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Open access article This work was supported by a Mildred Blaxter Post-Doctoral Fellowship from the Foundation for the Sociology of Health and Illness. This article discusses the influence of a chromosome condition affecting women’s reproductive capacity, Turner Syndrome (TS), on affected women’s social timing, examining the strategic decisions that are made within families in relation to reproduction, to navigate these disruptions. Based on photo elicitation interviews with 19 women with TS and 11 mothers of girls with TS in the UK, it presents findings from an under-researched topic, TS and reproductive choices. In a social context where motherhood is not only desirable, but expected (Suppes, 2020), the social imaginary of infertility anticipates a future of unhappiness and rejection, an undesirable condition that should be avoided. Accordingly, mothers of girls with TS often expect that their daughter will want to have children. Infertility diagnosed in childhood has a distinctive impact on reproductive timing, as future options may be anticipated for years. This article uses the concept of ‘crip time’ (Kafer, 2013) to explore how women with TS and mothers of girls with TS experience temporal misfitting based on a childhood diagnosis of infertility, and manage, resist and re-frame this to minimise stigma. The ‘curative imaginary’ (Kafer, 2013), a social norm where disabled people are expected to desire a cure for their condition, is used as an analogy for infertility, describing how mothers of girls with TS respond to social pressure to plan for their daughter’s reproductive future. These findings may be useful both for families navigating childhood infertility and practitioners who support them. This article demonstrates the cross-disciplinary potential of applying disability studies concepts to the context of infertility and chronic illness, where concepts shed new light on the dimensions of timing and anticipation in this context, improving our understanding of the lived experience of women with TS, and how they view and use reproductive technologies.

Ziel und Problemstellung: Die vorliegende Bachelorarbeit befasst sich mit dem orthoptischen Bezug bei Kindern mit Down-Syndrom. Down-Syndrom kann bereits im Kindesalter ophthalmologische und orthoptische Auffälligkeiten zeigen. Diese müssen früh genug diagnostiziert werden, damit einer optimalen Sehentwicklung nichts im Wege steht. Da das Down-Syndrom zusätzlich auch geistige Einschränkungen aufweisen kann, muss der orthoptische Untersuchungsablauf mögliche Beeinträchtigungen der Konzentration, Mitarbeit und des Verhaltens berücksichtigen. Orthoptist*innen sind daher angehalten, die Konsultation individuell anzupassen. Hintergrund: Es erfolgt eine Beschreibung der Chromosomenstörung Trisomie 21. Außerdem werden die Ursachen, Risikofaktoren und Formen von Down-Syndrom erörtert. Es erfolgt eine Erklärung von spezifische Augenerkrankungen, die mit dem Down-Syndrom in Verbindung stehen. Um orthoptische Diagnosen festzustellen, werden orthoptische Untersuchungsverfahren verwendet, welche im theoretischen Hintergrund erörtert werden. Methoden: Durch eine systematische Literaturrecherche in Datenbanken konnten sieben relevante Studien zur Häufigkeit von Augenbefunden bei Kindern mit Down-Syndrom und drei Studien zur Anpassung der orthoptischen Untersuchung bei Kindern mit Down- Syndrom gefunden werden. Zur Beurteilung der Qualität der Studien wurden Gütekriterien, psychometrische Eigenschaften und Messeigenschaften berücksichtigt. Ergebnisse: Die Ergebnisse befassen sich mit der Häufigkeit von Augenerkrankungen bei Kindern mit Down-Syndrom. Im zweiten Teil der Ergebnisse werden die möglichen Schwierigkeiten bei der orthoptischen Untersuchung bei Kindern mit Down-Syndrom erörtert. Diskussion: In diesem Kapitel erfolgt eine Beantwortung der Forschungsfragen. Eine Diskussion über die bearbeiteten Studien wird aufgezeigt und die Ansätze von verschiedenen Autor*innen der Studien werden in Korrelation gesetzt und kritisch hinterfragt. Objective and Problem: This bachelor thesis deals with the orthoptic reference in children with Down syndrome. Down syndrome can exhibit ophthalmological and orthoptic abnormalities already in childhood, which need to be diagnosed early enough to ensure optimal visual development. Additionally, Down syndrome can also involve intellectual limitations, the orthoptic examination procedure must consider possible impairments in concentration, cooperation and behavior. Therefore, orthoptists are obliged to adapt the consultation individually. Background: The background section provides a description of the chromosomal disorder Trisomy 21, along with an exploration of the causes, risk factors, and variations of Down syndrome. Specific eye diseases associated with Down syndrome are also explained. Orthoptic examination procedures used to determine orthoptic diagnoses, are discussed in the theoretical background. Methods: The methods employed involved a systematic literature review of databases, resulting in the identification of seven relevant studies on the prevalence of ocular findings in children with Down syndrome, as well as three studies on the adaptation of orthoptic examinations for this population. Quality criteria, psychometric properties, and measurement properties were considered to evaluate the quality of the studies. Results: The results deal with the frequency of eye diseases in children with Down syndrome. The second part of the results discusses the possible difficulties encountered in orthoptic examination in children with Down syndrome. Discussion: This chapter answers the research questions. A discussion of the processed studies is presented, and the approaches of various authors of the studies are compared and critically questioned.

