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Neonatal severe primary hyperparathyroidism is a rare disease caused by homozygous inactivating mutation in the calcium sensing receptor gene (CASR). (Ped 2007 Fox). Markedly elevated calcium and PTH characterize this disease. (Schwarz, Scan j and clin 2000). Untreated, this disorder may be lethal or may lead to skeletal deformities, developmental delay, hypotonia and poor feeding; early neonatal parathyroidectomy is required. (Cooper ped 1986 and Ross 1986). Heterozygous mutations of this gene cause Familial hypocalciuric hypercalcemia (FHH) which is an autosomal dominant inherited disease, characterized by asymptomatic hypercalcemia and hypocalciuria. We report on two patients with clinical features of neonatal severe primary hyperparathyroidism, found to have a novel mutation (G768V) in the CASR gene. In addition both patients have crainosynostosis which required surgical treatment.
The proband, a male, was born to a 24 year old G1P1 mother of Pakistani descent and a 28 year old father of the same descent. They are first cousins and the family history was unremarkable; there is no history of hypercalcaemia and endocrine tumors. The mother was healthy, and the pregnancy was uncomplicated. An ultrasound at 20 weeks gestation showed no major malformation and a repeat ultrasound at third trimester showed growth restriction. The labour was induced at 38 weeks due low biophysical profile and growth restriction. The baby was born by vaginal delivery, with APGAR scores of 8 and 9 at 1 and 5 minutes respectively. The birth weight was 1.7 kg (< 3rd centile), length 45 cm (< 3rd centile), and the head circumference was 29 cm (< 3rd centile). Physical examination showed SGA baby boy with hypertelorism, down slanted palpebral fissures and hypoplasia of maxilla. There was cranial deformation with turricephaly and brachycephaly. The anterior fontanale measured 1.5 cm x 2 cm and the bones of skull were ballottable. There was a prominent suture ridges indicating craniosynostosis. The limb examination is unremarkable and the neurological examination is normal at birth. Ophthalmological examination was normal, hearing test was normal. Biochemical investigations showed corrected serum calcium of 3.15 mmol/l(2.1-2.55), S. phosphate 1.44mmol/l (1.6 - 3.1), Alkaline phosphatase 697 U/l, S. Magnisium 1.0 mmol/l (0.7-1.0), S. Parathyroid Hormone 113.3 pmmol/l (1.6-9.3), Vitamin D-(1,25 Dihydroxy Vit D) 341 pmol/l (43-148), Vit D (25-OH) 67 nmol/l (22.5-93.8), Urinary calcium excretion 24 hrs 0.1 mmol/l (2.5-7.5), urinary creatinin excretion 0.5 mmol/l (9-19) is this right number please recheck again?, Urinary phosphate excretion 0.5 mmol/l (13-42), The repeated urinary tests showed urine calcium random 0.37 mmol/l (reference values) and urine creatinin random 1.1 mmol/l. (reference values). The urinary calcium creatinin ratio is 0.3.
Echocardiography detected moderate membranous VSD with no signs of heart failure. Ultrasound of the abdomen was normal, skeletal survey was normal apart from the skull; CT showed multiple sutures fusedÂ but most significant and operated for is unilateral coronal and sphenofrontal & Â frontoethemoidalÂ sutures. The karyotype showed a normal male (46, XY).
The second patient; sibling of the first patient is a female. She was born at full term with uneventful pregnancy and normal antenatal ultrasound. Mother was healthy during pregnancy. The baby was born by vaginal delivery, with normal APGAR score. Her weight, length and head circumference at birth were in the 50th percentil. Physical examination showed hypertelorism, and down slanted palpebral fissures. There was cranial deformation with turricephaly and brachycephaly and there was a prominent suture ridges, please confirm this. The limb examination is unremarkable and the neurological examination is normal. Other systemic examinations were within normal, including cardiovascular. Laboratory investigations showed hypercalcaemia with S.calcium 3.0 mmol/l (2.1-2.5 ) and hypophosphataemia of S. phosphate 1.29 mmol/l (1.6- 3.1) with very high S. Parathyroid hormone level; 193 pmol/l (1.6 - 9.3), serum1,25 didydroxy Vit-D. 405 pmol/l(43 -148). CT scan of the head showed fused sutures involving xxxxx. The Karotype showed normal female (46 XX)
Both parents S.Ca, S.Po4 and PTH were within normal limits done in two separate occasions. However the urinary Ca is 0.75 mmol/l (2.5- 7.5) random in the mother and in the father was X
The clinical features have prompted us to test CASR gene. The parents consented for DNA studies; genomic DNA was isolated from peripheral blood leukocytes by standard techniques. Gene test was done in Oxford Medical Genetics Laboratories (UK). PCR Amplification and Direct Sequencing of the CASR gene were carried out using standard methods. Patient sequences were compared to CASR gene; showed aÂ mutation in the gene encoding the calcium sensing receptor (CASR). It was found to be homozygous for a G>T point mutation at nucleotide c.2303 in exon 7 of CASR, resulting in the replacement of the amino acid Glycine with a Valine at codon 768. Both parents were tested and showed heterozygous mutation at the same site, assumption.
Both patients were treated by low calcium formula milk, calcitonine, hydrocortisone, and frusemide, however hypercalcemia had a poor response to treatment. Then a subtotal parathyoidectomy was done with autotransplantation of parathyroid to the nondominant arm. Currently both children are asymptomatic and they are off any medications. The serum calcium phosphate and PTH are within normal limits. The first patient currently 28 months old he showed motor and speech development delay, his developmental age is 18 months. This is probably due to delay in the parathyoidectomy which was done at age of X. The sister at present is X months old and she has normal development milestones.
