Endocrine Abstracts

Background: chromosome 22q11.2 deletion syndrome has been reported to occur in about 1 per 347 to 992 fetuses.1 Patients present with velocardiofacial syndrome (VCFS) or DiGeorge syndrome (DS). Hypocalcemia has been reported to occur in up to 80.4% of cases.2

Case report: a 28-year-old man, known with autism spectrum disorder (ASD), presented at the emergency department (ED) for muscle cramps. Medical history included chronic myeloid leukemia treated with tyrosine kinase inhibitor (TKI) the last 10 years, gastric bypass and recurrent fractures due to osteoporosis managed by alendronate. Four months prior to the admission, alendronate was switched to zoledronate because of digestive adverse effects. Under zoledronate, there was exacerbation of the muscle cramps. At the ED, temperature was 36.5°c, respiratory rate 22 cycles/min, heart rate 110 beats/min and upper limbs spasms (Trousseau sign) hindered blood pressure measurement. Shortly after arrival at the ED, the patient suddenly developed pulseless electric activity, requiring advanced cardiopulmonary resuscitation including endotracheal intubation followed by admission to the intensive care unit. Investigations revealed a long QTc at 513 msec, severe hypocalcemia (Ca 1.32 mmol/L [range 2.12- 2.60], ionized Ca 0.66 mmol/L [range 1.17-1.33]), normal magnesium (0.68 mmol/L [0.74-0.99]), hypophosphatemia (phosphor 0.49 mmol/L [0.78-1.42]), normal vitamin D 53 ng/L and inadequate low parathyroid hormone (PTH) level (38 ng/L [range 7-70]). Management included parenteral magnesium, calcium and oral calcitriol. Amiodarone was temporally administered for sustained ventricular tachycardia. TKI and biphosphonate were interrupted. The medical records showed low calcium level immediately after initiation of TKI ruling out gastric bypass and biphosphonate as primary etiologic factors. Genetic testing was requested based on low calcium level, inadequately low PTH and atypical facial features (asymmetric crying facies, malar flatness and hooded eyelid). This identified deletion of chromosome 22q11.2 spanning the region of catechol-O-methyltransferase (COMT) and T-box transcription factor 1 (TBX1) genes.3 Upon discharge, oral substitution of calcium, magnesium and calcitriol was continued.

Discussion: Severe hypocalcemia can represent a life-threatening condition. Etiologies of hypocalcemia are divided into PTH and non-PTH mediated causes.4 In our patient this could be due to TKI, malabsorption following gastric bypass, biphosphonate initiation and, besides his psychiatric past medical history, the patient’s phenotype suggested a congenital disorder. Identification of chromosome 22q11.2 deletion confirmed a constitutional defect in calcium metabolism which might have been sequentially exacerbated by initiation of TKI, gastric bypass and biphosphonate. Hypocalcemia in chromosome 22q11.2 deletion syndrome results from hypoparathyroidism and occurs not only in the neonatal period, but also in adulthood.2 Other clinical characteristics encompass cardiac defects, abnormal facies, thymic hypoplasia, cleft palate (and hypocalcemia) defined by the acronym CATCH-22. The disease spectrum is heterogeneous. In our patient, structural cardiac defects and immune deficiency have been excluded. While ascertainment of TBX1 deletion relates to the clinical presentation encompassing hypoparathyroidism that of COMT gene could be associated with autism spectrum disorder.3,5 Indeed, TBX1 gene has been reported to influence cell proliferation and differentiation as well as signaling pathways involving fibroblast growth factor, retinoic acid, bone morphogenic protein among others. Deletion of one copy of TBX1 impacts on the development of pharyngeal arch artery, leading to at least one of the common presentations of VCFS/DS. COMT enzyme degrades catecholamines, entailing dopamine. Genetic alteration involving COMT gene results in dopamine excess and has been linked to psychiatric defects including ASD and psychosis.

Conclusion: This case highlights the diagnostic complexity of hypocalcemia in a setting of multiple potential etiologic factors. It raises the call to keep in mind that chromosome 22q11.2 deletion syndrome is not that uncommon and can be revealed in adulthood. Specific phenotype, specifically PTH dependent low calcium level and facial dysmorphia, should prompt clinicians to order genetic testing independently of the patient’s age.

References: 1. McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1(1):15071.

2. Cheung ENM, George SR, Costain GA, et al. Prevalence of hypocalcaemia and its associated features in 22q11.2 deletion syndrome. Clin Endocrinol. 2014;81(2): 190–6.

3. Funato N. Craniofacial Phenotypes and Genetics of DiGeorge Syndrome. JDB. 13 mei 2022;10(2):18.

4. Pepe J, Colangelo L, Biamonte F, et al. Diagnosis and management of hypocalcemia. Endocrine. 2020;69(3):485–95.

5. Radoeva PD, Coman IL, Salazar CA, et al. Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. Psychiatric Genetics. 2014;24(6): 269–72.