[Aphallia - report of two cases]. / Aphallie ­ zwei Fallbeispiele.

Aphallia is an extremely rare congenital malformation of unknown cause. The incidence is reported in the literature to be 1 in 10-30 million live births. Almost 100 cases have been described to date. Aphallia is associated with other congenital malformations (in particular urogenital and gastrointestinal anomalies) in >50% of cases. The diagnosis is made clinically and shows the complete absence of the corpora cavernosa and the corpus spongiosum with a urethral opening along the perineal midline (most frequently ventral to the anus and in the ventral rectal wall). Two case reports from the authors' department: The first child was a male newborn (46,XY) with penis agenesis and additional bilateral intraabdominal testis, an anorectal malformation (ARM) with a rectovesical fistula, as well as left renal duplication and grade III vesico-ureteral reflux on the right side. The second child was a male newborn (46,XY) with aphallia without further urological or anorectal malformation. Only right inguinal hernia was present. In the first patient, several corrective surgeries were performed in the further course in view of the additional malformations. With regard to the aphallia, the various temporary treatment options (scrotal or parascrotal phalloplasty or penis prosthesis) were discussed with the parents. Masculinizing surgery by means of definitive phalloplasty was planned once the patient has reached puberty. Due to the technical demands of phallus reconstruction, feminization is still favored in some countries in the literature, which nowadays, however, cannot be justified medically or legally.

Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2.

Partial duplications of the long arm of chromosome 3, dup(3q), are a rare but well-described condition, sharing features of Cornelia de Lange syndrome. Around two thirds of cases are derived from unbalanced translocations, whereas pure dup(3q) have rarely been reported. Here, we provide an extensive review of the literature on dup(3q). This search revealed several patients with caudal malformations and anomalies, suggesting that caudal malformations or anomalies represent an inherent phenotypic feature of dup(3q). In this context, we report a patient with a pure de novo duplication 3q26.32-q27.2. The patient had the clinical diagnosis of Currarino syndrome (CS) (characterized by the triad of sacral anomalies, anorectal malformations and a presacral mass) and additional features, frequently detected in patients with a dup(3q). Mutations within the MNX1 gene were found to be causative in CS but no MNX1 mutation could be detected in our patient. Our comprehensive search for candidate genes located in the critical region of the duplication 3q syndrome, 3q26.3-q27, revealed a so far neglected phenotypic overlap of dup(3q) and the Pierpont syndrome, associated with a mutation of the TBL1XR1 gene on 3q26.32.

Clinical and diagnostic approach in unsolved CDG patients with a type 2 transferrin pattern.

Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999-2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect. Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability.

A case of 11beta-hydroxylase deficiency detected in a newborn screening program by second-tier LC-MS/MS.

BACKGROUND/AIM: 21-Hydroxylase deficiency congenital adrenal hyperplasia (CAH) is one of the target diseases in many newborn screening programs. 11beta-Hydroxylase defiency is less frequent and does not cause salt-losing crisis. Thus, it is not a target disease for newborn screening. However, affected newborns might show slightly elevated levels of 17-OH-progesterone (17-OHP) in the standard immunoassay screening test. The objective is to show that the diagnosis of 11beta-hydroxylase deficiency can be done using a dried blood spot from newborn screening. CASE REPORT: A male newborn was born at term. Blood sample for newborn screening was taken 36 h after birth. 17-OHP was slightly elevated using time-resolved fluorescence immunoassay (72.8 nmol/l; cut-off <60 nmol/l). RESULTS: We performed second-tier LC-MS/MS from the same blood sample and found elevated levels of 11-deoxycortisol and androstenedione and low cortisol. The family history was positive with an affected older sister born with ambiguous genitalia. Confirmation of diagnosis was done by hormonal analysis and molecular genetic testing of the CYP11B1 gene. A known CYP11B1 gene mutation W116C was identified in this family. CONCLUSIONS: The diagnosis of 11beta-hydroxylase deficiency can be made by second-tier LC-MS/MS from dried blood spots. This method is very helpful in the work-up of elevated immunoassay 17-OHP.

Molecular features and clinical phenotypes in androgen insensitivity syndrome in the absence and presence of androgen receptor gene mutations.

