pseudohypoparathyroidism ( php ) is a disorder of end - organ resistance primarily affecting the actions of parathyroid hormone ( pth)1 ) . it is characterized by hypocalcemia and hyperphosphatemia in association with increased secretion of pth due to decreased target tissue responsiveness to pth . patients with php ia are not only resistant to pth , but also to other hormones that bind to receptors coupled to stimulatory g protein ( gs alpha)2 ) . the gnas gene is located on chromosome 20q13.11 and consists of 13 exons and 12 introns3 ) . php - ia is caused by heterozygous mutations affecting one of the 13 gnas exons encoding gs alpha4 ) . we report here a 9-yr - old boy with php ia with a nonsense mutation of c.637 c > t in the gnas gene , which is novel . 9-year - old boy was admitted to hallym university medical center with painful subcutaneous soft tissue masses with calcifications on the right toes and posterior chest wall . he had a history of repeated convulsive episodes from the age of 2 months . physical examination showed short stature ( 120 cm , 3rd percentile ) , round face ( fig . 2 ) and subcutaneous ossifications on the 2nd toe tip and 1st web space of the right foot and the left lower posterior chest wall ( fig . 3 ) . his weight was 30 kg ( 50th percentile ) , thus having a normal body mass index ( 20.83 kg / m , 85th-90th percentile ) . he was born at full term by cesarean section with a birth weight of 3.3 kg . family history revealed that his maternal grandmother had features suggestive of aho , such as short stature , round face , obesity and brachydactyly . his mother had normal appearance apart from short stature , but two of her siblings had short stature , round face and obesity . we could not make further investigation because the patient lost contact with his mother and maternal family after his parents got divorced . laboratory tests revealed hypocalcemia ( 4.2 mg / dl ; normal range , 8.8 - 10.8 mg / dl ) , hyperphosphatemia ( 8.9 mg / dl ; normal range , 3.7 - 5.6 mg / dl ) and elevated serum pth ( 146.5 pg / ml ; normal range , 9 - 65 pg / ml ) . he also showed elevated plasma thyroid - stimulating hormone ( 6.978 iu / ml ; normal range , 0.5 - 4.8 iu / ml ) , follicle stimulating hormone ( 5.6 iu / ml ; normal range , 0.26 - 3.0 iu / ml ) , and luteinizing hormone ( 1.2 iu / ml ; normal range , 0.02 - 0.3 iu / ml ) , which suggest multiple hormone resistance . urinary phosphorous and cyclic adenosine monophosphate response after infusion of synthetic human pth ( teriparatide acetate ) was attenuated ( ellsworth - howard test ) ( table 1 ) . his intellegence scale ( korean educational development institute - wechsler intelligence scale for children ) indicated mild mental retardation ( intelligence quotient , 67 ) . he was diagnosed as having php ia based on physical and laboratory findings ; hypocalcemia , hyperphosphatemia , pth resistance , presence of aho , multiple hormone resistance and mental retardation . he was started on phosphate - binding substance ( aluminum hydroxide , 80 mg / kg / day ) , vitamin d ( alfacalcidol , 1 mcg / day ) and calcium carbonate ( 50 mg / kg / day ) . three months later , his serum calcium was elevated from 4.2 to 6.0 mg / dl , and phosphorus was decreased from 8.9 to 8.6 mg / dl . the patient 's clinical symptoms of pain , seizure and hyperactivity were reduced . to support the diagnosis of php ia , we performed dna analysis of the gnas gene . genomic dna was extracted from peripheral blood leukocytes using the wizard genomic dna purification kit following the manufacturer 's instructions ( promega , madison , wi , usa ) . all coding exons and their flanking introns of the gnas gene were amplified using primer sets designed by the authors . polymerase chain reaction was performed with a thermal cycler ( model 9700 , applied biosystems , foster city , ca , usa ) as follows : 32 cycles of denaturation at 94 for 30 seconds , annealing at 60 for 30 seconds , and extension at 72 of 30 seconds . after treatment of amplicon ( 5 ul ) with 10 u shrimp alkaline phosphatase and 2 u exonuclease i ( usb co. , cleveland , oh , usa ) , direct sequencing was performed with the bigdye terminator cycle sequencing ready reaction kit ( applied biosystems ) on the abi prism 31001 genetic analyzer ( applied biosystems ) . sequencing of the amplified gnas genomic dna fragments revealed a heterozygous nonsense mutation within exon 11 ( c.637 c > t ) ( fig . 