Oksana Lekarev

Temporal lobe volume determined by magnetic resonance imaging in schizotypal personality disorder and schizophrenia.

The volumes of the whole temporal lobe, the superior temporal gyrus and the corpus callosum were measured on magnetic resonance images from 13 patients with schizotypal personality disorder (SPD), 27 patients with schizophrenia, and 31 age- and sex-matched controls. Temporal lobe structures were traced on consecutive 1.2mm thick SPGR images. Both patient groups had smaller temporal lobes than normal volunteers, a difference that was more marked for the area outside the superior temporal gyrus than for the STG. Correcting for brain volume diminished differences between normal subjects and schizophrenia patients, but the differences between normal subjects and SPD patients remained. Normal volunteers and SPD patients showed significant correlations between the sagittal section area of the posterior portion of the corpus callosum, which carries temporal interhemispheric connections, and the white matter volume of the temporal lobe. While the sample size is modest, taken together, these results suggest that the psychopathological symptoms of SPD may be related to temporal gray matter loss with relatively intact white matter connectivity, while the cognitive and psychotic symptoms of schizophrenia may be related to temporal gray loss combined with disruption of normal patterns of white matter development.

An Update on Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia causes genital ambiguity in females affected with the severe form of the disease; yet the abnormality is preventable with prenatal dexamethasone treatment that must be given to the mother before the ninth week of gestation. In the period from 1978 to March 2011 we have made prenatal diagnosis in 719 pregnancies. Our results indicate that the average Prader score of those fetuses treated with dexamethasone was 1.7, which is much lower than the average Prader score of 3.73 in those not treated. While our data demonstrate no significant abnormalities in the long-range medical and cognitive outcomes in patients prenatally treated with dexamethasone, the current protocol involves invasive procedures such as chorionic villus sampling or amniocentesis, and all fetuses are treated unnecessarily for several weeks before the sex and the affection status of the fetus is known. We are collaborating with Dr. Dennis Lo in Hong Kong to develop a noninvasive protocol, whereby at the sixth to seventh week of gestation we can determine the sex and the affection status of the fetus by harvesting fetal DNA from the maternal plasma. The method will eliminate invasive procedures and unnecessary prenatal treatment and bring noninvasive prenatal diagnosis to underdeveloped areas where amniocentesis and chorionic villus sampling are not available.

Final Adult Height in Children with Congenital Adrenal Hyperplasia Treated with Growth Hormone

CONTEXT Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency typically reach a final adult height well below their mid-parental target height. OBJECTIVE The objective of this study was to examine whether GH alone or in combination with an LHRH analog (LHRHa) improved the final adult height in patients with CAH. DESIGN The study was a nonrandomized prospective study. SETTING The study was conducted at two university hospitals in New York City, NY. PARTICIPANTS Thirty-four patients with CAH treated with GH participated in this study. Nineteen males and 15 females who were predicted to be more than 2 SD below their mid-parental target height or more than 2 SD below the population mean received GH until reaching final adult height. In addition to GH, 27 patients (16 males, 11 females) were also treated with an LHRHa. INTERVENTION The mean duration of GH treatment was 5.6 ± 1.8 yr in males and 4.5 ± 1.6 yr in females. The mean duration of LHRHa therapy was 3.7 ± 1.7 yr for both sexes. MAIN OUTCOME MEASURES The primary endpoint variables were final adult height, final height discrepancy, and gain in height. RESULTS Males reached a significantly higher final adult height (172.0 ± 4.8 cm) than their initial predicted height (162.8 ± 7.7 cm) (P < 0.00001). Females also reached a significantly higher final adult height (162.2 ± 5.3 cm) than initially predicted (151.7 ± 5.2 cm) (P < 0.0000001). Mean gain in height was 9.2 ± 6.7 cm in males and 10.5 ± 3.7 cm in females. CONCLUSION Our results indicate that GH alone or in combination with LHRHa improves final adult height in patients with CAH.

Adrenal disease in pregnancy

Adrenal disorders in pregnancy are relatively rare, yet can lead to significant maternal and fetal morbidity. Making a diagnosis is challenging as pregnancy may alter the manifestation of disease, many signs and symptoms associated with pregnancy are also seen in adrenal disease, and the fetal-placental unit alters the maternal endocrine metabolism and hormonal feedback mechanisms. The most common cause of Cushings syndrome in pregnancy is an adrenal adenoma, followed by pituitary etiology, adrenal carcinoma, and other exceedingly rare causes. Medical therapy of Cushings syndrome includes metyrapone and ketoconazole, but generally surgical treatment is more effective. Exogenous corticosteroid administration is the most common cause of adrenal insufficiency, followed by the endogenous causes of ACTH or CRH secretion. Primary adrenal insufficiency is least common. A low early morning cortisol <3 mcg/dL (83 mmol/L) in the non-stressed state and in the setting of typical clinical symptoms confirms the diagnosis. In the second and third trimester cortisol rises to levels 2-3 fold above those in the non-pregnant state, therefore a baseline level of <30 mcg/dL (823 mmol/L) warrants further evaluation. ACTH stimulated normal cortisol values have been established for each trimester. Hydrocortisone, which does not cross the placenta, is the glucocorticoid treatment of choice, and fludrocortisone is used as mineralocorticoid replacement in patients with primary disease. Congenital adrenal hyperplasia is an autosomal recessive disorder; 21-hydroxylase deficiency (21OHD) is the most common form of the disease. Non-classical 21OHD is most common, followed by the salt-wasting and simple virilizing forms. The treatment of choice for pregnant women affected with CAH is hydrocortisone, and fludrocortisones is added for those with the salt-wasting form of the disease. If the fetus is at risk for classical CAH, dexamethasone treatment can be used prenatally to prevent masculinization of the genitalia in a female infant. Because dexamethasone crosses the placenta, it should not be used to treat pregnant women with CAH if the fetus is not at risk for the disease.

