Pseudohypoparathyroidism as a Cause of Refractory Seizures

Pseudohypoparathyroidism is a genetic disorder that is similar to hypoparathyroidism, but which results from the body’s lack of response to parathyroid hormone rather than its decreased production. Serum level of immunoreactive Parathormone are elevated instead. We report a four month old infant in status epilepticus associated with hypocalcemia, hyperphosphatemia and raised parathyroid hormone level. Hypocalcemia was resistant to calcium therapy initially but responded to vitamin D analogue therapy leading to diagnosis of Pseudohypoparathyroidism.


Introduction
P seudohypoparathyroidism (PHP) is a term used to describe several related disorders characterised by end organ unresponsiveness to parathormone, due to receptor or post receptor defects 1 .Serum level of immunoreac ve PTH are elevated even when pa ent is hypocalcaemia or normocalcemic 2 .PHP is listed as a rare disease by Offi ce of Rare Disease (ORD) of Na onal Ins tute of Health (NIH).This means that PHP or a subtype of PHP aff ects less than 200,000 people in US popula on 3 .The characteris c biochemical derangements include hypocalcemia, hyperphosphatemia and high serum parathormone levels 1 .Pa ents diagnosed with type1A PHP have short, stocky build, brachydactyly with dimpling of dorsum of hands.Other skeletal abnormali es such as short and wide phalanges, bowing, exostoses, and thickening of calvaria are also found.Pa ents with type1B and type 2 PHP are phenotypically normal 2 .

The Case
A four month old male child weighing 4 kg was brought to paediatric emergency with status epilep cus.Seizures were not controlled with IV loading Phenytoin, Phenobarbitone.Midazolam infusion was started and inves ga ons sent showed low serum calcium levels (6.8mg/dl).IV Calcium gluconate was infused slowly and seizures aborted within fi ve minutes.History of recurrent seizures was present since 20 th day of life.They were secondary generalized seizures which stopped spontaneously a er some me as said by mother.Child was on phenobarbitone since two months of age and was admi ed at 2.5 months of age with status epilep cus in a private hospital.Child was fi rst in birth order, born by caesarean sec on at term with birth weight of 2.5 kg.Immediate perinatal period was uneven ul with no history of birth asphyxia.Developmental milestones were slightly delayed.Sepsis workup and CSF examina on were normal.Thyroid profi le was also normal.Serum calcium level were repeated and found to be low (total calcium 7.3 mg/dl, ionic calcium frac on 3.3 mg/dl) despite con nuous IV maintenance calcium infusion.Serum magnesium levels were normal.Later PTH level by radioimmunoassay was found to be 120 pg/ ml (normal:10-70 pg/ml).Serum vitamin D2 levels were also sent but they were normal and serum phosphorus levels were elevated.Diagnosis of PHP was made and child was put on oral calcitriol (0.25 μg/day) along with oral calcium supplements.Child remained seizure free during subsequent stay in hospital and on follow up a er two months.An epilep cs were tapered and stopped.Child is on follow up had normal serum calcium and phosphorus levels.
Child didn't have any physical s gmata on examina on which are found usually in type1A PHP like short, stocky build, brachydactyly with dimpling of dorsum of hands.Other skeletal abnormali es such as short and wide phalanges, bowing, exostoses, and thickening of calvaria were also not found.

Discussion
PHP is a gene c disorder which manifests with parathyroid hormone (PTH) resistant hypocalcemia and hyperphosphatemia.In PHP, parathyroid glands are normal or hyperplas c histologically and neither endogenous nor administered PTH raises serum calcium level or lowers the level of phosphorus.The gene c defect in hormonal receptor adenylate cyclase system are classifi ed into various types depending on phenotypic and biochemical fi ndings 2 .
There are two main types: Type-1 and Type-2.Type-1 is characterised by low or absent urinary phosphates and cAMP produc on in response to exogenously infused PTH but Type-2 responds with normal increase in urinary cAMP but shows absent or subnormal phosphaturic response 4 .Type-1 is further subdivided into 1A and 1B.Type-1A pa ents have gene c defect of α subunit of s mulatory guanine nucleo de binding protein.This coupling factor is required for PTH bound to cell surface receptors to ac vate cAMP.Heterogeneous muta ons of Gsα gene have been documented; gene is located on 20q13.2.Defi ciency of the Gsα subunit is a generalized cellular defect and account for associa on of other endocrinal disorders with Type-1A PHP 2 .Type-1B pa ents have normal phenotypes and normal G protein ac vity.There is ssue specifi c resistance to PTH but not to other hormones 2 .Type-2 pa ents are phenotypically normal but hypocalcemia is present.Defect appears to be distal of cAMP because it is normally ac vated, but cell is unable to respond to the signal 2 .
Our case presented in status epilep cus due to hypocalcemia which was resistant to correc on with IV calcium.Serum phosphate levels were raised but serum magnesium levels and vitamin D levels were normal in presence of raised PTH found in our case which precludes hypoparathyroidism due to low magnesium levels and hypoparathyroidism due to overt vitamin D defi ciency hence confi rming diagnosis of PHP.But our case did not have any morphological features like obesity, short metacarpals or exostoses which are found in Type-1A or Albright Hereditary Osteodystrophy.
Main goal of therapy is to maintain normal calcium levels and to suppress PTH levels to normal with use of 1 α hydroxylated vitamin D metabolite such as calcitriol along with calcium supplements.This is important because elevated PTH levels in pa ents with PHP could cause increased bone remodelling and can lead to hyperparathyroid bone disease 5 .In our case child was managed with calcitriol (0.25 μg/day) along with calcium supplements and child responded well with normal serum calcium and phosphorus levels and was seizure free.But long term follow up is required to know the exact nature of disease as PHP some mes are transient.

Conclusion
PHP is a diseases of rare occurrence though exact incidence is not documented worldwide.So a case of resistant hypocalcemia and raised parathormone levels should raise suspicion of PHP.Administra on of oral calcium and 1 alpha hydroxylated vitamin D metabolites, such as calcitriol, remains the mainstay of treatment.The goals of therapy are to maintain serum total and ionized calcium levels within the reference range to avoid hypercalciuria and to suppress PTH levels to normal.This is important because elevated PTH levels in pa ents with PHP could cause increased bone remodeling and can lead to hyperparathyroid bone disease.