The not so benign maternal parathyroid adenoma: Siblings with hypocalcemic seizures

INTRODUCTION

Late-onset hypocalcemia may be asymptomatic in infants and may lead to seizures and long-term effects such as developmental delay or cognitive impairment. The most common cause of neonatal seizures is hypoxic-ischemic encephalopathy.^[1] When hypocalcemia is present, other etiologies, including maternal diabetes, prematurity, low birthweight, and vitamin D deficiency, must be considered.^[1,2] Inherited or congenital disorders (including DiGeorge syndrome and genetic mutations) are the most common cause of hypoparathyroidism in children. However, characteristic physical and laboratory findings to support these diagnoses are often absent in these cases.

Regulation of calcium in the fetus is accomplished by the placenta. Fetal calcium levels are often higher than maternal levels by 1–2mg/mL.^[3] Fetal parathyroid hormone (PTH) and calcitriol circulate at lower levels compared to the newborn period due to the relative hypercalcemia suppressing fetal PTH and stimulating calcitonin release.^[3] Thus, alterations in maternal calcium homeostasis can further raise fetal calcium levels, further suppressing PTH and elevating calcitonin.

Maternal history and evaluation may give a clue to the underlying etiology. Maternal vitamin D deficiency, magnesium supplementation, or use of specific anticonvulsant medications can alter neonatal calcium homeostasis. Other less common etiologies may cause neonatal calcium derangements including maternal hyperparathyroidism or tumors that secrete calcium, PTH, or vitamin D. We present cases of two siblings with neonatal hypocalcemia due to an undiagnosed maternal cause, which reiterates the importance of maternal history and evaluation.

CASE REPORT

A 10-day-old female presented to our emergency department (ED) with clonic seizures involving the left upper and lower limbs with leftward gaze deviation. She had seven seizure episodes before arriving in the ED and one observed in the ED. On examination, she had no focal neurological deficits with normal reflexes for age, appropriate tone, no postictal state, and no signs of trauma. A serious bacterial infection workup was completed (lumbar puncture, blood and urine cultures, viral surface swabs, inflammatory markers, and complete blood count), given the neonate’s age and presentation with focal seizure. A fingerstick glucose was obtained and was found to be 91 mg/dL (normal: 60–105 mg/dL). Laboratory results showed severe hypocalcemia at 6.3 mg/dL (normal: 8.0–11.0 mg/dL), hyperphosphatemia at 11.4 mg/dL (normal: 2.8–8.0 mg/dL), and hypomagnesemia at 1.2 mg/dL (normal: 1.6–2.5 mg/dL). PTH was found to be inappropriately normal at 19.4 pg/mL (normal: 8.5–75.0 pg/mL) and was not appropriately compensating for her hypocalcemia, suggestive of hypoparathyroidism.

She was admitted, and her serum calcium was corrected using intravenous (IV) calcium gluconate 100 mg/kg/dose, of which she required 2 doses. She also received IV magnesium repletion. Following correction of her electrolytes, she had no further seizures. Her formula was changed to a lower phosphorus formula (28 mg phosphorus per serving) compared to her initial formula (42 mg of phosphorus per serving), which she tolerated well. She was then transitioned to oral calcium carbonate 125 mg/kg/day, divided into four doses for maintenance. Her serum electrolytes remained within normal range on repeat testing during admission. She did well on this regimen, which was continued until outpatient endocrinology follow-up.

During her 3-week follow-up, she had no further seizures and was tolerating her feeds well. Repeat serum calcium level was normal at 10.4 mg/dL (normal 8.0–11.0 mg/dL). Monthly serum calcium showed normal calcium levels as her calcium supplementation was weaned off. By 4 months of age, she was maintaining normal calcium levels without any supplementation and was discharged from the endocrinology clinic.

On review of family history, the mother reported that her son, now 3 years old, also experienced seizures in the neonatal period. He was born term and presented on day of life 11 for 2 days of progressive “jittery” movements. The movements initially involved only the upper limbs and then progressed to the whole body. Parents sought care in the ED, where generalized tonic-clonic seizure episodes were observed along with a right facial droop and fixed gaze. These episodes lasted approximately 90 s each. He had postictal symptoms following the events. His laboratory tests revealed severe hypocalcemia of 6.2 mg/dL (normal: 8.0–11.0 mg/dL), hyperphosphatemia of 12.0 mg/dL (normal: 2.8–8.0 mg/dL), hypomagnesemia of 1.3 mg/dL (normal: 1.6–2.5 mg/dL), and an inappropriately normal PTH of 24.6 pg/mL (normal: 8.5– 75.0 pg/mL).

He was started on IV calcium gluconate 100 mg/kg/dose. After controlling his seizures and electrolyte disturbances, he was transitioned to oral calcium carbonate 125 mg/kg/day divided into four daily doses. His video EEG during admission captured the seizure episodes but overall did not detect signs of an underlying epileptic disorder, further confirming his seizures as hypocalcemic in nature. He followed with pediatric endocrinology outpatient and was able to wean off calcium supplementation by 4 months of age.

