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Dual diagnoses in 152 patients with Turner syndrome: Knowledge of the second condition may lead to modification of treatment and/or surveillance
Abstract
Turner syndrome is a sex chromosome abnormality in which a female has a single X chromosome or structurally deficient second sex chromosome. The phenotypic spectrum is broad, and atypical features prompt discussion of whether the known features of Turner syndrome should be further expanded. With the advent of clinical whole exome sequencing, there has been increased realization that some patients with genetic disorders carry a second genetic disorder, leading us to hypothesize that a “dual diagnosis” may be more common than suspected for Turner syndrome. We report five new patients with Turner syndrome and a co‐occurring genetic disorder including one patient with Li‐Fraumeni syndrome, Li‐Fraumeni and Noonan syndrome, mosaic trisomy 8, pathogenic variant in RERE, and blepharophimosis‐ptosis‐epicanthanus inversus syndrome. We also undertook an extensive literature review of 147 reports of patients with Turner syndrome and a second genetic condition. A total of 47 patients (31%) had trisomy 21, followed by 36 patients (24%) had one of 11 X‐linked disorders. Notably, 80% of the 147 reported patients with a dual diagnosis had mosaicism for Turner syndrome, approximately twice the frequency in the general Turner syndrome population. This article demonstrates the potential for co‐occurring syndromes in patients with Turner syndrome, prompting us to recommend a search for an additional genetic disorder in Turner patients with unusual features. Knowledge of the second condition may lead to modification of treatment and/or surveillance. We anticipate that increased awareness and improved diagnostic technologies will lead to the identification of more cases of Turner syndrome with a co‐occurring genetic syndrome.
... Крім істинної моносомії у всіх клітинах трапляються інші форми хромосомних аномалій за статевими хромосомами. Серед них делеції короткого або довгого плеча Х-хромосоми (46, X, Хр-; 46, X, Хq-) [267]. ...
... Тернера, при якому група клітин організму має аномальне число або структуру хромосом (пацієнти-мозаїки). Форми мозаїцизму (45,X/46,XX mosaicism) виявляються у понад 20-30 % усіх випадків [267,285,506], структурні аномалії у 14,4 % [506]. ...
... Клініка синдрому Тернера відрізняється за ступенем вираженості залежно від величини дефіциту матеріалу Х-хромосоми [143,267]. Синдром Тернера можна запідозрити при народженні, якщо новонароджена має пухку шкіру на задній частині шиї, лімфатичний набряк рук та ніг, широко розміщені соски, шум серця Рис. 1.3.11. ...
The textbook focuses on one of the important problems of
modern medical genetics and clinical dentistry – disorders of the
dental and maxillofacial system, which are associated with hereditary
diseases or syndromes.
The accumulation and systematization of data on the prevalence
of genetic diseases are becoming increasingly important in connection
with the increasing contribution of hereditary pathology in morbidity
and mortality. The study of the role of heredity in the pathology of
the oral cavity is complicated by a number of specific difficulties: the
variability of occlusion, toothlessness of the elderly and children, poor
public awareness of the oral cavity of their relatives.
Craniofacial anomalies, in particular morphological changes in
the teeth, can be caused by disorders of the chromosomal apparatus
(number of chromosomes, their aberrations), gene mutations, as well
as the combined action of many genes and environmental factors. As
the textbook uses the most common examples of genetic diseases,
special attention is paid to the following pathologies. Chromosomal
syndromes, which are accompanied by a change in the number of
autosomes while maintaining their structure (Down syndrome), as well
as sex X and Y chromosomes (Turner syndrome, Klinefelter syndrome).
Everyone knows the classification depending on the gene mutation
(autosomal dominant or recessive, linked to sex chromosomes,
mitochondrial). It is the latter that we have described common genetic
diseases: autosomal dominant (Marfan, Holt-Oram syndromes,
Huntington’s chorea, neurofibromatosis type I); autosomal recessive
(Gaucher, Wilson’s disease, cystic fibrosis, phenylketonuria): X-linked
dominant (hypophosphatemic rickets): X-linked recessive (hemophilia
A and B). Among the modern sources of the literature it was not possible to find a description of dental manifestations of mitochondrial
pathology (Leber’s hereditary optic neuropathy).
