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We recently identified mutations of ARX in nine genotypic males with X‐linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C‐terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure. Hum Mutat 23:147–159, 2004. © 2003 Wiley‐Liss, Inc.

Winner of an Honorable Mention in the Clinical Medicine category of the Professional and Scholarly Publishing Awards given by the Association of American Publishers At a time when medical technologies make it ever easier to enhance our minds and bodies, a debate has arisen about whether such efforts promote a process of \"normalization, \" which makes it ever harder to tolerate the natural anatomical differences among us. The debate becomes especially complicated when it addresses the surgical alteration, or \"shaping, \" of children. This volume explores the ethical and social issues raised by the recent proliferation of surgeries designed to make children born with physical differences look more normal. Using three cases—surgeries to eliminate craniofacial abnormalities such as cleft lip and palate, surgeries to correct ambiguous genitalia, and surgeries to lengthen the limbs of children born with dwarfism—the contributors consider the tensions parents experience when making such life-altering decisions on behalf of or with their children. The essays in this volume offer in-depth examinations of the significance and limits of surgical alteration through personal narratives, theoretical reflections, and concrete suggestions about how to improve the decision-making process. Written from the perspectives of affected children and their parents, health care providers, and leading scholars in philosophy, sociology, history, law, and medicine, this collection provides an integrated and comprehensive foundation from which to consider a complex and controversial issue. It takes the reader on a journey from reflections on the particulars of current medical practices to reflections on one of the deepest and most complex of human desires: the desire for normality. Contributors Priscilla Alderson, Adrienne Asch, Cassandra Aspinall, Alice Domurat Dreger, James C. Edwards, Todd C. Edwards, Ellen K. Feder, Arthur W. Frank, Lisa Abelow Hedley, Eva Fedder Kittay, Hilde Lindemann, Jeffery L. Marsh, Paul Steven Miller, Sherri G. Morris, Wendy E. Mouradian, Donald L. Patrick, Nichola Rumsey, Emily Sullivan Sanford, Tari D. Topolski

The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ∼31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including CRKL. CRKL encodes a srchomology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans. Here we show that Crkl mutant embryos exhibit gene dosage-dependent growth restriction, and homozygous mutants exhibit upper GU defects at a microdissection-detectable rate of 23%. RNA-sequencing revealed that 52 genes are differentially regulated in response to uncoupling Crkl from its signaling pathways in the developing kidney, including a fivefold up-regulation of Foxd1, a known regulator of nephron progenitor differentiation. Additionally, Crkl heterozygous adult males exhibit cryptorchidism, lower testis weight, lower sperm count, and subfertility. Together, these data indicate that CRKL is intimately involved in normal development of both the upper and lower GU tracts, and disruption of CRKL contributes to the high incidence of GU defects associated with deletion at 22q11.2.

An international workshop titled \"Assessing Endocrine-Related Endpoints within the First Years of Life\" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.

Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1-and PKR2-gene-disrupted mice ($Pkr1^{-/-}$and$Pkr2^{-/-}$, respectively). Phenotypic analysis indicated that not$Pkr1^{-/-}$but$Pkr2^{-/-}$mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the$Pkr2^{-/-}$mice. In addition, the$Pkr2^{-/-}$mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the$Pkr2^{-/-}$mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the$Pkr2^{-/-}$mice. The phenotype of the$Pkr2^{-/-}$mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.

Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.

Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene ( Arx ) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing γ-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia (XLAG) in humans. We found multiple loss-of-function mutations in ARX in individuals affected with XLAG and in some female relatives, and conclude that mutation of ARX causes XLAG. The present report is, to our knowledge, the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.

