It occurs due
to decreased intestinal absorption of magnesium and renal magnesium
wasting with secondary parathyroid insufficiency leading to hypocalcemia
[2]. If adequate magnesium is not supplemented orally, then children
continue to develop recurrent seizures secondary to hypocalcemia that
can lead to stagnation of development of milestones and even regression
of milestones. As it is customary to look for hypocalcemia in infants
with seizures, most pediatricians detect hypocalcemia in these children
and treat it symptomatically. Etiological work up of hypocalcemia is
usually not done. Many a times hypomagnesemia as a cause of hypocalcemia
is missed and even if picked up on investigation, it is not adequately
treated because of lack of oral magnesium formulations.
Case Report
Case 1: A 13-month-old boy born to second
degree consanguineously married couple presented with recurrent
generalised clonic seizures from one month of age. The seizures occurred
in clusters every 2-3 weeks despite use of three antiepileptic drugs.
Child presented at 13-months of age with status epilepticus (generalised
clonic and complex partial type). Child had developmental delay
affecting all domains (could just sit with support without pincer grasp
and had monosyllables only). Family history was significant that her
previous two children had died due to seizures at 2 month and 8 month of
age, respectively. They were not investigated in detail but parents
reported that their blood calcium levels were very low. Child was
referred to us as a probable neurodegenerative disorder.
On examination, the child had normal weight, height
and head circumference. There were no neurocutaneous markers or
meningeal signs. He was excessively irritable and had bilateral
horizontal nystagmus. There was mild hypotonia and reflexes were normal.
Work up revealed hypocalcemia (calcium:5.2 mg/dL) with normal levels of
phosphorous, alkaline phosphatase, electrolytes, arterial blood gases
and albumin. Renal and liver function tests were normal. Serum
parathormone level was slightly low 5.5 pg/mL (Range: 6-55). As his
serum calcium remained low despite intravenous calcium for two days,
serum magnesium levels were; these were low (0.4mg/dL; range:1.8-2.4).
EEG showed slow background activity without any epileptiform discharges
and MRI of brain showed mild diffuse cerebral atrophy. CT scan of brain
did not reveal any calcifications. USG abdomen and pelvis was normal
without any evidence of nephrocalcinosis. His urinary calcium was 397
mg/day (Normal: 25-300) and urinary magnesium was 9.5 mg/L (Normal:
110-210).
In view of severe hypomagnesemia, a possibility of
FHSH was considered. Genetic studies for the mutation could not be done.
Child was given intravenous magnesium at 50 mg/kg along with intravenous
calcium for three days after which the serum magnesium and calcium
levels got normalised. Child became seizure free and the nystagmus
subsided. Antiepileptics were withdrawn and child was discharged on oral
magnesium sulphate (parental magnesium sulphate was given orally).
Follow-up after a month showed that the baby was now seizure-free and
had attained independent sitting, standing with support and cruising,
along with bisyllable speech.
Discussion
FHSH is an autosomal-recessive condition caused by
mutations in the Transient Receptor Potential Melastatin-6 (TRPM6)
gene that is expressed in the intestine and the kidney and codes for a
transient receptor potential cation channel [3]. Patients present with
seizures, tetany, tremors or restlessness at 2-8 weeks of life due to
severe hypomagnesemia and secondary hypocalcemia. It leads to lethargy,
nystagmus and convulsions. If untreated it can lead to cerebral atrophy
like in our case and can also be fatal [4]. Hypomagnesemia causes
secondary hypocalcemia by impairing the release of PTH by the
parathyroid gland and through blunting of the tissue response to PTH
[2].
Hypomagnesemia may result from inadequate magnesium
intake, increased gastrointestinal or renal losses, or redistribution
from extracellular to intracellular space [1]. Gitelman and Bartter
syndrome are the most common autosomal recessive conditions associated
with hypomagnesemia. They must be ruled out by doing the urinary pH and
serum electrolytes [4]. Various drugs like Amphotericin, diuretics and
osmotic agents can also cause symptomatic hypomagnesemia.
Familial hypomagnesemia with hypercalciuira and
nephrocalcinosis is an autosomal recessive disorder caused by a mutation
in the gene CLDN16 and it also presents with symptoms of renal
magnesium wasting. This generally presents with high serum calcium
levels along with nephrocalcinosis or nephrolithiasis on the ultrasound
of the kidneys. Once the diagnosis of FHSH is made, the condition is
treated by parenteral magnesium followed by long term term therapy of
oral magnesium salt. Automatically the hypocalcemia gets corrected.
Hypomagnesemia which is a treatable condition in our
particular case probably led to the death of previous two children
despite the administration of oral calcium supplements to both the
children. Recurrent seizures and use of high doses of antiepileptic
drugs with repeated admissions may lead to developmental slowing.
Hypomagnesemia itself can lead to lethargy thereby contributing to
developmental delay.
Though genetic confirmation was not done in our case,
a timely diagnosis and appropriate simple intervention lead to complete
cessation of seizures and regaining of milestones. Our case report
highlights the importance of considering FHSH as a possibility in any
child with severe hypocalcemia with normal to low PTH levels especially
when intravenous calcium injections fail to correct hypocalcemia.
Parental preparation of magnesium sulphate can be used orally and works
well as oral magnesium syrups are not available. We had 5 other similar
cases in last two years presenting with refractory hypocalcemic seizures
and developmental delay highlighting the importance of increasing the
awareness of this rare condition among pediatricians.
FHSH, though very rare, is an eminently treatable
condition and because it is an autosomal recessive disorder there is
scope for genetic counselling.
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3. Chubanov V, Schlingmann K, Waring J, Heinzinger J,
Kaske S, Waldegger S, et al. Hypomagnesemia with secondary
hypocalcemia due to a missense mutation in the putative pore-forming
region of TRPM6. J Biolog Chem. 2007;282:7656-67.
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