thirteen patients with php type 1 visited the department of pediatrics at chiba university 
 hospital between 1995 and 2004 . the diagnosis of php was based on the following criteria:(1 ) 
 the presence of hypocalcemia ( serum calcium less than 8.5 mg / dl ) with elevated serum pth 
 levels ( above twice the upper normal limit);(2 ) normal renal function ( normal levels of 
 serum urea nitrogen and creatinine);(3 ) lack of urinary camp response to exogenous pth 
 infusion ( less than 10-fold increase ) . all patients were treated with vitamin d. four cases 
 with php1a ( 2 males and 2 females ) and six cases with php1b ( 3 males and 3 females ) who 
 reached adult height were enrolled in this study ( table 
 1table 1 the heights of the cases with php at diagnosis and in adulthood ) , and three patients who did nt reach adult height ( growth velocity < 2 cm 
 per 12 mo at the time of this study ) were excluded . the diagnosis of php1a was based on the 
 presence of either brachydactyly or heterotopic ossification in the soft tissue . the 
 diagnosis of php1b was based on the absence of these features of aho . the clinical diagnosis of php1b was confirmed by the methylation - specific 
 southern blot analysis , according to previously described methods ( 2 ) ( data not shown ) . all cases with php1a had subclinical hypothyroidism 
 and received levo - thyroxine supplementation to maintain normal tsh levels . we observed poor 
 gh response in provocative tests in cases 1 , 9 and 10 in this study . cases 1 and 4 were siblings and their mother had 
 pseudopseudohypoparathyroidism ( pphp ) . table 1 shows the height and height sd score 
 ( sds ) of php cases at the age of diagnosis and in adulthood . the adult heights of all php1a 
 cases were less than 2.0 sd and those of all php1b cases were within the normal range ( > 
 2.0 sd ) . although the adult heights of female cases with php1b were completely normal , 
 ( ranging between 0.21 and + 0.08 sd ) , those of male cases with php1b were relatively low , 
 ( ranging between 0.74 and 1.74 sd ) . in php1a cases the adult height sds was obviously 
 lower than the height sds at diagnosis , and similar trends were observed in php1b cases . open circles and closed circles indicate the 
 heights of cases 1 and 2 , respectively . although case 2 lacks informative data for prepubertal 
 growth , case 1 had mild growth reduction in the prepubertal period . open circles and closed circles indicate the 
 heights of cases 3 and 4 , respectively . reduced growth velocity in childhood 
 and a blunted growth spurt caused abnormally reduced adult height . taking these findings 
 together , at least three out of four cases with php1a showed progressive deviation from the 
 standard curve because of the reduction in growth velocity in childhood . open circles , closed circles and open squares 
 indicate the heights of cases 5 , 6 and 7 , respectively . prepubertal growth showed a normal 
 pattern , however , a relatively early growth spurt was observed in cases 6 and 7 and resulted 
 in mildly reduced adult height . open circles , closed circles and open squares 
 indicate the height of cases 8 , 9 and 10 , respectively . shows the growth charts of female php1b cases and all show completely normal growth 
 patterns . cases 2 and 3 
 ( sporadic php1a ) were very much shorter than their mid - parental heights ( 18.3 and 15.5 cm 
 compared with their mid - parental heights ) . all the male php1b cases had shorter adult height 
 than their mid - parental height ( 8.8 to 0 cm ) but female php1b cases had almost the same 
 height as their mid - parental height ( 2.3 to + 3.0 cm ) . open circles and closed circles indicate the 
 heights of cases 1 and 2 , respectively . open circles and closed circles indicate the 
 heights of cases 3 and 4 , respectively . open circles , closed circles and open squares 
 indicate the heights of cases 5 , 6 and 7 , respectively . open circles , closed circles and open squares 
 indicate the height of cases 8 , 9 and 10 , respectively . we evaluated growth charts of php patients and analyzed the differences between php1a and 
 php1b . short stature is considered to be one of the features of aho , however , in most cases 
 with php1a , short stature was not evident in childhood ; it developed in adolescence and was 
 evident in adults in this study . cases of php1a had quite specific growth patterns and the 
 adult height of php1a cases may be affected by at least three factors : gh status , the 
 severity of bone disease caused by heterozygous loss - of - function mutation of the gnas1 gene , 
 and onset and progression of sexual maturation . secretion of gh requires binding of ghrh to specific receptors on pituitary somatotrophs 
 that are coupled via gs to activation of adenylyl cyclase . gh deficiency in php1a occurs in 