The aims of the current study were twofold: (1) to assess the prevalence/severity of posttraumatic stress symptoms (PTSS) as well as cognitive and emotional responses in parents whose children were diagnosed with a disorder of sex development (DSD); and (2) to assess factors which contributed to PTSS. We hypothesized that parents would show elevated levels of PTSS and that negative cognitive and/or emotional responses would be predictive. Participants were parents of children diagnosed with a DSD. Thirty-six mothers and 11 fathers completed a measure of posttraumatic stress and reported difficulties in the domains of cognition (e.g., confusion) and emotion (e.g., grief). Using multiple regression, we determined factors contributing to parental PTSS. Reported PTSS was high: 31 % of mothers and 18 % of fathers met the threshold for caseness for Posttraumatic Stress Disorder. Regression included: child sex, parent sex, child age at diagnosis, years since diagnosis, genital ambiguity, father occupation, cognitive confusion, and emotional distress. Only cognitive confusion contributed significantly to variance in PTSS. Parents of children with DSD may experience the diagnosis as traumatic, evidenced by high rates of PTSS in the current report. Assessment of reactions to their children’s diagnoses revealed that cognitive confusion, and not emotional distress, predicted PTSS. In this case, direct cognitive interventions may be applicable. Though psychological support is widely recommended, no detailed intervention has been offered. Our findings suggest that we may directly apply models successful in other areas of pediatrics, such as pediatric oncology. Future studies may assess the usefulness of such an intervention.

BACKGROUND:Pre-existing diabetes has been associated with an increased risk of congenital malformations overall, but studies on genital anomalies in boys are conflicting and possible causal mechanisms are not well understood. Previous studies have mainly assessed pregestational and gestational diabetes in combination. Yet considering the vulnerable time windows for the genital anomalies, associations could well differ between types of diabetes and between the 2 genital anomalies and we therefore aimed to study this further. METHODS:A population-based cohort study of 2,416,246 singleton live-born boys from Denmark (1978–2012) and Sweden (1987–2012) was carried out using Danish and Swedish register-based data. Using Cox regression models, we estimated hazard ratios for hypospadias and cryptorchidism according to maternal diabetes. We considered type and severity of diabetes, as well as timing of diagnosis in relation to birth. RESULTS:Pregestational type 1 diabetes was associated with a higher risk of both genital anomalies. The highest risks were seen for boys of mothers with diabetic complications (hazard ratio for hypospadias = 2.33 [95% confidence interval, 1.48, 3.66] and hazard ratio for cryptorchidism = 1.92 [95% confidence interval, 1.39, 2.65]). Gestational diabetes was associated with slightly increased risks of both genital anomalies. CONCLUSIONS:These results are consistent with the hypothesis that poor glycemic control may interfere with fetal genital development in the critical early period of organogenesis. Given the widespread and increasing occurrence of diabetes, these results are of public health importance.

Aim of the studyMisdiagnosing a cloaca as a disorder of sex development may lead to inappropriate testing, treatment, and negative emotional consequences to families. We were impressed by the fact that a significant number of patients suffering from a cloaca were referred to us with the diagnosis of a “disorder of sex development” previously referred as “ambiguous genitalia” or “intersex”. On re-evaluation, none of them truly had a disorder of sex differentiation. This prompted us to conduct the following retrospective review to try to find the cause of the misdiagnosis and the way to prevent it.MethodsA retrospective review of our colorectal database was performed to identify the total number of patients with cloacas and the number initially diagnosed as “ambiguous genitalia, intersex”/disorder of sex development. The external appearance of their genitalia and unnecessary testing or treatment received were recorded.Main resultsA total of 605 patients with cloacas were identified. Of these, 77 (12.7%) were referred to us with the diagnosis of “ambiguous genitalia” and 13 of them (17%) went on to receive an intervention that was not indicated: karyotyping (10), steroids (3), and ovarian biopsy (1). The karyotype result in all patients was XX. The misdiagnosis was triggered by the external appearance of the perineum, simulating a case of virilization with a hypertrophic clitoris, but was simply prominent labial skin. Careful examination of the perineal structure allowed us to determine that it consisted of folded skin with no evidence of corpora.ConclusionPatients born with a cloaca are at risk for mismanagement from being erroneously labeled as disorders of sex development. The diagnosis of a cloacal anomaly is a clinical one. The practitioner must distinguish between phallus-like clitoral hypertrophy and a normal clitoris with prominent labial skin.