The next stage of material preparation was the choice of material
presentation scheme. By analyzing the relevant literature, which
mainly described dental diseases by nosological units and listed the
hereditary diseases that cause them, we adopted a different sequence
of data presentation. This was facilitated by the fact that hereditary
diseases combine several dental manifestations. For example, late
eruption of teeth is characteristic of Down and Turner syndromes,
hypophosphatemic syndrome, Gaucher disease, Bite disorders occurs
in Down syndrome, neurofibromatosis type I, Wilson’s disease;
hypoplasia of enamel, teeth – with Turner syndrome, Down syndrome,
neurofibromatosis type I; gingivitis – in Turner, Down and Klinefelter
syndromes (chronic catarrhal); periodontitis – in Down and Marfan
syndromes, Wilson’s disease (early), hypophosphatemic rickets
(periodontal abscesses); caries – in cystic fibrosis, phenylketonuria,
Wilson’s disease, hypophosphatemic rickets: bleeding – in Wilson’s
disease (after tooth extraction) and Gaucher, hemophilia A; enamel
defects – in Klinefelter’s syndrome, hypophosphatemic rickets
(microcleavage of enamel). A far from complete list indicates that a
large number of symptoms are combined in the same disease.
For modern diagnosis, prevention and treatment requires the
cooperation of a dentist with clinicians of various profiles, and in case
of suspicion of genetic pathology, with geneticists. The study of genetic
and epigenetic factors in the occurrence and development of dental
disease has established the role of individual genes and lifestyle (bad
habits, diet), compliance with hygienic rules of dental care.
An important factor in writing the manual in the chosen
sequence was the fact that according to the curricula in Ukraine,
medical genetics is not taught in higher medical educational
institutions for dentists.
... These cases shed light on the possibility that patient's with Turner's syndrome are more prone to other genetic abnormalities. Numerous co-occurring X-linked conditions have been reported including Fragile X syndrome, Duchenne muscular dystrophy, and hemophilia A and B. 16 However numerous co-occurring autosomal disorders have also been described in case reports, including Neurofibromatosis Type 1, Cornelia de Lange syndrome, Long QT syndrome, Li-Fraumeni syndrome and 17α hydroxylase deficiency. 16 Without population based studies, it is not possible to determine if these occur at a higher rate in patients with Turner's syndrome. ...
... Numerous co-occurring X-linked conditions have been reported including Fragile X syndrome, Duchenne muscular dystrophy, and hemophilia A and B. 16 However numerous co-occurring autosomal disorders have also been described in case reports, including Neurofibromatosis Type 1, Cornelia de Lange syndrome, Long QT syndrome, Li-Fraumeni syndrome and 17α hydroxylase deficiency. 16 Without population based studies, it is not possible to determine if these occur at a higher rate in patients with Turner's syndrome. ...
... Interestingly, literature review reveals that aneuploidies -notably Down syndrome, and trisomy 18, 13 and 8 -appear to be more common in Turner syndrome individuals. 16 Furthermore, these autosomal aneuploidies were largely associated with non-mosaic karyotypes, indicating a meiotic error could have lead to both disorders. 16 ...
Purpose
To report 2 cases of pediatric vitreoretinal disease in the setting of Turner's syndrome.
Observations
A 4-year-old girl with Turner's syndrome was referred for evaluation of a tractional retinal detachment in the right eye. Fundoscopic examination disclosed temporal dragging of the macula in the right eye, and vascular nonperfusion in the right and left eyes. Genetic testing revealed a novel frameshift mutation in the LRP5 gene consistent with familial exudative vitreoretinopathy (FEVR). The patient was treated with laser. A 14-year-old girl with Turner's syndrome presented with nyctalopia. Dilated fundus exam disclosed peri-foveal pigmentary changes and peripheral bone spicules. Full-field electroretinography demonstrated decreased rod and cone responses, consistent with retinitis pigmentosa (RP).