5 ) . the c > t transversion results in an amino acid substitution from gln to stop codon at codon 213 ( p.gln213 ) . to our knowledge , this is a novel mutation in gnas . we also performed dna sequencing of the gnas gene of his father , but no mutation was detected . php is a heterogeneous disease characterized by pth resistance and classified as types ia , ib , ic , and ii , according to its different pathogenesis and phenotype5 ) . in contrast to the situation in hypoparathyroidism , in php the parathyroid glands are normal or hyperplastic and they can synthesize and secrete pth6 ) . heterozygous inactivating mutations within gs alpha - encoding gnas exons are found in patients with php - ia , who also show resistance to other hormones and a constellation of physical features called aho . patients who exhibit aho features without evidence for hormone resistance , who are said to have pseudopseudohypoparathyroidism ( pphp ) , also carry heterozygous inactivating gs alpha mutations1,7 ) . there is some evidence to suggest that the gs alpha mutation is paternally transmitted in patients with pphp and maternally transmitted in patients with php - ia . the gene may be imprinted in a tissue - specific manner6,8,9 ) . in our case , dna sequencing of the patient and his father revealed that only the patient had mutations . the presence of slight aho in the mother 's side of the patient may suggest that the mutation came from his mother , but we were unable to confirm this because the dna of the patient 's mother or maternal family was not available at the time of the study . although we could not obtain molecular data from the maternal family of the patient , considering variation of phenotypes due to genomic imprinting , we were able to explain that the patient had the genotype and phenotype of php ia . in the maternal family of the patient , his mother had milder features suggestive of aho , whereas her mother and two siblings had characteristics that were more strongly suggestive of aho . we can suspect the possibility of a hypofunctioning gnas mutation like mosaicism , but it was impossible to validate . mutational analysis of gnas gene is a useful method for identifying genetic abnormalities as well as making diagnosis and differentiation of various subtypes of php10 ) . there are previous reports of korean patients with php ia and pphp who were confirmed by genetic analysis . park et al.11 ) reported a nonsense mutation of c.94a > t ( p.k32x ) and a frame shift mutation of c.344_345inst ( p.v117rfsx23 ) in patients with php ia , of which the former was novel . in a study of patients with php ia and pphp , jin et al.10 ) identified two novel mutations ; c.569_570del mutation ( p.tyr190cysfsx19 ) and a splicing mutation ( c.659 + 1g > a ) . gnas has been termed one of the most complex gene loci in the human genome3 ) . although many mutations have been identified in gnas , c.637 c > t nonsense mutation is deemed novel .
pseudohypoparathyroidism type ia ( php ia ) is a disorder characterized by multiform hormonal resistance including parathyroid hormone ( pth ) resistance and albright hereditary osteodystrophy ( aho ) . 
 it is caused by heterozygous inactivating mutations within the gs alpha - encoding gnas exons . 
 a 9-year - old boy presented with clinical and laboratory abnormalities including hypocalcemia , hyperphosphatemia , pth resistance , multihormone resistance and aho ( round face , short stature , obesity , brachydactyly and osteoma cutis ) which were typical of php ia . 
 he had a history of repeated convulsive episodes that started from the age of 2 months . 
 a cranial computed tomography scan showed bilateral calcifications in the basal ganglia and his intelligence quotient testing indicated mild mental retardation . 
 family history revealed that the patient 's maternal relatives , including his grandmother and 2 of his mother 's siblings , had features suggestive of aho . 
 sequencing of the gnas gene of the patient identified a heterozygous nonsense mutation within exon 11 ( c.637 c > t ) . 
 the c > t transversion results in an amino acid substitution from gln to stop codon at codon 213 ( p.gln213 * ) . 
 to our knowledge , this is a novel mutation in gnas .