Introduction
Pseudohypoparathyroidism is a very rare disorder, with estimated
prevalence between 0.3 and 1.1 cases per 100000 populations, only 60
cases have been reported worldwide as of December
20161.
Pseudohypoparathyroidism is defined as a heterogeneous group of rare
endocrine diseases characterized by normal renal function with
resistance to parathyroid hormone functions, manifesting with
hypocalcemia, hyperphosphatemia, and high levels of concentration in
serum parathyroid hormone (PTH)2. Diagnosis of
pseudohypoparathyroidism (PHP) is mainly biochemical, confirmed by
coexistence of hypocalcemia and hyperphosphatemia with elevated PTH
levels in the presence of normal vitamin D values, normal renal function
and the absence of hypercalciuria.
PHP can be additionally (confirmed) diagnosed by genetic testing for a
mutation in the GNAS1 gene and identification of subtypes. These
subtypes are divided based on several phenotypes:
Type Ia - caused by mutations in GNAS - and Type Ic: normal Gs-alpha
activity together with the absence of GNAS mutations.They have been
associated with Albright hereditary osteodystrophy, decreased response
to exogenous PTH as measured by urine cyclic adenosine monophosphate
(cAMP) and urine phosphorus, low serum calcium, generalized endocrine
resistance (affecting any hormone that relies on Gs-alpha signaling),
and autosomal dominant inheritance.
Type Ib is caused by mutations in GNAS.
In Type II, the underlying genetic mutation is unknown, characterized by
no association to skeletal phenotype, decreased response to exogenous
PTH as measured by urine cAMP and urine phosphorus, low serum Calcium,
and hormonal resistance limited to PTH target tissue; however, there are
an increasing number of cases associated with thyroid-stimulating
hormone resistance and inheritance is sporadic3.
The aim of this case report is to describe the clinical diversity of PHP
and to emphasize the importance of the basic approach using laboratory
tests in patients with symptomatic hypocalcemia. A calcium-phosphorus
profile properly interpreted should lead to an accurate diagnosis and
timely treatment of PHP. This report, besides being the first case
report from Sudan as a lower-income country with limited facilities, our
patient had an unusual presentation of meningeal calcification at late
adulthood. This brings novelty to our study because we suggest the
possibility of shortcomings in the diagnostic approach to patients with
hypocalcemia. Perhaps calcium disorders are underdiagnosed and sometimes
overlooked as a differential diagnosis of frequent clinical expressions,
such as seizures and other neuromuscular symptoms.
Case presentation :
A 35-year-old man, with a 18-year history of epilepsy, on Carbamazepine
400 mg once/daily, with a rate of 4 seizures per year. The patient was
referred from the neurosurgical department for controlling his seizures.
He was diagnosed with hydrocephalus complicated by severe optic atrophy
and underwent insertion of a ventriculoperitoneal shunt. Prior brain
imaging (CT/MRI) ( images 1.2.3.4) revealed the existence of
hydrocephalus and meningeal calcification. The patient had no other
symptoms suggesting motor, sensory, cerebellar, sphincter and autonomic
abnormalities. There was no past history of head trauma, childhood
cerebral infection or skin tumors. He is neither diabetic nor
hypertensive, and has a negative family history for both conditions.
On examination, the patient was 70kg in weight and 160cm in height.
Neurological examinations demonstrated a Glasgow Coma Scale (GCS) of 15
and orientation to time, place and person, normal behavioral and
cognitive function with no apparent dysmorphological or congenital
anomalies. Cranial nerves examination showed optic nerve abnormalities,
a significant decrease in visual acuity (legally blind) with evidence of
secondary severe optic disc atrophy and papilledema on Fundoscopic
examination.
Other cranial nerves were normal, with no acute abnormalities of motor,
sensory, cerebellar and sphincteric function. Additionally, there were
positive Chvostek and Trousseau signs. Otherwise systemic examination
was all clear.
Biochemical blood tests (table 1) showed low serum Calcium (6.8mg/dl),
normal vitamin D, urea and Creatinine. Elevated serum phosphate (6.2
mg/dl) and elevated parathyroid hormone (118pg/ml) were present.
Optical coherence tomography for retina (OCT) revealed optic disc edema.
Fundus photos showed secondary severe optic atrophy and moderate optic
disc edema.
Full body X-rays, echocardiography and ECG were normal.
The patient was given supplemental Vitamin D and Calcium oral tablets
for three months; subsequently all hypocalcemic signs have improved, and
seizures have subsided since.
He is scheduled for routine follow-up through monitoring of serum
calcium, phosphate, RFT, Vitamin D for 3 months, followed by one year,
then every 6 months for life, with annual brain imaging.
Discussion :
Our patient, a middle-aged man with a 17-year history of seizures
presented with hydrocephalus and extensive meningeal calcification.
Initially, falx cerebri calcification was misleading us toward nevoid
basal cell carcinoma syndrome as it presentes similarly, although the
absence of major and minor criteria excluded it as a
diagnosis4.
Brain calcification was usually investigated in PHP due to the
hyperphosphatemia.
In most conditions, seizures and epilepsy are the common clinical
manifestations resulting from the calcification of subcortical region
and basal ganglia, some patients present with cerebral and cerebellar
calcification as well as subcutaneous calcifications5.
However, few cases were ever reported with these manifestations, yet no
other cases similar to our case of falx cerebri exist in published
literature and supratentorial calcification along with secondary
hydrocephalus is an uncommon presentation for this syndrome.
On the other hand, the presence of low serum calcium, high phosphate,
and high parathyroid hormone despite normal RFT and vitamin D levels led
us to consider pseudohypoparathyroidism as a diagnosis.
In accordance with the recommendations of the recently published first
consensus statement on the diagnosis and management of
pseudohypoparathyroidism-related disorders, the diagnosis should be
based on clinical and biochemical characteristics, which will vary
according to the age of the patient6.
Absence of skeletal deformities and family history confirmed that this
patient has either type Ib or type II which are sporadic disorders;
unfortunately due to facility limitations in Sudan, confirming the
diagnosis with genetic phenotyping and mapping was
difficult7.
Although PHP is most commonly diagnosed during childhood or adolescence,
one case from Italy illustrated the history of a patient of
pseudohypoparathyroidism type 1A, which went undiagnosed until her 60s,
with multi-hormonal resistance and clinical complications throughout her
life6. Our case phenomenally describes late adulthood
diagnosis of the condition, thus highlighting the importance of
diagnosing this rare disease, which had a great impact on patients and
their family life as this is crucial to the appropriate treatment and
lifelong management of the disease and its complications. However, late
diagnosis led to development of complications such as hydrocephalus and
blindness which affected the social life of the patient
Starting the calcium and vitamin D supplemental treatment promptly
corrected the patient’s hypocalcemia, and stopped both muscle spasms and
seizures as hypocalcemia and the development of meningeal calcifications
could have contributed to the development of these
seizures8.