Background Cat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2). Case presentation We report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis. Conclusions CES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Ring chromosome 10 [r(10)] syndrome is a rare genetic condition, currently described in the medical literature in a small number of case report studies. Typical clinical features include microcephaly, short stature, facial dysmorphisms, ophthalmologic abnormalities and genitourinary malformations. We report a novel case of r(10) syndrome and review the neurological and neuroradiological phenotypes of the previously described cases. Our patient, a 3 year old Italian girl, represents the 20th case of r(10) syndrome described to date. Intellectual disability/developmental delay (ID/DD), microcephaly, strabismus, hypotonia, stereotyped/aggressive behaviors and electroencephalographic abnormalities were identified in our patient, and in a series of previous cases. A brain MRI disclosed a complex malformation involving both the vermis and cerebellar hemispheres, in the literature, posterior cranial fossa abnormalities were documented by CT scan in another case. Two genes deleted in our case (ZMYND11 in 10p and EBF3 in 10q) are involved in autosomal dominant neurodevelopmental disorders, characterized by different expressions of brain and posterior cranial fossa abnormalities, ID/DD, hypotonia and behavioral problems. Our case expands the neurological and neuroradiological phenotype of r(10) syndrome. Although r(10) syndrome represents an extremely rare condition, with a clinical characterization limited to case reports, the recurrence of specific neurological and neuroradiological features suggests the need for specific genotype-phenotype studies.

Klinefelter syndrome (KS) is the most common sex chromosome disorder in males. It is the result of two or more X chromosomes in a phenotypic male. In addition to primary hypogonadism affecting male sexual development, it is associated with a series of comorbidities such as osteoporosis, psychiatric and cognitive disorders, metabolic syndromes, and autoimmune diseases. A broad spectrum of phenotypes has been described and many cases remain undiagnosed throughout their lifespan. In this case report, we describe a case of mosaic KS unmasked by acute vertebral fracture.

Background Down syndrome (DS) is a common numerical chromosome disorder that has its burden on both family and community. The well-known risk factor for chromosome 21 nondisjunction is advanced maternal age which failed to explain the occurrence of Down syndrome born to mothers less than 35 years. This study aimed to assess the effect of demographic data (consanguinity, residency area, and socioeconomic state) and chromosome/chromatid breaks as biomarkers for genome integrity on the susceptibility of young mothers to have a child with Down syndrome. Results Fifty mothers with a history of at least one DS pregnancy before the age of 35 were compared to 50 control mothers. There was a significant increase in DS births in consanguineous parents (46%) compared to 20% in non-consanguineous ones (OR = 3.40; 95% CI = 1.4–8.20, P = 0.006). Young mothers with DS children were more likely to be from rural areas (60%) than urban areas (40%) (OR = 2.66; 95%, CI = 1.18–5.98, P = 0.017) and of a low socioeconomic status (62%) rather than a high socioeconomic status (38%) (OR = 3.80; 95%, CI = 1.65–8.74, P = 0.001). Chromosome/chromatid breaks were detected in 76% of DS young mothers and 32% of control mothers (P < 0.001). There was an odds ratio of chromatid breaks of 8.50 (3.411–21.17) and chromosome breaks of 3.93 (1.40–11.05) with significant difference between the studied groups (P < 0.001 and P = 0.009 respectively). Conclusion In addition to advanced maternal age, consanguinity, residency in rural areas, and low socioeconomic status could be considered as possible risk factors for Down syndrome. The high frequency of chromosome/chromatid breaks in young mothers with a previous history of DS children highlights the impact of genome integrity on the tendency to chromosome 21 nondisjunction. These findings are valuable in predicting having a Down syndrome baby and providing proper genetic counseling for high-risk families.