We report on two patients presented with the clinical syndrome of neonatal severe primary hyperparathyroidism. Both patients have Hypercalcemia, hypophosphatemia, high normal Mg, extremely high PTH, and hypocalceuria. The parents have normal serum calcium and phosphate levels tested repeatedly. The mother and the father had hypocalceuria. We identified a novel homozygous mutation in the CASR gene; point mutation at nucleotide c.2303 (G>T) in exon 7, resulting in the replacement of the amino acid Glycine with a Valine at codon 768. Both parents had heterozygous mutation at the same site.
This variant has not previously been reported. Glycine at codon 768 is highly conserved across species within CaSR orthologs. Conservation of amino acids within the protein family through evolutionary constrains; indicate the biological importance for maintaining the three-dimensional structure of a protein and its function. (j clini endo and met 2009 lietman). We used the PolyPhen program (http://genetics.bwh.harvard.edu/pph/) to investigate the amino acid substitution effect on the CaSR structure and function. The G768V substation is predicted to be probably damaging; it is with high confidence supposed to affect protein function or structure.
Extracellular calcium-sensing receptor (CaSR) is a protein of 1078 amino acids. It displays seven putative membrane-spanning regions common to G protein-coupled receptors. (Garrett 1995). Also consist of N-terminal extracellular domain (ECD), and an intracellular C-tail segment. The missense mutation G768V is located at the predicated Trans membrane domain 5 encoded by exon 7. (Pollak 1993) CaSR Senses changes in the extracellular concentration of calcium ions, thus restore and maintain calcium ion concentrations to within the normal range. PTH secretion and renal tubular calcium absorption increase to counteract decreases in calcium serum levels. (Ramasamy , Clini chemic acta 2008.) Loss-of-function mutations of CASR cause a higher calcium sensing set point and so impair suppression of PTH secretion in response to extracellular usual Calcium levels. Such mutations also cause increase reabsorption of calcium (and magnesium) in the distal renal tubule. (Lietman 2009)
NSHPT is most likely an autosomal recessive disease. (Egbuna 2008) Homozygous mutations of CASR gene are recognized to cause this disease however, to date there are three reports with de novo heterozygous mutations causing NSHPT phenotype (Pearce 1995 and Bai 1997). The phenotype- genotype is not well understood, Schwarz et. al. report on a girl and her sister with the same single mutant allele, where she manifested NSHPT, and the sister manifested phenotypic FHH. The parents of our patients had normal calcium and PTH tested repeatedly, but both showed hypocalcuria. They both carried the heterozygous mutation of the same allele. They had unusual form of FHH.
The clinical phenotype of the NSHPT includes polyuria, dehydration, hypotonia and failure to thrive. They have PTH-dependent hypercalcaemia. There are prone to skeletal abnormilites include multiple fractures, Irregular metaphyses, metaphesal fractures and demineralization. In most patients NSHPT presents within the first 6 months of life. The mortality rate is up to 50% reported in some series. Common causes of death are severe hypercalcemia, respiratory failure secondary to thoracic deformation, and/or respiratory infection. (Egbuna 2008, fox 2007). Our patients presented with sings of hypercalcemia and hyperparathyroidism. In addition to the usual clinical manifestations of the NSHPT , both patients had carinosynostosis. The CT scan head prove multiple sutures involvement mainly unilateral coronal, sphenofrontal and Â frontoethemoidalÂ sutures. This is unusual feature first time to be reported. The patients did not have other features suggestive of other carinosynostosis syndrome.
Many reports have shown that CaSR play a role in osteoblast and osteoclast function. It was shown that CaSR transcripts present in the osteoblasts, osteocytes, and bone marrow cells. (Chang 1999. Kanatani 1999). Calcium inhibits the formation and activity of osteoclasts and stimulates the activity of osteoblasts. It is believed that this function is mediated via CaSR. (Egbuna 2008). This receptor also contributes to survival and normal development of the growth plate and long bone growth. (Brown 2008) Chattopadhyay et.al. (2004) have shown the physical presence and functional role of the CaSR in calvarial osteoblasts in mice. Mice with osteoblast-specific deletion of CaSR exhibited profound bone defects. (Brown 2008) In our patients both had carinosynsotsis. Many known growth factors of both systemic and local origins, like BMP-2, IGF-I, and FGF, exert mitogenic effects on osteoblast, High Ca+2 dependent CaSR mediated effect on this growth factors have been shown in the past.(Chattopadhyay 2004 ), However there is a divergent result and it is non-consistent when it comes to the function and role of CaSR in osteoblast and osteoclast function. (Egbuna 2008)
Lowering the hypercalcaemia in patients with NSHPT is usually difficult, both our patients were treated by low calcium formula milk, calcitonine, hydrocortisone, and frusemide, but they showed poor response. Total parathyroidectomy is the main stay of treatment and may be life saving for severely affected infants. (Fox 2007, Sally 1989, and Goldbloom 1972). Both our patients had parathyoidectomy the eldest sibling at age of X and the other at age of X. The boy at age of 28 months showed motor and speech delay, we believe due to delayed surgical treatment. After the operation they have had normal calcium and PTH levels, and they did not require any medications. They are thriving well.
We reported on two siblings with clinical features of NSPTH. We found a novel missense mutation (G768V) in the CASR gene. Both patients have had crainosynostosis which required surgical treatment. This is the first report of sutures abnormality in patients with NSPTH. We are not certain if it is related to the CaSR. Our patients responded well to the parathyoidectomy.