Congenital adrenal hyperplasia (CAH) represents a disorder that takes place secondary to the deficiency of the adrenal enzymes, most commonly 21 hydroxylases (21OH) along with the commonest autosomal recessive condition in humans. In case of milder non canonical type (NCCAH), normal quantities are generated   at the cost of adrenocorticotropic hormone quantities that in turn results in Clinical hyperandrogenism that gets presented from childhood via early adult period. A remarkable resemblance of signs along with symptoms with those of Polycystic ovary syndrome (PCOS). Hence NCCAH constitutes a significant differential diagnosis, in case of women   manifesting acne, hirsutism, menstrual aberrations along with infertility.

Congenital adrenal hyperplasia (CAH) represents a disorder that takes place secondary to the deficiency of the adrenal enzymes, most commonly 21 hydroxylases(21OH) along with the commonest autosomal recessive condition in humans [1]. In case of milder non canonical type (NCCAH), normal quantities are generated   at the cost of adrenocorticotropic hormone quantities that in turn results  in Clinical hyperandrogenism that gets presented from childhood via early adult period [2]. A remarkable resemblance of signs along with symptoms with those   of Polycystic ovary syndrome (PCOS). Hence NCCAH constitutes a significant differential diagnosis, in case of women   manifesting acne, hirsutism, menstrual aberrations along with infertility [3].

The diagnosis of NCCAH is basically dependent on escalated basal in addition to cosyntropin stimulated quantities of the 21OH substrate 17 hydroxy progesterone (17 OHPg) in addition to 21deoxy cortisol(21DF), both of which are biochemical markers of 21OH deficiency [4,5]. Nevertheless, the present   basal in addition to cosyntropin stimulated quantities  of the 17 OHPg cut-off values are dependent on old method that is no standardized immunological approach that is considered outdated now [6]. In the ideal conditions the basal blood sample is required to be drawn at the time of early menstrual follicular phase, however in case of irregular along with scanty occasional menstruation it becomes tough to collect accurately timed sample.

In recent decade liquid chromatography, which is coupled with tandem mass spectrometry (LC- MS/ MS) is utilized   for quantitative estimation of steroid hormones whose implementation is being done escalating, being advocated in the form of gold standard [7]. LC- MS/ MS provides superior analytic specificity in contrast to immunoassays along with possess the   capacity of reproducibility in addition to traceability depending on one accuracy (i.e., international reference materials) that aids in contrasting the outcomes across approaches, time as well as place. its having multiplexing capacities aids in evaluation of various steroid hormones in a single analytic run for the generation of a single ‘’steroid fingerprint ‘’ that is the other main benefit. Newer reference ranges in addition to cut-off values as well as validation is the need of the hour as appreciated by the Endocrine Society [8] on introducing the newer analytic approaches.

Cosyntropin test gets utilized   for the diagnosis of partial enzymes abnormalities in NCCAH. An escalation of serum 17 OHPg>30-45nmol/L(10-15ng/ml)60’ subsequent to Cosyntropin stimulation is believed to be diagnostic for CAH/ NCCAH [9], when immunoassay is used.Ueland etal [10]. earlier observed that cosyntropin stimulated quantities of 17 OHPg<9nmol>

Corroboration of diagnosis of NCCAH is required with   the utilization of CYP21A2 genotyping.The etiology of  CAH/ NCCAH syndrome is deletions, macroconversions,  microconversions or variants of a  pseudogene for the area  CYP21A2 on chromosome .Large variations in adrenal steroidprofiling despite the same genotype that highlights the variations amongst  the genotype along  with     phenotype of these diseases[10]. Heterozygous carriers might illustrate mild hyperandrogenism, with this condition being frequent a risk of carriers of transmitting the disease to their offspring.The precise risk correlated with fertility, pregnancy, along with    delivery as well a offsprings in Heterozygous  carriers is not clear.

Lesser frequent enzymes deficiencies, In the adrenal steroid   generation might be thought off by       escalated quantities of precursors that are upstream in the   steroid pathways. Adrenal steroid profiling   might reveal such rare aberrations. 