 about 70% of cases ( 6 , 7 ) , but the relevancy of gh deficiency on adult height in php1a is unknown at 
 present . patients with pphp , although not displaying any endocrine abnormality , are 
 characterized by short stature as are their relatives with php1a ; therefore , a crucial role 
 for gh deficiency in the determination of short stature in these patients seems unlikely 
 ( 1 ) . reported that among php1a 
 patients gh deficient adults were shorter than gh sufficient adults , although gh deficient 
 children are not shorter than gh sufficient children ( 6 ) . in our study , patients with php1a , except for case 2 who did nt have a growth 
 record before the age of 11 yr 11 mo , showed increasing deviation from the mean height with 
 age during prepubertal growth . the expression of the gnas1 gene is biallelic in most tissues ; however , genomic imprinting 
 occurs in particular tissues ( 2 , 4 , 5 ) . the inactivating mutations of 
 the gnas1 gene on the paternal allele have no effect on hormone resistance . maternal allele 
 dominant or exclusive expression has been reported in human endocrine organs including the 
 pituitary , thyroid , and ovarian cells ( 4 , 5 ) . although this imprinting mechanism is not well 
 understood , differentially methylated regions in the regulatory sequences of the gnas1 gene 
 is reported to be necessary for maternal allele specific expression of gs protein ( 2 ) . the methylation of cytokine residues of cpgs in the 
 exon 1a ( also referred to as exon a / b ) region upstream of the gnas1 gene is critical but not 
 sufficient for the expression of gs protein in imprinted tissues . loss of this methylation 
 on the maternal allele ( i.e. , both alleles are demethylated ) is associated with php1b . in 
 this context , the gs protein level may be decreased in the pituitary gland of patients with 
 php1b although gh status in php1b has not been reported in the literature . we observed poor 
 gh response in provocative tests in some cases in this study , but the growth charts of all 
 php1b cases showed normal growth patterns in the prepubertal period . in this study , we found 
 no evident relationship between gh secretion and growth patterns in php1b patients . gh 
 status and growth patterns in php1b must be studied in large numbers of patients to 
 determine whether or not gh deficiency affects the growth of php1b . the bone age of patients with aho is advanced 2 to 3 yr in the majority of patients with 
 php1a ( 8) . unfortunately , we were not able to present 
 the data related to bone maturation in this study because the availability of hand x - rays 
 was insufficient . reduced height gain and premature cessation of growth after the beginning 
 of the growth spurt in php1a in our study were concordant with previous studies ( 3 , 8) . active gs 
 protein is reduced in bone cells with aho because both paternally and maternally inherited 
 inactivating mutations in gnas1 cause aho . genomic imprinting is not shown in bone cells , 
 therefore , the amount of active gs protein in bone cells of php1b patients must be normal . haploinsufficiency of the gnas1 gene may be responsible for the advanced bone maturation and 
 poor growth potential in the growth spurt because reduced height gain and premature 
 cessation of growth after the beginning of the growth spurt was not observed in the php1b 
 patients . php1a patients often have reproductive dysfunction because of partial resistance to 
 gonadotropins ( 9 ) . one report suggests that early 
 puberty and advanced bone maturation cause the blunted growth spurt in php1a ( 3 ) , however , the growth pattern of php1a cases in this 
 study was not suggestive of early puberty in php1a . early puberty in php1a seems to be 
 unlikely because of these facts , but further investigation is required . it is very important that in such studies the diagnosis of 
 php1b must be based on the molecular analysis because some php1a patients with mutations in 
 gs often lack physical features of aho . the reason why php1b females showed a completely normal growth pattern which 
 was different from php1b males is unclear . a possible explanation for this sex difference is 
 that cell - specific imprinting of gnas1 expression may affect the maturation of the 
 hypothalamic - pituitary - gonadal axis in different ways between males and females . the growth of php1a cases was 
 characterized by mild growth impairment in the prepubertal period , a blunted growth spurt 
 and premature cessation of the growth spurt . an early growth spurt was observed only in male 
 patients with php1b , and it may reduce the adult height of male patients with php1b . this 
 warrants further investigation into the growth and pubertal development of php1b 
 patients .