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

Acromegaly is a rare disorder with incidence of 3-4 patients per million per year (1). Klinefelter syndrome (KS) is the most common sex chromosome disorder occurring in about 1/500th live male births (2).The coincidence of multiple endocrinopathies is rare, but possible. We report the case of a 33 years old man diagnosed with both of those rare conditions - acromegaly and 47, XXY Klinefelter syndrome.

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Klinefelter syndrome is the most frequent chromosome disorder in men, but it is largely undiagnosed or receives a late diagnosis in adulthood. This condition is characterized by an extra X-chromoso...

Klinefelter syndrome is the most common sex chromosome disorder, manifested as hypogonadism, gynecomastia, and impaired spermatogenesis. It is characterized by the presence of one or more extra X chromosomes. Patients with Klinefelter syndrome are highly susceptible to psychiatric disturbances as compared to the general population. These include personality changes, depression, and psychosis. Rarely, these psychiatric disturbances can be the presenting manifestations in these individuals. Hence, meticulous clinical examination should be performed in every patient of psychiatric illness to rule out systemic illness like hypogonadism, as the treatment of underlying medical condition can be beneficial in alleviation of the psychiatric illness.

Background: 22q11.2 deletion syndrome (22q) is a chromosome disorder, where a segment of chromosome 22, located at 811.2, is missing. This study aims to investigate the relationship between a number of parent-reported comorbid conditions including gastrointestinal symptoms, sleep problems, autism spectrum disorder (ASD) symptoms and behavior problems in children and adolescents with 22q deletion syndrome.Method: The Gastrointestinal Symptom Inventory, Children's Sleep Habits Questionnaire, Behavior Problem Inventory-Short Form and the Social Communication Questionnaire were completed by parents of 149 children and adolescents aged 3-18 years with a diagnosis of 22q.Results: A series of correlations and hierarchical multiple regressions were conducted to examine the relationships between GI symptoms, sleep problems and behavior problems in children and adolescents with 22q deletion syndrome. A significant moderate relationship was found between GI symptoms and sleep problems. Gender and ASD symptoms predicted GI symptoms. Significant small relationships were found between GI symptoms and self-injurious behavior. Significant small to moderate relationships were found between sleep problems and self-injurious behavior, aggressive/destructive behavior, and sterotyped behavior. Sleep problems predicted challenging behavior.Conclusions: This research demonstrated the importance of studying the relationship between comorbidities, including gastrointestinal symptoms, sleep problems, and behavior problems and how they shape the phenotype of 22q deletion syndrome. peer-reviewed 2021-05-28

More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

Unbalanced X;autosome translocations are a rare occurrence with a wide variability in clinical presentation in which the X chromosome unbalance is usually mitigated by a favorable X inactivation pattern. In most cases, this compensation mechanism is incomplete, and the patients show a syndromic clinical presentation. We report the case of a family with 4 women, of 3 different generations, carrying an unbalanced X;7 translocation with a derivative X;7 chromosome and showing a skewed X inactivation pattern with a preferential activation of the normal X. None of the carriers show intellectual disability, and all of them have a very mild clinical presentation mainly characterized by gynecological/hormonal issues and autoimmune disorders. We underline the necessity of family testing for a correct genetic consultation, especially in the field of prenatal diagnosis. We indeed discuss the fact that X;autosome translocations may lead to self-immunization, as skewed X chromosome inactivation has already been proved to be related to autoimmune disorders.

