A Rare Etiology of Hypocalcemic Seizures in Adulthood: Clues to Diagnosis from Facial Dysmorphism
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.310108
Source of Support: None, Conflict of Interest: None
Keywords: 22q11.2 deletion syndrome (22q11.2DS), DiGeorge syndrome, hypocalcemia, hypoparathyroidism
Hypoparathyroidism in adults usually occurs in the setting of acquired conditions such as iatrogenic damage due to neck surgery or an autoimmune process. Hypoparathyroidism due to 22q11.2DS is an unusual cause of hypocalcemia presenting in adulthood and therefore there is limited awareness of this phenotype in the general medical community. A diagnosis of 22q11.2DS has important implications as it has a multisystemic involvement with a varied phenotypic presentation. Timely diagnosis of individuals with the condition would lead to an improved long term outcome and also help in genetic counselling of affected families. We report a patient who presented with hypocalcemia due to 22q11.2DS for the first time in the fifth decade of life. Our case highlights that 22q11.2DS can have a delayed presentation in adulthood and that subtle clinical signs may provide a clue to the diagnosis.
A 40-year-old male presented to the emergency department with a history of two episodes of seizures since the morning of the day of presentation, with seven to eight similar episodes in the past month. The seizures were generalized tonic clonic in type, associated with loss of consciousness and lasted for a few minutes followed by self recovery. There was no associated history of headache, fever, vomiting or blurring of vision.
On enquiry there was a history of perioral tingling and numbness with intermittent muscle cramps for the last few months before the onset of clinical seizures; however, no medical care was sought for these symptoms. There was no previous history of seizures; however, a significant history of delayed attainment of speech and motor milestones in childhood was elicited. The patient also had a profound learning disability to the extent that he could not complete even primary school and was currently employed as an unskilled labourer. He also had a notable past history of having undergone cataract surgery in both eyes at the relatively young age of 35 years. There was no relevant history of previous surgery, autoimmune disorders, recurrent infections, cardiac or renal involvement, or similar illness in the family. The patient was married with two children, both apparently healthy with no history of seizures or problems with intellect.
On examination, patient was conscious, well oriented to time, place, and person. He was found to have short stature with a height of 152.2 cm (mid parental height: 169 cm), weight 48 kg and body mass index (BMI) of 20.7 kg/m2. He had abnormal facies in form of bulbous nose, overfolded ear helices, and elongated face [Figure 1]. There was no evidence of any dental or palatal abnormalities. Trousseau sign was elicitable at the time of presentation. Systemic examination was unremarkable.
Laboratory investigations revealed hypocalcemia, hyperphosphatemia, and low serum PTH [Table 1]; therefore, hypocalcemia secondary to hypoparathyroidism was diagnosed. Brain computed tomography showed multiple patchy and confluent areas of calcifications in bilateral frontal, parietal, occipital, thalami, gangliocapsular regions, and cerebellar hemispheres [Figure 2]. The patient had a prolonged QTc interval of 480 ms (<450 ms, males) and therefore intravenous calcium gluconate was given as a bolus dose followed by infusion at 1 mg elemental calcium/kg/h with concomitant oral calcium, magnesium replacement and vitamin D analogues.
Hypoparathyroidism in association with learning disabilities, short stature, and facial dysmorphism led to the suspicion of 22q11 microdeletion syndrome (22q11.2DS). Hence, MLPA analysis was done, which showed heterozygous deletion at 22q11.2.21 [Figure 3] suggestive of 22q11.2DS. Further investigations including transthoracic echocardiography, renal ultrasonography and audiometry were normal. He had no neuropsychiatric manifestations. Genetic counselling was given to him and his family. The patient was discharged with advice to take 2000 mg elemental calcium and 0.5 μg calcitriol twice daily. During subsequent follow-up, his calcium levels were maintained in the low normal range and there was no recurrence of hypocalcemic symptoms or seizures.
22q11.2 deletion syndrome (22q11.2DS), formerly known as DiGeorge syndrome or Velocardiofacial syndrome (VCFS), is one of the most common microdeletions with a reported incidence as high as 1:4000 livebirths; however, it is often underdiagnosed due to high variability in the phenotypic features.
Most patients receive a diagnosis in childhood due to the presence of cardiac anomalies, immune deficiency from thymic hypoplasia, and hypocalcemia; however, a delayed presentation and diagnosis in adulthood, as in our case, has been reported. Cardiac defects are typically the initial abnormalities noted in children and commonly include conotruncal defects such as interrupted aortic arch, truncus arteriosus, tetralogy of fallot, atrial or ventricular septal defects, and vascular rings. Palatal abnormalities, feeding difficulties, genitourinary anomalies, and developmental delay are other common presentations seen in childhood.,,
Adult presentations of 22q11.2DS have limited descriptions and in the largest available retrospective case series of 126 adults with DGS, 60% were parents of affected children, and the others were patients in craniofacial, cardiology, genetics, and psychiatry clinics. Hypocalcemia as the first presentation of 22q11.2DS in adulthood can be an atypical isolated manifestation of this syndrome even in the absence of other classical features and has been described in adults who presented in a similar manner to our case.,,
Our patient presented with the features of late onset hypocalcemia at the age of 40. Associated dysmorphic facies, short stature, and intellectual impairment led to a suspicion of 22q11.2DS. The patient did not show any other typical 22q11DS-associated cardiac, velopharyngeal, renal or psychiatric problems. Although the reason for the late onset hypocalcemia/hypoparathyroidism in our patient is unclear, we speculate that he may have had a reduced parathyroid reserve with normocalcemia, to begin with, and became frankly hypocalcemic in response to a stressor which could be severe co-existent vitamin D and magnesium deficiency. It is likely that he had longstanding subclinical hypocalcemia as supported by the presence of brain calcifications and remained symptom-free due to the slow decline in parathyroid reserve.
Adult patients with 22q11.2DS have a different spectrum of clinical manifestations when compared to children, with lower rates of cardiac anomalies (30%) and higher rates of palatal abnormalities (88%), mental disabilities (94%), and psychiatric conditions (36%) which makes the underlying genetic cause often difficult to suspect and diagnose. Our patient has no neuropsychiatric manifestations currently; however, considering the increased risk of psychiatric and neurodegenerative disorders, periodic neurological assessment is planned.
Majority of patients with 22q11.2DS have de novo mutations, as was the case in our patient, through an autosomal dominant inheritance has been described and affected individuals have a 50% chance of having affected progeny. Hence, confirming the diagnosis is important not only for long term surveillance of the myriad-associated medical conditions but also for genetic counselling for the family.
To the best of our knowledge, our patient is the first reported case of adult onset hypoparathyroidism due to 22q11.2DS from India. Our case highlights that hypoparathyroidism in adult patients if associated with facial dysmorphism, should prompt a search for an underlying genetic cause. As many typical 22q11.2DS features are not seen in adults, findings such as intellectual disability and dysmorphism could help clinicians in identification of the condition.
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[Figure 1], [Figure 2], [Figure 3]