familial glucocorticoid deficiency ( fgd ) is a rare autosomal recessive disorder resulting from adrenal unresponsiveness to adrenocorticotropic hormone ( acth ) .
this disease is characterized by low serum cortisol concentrations in the presence of grossly elevated plasma acth levels .
affected individuals typically present with hyperpigmentation , hypoglycemic seizures , failure to thrive , failure to thrive and recurrent infections .
causal mutations of fgd have been identified in mc2r , mrap , mcm4 , txnrd2 , star   and nnt .
mc2r accessory protein ( mrap ) , a 19-kda single - transmembrane domain protein , is essential for trafficking of mc2r from the endoplasmic reticulum ( er ) to the cell surface and subsequent signaling in response to acth .
mutations in mrap are responsible for 1520% of fgd cases , named fgd type 2 . until now
, this mutation has not been reported in chinese han cases of fgd . in the current paper
, we describe a chinese han child who presented with isolated hyperpigmentation at birth and a homozygous splice mutation ( c.106  +  1delg ) in mrap .
a female infant was referred to our neonatal unit at the age of nine days for evaluation of hyperpigmentation of the skin . she was the product of an uncomplicated pregnancy and was born by caesarian section for concerning cardiotocographic changes during labor .
her sibling had died on the third day of life with hyperpigmentation of the skin .
birth size was normal ( weight 2800  g ,   0.99 sds ; length 46  cm ,   1.69 sds ; head circumference 33  cm ,   0.74 sds ) and apgar scores was 8 and 9 at 1st and 5th minute , respectively . on physical examination ,
weight was 2740  g (   1.31 sds ) , length 47  cm (   2.47 sds ) , and head circumference was 34.5  cm (   1.5 sds ) .
endocrine investigations revealed low baseline 8  am serum cortisol ( <  1.0  g / dl ) with extremely elevated acth ( 1250  pg / ml ) .
testosterone , 17-oh progesterone , estradiol , progesterone , luteinizing hormone , folliculin , and prolactin , free t4 , and tsh levels were normal .
based on these findings , a familial glucocorticoid deficiency was suspected and oral hydrocortisone treatment at dose of 20  mg / m per day was started .
hydrocortisone dose ( varying from 10 to 15  mg / m per day ) adjustment was based on acth and cortisol concentrations .
after 4  weeks , acth level was 278.0  pg / ml and cortisol level was 42.4  g / dl , and hydrocortisone dose was reduced to 15  mg / m per day ( given in divided doses twice daily ) .
the acth level was suppressed to slightly above the normal limit and the cortisol level is normal during the follow - up period . on her most recent visit , at the age of 12  months ,
hydrocortisone dose was 11  mg / m per day ( 5  mg was give once daily in the morning ) , the acth level was 25.10  pg / ml and cortisol level was 33.4  g / dl , and her skin was slightly lightened ( fig .
her weight was 10  kg ( 0.84 sds ) , length 70  cm (   1.67 sds ) , and head circumference was 46.5  cm ( 1.12 sds ) .
genomic dna was extracted from peripheral blood leucocytes from the infant and her family after informed consent was obtained . for the molecular diagnosis
, a custom panel - based next - generation sequencing approach has been used to sequence all known adrenal gland diseases - associated genes in this child .
we found a homozygous deletion of one nucleotide at the canonical 5 donor splice site ( c.106  +  1delg ) in intron 3 of mrap gene .
this would result in the skipping of exon 3 and a prematurely terminated translation product ( ( 1 ) ) .
her parents and maternal grandmother were found to be heterozygous carrier for the same mutation ( fig .
we report a case of fgd with homozygous mutation of mrap in a chinese han neonate .
this girl presented with isolated hyperpigmentation , have low cortisol and high acth with normal electrolytes . a homozygous splice mutation ( c.106  +  1delg ) of mrap confirmed the diagnosis of fgd type 2 . her parents and maternal grandmother had the same mutation .
until now , this mutation has not been reported in chinese han cases of fgd .
fgd is a rare autosomal recessive disorder characterized in laboratory testing by glucocorticoid deficiency and markedly elevated acth levels .
patients with fgd usually present during neonatal period to late childhood with symptoms related to cortisol deficiency and acth excess . in the neonatal period
, these symptoms may include hyperpigmentation , hypoglycemia , irritability , jitteriness , lethargy , respiratory distress , cyanosis , apnea , hypotonia , seizures , shock , or sudden death .