The latest United Kingdom (UK) strategy for rare diseases emphasises the need to empower affected populations to improve diagnosis, intervention, and coordination of care. Families who have a child with a rare chromosome disorder (RCD) are a challenging group to include. We report the findings of 2 large-scale surveys, undertaken by the UK RCD Support Group Unique, of these families' experiences over a 10-year period. Seven stages of the patient journey were examined. From pre-testing, through diagnosis, genetics consultation, clinical follow-up and peer support. Overall, 1158 families replied; 36.4% response rate (2003) and 53.6% (2013). Analysis of responses identifies significant differences (P < .001) over time with a decrease in results reported face to face (76%-62%), doubling by telephone (12%-22%), improved explanation of chromosome disorder (57%-75%), and increased signposting to peer support group (34%-62%). However, conduct of the consultation raises a number of important questions. Overall, 28 aspects of the patient journey are recognised as requiring improvement; only 12/28 are currently incorporated in UK service specifications. Involvement of RCD families has identified key service improvements. This approach can empower those affected by such extremely rare disorders, and also enable professionals to design improved services in partnership with "expert families." Further surveys are planned.

Background Small supernumerary marker chromosomes (sSMCs) are common structurally abnormal chromosomes that occur in 0.288% of cases of mental retardation. Isodicentric 15 (idic(15)) is common in sSMCs and usually leads to a rare chromosome disorder with distinctive clinical phenotypes, including early central hypotonia, developmental delay, epilepsy, and autistic behavior. It was previously shown that the partial tetrasomy 15q and partial hexasomy 15q syndromes are usually caused by one and two extra idic(15), respectively. Karyotypes containing a mosaic partial octosomy 15q resulting from three extra idic(15) have rarely been reported. Case presentation Two patients with profound intellectual impairment, development delay and hyperpigmentation were recruited for this study. The phenotype was relatively more severe in patient 1 than in patient 2. Conventional cytogenetic analysis of peripheral blood obtained from patients 1 and 2 revealed rare mosaic karyotypes containing sSMCs, i.e., mos 49,XX,+mar × 3[83]/48,XX,+mar × 2[7]/46,XX[10] and mos 48,XX,+mar × 2[72]/47,XX,+mar[28], respectively. The results of analyses of copy number variation (CNV) and fluorescence in situ hybridization (FISH) analyses, showed that the sSMCs were found to be idic(15) involving the Prader-Willi/Angelman Syndrome Critical Region (PWACR) genes and the P gene, with duplication sizes of 6.3 Mb and 9.7 Mb, respectively. DNA fingerprinting analysis of patient 1 showed a maternal origin for the idic(15). Both patients had mosaic idic(15) karyotypes: patient 1 had cells with a 15q partial octosomy (83%), and patient 2 had cells with a 15q partial hexasomy (72%). Conclusions We detected two rare mosaic idic(15) karyotypes that were associated with congenital abnormalities, including a rare mosaic octosomy of 15q11-q13. Our cases further validate the notion that the phenotypic severity is correlated with the level of mosaicism and the dosage effect of related genes in the proximal 15q.

Turner syndrome is a common sex chromosome disorder characterized by complete or partial absence of an X chromosome. The spectrum of its clinical features and cytogenetics are various. We report new chromosomal formula revealed by DSD and associated with translocation (13,14). To our knowledge, this is the first case of 45X, t(13;14) de novo translocation as a variation of Turner syndrome in a patient with this clinical presentation.

The aim of this research was to investigate the experiences of families whose child was diagnosed with a rare, and apparently unique, chromosome disorder. The participants were 22 parents who had been told that their child was the only one in the world with a specific chromosome abnormality. The parents completed an online questionnaire about the information and support they had accessed following diagnosis, and the difficulties associated with their child’s unique disorder. There were 24 affected children, aged 1 to 17 years, and one young adult in the participating families. Most experienced significant delays with cognitive, language and motor development. Problems with general health and behaviour were also common. Parents reported that they received the most useful information from support groups. The most important sources of support were allied health professionals, support groups and other parents. The parents described the ways in which they had been affected by the lack of knowledge about their child’s specific disorder. Common themes included uncertainty and confusion, feelings of isolation, fears for the future, mental health issues, and frustration because the chromosome disorder had no associated syndrome name.