Thus, Ueland etal [11]. Conducted a prospective cohort evaluation of 121 healthy adults along with   65patients assessed for probable NCCAH (Corroboration cohort). The cut-off values for11 steroids as estimated by LC- MS/ MS (basal in addition to cosyntropin stimulated quantities had a definition of 2.5% and 97.5% percentile in healthy individuals. Corroboration cohort was utilized for contrasting. They observed that of the 65PCOS like patients assessed for probable NCCAH,8 (12.5%) were observed besides corroborated genetically with 2 having classic Congenital adrenal hyperplasia. Maximum provision of diagnostic precision for NCCAH was offered by cosyntropin stimulated quantities of the 21OH substrate 17 hydroxy progesterone (17 OHPg) in an area of curve of 0.95(0.89—1.0) with a sensitivity of 86% as well as specificity of 88%. 21hydroxycortisol along with   17 OHPg were escalated in homozygote patients, whereas in heterozygote patients just 17 OHPg(be it basal or stimulated were enhanced .(see figure1 and2)4 patients , In the Corroboration cohort had  17 OHPg above the basal cut-off. Thus concluding that NCCAH syndrome is common amongst patients where PCOS is speculated  along with  needs to be taken  into account     In the form of a routine screening while evaluating for infertility.They advocated serum steroid profiling  inclusive of 21deoxy cortisol  in addition to Cosyntropin stimulation test with  17 OHPg .As per there data,a 17 OHPg cutoff of 8.5nmol/L(2.8ng/ml)60min subsequent to Cosyntropin stimulation on estimation with LC- MS/ MS,that   is  significantly  lesser in contrast to European Guidelines [11]. 

Hence this article by Ueland et al.[11], needs to switch the pattern of for assessment of women with speculated PCOS or  NCCAH.As outlined before .Ueland etal.[10], had earlier provided the cut-off values  for  ruling out the diagnosis of NCCAH with the utilization of LC- MS/ MS,ACTH  stimulated 17OHP quantities  under3ng/mlthat was a quantity much lesser in contrast to 10-15ng/ml earlier believed  to be diagnostic  for in Classic Congenital adrenal hyperplasiaor NCCAH on use of immunoassays. In the    present study Ueland et al.[11], obtained a reference range regarding  besides17OHP quantities, 21deoxy cortisol, 11deoxy cortisol, corticosterone,  17 hydroxy pregnenolone, cortisol, cortisone ,androstenedione, testosterone (T) in addition to Dehydroepiandrosterone sulphate (DHEAS).Of the 63 women with hirsutism,  infertility as well as /or atypical manifestation  of PCOS were evaluated as Corroboration cohort which were inclusive of 2 cases with Classic CAH along with    8(12.6%)having genetically corroborated  NCCAH,3 homozygotes  along with    5 heterozygous carriers. None of the remaining 55cases had NCCAH. 17 OHPg proved to be the marker possessing maximum accuracy; nevertheless, stimulated 21deoxy cortisol escalated the diagnostic precision.

Taking   into account the outcomes of this publication is significant for reproductiveendocrinologiststo realize the assay that their local laboratory utilizes for determination of 17 OHPg along with 21deoxy cortisol.In case  LC- MS/ MS assay used ,these new standards documented by Ueland et al.[11], for prevention of under diagnosis of  NCCAH.   In view of the present commercial investigations do not possessthe capacity of differentiating amongst the pathological   CYP21A2 gene aberrations along with the pseudogene, hormonal evaluation continues to be significant in the   current time where expanding carriers screening is in vogue.

Despite,re generating  the  diagnostic criteria of  NCCAH is of considerable significance,there might be broader Clinical importance for NCCAH along  with PCOS in view of the overlapping manifestations clinically. While PCOS diagnosis is made by excluding NCCAH, NCCAH diagnosis needs particular criteria. By altering these diagnostic criteria changes both groups.Like having 90 cases in one group awa 10 in other,shifting 5 from thegroup of  90 along  with  addition of these 5 to the group of 10 would alter both groups.Although depleting 5 from the group of  90 would apparently not cause an appreciable  alteration; nevertheless this alteration might become significant regarding escalation from 10 to15.By altering the classification for NCCAH,our insight for both the disorders would alter, which will be much greater for those diagnosed with  NCCAH.

Hence it is mandatory to bother about this NCCAH prototype shift. Precise diagnosis of NCCAH might lead to a more advantageous insight along with treatment for women presenting with hirsutism or Clinical hyperandrogenism [12].