbefon CY, Sobral CPS, Caldas A, Rocha VCC, Azulay RSS, Nascimento GC, et al. Genetic screening of patients with Thyrotoxic hypokalemic periodic paralysis: an experience from a tertiary Care Hospital in the Northeast of Brazil. Endocr Metab Immune Disord Drug Targets. 2021;21(12):2231–7. https://doi.org/10.2174/1871530321666210719114937 PMID: 34554906.
Haider M, Chachar AZK, Munir A. Thyrotoxic periodic paralysis. J Ayub Med Coll Abbottabad. 2019;31(4):619–21.
Meseeha M, Parsamehr B, Kissell K, Attia M. Thyrotoxic periodic paralysis: a case study and review of the literature. J Community Hosp Intern Med Perspect. 2017;7:103–6. https://doi.org/10.1080/20009666.2017.1316906.
Noso S, Babaya N, Hiromine Y, Ito H, Taketomo Y, Yoshida S, et al. Contribution of Asian haplotype of KCNJ18 to susceptibility to and ethnic differences in Thyrotoxic periodic paralysis. J Clin Endocrinol Metab. 2019;104:6338–44. https://doi.org/10.1210/jc.2019-00672.
Park S, Kim TY, Sim S, Oh H-S, Song E, Kim M, et al. Association of KCNJ2 genetic variants with susceptibility to Thyrotoxic periodic paralysis in patients with graves’ disease. J Ger Soc Endocrinol Ger Diabetes. 2017;125:75–8. https://doi.org/10.1055/s-0042-119527.
Pothiwala P, Levine SN. Analytic review: Thyrotoxic periodic paralysis: a review. J Intensive Care Med. 2010;25(2):71–7. https://doi.org/10.1177/0885066609358849.
Rasheed E, Seheult J, Gibney J, Boran G. Does thyrotoxic periodic paralysis have a genetic predisposition? A case report. Ann Clin Biochem Int J Lab Med. 2018;55:713–6. https://doi.org/10.1177/0004563218785395.
Rolim ALR, Lindsey SC, Kunii IS, Crispim F, Moisés RCMS, Maciel RMB, et al. The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis. J Mol Endocrinol. 2014;53:295–301. https://doi.org/10.1530/JME-14-0083.
Ryan DP, Dias da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AWC, et al. Mutations in Potassium Channel Kir2.6 cause susceptibility to Thyrotoxic hypokalemic periodic paralysis. Cell. 2010;140:88–98. https://doi.org/10.1016/j.cell.2009.12.024.
Thethi TK, Parks R, Katalenich B, Chhabra P, McCaw J, Syu S, et al. Case of Thyrotoxic periodic paralysis in a Caucasian male and review of literature. Case Rep Med. 2014;2014:1–5. https://doi.org/10.1155/2014/314262.
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Heydorn, A., Bertelsen, B., Nolsöe, R.L.M. et al. Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report. Thyroid Res 16, 10 (2023). https://doi.org/10.1186/s13044-023-00152-w
- Thyrotoxic periodic paralysis
- Graves’ disease
- Muscle weakness
- Periodic episodes