Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism.

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Genetic Counseling and Prenatal Diagnosis of Triploidy During the Second Trimester of Pregnancy.

INTRODUCTION: Triploidy is a lethal chromosomal numeric abnormality, characterized on extra haploid set of chromosomes. It occurs in 2 to 3% of conceptuses and accounts for approximately 20% of chromosomally abnormal first-trimester miscarriages. As such, triploidy is estimated to occur in 1 of 3,500 pregnancies at 12 weeks', 1 in 30,000 at 16 weeks', and 1 in 250,000 at 20 weeks' gestation. CASE REPORT: We present a case of second-trimester triploidy diagnosed prenataly at our center. 28-years-old gravida with a first spontaneous pregnancy had early gestational hypertension. Ultrasound examination in 146/7 weeks' gestation revealed asymmetric intrauterine growth retardation. We recommended biochemical maternal serum screening during second trimester of pregnancy (AFP, HCG, uE3). Result of biochemical screening was indication for cytogenetic analysis from amniotic fluid cells and we recommended early amniocentesis in 156/7 weeks' gestation. Result showed abnormal karyotype of the fetus (69,XXX triploidy), and DNA analysis confirmed Type-2 Diginy. Parents decided to terminate this pregnancy, and it was done at 22 weeks' gestation. CONCLUSION: We emphasize the importance of non-invasive prenatal exminationes-biochemical serum screening during second trimester of pregnancy, and ultrasound examinations in prenatal screening of syndroma Down and other chromosomal abnormalities.

Novel patched 1 mutations in patients with nevoid basal cell carcinoma syndrome--case report.

Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare autosomal dominant disorder characterized by numerous basal cell carcinomas, keratocystic odontogenic tumors of the jaws, and diverse developmental defects. This disorder is associated with mutations in tumor suppressor gene Patched 1 (PTCH1). We present two patients with Gorlin syndrome, one sporadic and one familial. Clinical examination, radiological and CT imaging, and mutation screening of PTCH1 gene were performed. Family members, as well as eleven healthy controls were included in the study. Both patients fulfilled the specific criteria for diagnosis of Gorlin syndrome. Molecular analysis of the first patient showed a novel frameshift mutation in exon 6 of PTCH1gene (c.903delT). Additionally, a somatic frameshift mutation in exon 21 (c.3524delT) along with germline mutation in exon 6 was detected in tumor-derived tissue sample of this patient. Analysis of the second patient, as well as two affected family members, revealed a novel nonsense germline mutation in exon 8 (c.1148 C>A).

Accessory scrotum attached to a peduncular perineal lipoma.

In this study, we report on the case of a newborn boy diagnosed after birth with an accessory scrotum attached to a peduncular type of perineal lipoma without any other associated congenital anomalies. The neonate underwent a simple surgical excision of the lipoma and accessory scrotum in the first month of life, and his postoperative course was uneventful. Histologic examination revealed normal scrotal skin and adipose tissue. Accessory scrotum has a high incidence of association with perineal lipoma (83% of reported cases) and other urogenital and anorectal anomalies, but urogenital or anorectal anomalies were not seen in our patient.

Characteristics and quality of life of substance users and their caregivers.

The correlation between substance use and depression has been emphasized in the literature. Substance use disorders can also adversely affect the caregivers of drug-addicted persons. A cross-sectional study was conducted at the Special Hospital for Addiction Diseases in Belgrade in 2015 to analyze the characteristics, consequences, and health-related quality of life of drug users and their caregivers. The sample comprised 136 users of various substances, and 136 caregivers. A questionnaire on socio-demographic characteristics, the Short Form Health Survey 36 (SF-36), and Beck Depression Inventory were administered to all participants. According to multivariate logistic regression analysis, compared with caregivers, substance users were significantly more frequently male (P < .001), ≤ 39 years old (P < .001), and more frequently reported the use of sedatives (P = .009) and smoking (P < .001). Some level of depression was present in all participants, but severe forms were more frequent in substance users (P = .010). Among substance users, mean scores of SF-36 domains ranged from 56.62‒87.17, and among their caregivers, from 50.37‒75.07; however, the difference was significant only for the health change domain (P = .037), the score for which was lower in caregivers. Substance users suffered from more severe forms of depression compared to their caregivers, who had lower SF-36 scores in the domain of health change.

[Idiopathic short stature].