Congenital adrenal hyperplasia patient perception of ‘disorders of sex development’ nomenclature

BackgroundAs the benefits of patient-centered care have become more widely recognized, it is important to understand patients’ sentiments regarding aspects affecting their care. In an effort to display more sensitivity to patient concerns, the term “disorders of sex development” (DSD) was proposed in 2006 as new nomenclature to replace older terms that were considered to have negative connotations.MethodsThe objective of the study was to examine the views of congenital adrenal hyperplasia (CAH) patients and their caregivers regarding the new nomenclature. The study was observational to evaluate the views of the CAH community, and the primary endpoint was perception of the term DSD. The study was conducted as a survey about views regarding DSD nomenclature. The survey was sent via email to eligible subjects. Along with a short introduction explaining the term DSD, the survey was sent to eligible CAH patients and their caregivers. 589 CAH patients or family members participated in the survey.ResultsA total of 589 responses were received (255 classical females, 104 non-classical females, 174 males, 56 not specified) (547 U.S., 42 international) (128 CAH patients, 408 parents or other family members). 70.6% had never heard the term DSD. 71.0% disliked or strongly disliked the term DSD. 83.6% stated they did not identify with the term DSD. 76.0% felt that the term DSD has a negative effect on the CAH community. There was no significant difference in opinion of DSD between classical females and other CAH patients, between US and international, between surgical and non-surgical patients, or between patients and parents. There was no correlation with patient age.ConclusionsOur results indicate that the majority of parents and patients with CAH are dissatisfied with the term DSD. Our results highlight the challenges within the field of DSD to reach a consensus regarding a sensitive topic and to bridge the gap between current medical practice and patient satisfaction. It is the authors’ belief that reconsideration of the current nomenclature and ongoing dialogue between the medical community and patients will eventually lead to removal of stigmatization, better management protocols, and improved outcomes.

Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

Abstract Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive genetic disorders that arise from defective steroidogenesis. The 21-hydroxylase deficiency (21OHD) is the most common form of CAH, accounting for more than 90% of cases. It is the most common disorder of sexual development (DSD) in females. The gene is encoded by CYP21A2, which is located on the short arm of chromosome 6 (6p21.3). The activity of the enzyme 21-hydroxylase, encoded by the CYP21A2 gene, is deficient, leading to an accumulation of 17-hydroxyprogesterone (17-OHP) and subsequent elevation of androgens. The three forms of 21OHD are the salt-wasting form, simple-virilizing form, and non-classical form. The first two forms are classical forms of the disease where the hallmark finding is ambiguity of the genitalia in affected female newborns. Patients with the non-classical form have normal genitalia, yet may present with signs of early sexual development and other symptoms of hyperandrogenemia such as short stature, hirsutism, acne, and impaired fertility. Hormonal testing is important in making the diagnosis of 21-hydroxylase deficiency, yet genetic testing is crucial to secure the diagnosis. More than 100 mutations have been identified caused by gene conversions, large scale gene deletions, and de novo mutations, and novel mutations are continuously being identified. Genotype–phenotype non-concordance is observed in a significant number of patients.

Infertility and Reproductive Function in Patients with Congenital Adrenal Hyperplasia Pathophysiology, Advances in Management, and Recent Outcomes

Individuals with congenital adrenal hyperplasia have reduced fertility. However, reproductive outcomes have improved over the years. This review provides an update on the multiple pathologic processes that contribute to reduced fertility in both sexes, from alterations of the hypothalamic-pituitary-gonadal axis to the direct effect on gonadal function by elevated circulating adrenal androgens. In addition, elevated serum progesterone concentrations may hinder ovulation and embryo implantation in women, whereas in men testicular adrenal rest tumors can be a major cause of infertility. Suppression of adrenal androgen secretion represents the first line of therapy toward spontaneous conception in both sexes.

Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment. Conclusion: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.

Atypical Presentation and Novel StAR Protein Gene Mutation in a 46,XY Female with Lipoid Congenital Adrenal Hyperplasia

Congenital lipoid adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis and is the most severe form of congenital adrenal hyperplasia. It is an autosomal recessive disorder caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. The StAR protein facilitates the entry of cholesterol into the mitochondria. When this protein is defective, cholesterol cannot be converted to pregnenolone, and hence steroidogenesis cannot be initiated. Eventually all adrenal and gonadal steroidogenesis is destroyed. Patients usually present with adrenal salt-wasting crisis in the first 2 months of life. Those with a 46,XY karyotype have complete sex reversal; however, the phenotype can be variable. Adrenal insufficiency has been reported to occur later in life and patients can have partially virilized or even normal male genitalia. We report an atypical female patient with a 46,XY karyotype, who had mild genital virilization and presented with adrenal crisis at 6 months of age. She carries a previously unreported StAR protein gene mutation.

Growth Hormone Therapy to Improve Adult Height in Patients with Congenital Adrenal Hyperplasia

Abstract Many patients with congenital adrenal hyperplasia (CAH) do not reach a final adult height within their parentally determined target height range. Our group has reported the effect of growth hormone (GH) alone or in combination with luteinizing hormone releasing hormone analog (LHRHa) on final adult height in 34 patients with CAH. Final adult height was significantly higher than baseline predicted height in both males (172.0 + 4.8 cm versus 162.8 + 7.7 cm, P