Neonatal Severe Hyperparathyroidism: A Fatal Case
Gawri Abeynayake1*, Eresha Jasinge2 , Ramya Ediriweera3 and Michael A. Levine4
1MD, Senior Registrar, Department of Chemical Pathology, National Hospital of Sri Lanka, Colombo 01000, Sri Lanka
2MD, Consultant Chemical Pathologist, Lady Ridgeway Hospital for Children, Colombo 00800, Sri Lanka,
3MD, Consultant Pediatrician, Lady Ridgeway Hospital for Children, Colombo 00800, Sri Lanka
4MD,FAAP,FACP,MACE, Chief, Division of Endocrinology and Diabetes, Director, Centre for Bone Health, Children’s
Hospital of Philadelphia, 3401 Civic Center Blvd., Suite 11NW 30, Philadelphia, PA, 19104, USA
Gawri P.N. Abeynayake, MD, Senior Registrar, Department of Chemical Pathology, National Hospital of Sri Lanka, Colombo 01000, Sri Lanka; Tel: +94718679919 ; E-mail address:
Received: December 16, 2017; Accepted: January 08, 2018; Published: January 15, 2018
Abeynayake G, EreshaJ, et al. (2018) Neonatal Severe Hyperparathyroidism: A Fatal Case. J Endocrinol Diab.5(1): 1-4. DOI: 10.15226/2374-6890/5/1/00193
Background: Neonatal severe primary hyperparathyroidism (NSHPT) is a rare disorder that is usually caused by homozygous inactivating mutations in the CASR gene encoding the calcium sensing receptor (CaSR). Although parathyroidectomy is the treatment of choice, bisphosphonates
and calcimimetics such as cinacalcet have been used to improve hypercalcemia prior to or in lieu of surgery.
Case Presentation : A female neonate born to consanguineous parents with paternal history of renal calculi was admitted at 1 month of age
for suspected respiratory distress due to aspiration pneumonia. Laboratory testing revealed severe hypercalcaemia, elevated parathyroid hormone,
hypophosphataemia, increased alkaline phosphatase and low fractional excretion of calcium (FeCA) of 0.01. Radiographs demonstrated osteopaenia.
Treatment was initiated with pamidronate after completion of investigations, which reduced serum calcium level. Nevertheless, the baby expired.
Genetic analyses revealed homozygosity for a novel CASR gene terminator mutation in exon 4 (c.679 C>T, p.227 R>X). The parents refused genetic
Conclusion: his neonate with respiratory distress, osteopaenia, severe hypercalcaemia and hyperparathyroidism was found to have a novel
omozygous mutation of CASR gene, consistent with the diagnosis of NSHPT.
Keywords: Hypercalcaemia; neonate; calcium sensing receptor; neonatal severe hyperparathyroidism; familial benign hypercalcemic;
Abbreviations: ALP: Alkaline Phosphatase; CASR: Calcium Sensing Receptor; FeCA: Fractional Excretion Of Calcium; FHH : Familial benign
Hypercalcaemic Hypocalciuria; NSHPT : Neonatal Severe Hyperparathyroidism; PTH : Parathyroid Hormone
Levels of extracellular ionized calcium are tightly regulated,
principally through the action of parathyroid hormone (PTH),
which is secreted from parathyroid cells in response to signals
from membrane-bound calcium sensing receptors (CaSR).
Genetic mutations that impair calcium sensing result in mild to
moderate increases in PTH, hypercalcemia, and Hypocalciuria, a
condition termed familial benign Hypercalcaemic Hypocalciuria
(FHH). FHH is usually an autosomal dominant condition due to
heterozygous loss-of-function mutations in the CASR gene [1-3],
but autosomal recessive inheritance may occur as well . FHH
also can result from inactivating mutations in the GNA11 and
AP2S1 genes that encode additional proteins that are required
for CaSR signaling [5,6]. By contrast to FHH, biallelic inactivating
CASR mutations are associated with life-threatening neonatal
severe primary hyperparathyroidism (NSHPT) [1-3], which
results in generalized skeletal demineralization, neurological
disabilities, constipation, failure to thrive, respiratory distress
and irritability . In the absence of early recognition and urgent
intervention, NSHPT is usually a fatal condition. We report the
first case of a newborn girl diagnosed with NSHPT in Sri Lanka
and found to have a novel homozygous inactivating mutation of
the CASR gene.