Androgen insensitivity syndrome (AIS) is characterized by deficient or absent virilization in 46,XY individuals despite normal or even elevated androgen levels. AIS is usually caused by mutations in the androgen receptor (AR) gene. We aimed at contrasting clinical, biochemical, and molecular genetic characteristics of three patients (P1-P3) with clinically evident partial (P1) and complete (P2, P3) AIS with and without AR gene mutations. AR expression was studied in cultured genital skin fibroblasts (GSF) by Western immunoblotting, ligand binding analyses, Northern blotting, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), and RT-PCR spanning exons 1-8. AR gene DNA sequence was analyzed by single-strand conformation analysis (SSCA), and DNA sequencing. GSF revealed reduced (P1) or absent (P2, P3) ligand binding. Northern blots showed either slightly reduced hybridization of the 10.5-kb AR transcript (P3) or no hybridization (P1, P2), as confirmed by semiquantitative RT-PCR. RT-PCR spanning exons 1-8 detected single AR mRNA bands in P1-P3 excluding splicing errors. Western analyses showed either low (P1) or no (P2, P3) AR protein. While SSCA initially did not reveal any molecular abnormality, sequencing showed a novel CAG (Gln) to TAG (stop) mutation at codon 59 (P3) and a previously described 2-bp deletion at codon 472, leading to a frameshift and premature stop in codon 499 (P2). Intriguingly, P1 showed an unaltered DNA sequence of the coding region of the AR gene including all intron-exon boundaries. In conclusion, patients with clinically evident complete AIS are likely to harbor an AR gene mutation, demanding that the two polymorphic regions must always be included in molecular analyses of the AR gene. Moreover, our data support the concept that in a subset of AIS patients, particularly those with partial AIS, molecular alterations outside the coding region of the AR gene must be presumed.

Novel insertion frameshift mutation of the LH receptor gene: problematic clinical distinction of Leydig cell hypoplasia from enzyme defects primarily affecting testosterone biosynthesis.

Leydig cell hypoplasia (LCH) is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals and is caused by inactivating mutations of the LH receptor gene. The clinical and biochemical diagnostic parameters of LCH are not always specific and may therefore show significant overlap with other causes of insufficient testicular steroid biosynthesis. We have studied a 46,XY newborn with completely female external genitalia and palpable testes. Due to an increased basal serum ratio of androstenedione/testosterone, 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD 3) deficiency was initially suspected. DNA analysis of the corresponding HSD17B3 gene, however, showed no abnormalities in the entire coding region. In contrast, direct sequencing of the LH receptor gene revealed a novel homozygous single nucleotide insertion in exon 11 (codon A589fs) producing a frame shift in the open reading frame predicting for premature termination of translation 17 amino acids downstream. From the genetic perspective, this mutation represents the first frame shift mutation in the LH receptor gene ever reported to date. From the clinical standpoint, LCH should always be considered in the differential diagnosis as steroid profiles may not be informative. Therefore, molecular genetic analysis should be warranted for androgen biosynthesis defects in all cases.

Childhood asthma knowledge among first year nursing students in three European cities.

BACKGROUND: There are no available studies that assess and compare knowledge of childhood asthma among subjects living in different European countries. The objective of this study was to determine knowledge of childhood asthma among first year nursing students during the first week of their training in three European countries. The participants' sources of information and other factors that might influence their asthma knowledge score (AKS) were also evaluated. METHODS: Cross-sectional design using a modified version of a previously validated questionnaire. The study was undertaken in 261 students in Cartagena (Spain), 202 in Manchester (UK) and 94 in Cologne (Germany). RESULTS: AKS (maximum score, 27) was significantly higher in students from Manchester (18.3 +/- 2.6) than in those from Cartagena (15.9 +/- 3.1) and Cologne (15.1 +/- 3.6). In all three cities, more than 70 % of the students answered 10 out of the 27 questions correctly. Knowledge of asthma relievers or preventers was very limited. AKS showed a positive but marginal correlation with student age (r = 0.11, p = 0.07). Only knowledge gained from personal experience was significantly associated (r = 0.27, p < 0.001) with AKS. CONCLUSIONS: This study provides valuable new information about the variations, sources and factors that influence knowledge of asthma among educated individuals living in three European countries. The better AKS of Manchester students might be due to the higher prevalence of asthma in the UK.

