X-linked congenital adrenal hypoplasia is a rare disease with a prevalence rate of approximately one in 12,500 in the USA ; its prevalence in Egypt is unknown. DAX-1 is expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary and is essential for the normal development of the steroidogenic axis and sex determination. Over 80 mutations of varying types have been identified in this gene . Patients with a mutation of the DAX-1 gene usually present with primary adrenal insufficiency in early infancy or childhood, and hypogonadotropic hypogonadism during puberty .
Chromosome X-linked heredity is usually recessive in women. In our case, our patient’s mother was heterozygous for the mutation and was therefore a carrier, because the normal dominant allele prevented expression of the affected gene. Her XY sons were hemizygous for the mutation and were therefore affected by the condition . There is phenotypic heterogeneity associated with DAX-1 mutations. The lack of genotype-phenotype correlation in some mutations is presumably caused by the influence of other modifying genes, which lead to significant within-family variations in age at onset and expression. Adrenal failure may be transient, asymptomatic or manifest in adulthood. However, in the absence of adrenal insufficiency, DAX-1 mutations are an uncommon cause of hypogonadotropic hypogonadism or pubertal delay . The X-linked type of mutation can be associated with Duchenne muscular dystrophy and/or glycerol kinase deficiency as part of a contiguous gene syndrome. Other unusual presentations, such as progressive high-frequency hearing loss, profound hyperpigmentation, and monosomy have also been described .
A clinical diagnosis of congenital adrenal hypoplasia due to DAX-1 mutations is not always easily made. Boys who present in the neonatal period with salt wasting and adrenal insufficiency are sometimes misdiagnosed with the more common disorder, 21-hydroxylase deficiency (congenital adrenal hyperplasia), although the adrenal steroid profiles of these conditions are quite different. In congenital adrenal hypoplasia, 17-hydroxyprogesterone levels are low, whereas they are increased in congenital adrenal hyperplasia. Distinguishing these two disorders is important because they differ in their clinical course, steroid management and genetic counseling. The recessive form of congenital adrenal hypoplasia should also be considered as a cause of primary adrenal insufficiency in infancy. It has a distinct miniature adult adrenal morphology, characterized by small glands with a permanent cortical zone but a diminished fetal zone. The genetic basis of the recessive form of congenital adrenal hypoplasia is unknown .
Normal penile and urethral development begins in the sixth week of gestation with the formation of the urogenital sinus, which eventually becomes masculinized under the direction of testosterone and its more potent form, dihydrotestosterone. Without the presence of adequate levels of testosterone or a functioning androgen receptor, the genital structures become female in appearance, as seen in the most severe cases of hypospadias . Our patient had penile hypospadias without cryptorchidism or genital malformations. Further, his basal values of luteinizing hormone and follicle-stimulating hormone were appropriate for his age, which suggested normal hypophyseal function. An hCG loading test confirmed intact testosterone biosynthesis in his testes. The testosterone/DHT ratio after hCG loading, a test reported to be useful in the evaluation of 5-α-reductase-2 activity was within the normal range at 7.3:1 . These data imply that his androgen biosynthetic pathway was normal. The overwhelming majority of cases of hypospadias remain unexplained, particularly the milder forms. Genes have been implicated as a possible etiology for hypospadias. One of the candidate genes identified for the development of the male genitalia is MAMLD1. The mechanism by which MAMLD1 mutations induce hypospadias remains to be elucidated . Kalfa et al.  documented that the occurrence of an early nonsense codon in MAMLD1 is frequently associated with hypospadias.
Hypospadias occurs as an isolated defect or, less commonly, as a feature of numerous genetic syndromes. The isolated form is usually sporadic, however, familial occurrence has been reported. Hypospadias, which is often of variable degree, is not a consistent or pathognomonic feature in syndromic conditions .