Conclusions and importance
Vitreoretinal disease, including RP and FEVR, is rarely observed in patients with Turner's syndrome.
... Interestingly, 24% of these comorbidities were connected to X-linked diseases, yet none were associated with hemophilia. In the literature, there are only about 8 clinical cases including haemophilia associated with Turner syndrome [41]. ...
... A coincidental occurrence of severe haemophilia A and Turner syndrome is extremely rare, with the PubMed database containing not more than 10 reported cases (Table 3) [37][38][39][40][41][42]. The characteristic of our case is the occurrence of the structural chromosomal abnormality, i(Xq), responsible for the development of the Turner syndrome, and at the same time, for a detrimental transformation of an obligate carrier into a severe haemophilia, two distinct provocative pathological entities. ...
A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is indispensable. The article presents an eight-year-old girl, with a family history of haemophilia, without significant disease signs (only post-dental extraction bleeding and a shorter stature). Discordantly, however, the investigations revealed a challenging condition: a genotype of 46,X,i(Xq), with an Isochromosome Xq responsible for the Turner syndrome and simultaneously, for the detrimental transformation, interfering with X chromosome inactivation, of an obligate hemophilia carrier into a severe hemophilia case—two distinct and provocative diseases.
... Use of clinical whole-exome sequencing, has shown that, some patients with genetic disorders carry a second genetic disorder and dual diagnosis may be more common than suspected of the TS [2]. Of the investigated cases with TS, 80% had mosaicism for TS and dual diagnosis, approximately twice the frequency than in the general TS population [2]. ...
... Use of clinical whole-exome sequencing, has shown that, some patients with genetic disorders carry a second genetic disorder and dual diagnosis may be more common than suspected of the TS [2]. Of the investigated cases with TS, 80% had mosaicism for TS and dual diagnosis, approximately twice the frequency than in the general TS population [2]. ...
Purpose
To present a case with a woman with Turner syndrome (TS) with acromegaly and breast cancer, in her medical history.
Method
A descriptive case report of a single patient.
Results
The woman had short stature and lack of puberty and was not treated with hormones. When she was 36-year-old, acromegaly was diagnosed. She was treated with transsphenoidal surgery, followed by external radiation on the adenoma, without any affection on the pituitary gland. Annual controls revealed ordinary pituitary axes during 40 years’ follow-up. She was treated for hypertension, had an aortic dilatation and started menopausal hormone therapy (MHT),1 mg estradiol and 0.5 mg norethisterone acetate daily, at the age of 50, due to osteoporosis. At the age of 60, she was diagnosed with breast cancer at the mammography screening. After, mastectomy, neoadjuvant radiation, and treatment with tamoxifen citrate were given due to the tubular breast cancer.
Conclusions
Despite a possible growth hormone (GH) resistance and lack of endogenous estradiol in women with TS, this patient was diagnosed with acromegaly and breast cancer. This case demonstrates the potential for co-occurring two hormonally active tumors in a woman with TS with monosomy karyotype.
... KL Jones et al. described 5 patients with Turner syndrome who were also diagnosed with some other genetic condition, i.e. Li-Fraumeni syndrome, Noonan syndrome, mosaic trisomy 8, pathogenic variant in the RERE gene, and blepharophimosis-ptosis-epicanthanus inversus syndrome [28]. In the course of his clinical medical practice between 2010 and 2017, Jones proved that 1% of 172 patients with TS, who remained under the care of the MGH Turner Syndrome Clinic, had a second genetic disease. ...
... Jones also analysed the literature on the subject and evaluated the coincidence of genetic disorders in Turner syndrome. It was found that 51% of patients had autosomal aneuploidy disorders (trisomy 21 being the most frequent) and 24% of the analysed cases had a disease connected with X-linked inheritance [28]. ...