Childhood asthma knowledge among first year nursing students in three european cities

Background: There are no available studies that assess and compare knowledge of childhood asthma among subjects living in different European countries. The objective of this study was to determine knowledge of childhood asthma among first year nursing students during the first week of their training in three European countries. The participants' sources of information and other factors that might influence their asthma knowledge score (AKS) were also evaluated. Methods: Cross-sectional design using a modified version of a previously validated questionnaire. The study was undertaken in 261 students in Cartagena (Spain), 202 in Manchester (UK) and 94 in Cologne (Germany). Results: AKS (maximum score, 27) was significantly higher in students from Manchester (18.3 +/­2.6) than in those from Cartagena (15.9 +/­3.1) and Cologne (15.1 +/­3.6). In all three cities, more than 70 % of the students answered 10 out of the 27 questions correctly. Knowledge of asthma relievers or preventers was very limited. AKS showed a positive but marginal correlation with student age (r = 0.11, p = 0.07). Only knowledge gained from personal experience was significantly associated (r = 0.27, p < 0.001) with AKS. Conclusions: This study provides valuable new information about the variations, sources and factors that influence knowledge of asthma among educated individuals living in three European countries. The better AKS of Manchester students might be due to the higher prevalence of asthma in the UK (AU)

Información preliminar: No se dispone de estudios que hayan evaluado y comparado el conocimiento del asma infantil entre sujetos residentes en distintas ciudades europeas. El objetivo de este estudio era determinar el conocimiento del asma infantil entre estudiantes de primer curso de enfermería durante la primera semana de su formación en tres ciudades europeas. También se evaluaron las fuentes de información de los participantes y otros factores que podrían haber influido en su puntuación de conocimiento del asma (PCA). Métodos: Diseño transversal utilizando un cuestionario modificado validado previamente. El estudio se llevó a cabo con 261 estudiantes de Cartagena (España), 202 de Manchester (RU) y 94 de Colonia (Alemania). Resultados: La PCA (puntuación máxima, 27) fue significativamente mejor en los estudiantes de Manchester (18,3 +/-2,6) que en los de Cartagena (15,9 +/-3,1) o Colonia (15,1 +/-3,6). Más del 70 por ciento de los estudiantes de las tres ciudades respondieron correctamente a 10 de las 27 preguntas. Los conocimientos sobre los fármacos para paliar o prevenir el asma eran muy limitados. La PCA reveló una correlación positiva pero débil con la edad de los estudiantes (r = 0,11, p = 0,07). Sólo se asociaron significativamente a la PCA los conocimientos adquiridos a partir de la experiencia personal (r = 0,27, p < 0,001). Conclusiones: Este estudio proporciona nueva información de valor sobre las variaciones, las fuentes y los factores que influyen en el conocimiento del asma entre sujetos con estudios residentes en tres países europeos. La mayor prevalencia del asma en el Reino Unido podría justificar la mejor PCA de los estudiantes de Manchester (AU)

Impaired autonomic control of the heart by SOX10 mutation.

The autonomic nervous system plays an important role in the generation of complex heart rate dynamics that enable an organism to adapt to stress. Little is known about genes influencing the development of this autonomic control of the heart. We suggest the SOX10 gene to be a candidate for this process.

Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.

Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.

Gonadal histology with testicular carcinoma in situ in a 15-year-old 46,XY female patient with a premature termination in the steroidogenic acute regulatory protein causing congenital lipoid adrenal hyperplasia.

Mutations in the steroidogenic acute regulatory protein (StAR) gene cause congenital lipoid adrenal hyperplasia, characterized by diminished or absence of adrenal and gonadal steroids, resulting in severe adrenal insufficiency and ambiguous or complete female external genitalia in genetic males. We report on a 15-yr-old 46,XY phenotypic female, referred because of lack of pubertal development. ACTH and gonadotropin concentrations were elevated; and aldosterone, cortisol and its precursors, and sex steroids before and after stimulation were below the lower limit of detection. In the StAR gene, a homozygous nonsense mutation (TGG --> TAG) in exon 7 (W250X) was identified. Histologic examination after gonadectomy showed seminiferous tubules containing immature Sertoli cells and a few single germ cells with positive placental-like alkaline phosphatase immunoreactivity, indicating carcinoma in situ. This is the first report on testicular morphology, at a pubertal age, in a female patient with 46,XY karyotype and a mutation in the StAR gene, in whom gonadal neoplasia had developed.

