A Family Report Of Adrenoleukodystrophy Present As Adrenal Insufficiency

Objectives To review and summarize the diagnosis and treatment processes of a family case with adrenoleukodystrophy presenting as adrenal insufficiency.The aim is to remind the clinicians to take adrenoleukodystrophy into consideration when you confront a patient with adrenal insufficiency,and to explore the feasibility of new way to diagnose the inherited metabolic disorders.Methods We investigated a non-consanguineous family including the proband,his brother and Cousins.Firstly,we collected the clinical materials consisting of medical history,physical examination and relevant auxiliary examination,and then summarized the characteristics of all cases.Secondly,we searched literatures with congenital,primary and adrenal insufficiency as keyword,compared the disease that we got with the characteristics of our cases.Lastly,genomic DNA was extracted from peripheral blood leukocytes of the patient,his parents and his brother.All coding exons and proximal splice sites of the DAX1,MRAP 、 MC2 R,ABCD1 gene were amplified by PCR with DAX1,MRAP,MC2 R,ABCD1-specific primers for the proband,respectively.Results We summarized the characteristics of all cases that included:(1)a large span of onset age,which was from infancy to adolescence;(2)all the patients were boys;(3)all the patients complained that the gum and oral mucosa were black;(4)physical examination,we only found the blackened gums and oral mucosa;they had good growth and development,and their sexual development were normal;(5)serum ACTH levels were increased significantly,serum cortisol levels were low or in normal ranges,and serum electrolyte and sex hormones were in normal ranges;(6)the proband suffers from subclinical hypothyroidism,but the thyroid function of the other two patients are normal;(7)the patients received the cortical hormone replacement,which showed effective;(8)the proband’s mother’s brother died of severe encephalitis when he was adolescence.Five related diseases were identified: X-linked adrenal hypoplasia congenita,familial glucocorticoid deficiency,adrenoleukodystrophy,congenital adrenal hyperplasia(CAH),3A syndrome and et al.Further reading of related literatures to understand the characteristics of diseases and laboratory tests,the clinical diagnosis of CAH and 3A syndrome were excluded.The genes of first three related diseases were DAX1,MRAP、MC2R,and ABCD1,respectively.Direct sequencing of the DAX1,MRAP,MC2 R gene from genomic DNA revealed no novel mution.DNA sequence analysis of the ABCD1 in the proband revealed one new mution comprising an T→C transition at c.1858 in exon 8,which predicted the missense mutations Tyr 620 His.Further familial gene validation indicated that the proband’s mother and younger brother,the proband’s older cousin and aunt revealed the same missense mutation,while the proband’s father,uncle and younger cousin had no missense mutation fortunately.In addition,the effect of the c.1858 T>C mutation was predicted to be probably damaging with a score of 0.886 using the structurebased approach Poly Phen-2.The serum concentration of very long chain fatty acids for the proband’s younger brother were increased significantly.Conclusions(1)It plays an important role in correct diagnosis that all patients see a doctor timely.Meantime,we report a youngest patient aged 9 months with adrenoleukodystrophy in the world.(2)Here we first report three cases of adrenal insufficiency only adrenoleukodystrophy in a family who are identified with the Tyr620His(c.1858T>C)missense mutation in China.(3)If different members of one family have similar clinical manifestations,physician should consider the diagnosis of inherited metabolic disorders.Full analysis of disease-related traits and targeted gene testing is one of the effective methods for accurate diagnosis of inherited metabolic disorders.This is also one of useful way to shorten the period for rare disease diagnosis.