Growth is a complex process and the basic characteristic of childhood growth monitoring provides insight into the physiological and pathological events in the body. Statistically, the short stature means departure from the values of height for age and sex (in a particular environment), which is below -2 standard deviation score, or less than -2 standard deviation, i.e. below the third percentile. Advances in molecular genetics have contributed to the improvement of diagnostics in endocrinology. Analysis of patients' genotypes should not be performed before taking a classical history, detailed clinical examination and appropriate tests. In patients with idiopathic short stature specific causes are excluded, such as growth hormone deficiency,Turner syndrome, short stature due to low birth weight, intrauterine growth retardation, small for gestational age, dysmorphology syndromes and chronic childhood diseases. The exclusion of abovementioned conditions leaves a large number of children with short stature whose etiology includes patients with genetic short stature or familial short stature and those who are low in relation to genetic potential, and who could also have some unrecognized endocrine defect. Idiopathic short stature represents a short stature of unknown cause of heterogeneous etiology, and is characterized by a normal response of growth hormone during stimulation tests (>10 ng/ml or 20 mJ/I), without other disorders, of normal body mass and length at birth. In idiopathic short stature standard deviation score rates <-2.25 (-2 to -3) or <1.2 percentile. These are also criteria for the initiation of growth hormone therapy. In children with short stature there is also the presence of psychological and social suffering. Goals of treatment with growth hormone involve achieving normal height and normal growth rate during childhood.

Autism and hypoplastic corpus callosum in a case of monocentric marker chromosome 15.

An 8-year-old boy was diagnosed with autism, along with development delay, seizures, and hypoplastic corpus callosum. His karyotype was 47, XY, +mar.ish (15) (D15Z1+, SNRPN+, GABRB3+, PML-(de novo?). The supernumerary marker chromosome 15 with euchromatin was monosatellited and monocentric. Although autism, seizures, and mental and developmental retardation are not rare in association with a dicentric, bisatellited supernumerary marker chromosome 15, the present case is novel for a monocentric, monosatellited supernumerary marker chromosome 15 and the additional feature of hypoplastic corpus callosum. The present case provides support for the hypotheses that additional copies of different segments of proximal 15q are related to autism and to malformations of corpus callosum.

[Congenital adrenal hyperplasia due to 21 hydroxylase deficiency--case report].

A girl with congenital adrenal hyperplasia due to 21 hydroxylase (CYP 21, p450c21) deficiency is the reviewed case. The clinical features (virilisation, clitoromegaly, rapid somatic growth, accelerated skeletal maturation) and laboratory findings (high levels of plasma 17hydroxy-progesterone, corticotrophin--ACTH, testosterone and dehydroepiandrostenedione--DHEA, low level of plasma cortisol, high level of urine 17-ketosteroids, synacthen and luteinising hormone releasing hormone--LHRH test) and the response to hydrocortisone therapy pointed at heterosexual gonadotrophin independent puberty due to irregular production of cortisol caused by 21 hydroxylase deficiency that leads to elevated ACTH and 17-hydroxy progesterone secretion and makes congenital adrenal hyperplasia as entity. The six-month therapy resulted in the clinical and laboratory findings improvement, such as the decreased annual growth of body height and the stagnation in the development of the secondary sexual features.

[The results of cytogenetic analyses in prenatal diagnosis].

INTRODUCTION: G-banding and other classical cytogenetic methods are still in use, together with molecular cytogenetic techniques such as FISH (Fluorescence In Situ Hybridization) and SKY (Spectral Karyotyping). MATERIAL AND METHODS: This retrospective study evaluated clinical data on individuaols seeking genetic counseling over a 15-year period (1992 - 2007) at the Medical Genetic Center, Child and Youth Health Care Institute of Vojvodina in Novi Sad. The study included 37.191 genetic counselings, and 20.607 prenatal analyses (amniocentesis and cordocentesis). RESULTS: Over a 15-year period (1992 - 2007) 17.937 amniotic fluid samples were analyzed and 274 abnormal karyotypes were found; out of 2.670 fetal blood samples, there were 78 abnormal karyotypes. During a 15-year period, prenatal diagnosis, using amniocentesis and/or cordocentesis, showed 352 fetuses with chromosomal aberrations. DISCUSSION: On average, over the past 15-year period, 8% of pregnancies were controlled with invasive prenatal procedures. The percentage has changed; in fact, it is increasing from year to year. In 1992, only 0.82% (N=139/17000) of pregnant women in Vojvodina underwent invasive prenatal procedures, and in 2006 the rate increased to 15.65% (N=2660/17000). CONCLUSION: It is necessary to improve and promote the possibilities of genetic counseling and invasive prenatal diagnosis in order to prevent the occurrence of chromosomal aberrations and other genetic diseases.