Natural rubber latex allergy: prevalence and risk factors in patients with spina bifida compared with atopic children and controls.

UNLABELLED: Type 1 allergy against natural rubber latex is an increasing problem in health care workers and children with spina bifida or urogenital malformations. The aim of our study was to evaluate the prevalence of latex IgE antibodies and cross-reacting fruit antibodies in patients with spina bifida compared with atopic and non-atopic controls. Risk factors for sensitization should be determined. Sera of 148 patients with spina bifida and 98 controls (44 with atopy) were screened for IgE antibodies against latex, banana and kiwi by fluorescence enzyme immunoassay (CAP system). Atopies, allergic symptoms after latex contacts and the number of operations were compiled by a questionnaire. Patients with spina bifida developed latex IgE antibodies (> or =0.7 kU/l) more frequently (40.5%) than atopic children (11.4%) or healthy controls (1.9%). All 18 symptomatic patients belonged to the spina bifida group and had high values of latex antibodies. The risk for developing latex antibodies increases with the number of operations. There was no difference in the history of atopic diseases and in a screening test of IgE antibodies against inhalative allergens between latex sensitized and not sensitized children with spina bifida. Antibodies against banana were more frequent in the latex sensitized children with spina bifida. (18.3% vs 3.4%, P = 0.002). CONCLUSION: The high prevalence of latex antibodies in children with spina bifida justifies a primary prophylaxis by avoiding latex contacts, especially during anaesthesia and surgery, a correlation between the number of operations and the development of latex antibodies exists.

[Secondary myocardial hypertrophy in a very small premature infant treated with dexamethasone]. / Sekundäre Myokardhypertrophie bei sehr kleinen Frühgeborenen unter Dexamethasontherapie.

BACKGROUND: There is an increasing number of reports about the use of dexamethasone in the treatment of preterm infants at high risk for bronchopulmonary dysplasia. The possibility of myocardial hypertrophy developing during this treatment has not been examined. METHODS: As an example the course of one patient is described. We examined seven preterm infants (mean birth weight 791 g, mean gestational age 26 weeks) with eight treatments of dexamethasone retrospectively. The therapy was associated with a significant increase of the mean thickness of the interventricular septum and of the left ventricular posterior wall. After the termination of dexamethasone therapy the abnormal echocardiographic findings disappeared. CONCLUSION: We suggest careful monitoring of preterm infants treated with dexamethasone by performing serial echocardiographic investigations.

[Familial manifestation of idiopathic atrial flutter]. / Familiäres Vorkommen von idiopathischem Vorhofflattern.

We describe, to the best of our knowledge for the first time, the occurrence of idiopathic atrial flutter (AF) in two male children of a family. The two brothers are the third and sixth of seven children, and the only males. The parents do not suffer from any heart disease. The first sister died in Turkey at the age of twenty days. The parents do not know the cause of death. The fourth sister died at de age of five years, also in Turkey, probably because of meningitis. Electrocardiograms of the parents and the other three sisters are normal. Besides the unique familial occurrence, the AF themselves offer some unusual features. In the first patient, the AF could not be converted to sinus rhythm. In the second patient, the AF occurred paroxysmally, and in addition to the AF, the electrocardiogram tracings revealed paroxysmal atrial tachycardia.

[Extracranial congenital arteriovenous fistula in a newborn infant]. / Extrakranielle kongenitale arteriovenöse Fistel bei einem Neugeborenen.

A child with a congenital arteriovenous fistula between the arteria carotis externa and sinus sigmoideus is presented. This case showed further complications by the development of congestive heart failure and a Kasabach-Merritt syndrome. By an early excision already in the neonate age after diagnosis by digital subtraction angiography, the child could be saved.