Adrenal hypoplasia

The genetic defects for two of the more common X-linked subtypes of IHH, congenital IHH with anosmia (or Kalhnann syndrome, KS), and IHH with adrenal insufficiency (adrenal hypoplasia congenita) are distinct from the forms of the disease caused by GnRH receptor (GnRHR) mutations. These forms of IHH are included for the sake of clarity. 

The KS mutations were identified in the KAL gene and result in abnormal olfactory bulb development (99,100). The mutations responsible for the X-linked IHH with adrenal hypoplasia congenita were identified in the DAXl gene. DAXl encodes an orphan nuclear hormone receptor that regulates portions of reproductive development (101,102). 

Habiby, R. L., Boepple, P., NachtigaU, L., Sluss, P. M., Crowley, W. F., and Jameson, J. L. (1996) Adrenal hypoplasia congenita with hypogonadotropic hypogonadism—evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. J. Clin. Invest. 98, 1055-1062. 

Infants with salt-losing crisis and adrenal insufficiency in infancy may have adrenal hypoplasia congenita. This can be of two types recessive, for which the cause has not been defined and which affects mostly the fetal zone, and X-linked, which is caused by mutations in the DAX-1 gene, which (with steroidogenic factor-1) controls definitive zone development and steroidogenesis [71]. GC-MS analysis of patients with the disorder show variant patterns from absence of neonatal A5 steroids, appropriate for the recessive form [81], to extremely low cortisol production and transient 11/Lhy-droxylase deficiency, as evidenced through increased THS excretion (Malunowicz, personal communication). 

Fujieda K, Okuhara K, Abe S, Tajima T, Mukai T, Nakae J (2003) Molecular pathogenesis of lipoid adrenal hyperplasia and adrenal hypoplasia congenita. J Steroid Biochem Mol Biol 85 483-489... 

Reutens AT, Achermann JC, Ito M, Ito M, Gu W-X, Habiby RL, Donohoue PA, Pang S, Hind-marsh PC, Jameson JL (1999) Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab 84 504-511... 

Adrenal hypoplasia Glycerol kinase deficiency Chronic granulomatous disease Retinitis pigmentosa-3 Duchenne muscular dystrophy Becker muscular dystrophy... 

Hemochromatosis Adreiioleukodystrophies Congenital adrenal hypoplasia ACTH resistance syndromes HIV... 

F. Muscatelli, T. M. Strom, A. P. Walker, and others Mutations in the DAXC-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadtropic hypogonadism. Nature 372, 672 (1994). 

Cortisol and cortisone have been identified and assayed in cord blood by several groups (B37, H9, J3, U4, Table 5), and the implications of the results have been discussed in Section 4.2.3. Little information is available on the concentration in abnormal infants. Cathro and Coyle (C4) found a low level of cortisol in an infant with congenital adrenal hypoplasia (3.3, ag/100 ml), and James (J3) measured the concentration of cortisol and cortisone in the cord blood of two infants born to mothers with acute adrenal insufficiency. The compounds must have been formed almost entirely by the fetus since negligible quantities of cortisol were found in the maternal blood. The low levels of cortisol (2.5 /ig/100 ml) and cortisone (4 /ng/100 ml) found for these fetuses is difficult to explain unless they represent the true levels of the steroids in the fetoplacental circulation, which are normally boosted by transfer from the mother during the stress of childbirth (see Section 4.2.3). 

Table 16 shows the major points of interest in patients with these abnormalities they will be discussed in the order congenital adrenal hyperplasia, congenital adrenal hypoplasia, and hypoaldosteronism. 

Congenital adrenal hypoplasia All steroid-forming mechanisms Not known (low maternal estriol excretion prior to delivery) Low ... 

Acute adrenal insufficiency in infancy may be due to congenital adrenal hypoplasia. This may be in association with hypoplasia or absence of the pituitary gland (B20, B35, E7, M19, Rl) or as isolated congenital adrenal hypoplasia (B33, C4, M17, R15). 

Cathro and Coyle (C4) have described the second pregnancy of a woman who had already given birth to an infant with adrenal hypoplasia. The first infant died of respiratory failure 18 hours after birth and postmortem examination revealed very small adrenal glands but no other detectable endocrine abnormality. During the latter part of the second pregnancy, the maternal estriol excretion was low (1 mg/24 hours), an expected finding since 16a-OH-DHA produced by the fetus is an important precursor of estriol (D6, D9) (Section 4.1.1.). Evidence for adrenocortical insufficiency in the infant was obtained from the low level of cortisol in the umbilical cord blood. The infant was satisfactorily treated at birth with steroid therapy. 

The first indication of possible adrenal hypoplasia in an infant studied by the authors was the finding of an abnormally low level of estriol in plasma obtained from the mother prior to delivery. The urinary excretion of 16a-OH-DHA, 16-oxo-androstenediol, and 16a-OH-pregnenolone was only about one-tenth that expected for normal newborn infants. This infant died of respiratory failure 30 hours after birth postmortem examination showed very small adrenal glands. 

Adrenal cortical hypoplasia in two male siblings, who both died in the neonatal period, has been reported by Boyd and McDonald (B33). Mitchell and Rhaney (M17) also observed two male siblings with adrenal hypoplasia, one died at the age of 2 months and the second was treated successfully with fiuorocortisol. 

E7. Ehrlich, R, M, Ectopic and hypoplastic pituitary with adrenal hypoplasia. J. Pediat. 51, 377-384 (1957). 

E. R. B. McCabe Adrenal hypoplasias and aplasias. The Metabolic and Molecular Bases of Inherited Disease. 8th Edition. C. R. Scriver, A. L. Beaudet, W. S. Sly, D. Valle, B. Childs, and B. Vogelstein, editors. New York McGraw-Hill, 2001. 

E. Zanaria, F. Muscatelli, B. Bardoni, T. M. Strom, S. Guioli, W. Guo, E. Lalli, C. Moser, A. P. Walker, E. R. B. McCabe, T. Meitinger, A. P. Monaco, P. Sassone-Corsi, and G. Camerino An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372 635-641, 1994. 

E. R. B. McCabe, J. Towbin, J. Chamberlain, L. Baumbach, J. Witkowski, G. J. B. van Ommen, M. Koenig, L. M. Kunkel, and W. K. Seltzer Complementary DNA probes for the Duchenne muscular dystrophy locus demonstrate a previously undetectable deletion in a patient with dystrophic myopathy, glycerol kinase deficiency and congenital adrenal hypoplasia. J Clin Invest 83 95-99, 1989. 

AdrenalInsufGclency. Low excretion of glucocorticoid metabolites and adrenal androgen metabolites characterize the steroid profile. However, the different causes (Addison s disease, lipoid adrenal hyperplasia, and congenital adrenal hypoplasia) cannot be differentiated using urinary steroid profiling. 

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