Given the history of two of her children having hypocalcemia-induced seizures, the mother’s medical history was examined more closely. Her prenatal laboratory tests had been normal, including her glucose tolerance tests. She stated that she had high calcium during her first pregnancy, but this was never followed up on. On chart review, she had a mildly high calcium on a few previous checks before her pregnancies (ranging from 10.6 to 11.16 mg/dL), which could explain the low level of concern at that time. She was treated for kidney stones 2 weeks after the birth of her daughter.

We advised her to follow-up with her primary care provider (PCP) to investigate the cause of her hypercalcemia as a cause for her children’s hypocalcemia. She had laboratories drawn by her PCP, and her intact PTH was elevated at 200 pg/mL (normal: 8.5–77.0 pg/mL). Her symptoms at that time included anxiety, forgetfulness, and fatigue. She was referred to an endocrine surgeon, where a thyroid ultrasound showed a hypoechoic area deep to the left superior thyroid pole, suggesting an abnormal left superior parathyroid gland. She underwent a left superior parathyroidectomy, and surgical pathology confirmed a parathyroid adenoma. She had significantly improved symptoms following resection, and her intact PTH returned to the normal range. The biochemical markers in the mother and both children are summarized in Table 1.

DISCUSSION

These two cases of siblings presenting with similar episodes of seizure in the neonatal period demonstrate the importance of following up abnormal laboratory results, especially in expectant mothers. It can be easy to forget that once the babies are born, their medical stability can depend on maternal factors. As such, the mother’s history should be noted and reviewed as part of all routine newborn care. This mother had symptomatic, mildly elevated calcium, with fatigue and kidney stones, which were never followed up on. There were subtle findings of parathyroid adenoma. The delay in diagnosis led to her children experiencing hypocalcemic seizures.

During pregnancy, a mother’s physiology changes significantly to support the appropriate growth and development of the fetus. Maternal calcium levels are noted to remain relatively stable during the first two trimesters before decreasing in the third trimester.^[3] This was originally considered to be linked to the increased need for calcium in the fetus for bone development, but more likely, this is secondary to the decrease in albumin during pregnancy.^[3] It is noted that PTH tends to decrease during pregnancy, possibly due to lower secretory reserve, before increasing again near the end of pregnancy.^[3] This increase is likely related to compensation for lower calcium levels throughout pregnancy.

However, in this case, the mother already had elevated calcium levels secondary to undiagnosed hyperparathyroidism. PTH cannot cross the placenta, whereas calcium is actively transported across.^[4] Normally, there is a 1–2 mg/mL increase on the fetal side as compared to the mother across the placenta.^[3,4] Maternal hypercalcemia causes increased transfer of calcium to the fetus across the placenta.^[3,4] leading to even higher levels of calcium in the fetus. When this occurs, the fetus’s parathyroid glands overcompensate and secrete excess calcitonin.^[4] Following delivery, the infant is no longer exposed to excess calcium, but calcitonin levels respond more slowly, which can cause a significant drop in calcium.^[3,4] Meanwhile, the previously elevated calcium in the infant’s system would have suppressed their own PTH, leading to poor compensation when their calcium levels drop after birth. The subsequent hypocalcemia can lead to sequelae as described above, namely seizures.

This report is interesting in that an undiagnosed maternal parathyroid adenoma led to significant sequelae not in the affected patient but in two of her children. Parathyroid adenomas are generally found in middle-aged women, with the incidence in women of childbearing age being reported as 8 in 100,000.^[5] Less than 2% of women diagnosed with parathyroid adenomas present in pregnancy,^[5] making our 25-year-old mother with two affected children interesting. This condition, though rare, is known to cause significant neonatal morbidity, including neonatal tetany, seizures, and stillbirth, if untreated.^[5]

In normal newborn physiology, mild hypocalcemia is expected in the 1^st 24–48 h after birth.^[6] Newborn calcium levels decrease until they reach their nadir around 48 h.^[6] The nadir of the calcium is inversely related to the gestational week of the infant, so the more premature the infant, the lower the expected nadir.^[6] As the infant’s calcium decreases, they begin to secrete PTH to compensate; this occurs around 48 h of life.^[6] This highlights the importance of seeking out the etiology of unexplained, late hypocalcemia in a newborn, especially in cases where the infant lacked the typical risk factors of prematurity, low birth weight, or being an infant of a diabetic mother. While primary causes of newborn hypocalcemia are important to explore, secondary and exogenous causes should be considered in symptomatic hypocalcemia.

CONCLUSION

This case report highlights the importance of obtaining a thorough maternal history and understanding fetal and neonatal calcium homeostasis. It underscores the importance of a broad differential and high index of suspicion when diagnosing and treating calcium abnormalities in the newborn. Neither of these infants had the typical risk factors for hypocalcemia, including prematurity, low birth weight, gestational diabetes, or perinatal asphyxia. Their mother’s own levels of calcium were only mildly elevated before and during pregnancy. Keeping an open mind when approaching an uncommon clinical scenario is key to treating the affected individual and, perhaps, preventing future siblings from experiencing the same sequelae.