newborns can present with a positive family history of early - unexplained infant deaths or other affected family members supports a diagnosis .
the severe pigmentation of the skin is due to the over - stimulation of mc1r ( cutaneous msh receptors ) by high circulating msh which is a byproduct of acth synthesis from proopiomelanocortin .
this hyperpigmentation fades once proper treatment is initiated with glucocorticoids , which reduce acth concentrations .
this would suggest that the fetal corticotrophs could produce excessive plasma acth in response to low fetal cortisol , which in turn acts on melanocytes to promote eumelanin synthesis before birth . in most of the fgd patients suppression of acth levels
is difficult , and therefore is not used as a goal for therapy . in this case , replacement treatment with hydrocortisone suppressed acth level to slightly above the normal limit and partially resolved the hyperpigmentation . acquired causes of adrenal insufficiency such as adrenal hemorrhage , trauma and infections were excluded by history and laboratory findings .
congenital adrenal hyperplasia was excluded by hormone analysis ; congenital adrenal hypoplasia was also unlikely , because she had normal serum 17-oh progesterone and no mutation of the dax1 gene .
mrap , located at 21q22.1 , is a small single - pass transmembrane domain protein , which is essential for the processing of the acth receptor ( melanocortin 2 receptor , mc2r ) and its trafficking from the er to the cell surface .
this mutation will lead to skipping of exon 3 and early truncation of the protein and the absence of the mc2r interacting transmembrane domain . as a result
, mc2r is retained within the er and fails to reach the cell surface which lead to acth resistance and adrenal insufficiency .
mutations in mrap causing fgd2 were first described in 2005 . so far over 9 different mutations of mrap in fgd type 2 patients
have been documented all of which are splice site or nonsense mutations and are predicted to produce proteins lacking the transmembrane domain essential for interaction with mc2r , . in our patient , we found a newborn with fgd type 2 , presenting with severe hyperpigmentation .
she was found to have a splice - site mutation in the mrap gene , hence explaining the early presentation seen in the case . in their study , metherell et al .   identified the 1-bp deletion , c. 106  +  1delg , in 6 individuals from 5 families with glucocorticoid deficiency , making this the second frequent mutation causing fgd unrelated to defects in the mc2r gene . to our current knowledge , 1-bp deletion ( c. 106  +  1delg ) in intron 3 of mrap gene , identified in the dna of the patient ,
cases of the condition have been reported in white , , black , indian , and middle eastern   populations . to our knowledge
, our patient is the first reported chinese han patient with fgd type 2 , with a known mrap mutation .
the patient was the offspring of non - consanguineous parents and her sibling had died in the neonatal period , possibly due to glucocorticoid insufficiency .
prolonged acth excess or glucocorticoid deficiency increases linear growth , while early diagnosis and appropriate therapy in this case enabled the patient to achieve normal developmental milestones .
further studies describing new cases and mutations causing fgd will contribute to understanding the mechanism of this rare and potentially life - threatening disease .
 familial glucocorticoid deficiency ( fgd ) is a rare autosomal recessive disorder in which the adrenal cortex fails to respond appropriately to stimulation by adrenocorticotropic hormone ( acth ) to produce cortisol . 
 the disease is characterized in laboratory testing by glucocorticoid deficiency and markedly elevated acth levels . 
 fgd may present in infancy or early childhood with symptoms related to low cortisol and high acth , such as hyperpigmentation , severe hypoglycemia , failure to thrive and recurrent infections . 
 mutations in the mc2r accessory protein ( mrap ) cause fgd types 2 , which accounts for approximately 1520% of fgd cases . here , we report a female neonate of chinese han origin , who presented with noted hyperpigmentation at birth . 
 laboratory investigations revealed hypocortisolaemia ( cortisol <  1.0  g / dl ) and elevated plasma acth ( 1051  pg / ml ) . 
 she responded to hydrocortisone treatment . 
 genetic studies confirmed the diagnosis showing homozygous deletion ( c. 106  +  1delg ) in intron 3 of mrap gene , a mutation already reported as responsible for fdg type 2 . 
 this mutation can cause complete lack of acth response thus explaining the early presentation in this case . 
 her parents and maternal grandmother were heterozygous for the same mutation . 
 to our knowledge , this is the first chinese han patient reported with fgd type 2 due to a known mrap mutation . 