Background: The aim of this study was to retrospectively investigate the 18-year experience of prenatal diagnosis of fetal karyotype analysis by amniocentesis. Methods: In this study, the authors reviewed the cytogenetic results of 40,208 fetuses with indications for amniocentesis enrolled from December 1998 to December 2015. Cytogenetic analysis of amniotic fluid was performed in all these pregnancies. Eight indications for amniocentesis were included. The detection rate and distribution of abnormal karyotypes were observed in each indication. Results: Among all these samples, abnormal maternal serum screening test was the most common indication for amniocentesis (17,536, 43.67%), followed by advanced maternal age (11,734, 29.18%), abnormal ultrasound findings (5,328, 13.25%), and required by pregnant women (2,557, 6.36%). Chromosomal abnormality was detected in 1,349 (3.36%) samples, 63.01% of the abnormalities were numerical, and 36.99% were structural. The detection rates of abnormal karyotype were 55.60% in one of the couple with chromosomal abnormality, 4.43% in the pregnant women with pathological ultrasound finding, 2.83% in the pregnant women with advanced age, and 2.73% in women with abnormal maternal serum screening tests. Of the fetuses with chromosome aberrations, 680 (50.41%) had trisomy 13, trisomy 18, or trisomy 21, and 138 (10.23%) had sex chromosome disorder. The other 531 abnormal samples included translocation, mosaicism, inversion, deletion, addition, and marker chromosome. Conclusions: Cytogenetic analysis, therefore, remained an effective approach to decrease the birth defects of fetuses with indications for amniocentesis. These results could provide meaningful suggestions for clinical genetic consulting and prenatal diagnosis.

Turner syndrome is a common sex chromosome disorder affecting females. The disorder is caused by a partial loss, complete absence, or structural abnormality of one X chromosome. The clinical presentation is broad and ranges from the classic phenotype to minimal clinical manifestations. Ocular abnormalities associated with the syndrome are common. Reports describing abnormal eye features in individuals with Turner syndrome generally involve refractive errors (myopia or hyperopia), strabismus, and external or anterior segment abnormalities including hypertelorism, epicanthal folds, and ptosis. Posterior ocular segment anomalies involving the optic nerve and retina in Turner syndrome have been rarely reported. We report a rare presentation of an 11-year-old female with Turner syndrome and unilateral morning glory disc anomaly.

Introduction Pallister-Killian Syndrome (PKS) (OMIM # 601803 ) is a rare genetic disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. Epilepsy is a frequent concern in PKS patients. Methods we report 3 PKS patients, with early-onset myoclonic epilepsy and photosensitivity. In these children, we analysed epileptic history and the EEG phenotype. Results Epilepsy onset was in the first 2 years of life in all patients and in 2 of them myoclonic seizures were the only seizure type. In all children photosensitivity was observed and myoclonic seizures were mainly related to low-frequency (1–6 Hz) intermittent photic stimulation. Levetiracetam was effective and well tolerated in the 2 treated patients. Conclusions early-onset myoclonic epilepsy is a possible clinical manifestation of PKS. Low-frequency photosensitivity is a peculiar bioelectrical marker in these children.

The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Kruppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.

Objective: To determine the classification and etiological diagnosis of children presented with ambiguous genitalia/atypical genitalia according to the newer classification system of Disorder of Sex Development (DSD). Methods: This observational, cross-sectional study was conducted at the Department of Pediatric Endocrinology and Diabetes at The Children’s Hospital &Institute of Child Health, Lahore from January, 2007 to December; 2014. Files of all the children with ambiguous genitalia were retrospectively analyzed and relevant data was retrieved. All the information was recorded on predesigned proforma and analyzed accordingly. Results: A total of 300 cases of ambiguous genitalia classified according to the new DSD classification. 46, XX DSD were 54.3% (n=163), 46, XY DSD were 43.7% (n=131), sex chromosome DSD were 2% (n=6). Among 46, XX DSD cases, the most common cause was congenital adrenal hyperplasia (97%, n=158). However, in 46, XY DSD partial androgen insensitivity/5α-reductase deficiency (62%. n=81) constituted the most commonest disorder. Other causes of 46XY DSD include testosterone synthesis defect(23%), congenital adrenal hyperplasia (CAH,12%), testis regression syndrome (1.5%) and persistent mullerian duct syndrome (PMDS,1.5%). Sex chromosome disorder constituted one case of iso-chromosome X turner syndrome, mixed gonadal dysgenesis (n=3), ovotesticular DSD/chimerism (n=2). Conclusion: Ambiguous genitalia have varied etiologies, 46; XXDSD found being the commonest of all, showing predominance of CAH especially salt loosing type. The early detection and prompt treatment of cases of ambiguous genitalia plays a pivotal role in the management of acute life threatening condition and gender assignment. How to cite this:Manzoor J, Aftab S, Yaqoob M. Ambiguous genitalia: An overview of 7 years experience at the Children’s Hospital & Institute of Child Health, Lahore, Pakistan. Pak J Med Sci. 2019;35(1):151-155. doi: https://doi.org/10.12669/pjms.35.1.289 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Circulating cell-free DNA, having no procedural risk of miscarriage, is the most suitable sample for a noninvasive prenatal testing (NIPT). Here we report on a boy, who came to our attention for hypotonia and psychomotor delay when he was 16 months old. During the pregnancy his mother performed a NIPT that resulted compatible with the presence of trisomy 18. A confirmatory invasive procedure has been proposed, but not performed, because the family preferred to follow a conservative line. A series of ultrasound excluded the presence of any major malformations. Genetic tests, performed after birth, revealed the presence of a tetrasomy 18p with an extra isochromosome 18p. Our report wants to underline the importance of an invasive procedure and consequent cytogenetic analysis in case of NIPT results indicating autosomal trisomies because under it may hide the presence of other structural chromosomal anomalies. These conditions are normally not visible at prenatal ultrasound or using combined test (CT) and the only identifiable not invasive sign could be the results of high risk at NIPT.