The proband was a female infant who was born full term to
consanguineous parents. The baby was delivered via caesarean
section due to pregnancy induced hypertension, and presented
at 1 month of age with cough, dyspnea, and poor intake of infant
formula. The baby was admitted to hospital for evaluation; she
appeared ill and her length and weight were below -2SD with
microcephaly. The baby was intubated and transferred to medical
intensive care unit. Her chest X-revealed inflammatory shadows,
but the most striking feature noted was osteopaenia. Laboratory
analysis revealed severe hypercalcemia (4.64 mmol/L),
hypophosphatemia (0.65 mmol/L), an increased serum ALP
(1782 U/L) and a very low urinary calcium : creatinin clearance
ratio (0.01). Her plasma intact PTH was remarkably high (1142
pg/mL) but ultra-sound scan of neck did not reveal a parathyroid
gland abnormality. Her echocardiography showed biventricular
hypertrophy with no other abnormalities. An ultrasound scan of
the abdomen was normal and there were no renal calcifications.
She was treated with intravenous pamidronate (1mg/kg) in
preparation for parathyroid surgery. Although pamidronate
treatment reduced serum the calcium level significantly, the
baby expired due to respiratory arrest. A diagnosis of NSHPT
was made, and after informed assent, DNA was extracted from
peripheral blood mononuclear cells and the CASR gene was
analyzed for mutations as previously described . Molecular
studies revealed that a patient was homozygous for a novel
terminator mutation in exon 4, c.679 C>T, p.227 R>X, (Figure 1).
The consanguineous parents (Figure 2) and one sister (IV-2) have
normal calcium levels, while one other sister (IV-3) has a slightly
elevated serum calcium level (Table 1). A brother has a history of
rickets, likely due to vitamin D and calcium deficiency. Her father
and paternal two uncles have histories of renal stones. There is a
past history of infantile death of uncertain cause in a brother at
the age of 7 months. The rest of the family refused CASR mutation
Figure 1: Homozygous novel inactivating mutation in CASR, terminator mutation in exon 4, c.679 C>T, p.227 R>X (lower panel) compared to normal CASR sequence in the upper panel
Figure 2: Family pedigree. The arrow indicates the proband and the double horizontal line indicates parental consanguinity.
Serum Calcium Reference
Serum Phosphate Reference
< 2 yrs(1.45-2.16)
2-12 yrs (1.45-1.78) >12
Serum ALP Reference
Fraction excretion of Calcium
To our knowledge this is the first report of NSHPT in Sri Lanka
confirmed with genetic studies. NSHPT is an uncommon disorder
that usually results from biallelic loss of function mutations in
CASR gene although heterozygous dominant inhibitor mutations
have also been reported . Loss of calcium sensing will lead
to parathyroid hyperplasia and increased PTH secretion and
decreased renal excretion of calcium. These babies present with
failure to thrive, hypotonia, respiratory distress, constipation and
bone abnormalities such as demineralisation, rib cage deformity,
subperiosteal erosions and metaphyseal widening of long
bones. In the case we report here, the baby had failure to thrive,
hypotonia, osteopaenia and was hospitalised due to respiratory
distress. The differential diagnosis of hypercalcemia in babies
this age would include idiopathic infantile hypercalcaemia,
Williams syndrome, vitamin D intoxication, IMAGE, infantile
hypophosphatasia and FHH, but in none of these conditions is
the PTH so elevated and the urinary calcium so low as in NSHPT.
FHH, NSHPT and antenatal Bartter syndrome type 1 due to
SLC12A1  are the most common causes of PTH dependent
hypercalcaemia in this young age group and the very low FeCA
and clinical severity strongly favoured NSHPT. On the other hand
CASR mutation testing including functional analysis will provide
confirmatory evidence in differentiating hypercalcaemic status
and it also helps in guiding the treatment . Unfortunately,
the baby expired and the diagnosis of NSHPT was confirmed
post mortem by genetic studies. Review of the family suggests
the parents, who are consanguineous, and the other children
are heterozygous for the p.227 R>X mutation, but the rest of
the family would not agree to undergo testing. Interestingly, the
father has a history of renal stones, but the type is unknown.
Renal stones have previously been reported in patients with FHH,
and are often urate [11, 12].
In NSHPT, medical management is inadequate and total
parathyroidectomy is the treatment of choice and it is effective
in most cases . Intravenous bisphosphonates such as
pamidronate have often been used in neonates to treat
severe hypercalcaemia until surgery could be performed. The
calcimimetic cinacalcet has been used successfully in several
cases of NSHPT in which a wild type CaSR was present or in
which abnormal CaSRs were able to respond . In the case we
present here the terminator mutation would predict the absence
of any CaSRs on the cell surface, and one would not expect any
response from calcimimetic therapy.
In conclusion, this case clearly illustrates, although NSHPT is
a rare disease, it should be considered in differential diagnosis
of neonatal hypercalcemia as prompt diagnosis and surgical
intervention will be life-saving.
Sources of support
GPNA` acquired relevant clinical information and wrote the
first draft of the manuscript
EJ conceived of the case report, supervised and assisted in
editing of the manuscript
RE supervised the work MAL edited and finalized the
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