PMC9243302_01
Family Pedigree. Symbols represent males (squares), females (circles), affected subjects (solid symbols), carriers (dotted symbols), and the proband (arrow). The propositus is indicated by an arrow.
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The pedigree in  Figure 1  shows the inheritance pattern of the X-linked recessive disorder. To validate the suspected variant in the proband, PCR and Sanger sequencing were performed on DNA samples of all available family members (II-2, II-3, II-6, III-1, III-2, III-3, III-4, and III-5), which revealed a hemizygous state in affected males (II-3 and III-3) and a heterozygous state in healthy female carriers (II-2 and III-1) ( Figure 1 ).
Clinical characteristics of the proband. (A) Significant melanosis could be seen in the wrinkles of the face, gums, tongue, and limbs. (B) A few hyperpigmented macules were noted on the lips and oral mucosa. (C-F) Inconspicuous male secondary sexual characteristics: no beard, axillary hair, no obvious laryngeal knot, inverted triangle distributed pubic hair, significantly reduced bilateral testicles. (G, H). Scanning results (adrenal hypoplasia, hypogonadotropic hypogonadism, small bilateral testes, olfactory sulci and pituitary, mild fatty liver).
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Physical examination revealed generalized hyperpigmentation ( Figures 2A, B ) and delayed puberty, with the absence of secondary sexual characteristics ( Figures 2C-F ). Abdominal computed tomography revealed bilateral adrenal gland hypoplasia ( Figure 2G ). Magnetic resonance imaging of the olfactory sulci and pituitary gland was normal ( Figure 2H ).
Representative chromatogram of the NR0B1 gene. The position of the mutation is indicated by special symbols ("" for the mutation, and "*" for Premature stop code). (A) The proband's mother (II-2) inherited the c.1034delC variant in heterozygous status. (B) His health sister (III-2) presented with homozygous wild-type of the NR0B1 gene. (C) The proband was hemizygous for the c.1034delC variant in the NROB1 gene. (D) His maternal cousin (III-5) showed hemizygosity for wild-type of the NROB1gene.
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A cytosine deletion at c.1034 caused a frameshift change, with proline-345 being the first affected amino acid by becoming arginine and forming a new reading frame resulting in a premature stop codon 27 amino acids further down ( Figure 3 ).