Background:
Bleedings are more frequent in the population of preterm children than among those born at term, much less in older children. The reasons for such bleedings in preterms include plasma factor deficiencies, immaturity of small vessels in the germinal matrix region, prenatal hypoxia or sepsis. They affect the brain tissue, the gastrointestinal tract and the respiratory system, or are manifested by prolonged bleedings from injection sites. Haemophilia is a rare cause of haemorrhages in the neonatal period, and in the female population it is even seen as an extremely rare disorder. Its aetiology in girls is diverse: inheriting defective genes from their parents, skewed X inactivation or a single X chromosome.
Case presentation:
The article presents a case of a preterm girl born in the 28th week of pregnancy, who was diagnosed with severe haemophilia A stemming from the absence of the X chromosome. The girl's father is healthy, but her mother's brother suffers from haemophilia. On the second day of the child's life, a prolonged bleeding from the injection site was observed. A coagulation profile revealed prolonged APTT which pointed to haemophilia A diagnosis. Moreover, a marked clinical dysmorphy, female sex and a negative family history on the father's side led the treating team to extend the diagnostic procedures to encompass karyotype evaluation. The girl was diagnosed with Turner syndrome. No bleeding to the central nervous system was observed during her hospital stay.
Conclusions:
Preterm children belong to the risk group of bleeding into the central nervous system or haemorrhages in the course of sepsis. Rare causes of such bleedings should also be borne in mind, including haemophilia. The initial symptoms of haemophilia in preterm children occur in the first days of their lives, which is connected with a number of invasive procedures required in that period. Genetic conditions may coexist with one another. Arriving at one diagnosis does not mean one should abandon further diagnostic procedures in cases where additional atypical symptoms are present which do not match the clinical image of a primary disease.
... X chromosome monosomies are the most frequent genetic abnormalities in humans and account for 2% of all pregnancies (Álvarez-Nava & Lanes, 2018). Turner Syndrome (TS) is a genetic disorder caused by the partial or total loss of the second X chromosome, affecting multiple organs and body systems in women at any age (Haltrich, 2019;Jones et al., 2018;Swauger et al., 2021). With a prevalence between 1:2000 and 1:2500 live-born females (Apperley et al., 2018;Zhang et al., 2021), most studies on TS show how the 45,X karyotype is present in 60/100,000 live-born women (Berglund et al., 2019). ...
Aim and objectives:
The aim of this study was to describe and understand how heterosexual women with Turner Syndrome experience sexuality.
Background:
Turner Syndrome is a genetic condition that is the result of one of the X chromosomes missing or partially missing, and it affects women of all ages. Turner Syndrome may lead to psychological, relational and sex life disorders.
Design:
This is a qualitative study, and the COREQ checklist was employed to report on the current study.
Methods:
The study was conducted in a region of southern Spain. Convenience and snowball sampling were used to recruit 18 women, aged 22-51 years, who had been diagnosed with Turner Syndrome. Participants' experiences were explored through semi-structured interviews between January and May 2021. Thematic analysis was used for data analysis.
Results:
Three main themes and eight sub-themes emerge from the data analysis: (1) Sexuality linked to corporeality, with the sub-themes: 'Discovering that your body is different', 'Social stigma limits one's sex life' and 'Fear of penetration surpresses sexual desire'. (2) Adapting one's sexuality to Turner Syndrome, with the sub-themes: 'Feeling like a woman' and 'Suffering from and adapting to comorbidities'. (3) When infertility overshadows sexuality, with the sub-themes: 'Prolonging childhood by ignoring sexuality', 'Fertility treatment: always a possibility' and 'Lack of specialised professional knowledge'.
Conclusion:
Heterosexual women with Turner Syndrome suffer from sexual problems, delayed diagnosis and treatment, and lack of information. Unawareness and relational problems may also lead to scarce and late sexual relations, jealousy and a fear of being left. The women with Turner Syndrome refer to little self-exploration or masturbation as well as a fear of penetration.
Relevance to clinical practice:
Understanding the experiences of sexuality in heterosexual women with Turner Syndrome is a challenge for clinical nurses, who could provide quality care to these women in contextualised services.