Pierre Robin sequence (PRS) is an important craniofacial anomaly that can be seen as an isolated finding or manifestation of multiple syndromes. 22q11.2 deletion and Stickler syndrome are cited as the two most common conditions associated with PRS, but their frequencies are debated. We performed a retrospective study of 66 patients with PRS and reviewed their genetic testing, diagnoses, and clinical findings. The case series is complemented by a comprehensive literature review of the nature and frequency of genetic diagnosis in PRS. In our cohort 65% of patients had associated anomalies; of these, a genetic diagnosis was established in 56%. Stickler syndrome was the most common diagnosis, comprising approximately 11% of all cases, followed by Treacher Collins syndrome (9%). The frequency of 22q11.2 deletion was 1.5%. Chromosome arrays, performed for 72% of idiopathic PRS with associated anomalies, revealed two cases of 18q22→qter deletion, a region not previously reported in association with PRS. A review of the cytogenetic anomalies identified in this population supports an association between the 4q33-qter, 17q24.3, 2q33.1, and 11q23 chromosomal loci and PRS. We found a low frequency of 22q11.2 deletion in PRS, suggesting it is less commonly implicated in this malformation. Our data also indicate a higher frequency of cytogenetic anomalies in PRS patients with associated anomalies, and a potential new link with the 18q22→qter locus. The present findings underscore the utility of chromosomal microarrays in cases of PRS with associated anomalies and suggest that delaying testing for apparently isolated cases should be considered.

Objective To assess the potential performance of screening for fetal trisomies 21, 18 and 13 by cell-free DNA (cfDNA) analysis of maternal blood using the IONA® test. Methods This was a nested case–control study of cfDNA analysis of maternal plasma using the IONA test. Samples were obtained at 11–13 weeks' gestation, before chorionic villus sampling, from 201 euploid pregnancies, 35 with trisomy 21, four with trisomy 18 and two with trisomy 13. Laboratory personnel were blinded to the fetal karyotype. Results Probability scores for trisomies 21, 18 and 13 were given for 241/242 samples analyzed. No probability score was provided for one (0.5%) euploid pregnancy because of low fetal fraction. In all 35 cases of trisomy 21 the probability score for trisomy 21 was > 95% and the scores for trisomies 18 and 13 were ≤ 0.0001%. In all four cases of trisomy 18, the probability score for trisomy 18 was > 77% and the scores for trisomies 21 and 13 were ≤ 0.0001%. In the two cases of trisomy 13, the probability score for trisomy 13 was > 59% and the scores for trisomies 21 and 18 were ≤ 0.0001%. In the 200 euploid pregnancies with a test result, the probability score was < 0.08% for trisomy 21, < 0.001% for trisomy 18 and < 0.002% for trisomy 13. Therefore, the IONA test detected 100% of all three trisomies, with a false-positive rate of 0%. Conclusion The IONA test successfully differentiated all cases of trisomies 21, 18 and 13 from euploid pregnancies. © 2015 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Background The 13q deletion syndrome is a rare chromosome disorder associated with wide phenotypic spectrum, which is related to size and location of the deleted region and includes intellectual disability, growth retardation, craniofacial dysmorphisms, congenital malformations, and increased risk of retinoblastoma. Case presentation Here, we report on a teenage boy with a mild phenotype characterized by obesity, hyperactivity, dysphagia, dysgraphia, sleep disturbance, and minor dysmorphic features (round face, bushy eyebrows, and stubby hands). Array Comparative Genomic Hybridization on blood identified a mosaic 13q14.13-13q31.1 deletion, with a mosaicism rate around 40%, which was confirmed by quantitative PCR and interphase Fluorescent In Situ Hybridization (iFISH) on both blood genomic DNA and cultured/uncultured blood lymphocytes, respectively. Conversely, karyotype analysis on blood estimated a mosaicism rate of 24% and iFISH on buccal smears revealed a borderline value of 0.4%, suggesting the absence of 13q deletion in this cell line. Conclusions The comparison with previous patients carrying similar deletions informed that the proband clinical presentation is the mildest reported to date, thus supporting the burden of mosaicism in modulating the phenotype also in case of large chromosomal rearrangements. Characterization of further cases by in-depth mosaicism rate in tissues with different embryonic origins might contribute in the future to a better definition of genotype-phenotype correlation, including tumor risk.

