Five patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (one with associated neuroblastoma) discovered in three generations of one family.

BACKGROUND: Most patients with 21-hydroxylase deficiency (21-OHD) are compound heterozygous carriers. Their phenotype usually reflects a less severe allelic mutation, although discordance between the genotype and the phenotype has been observed. CASE REPORT: We present 5 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD belonging to the 3 generations of the same family (grandmother, parents and their 2 children). As each patient carries at least one mild mutation of the CYP21 gene, their genotypes correspond to nonclassical CAH. The propositus is the older brother, who is compound heterozygous with a mild and severe CYP21 mutation (P30L/R356W). In spite of one mild CYP21 mutation, he presented with the clinical picture of a simple virilizing form of 21-OHD and required glucocorticoid replacement therapy from the age of 4. Both probands' parents are compound heterozygous carriers of different CYP21 gene mutations causing various degrees of enzymatic activity impairment, which explains the different genotypes and phenotypes in their offspring. The probands' mother, besides the nonclassical 21-OHD, also had neuroblastoma of the adrenal gland. CONCLUSION: The potential discordance between the genotype and the phenotype in some patients with CAH is emphasized. The existence of a mild CYP21 mutation P30L in a compound heterozygous with CAH might be associated with progressive virilization requiring glucocorticoid therapy from early childhood. The occurrence of neuroblastoma with 21-OHD may support the hypothesis that an impairment in the synthesis and secretion of glucocorticoids may play role in the development and functioning of the adrenal medulla.

[Primary pigmented nodular adrenocortical disease as cause of Cushing's syndrome associated with Carney complex]. / Primarna pigmentna nodularna adrenokortikalna bolest kao uzrok Cushingova sindroma u sklopu Carneyeva kompleksa.

We report a 11-year-old girl and two 14-year-old boys with Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In these patients, hypercortisolism is a consequence of autonomous cortisol secretion from adrenal glands and is ACTH-independent. Besides PPNAD, the girl had lentigines, spotty pigmentation on her bucal mucosa and lips and she also had schwannoma. One of the reported boys had prolactinoma. Considering this, those two patients fulfill the criteria for Carney complex which is a type of multiple endocrine neoplasia syndromes inherited in an autosomal dominant trait. The other boy had PPNAD but no other obvious signs of Carney complex were noticed. Family study didn't reveal any clinical or laboratory signs of Carney complex in our patients' first relatives. All of our patients underwent bilateral adrenalectomy (in one of the boys laparoscopic surgery was performed). Glucocorticoid and mineralocorticoid substitution has been started. Adrenal glands were macroscopically normal but pathohistological analysis confirmed the diagnosis of PPNAD.

Nonclassic 21-hydroxylase deficiency in Croatia.

This is the first report of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency in Croatia in which the patients have been evaluated clinically, hormonally, and by molecular genetic analysis. Genetic analysis was performed on 18 Croatian patients with nonclassic CAH due to 21-OH deficiency using allele-specific PCR. ACTH stimulation testing and HLA typing were used to evaluate patients hormonally. Molecular genetic analysis revealed a variety of mutations in individuals with different clinical symptoms, including precocious pubarche, hirsutism, (dysmenorrhea, subfertility and clitoromegaly. Serum stimulated 17-hydroxyprogesterone (17-OHP) levels indicated that all patients fell within the acceptable range for nonclassic congenital adrenal hyperplasia. Clinical and genetic analysis confirmed nonclassic 21-OH deficiency in our Croatian sample of ten males and eight females. This study shows that genotype does not necessarily predict fertility status in our group of affected patients.

[X-linked adrenoleukodystrophy--case reports of 4 patients in a family]. / X-vezana adrenoleukodistrofija--prikaz obitelji s cetiri bolesnika.

A result of a thorough clinical and laboratory study of 27 family members from three generations showed three patients with adrenoleukodystrophy (ALD), one with adrenomyeloneuropathy (AMN) and five females heterozygous for ALD, three of which were psychiatric patients. Four males died at younger age under mysterious circumstances and it is certain that three of them had dark pigment. Based on this information, and on their position in the family tree, it can be presumed that all of them, or three at least, had ALD or AMN. It is necessary to measure very long chain fatty acids level (VLCFA) in the blood of males with Addison's disease in families with ALD or AMN cases, as well as in persons showing signs of demyelinization of white substance followed by progressive neurological symptomatology of unknown cause. All the ALD and AMN patients detected up to now were diagnosed at the Department of Pediatrics, University Hospital Rebro Zagreb. It undoubtedly indicated that there are still a significant number of undetected cases among children and adults in Croatia. In view of the recently provided possibilities of VLCFA level measurements in Croatia, a larger number of detected cases can be expected. Early detection of patients and heterozygotes for ALD, as well as the prenatal diagnostics, enable the families at risk to plan their descendants. Adrenal insufficiency in these patients is very successfully cured with gluco and mineralcorticoid substitution therapy. Unfortunately, there are still no methods of stopping or curing progressive neurological disorders.