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Thalassemia major (beta-thalassemia) affects a significant segment of the population in certain areas of the world. Alterations in migration patterns have changed the geographic distribution of this disease and made it a worldwide health problem. Over the course of the past 2-3 decades hypertransfusion therapy has significantly increased the life expectancy, and improved the quality of life of these patients. At the same time there has been an increase in the frequency of complications of this therapy caused by iron overload. Endocrine gland abnormalities contributed little to the morbidity or mortality of beta-thalassemia in the past. As a result of hypertransfusion therapy and increased longevity, however, endocrinopathies have become more common and contribute significantly to morbidity in these patients. In this article we briefly review the current understanding of endocrine gland abnormalities, primarily caused by iron overload, in patients with thalassemia major.

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The G of the CHARGE association represents genital hypoplasia, which is typically recognized only in males (micropenis/cryptorchidism). The cause of genital hypoplasia in this disorder has not been determined. We now report the cases of nine individuals with CHARGE association and hypogonadotropic hypogonadism, manifested by hypogenitalism and gonadotropins at or below minimal detectable levels at ages when these hormones should be readily measurable. We suggest that central hypogonadism is responsible not only for the genital hypoplasia in male patients but also for the lack of secondary sexual development in patients of both sexes. Since hypogonadotropic hypogonadism appears to be the usual cause of genital and pubertal abnormalities in CHARGE association, measurement of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations in infants up to 2-3 months of age who are suspected of having this disorder could help establish the diagnosis. Determination of serum LH and FSH concentrations in teenagers with CHARGE association could result in early diagnosis of hypogonadotropic hypogonadism, allowing for treatment of hormonal deficiencies and minimization of potential secondary psychosocial and medical problems.

Adrenoleukodystrophy, a sex-linked peroxisomal disorder that results in the impaired oxidation of long-chain saturated fatty acids and causes neurologic impairment, is a rare cause of Addison's disease in children. Adrenomyeloneuropathy is the name given to a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy that affects young adults, in whom adrenal insufficiency may long precede nervous system dysfunction. The transmission of adrenomyeloneuropathy, like that of most cases of adrenoleukodystrophy, is sex-linked. Because of a preponderance of male patients among a group of patients with the onset of adrenal failure in childhood, we questioned whether this condition might be the initial manifestation of adrenomyeloneuropathy. We therefore measured the plasma concentrations of very-long-chain saturated fatty acids in eight patients with adrenal insufficiency; of these, five had elevated plasma hexacosanoic acid concentrations (range, 2.42 to 6.43 mumol per liter; mean normal level [+/- SD], 0.83 +/- 0.45), confirming the presence of adrenomyeloneuropathy. Magnetic resonance imaging showed clear evidence of brain involvement in all five patients. Reexploration of the family histories revealed additional missed cases. We conclude that the possibility of adrenomyeloneuropathy should be considered in any boy with Addison's disease.

Recent studies indicate that mutations in the androgen receptor gene are associated with androgen insensitivity syndromes, a heterogeneous group of related disorders involving defective sexual differentiation in karyotypic males. In this report, we address the possibility of rapid mutational analysis of the androgen receptor gene for initial diagnosis, genetic counseling, and molecular subclassification of affected patients and their families. DNA from peripheral blood leukocytes of six patients from five families with various degrees of androgen insensitivity was studied. Exons 2 to 8 of the androgen receptor gene were analyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also studied to identify heterozygote carriers. Point mutations in the AR gene were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. Our data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome. Molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy, and can provide a basis for distinguishing heterozygous carriers in familial androgen resistance. The identification of carriers is of substantial clinical importance for genetic counseling.

Summary Introduction Mutations in the transcription factor HESX1 can cause Isolated Growth Hormone Deficiency (IGHD) or Combined Pituitary Hormone Deficiency (CPHD) with or without Septo-Optic Dysplasia (SOD). So far there is no clear genotype-phenotype correlation. Patients and Results We report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH. Conclusion These three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.

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