Objectives Atrioventricular septal defect is associated with a high risk of a chromosomal abnormality, particularly trisomy 21. The aim of this study is to assess the rate of trisomy 21 in fetuses diagnosed with an atrioventricular septal defect and to examine the influence of prior screening on the rate of trisomy 21. Methods Electronic ultrasound database was searched to identify fetuses diagnoses with an atrioventricular septal defect from 2002 to 2014. Rate of trisomy 21 and other aneuploidies was calculated among fetuses with normal situs. The prevalence of trisomy 21 and other aneuploidies was assessed in women with low and high first trimester risk for trisomy 21, using a cut-off value of 1:150 and 1:250. Results total 110 fetuses with a diagnosis of atrioventricular septal defect were identified. Among the 98 fetuses with normal situs, the prevalence of trisomy 21 was 46% (95% CI: 36–56%). Using a 1:150 threshold, the rate of trisomy 21 within the low-risk group was 41% (95% CI: 27–57%) while in the high-risk group it was 70% (95% CI: 52–83%), significantly higher than in the low risk group (p = 0.028). Similar results were obtained when the 1:250 threshold was applied (66% versus 41%, p = 0.055). Conclusions The rate of trisomy 21 among fetuses identified with an atrioventricular septal defect in the second trimester is high even in those that undergo first trimester combined screening. Some fetuses with a high-risk screening result show a normal karyotype. Therefore, an offer of an invasive procedure to check fetal karyotyping is indicated. Knowledge of these rates may be helpful for parents in the decision making process.

This chapter reviews the archetypical chromosome disorder, namely Down syndrome (DS; trisomy 21), and the various different chromosomal forms that may be the basis of it: standard trisomy 21, translocation trisomy, both de novo and inherited, and other rare forms. The concept of dosage imbalance as the basis of the pathogenesis is reviewed, and the “DS critical region” on chromosome 21 is examined. Reproductive risks associated with each of these DS types are discussed. The chapter considers the other full autosomal trisomies, T13 and T18, and also (mosaic) T9. Triploidy, as the basis of hydatidiform mole, is reviewed. Also reviewed are the influence of parental, mostly maternal, age, in the genesis of these aneuploidies, and the effect of secular change on these observations. Tables provide precise age-related risk figures for recurrence risk of T21 and more general figures for other trisomies.

Introduction: Congenital absence of the ductus venosus (ADV) is a rare vascular anomaly often associated with fetal cardiac and extracardiac anomalies, aneuploidies, and hydrops. The prognosis depends on the patterns of abnormal venous circulation, on the associated malformations and on chromosomal aberrations.Methods: We performed a retrospective audit of all consecutive cases with ADV referred in our centres and analysed the outcomes.Results: A total of six cases with prenatally diagnosed ADV were identified. The gestational age at diagnosis ranged from 15 to 35 weeks. Karyotyping was performed in all cases. Normal karyotype was found in five out of the six cases. Overall, four neonates survived at 28 days follow-up. The other two died 48 h after delivery: both of them had extrahepatic ADV.Discussion: Absence of the ductus venosus may be compatible with normal fetal development without relevant disturbance of circulation and oxygenation independently from type of abnormal venous circulation.

Pallister-Killian syndrome (PKS) is a tissue limited mosaic disorder, characterized by variable degrees of neurodevelopmental delay and intellectual disability, typical craniofacial findings, skin pigmentation anomalies and multiple congenital malformations. The wide phenotypic spectrum of PKS in conjunction with the mosaic distribution of the i(12p) makes PKS an underdiagnosed disorder. Recognition of prenatal findings that should raise a suspicion of PKS is complicated by the fragmentation of data currently available in the literature and challenges in diagnosing a mosaic diagnosis on prenatal testing. Ultrasound anomalies, especially congenital diaphragmatic hernia, congenital heart defects, and rhizomelic limb shortening, have been related to PKS, but they are singularly not specific and are not present in all affected fetuses. We have combined prenatal data from 86 previously published reports and from our cohort of 114 PKS probands (retrospectively reviewed). Summarizing this data we have defined a prenatal growth profile and identified markers of perinatal outcome which collectively provide guidelines for early recognition of the distinctive prenatal profile and consideration of a diagnosis of PKS as well as for management and genetic counseling.

Turner’s syndrome (TS) is a sex chromosome disorder associated with a female phenotype. The loss of all or part of X chromosome that is affected the shape and the size of craniofacial structures in TS. Several studies have revealed concerning oral status in patients with TS that orthodontic anomalies such as deep-bite, open-bite, crowding, diastema, Class-II malocclusion and dental anomalies such as congenitally missing and supplementary teeth, decreased dental crown width, anomalous teeth were more frequent. The values for decayed, missing, filled teeth were lower although periodontal problem was higher for the patients with TS. Dentofacial findings in TS patients is important because of the dentists may contribute to early diagnosis.

45,X/46,XY mosaicism is a rare sex chromosome disorder of sex development. Short stature is a main feature of boys with this condition. Different causes likely contribute to growth impairment. Growth hormone (GH) has been administered to treat short stature in boys with 45,X/46,XY mosaicism, but conflicting data are available. Here, spontaneous growth patterns as well as short- and long-term follow-up studies during GH therapy in these patients are reviewed. Short- and mid-term data showed an improvement of the growth pattern in GH-treated boys, mainly when hormonal therapy was started early, while long-term follow-up demonstrated similar adult heights in GH-treated and untreated patients. Individual biological factors (e.g. different chromosome constitution, different mosaicism among various tissues, impaired pubertal growth spurt), non-homogeneous GH doses and different ages at start of therapy may contribute to the variable results. Thus, early GH therapy at pharmacological doses may improve the growth pattern of short boys with 45,X/46,XY mosaicism, but data on adult height are disappointing. Evaluation of larger patient samples treated by homogeneous doses and long-term follow-up studies assessing adult height and safety are needed to reach definitive conclusions on GH therapy in boys with 45,X/46,XY mosaicism.

Wolf–Hirschhorn syndrome (WHS) is a chromosome disorder (4p-syndrome) which is characterized by craniofacial features and epileptic seizures. Here, we report a case of WHS with West syndrome, in whom the seizures were refractory to several antiepileptic drugs but were responsive to the addition of lamotrigine. The patient had epileptic spasms at age seven months. The interictal electroencephalogram was hypsarrhythmic. After adding lamotrigine, seizures decreased remarkably, and spasms disappeared. We have identified and described the very rare case of a girl with WHS who also developed West syndrome. In this case, adding lamotrigine to her medications effectively treated the spasms.

Turner syndrome (TS) with 45,X/46,XY mosaic karyotype is a rare sex chromosome disorder with an occurrence of 0.15‰ at birth. We report the generation of an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a Chinese adult male with 45,X/46,XY mosaicism. The iPSC line retains the original 45,X/46,XY mosaic karyotype, expresses pluripotency markers and undergoes trilineage differentiation. Therefore, it offers an unprecedented cellular model to investigate the profound symptoms like infertility of TS in the male, and serve as a useful tool to develop therapies for the disease.