... This chromosome is inherited from their mother, and the altered gene can be carried by her, usually asymptomatically, or arise from de novo mutation. Fully affected females are rare, either being homozygous through having mutations in both copies of their X-linked gene (one of which will be the copy from their father, who may himself have the same condition) [11], or through having only a single intact X-chromosome (as in Turner syndrome), and which happens to carry a mutation in the relevant gene. However, in several X-linked "recessive" disorders, patients' mothers can have some clinical evidence of the condition because of functional mosaicism [12]. ...
Turner syndrome (gonadal dysgenesis with short stature and sterility) is characterized by chromosomal karyotype 45,X in 50% of cases or by mosaicism (45,X/46,XX and 45,X/46,XY) in 30-40% or X structural defects (deletions, long arm isochromosome, ring chromosome). When mosaic Turner syndrome (TS) occurs with a Y chromosome, there may be ambiguous genitalia. Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disease with an X-Linked recessive pattern of inheritance that predominantly affects males, while females are usually asymptomatic. DMD has also been observed in groups of females affected by TS, not homozygous for the mutation. Here, we report a case of an Indian neonate born with ambiguous genitalia diagnosed prenatally by ultrasound who had a karyotype of 45,X/46,XY and who also had Duchenne muscular dystrophy caused by a de novo mutation in the DMD gene. Physical examination was normal without the typical dysmorphic features of TS with the exception of the genitourinary system showing ambiguous genitalia. Gender was assigned as female. At the age of three years, she had increasing difficulty walking, running, jumping and climbing stairs, proximal upper and lower extremity muscle weakness and a positive Gowers' sign. In addition, the serum creatine kinase (CK) value was over 30X the upper limit of normal. This study shows that DMD can occur in females with TS having 45,X/46,XY mosaicism and that this coexistence should be considered in women affected by TS who start to develop potential typical symptoms such as motor or developmental delay.
... It also raises the possibility that not all associated features may present within the neonatal period, as with KS. Further work is needed to identify and compile rare double aneuploidy cases, both mosaic and complete forms, to improve genotype-phenotype correlations [59,60]. ...
Double aneuploidy is the co-occurrence of aneuploidy of two different chromosomes within the same individual. Genomic imbalance associated with two aneuploidies in humans is associated with early lethality, and observation in live-born humans is rare. In isolation, trisomy of chromosomes 13, 18, 21, X, and Y may be better tolerated, whereas monosomy of X is the only such type of aberration that may be compatible with life. It is hypothesized that two successive malsegregation events must occur in early development to be observed constitutionally. Mechanisms like trisomy rescue or selection against aneuploidies may result in mosaicism and promote subsequent survival in live-born individuals, depending on the chromosomes involved. From the literature, double aneuploidy in the live-born is rare, with (acrocentric) autosomal with gonosomal aneuploidy more common than double autosomal aneuploidy. A retrospective case study of patients who underwent routine postnatal cytogenetic testing at The Johns Hopkins Hospital (JHH) Cytogenomics Laboratory (from its inception in the early 1960s-present) was carried out to identify mosaic and/or non-mosaic forms of double aneuploidy. One case each of non-mosaic [Klinefelter with Edwards Syndrome] and non-mosaic [Klinefelter with Down Syndrome] is identified. No gonosomal and autosomal cases in females nor double autosomal trisomies were identified in live-born individuals at the JHH Cytogenomics Laboratory. Given the advancements in non-invasive prenatal screening for common aneuploidies, the need for diagnostic confirmation studies persists. Providers should be aware of the possibility of early detection of pregnancies bearing double aneuploidy (common or rare) when maternal malignancy is not suspected. Additionally, clinicians should consider the possibility of double aneuploidy in rare situations of atypical or blended phenotypes reminiscent of dual diagnoses. Further work is needed to identify and compile these and even rarer double aneuploidy cases to improve genotype-phenotype correlations.
... This abnormality affected 1:2500 female birth. More than half of Turner syndrome patients are diagnosed after 12-14 years old, with the main complaints being amenorrhea and lack of spontaneous pubertal signs [1]. However, thalassemia is an X-linked hereditary disorder that affects globin chain synthesis. ...
Background
Turner syndrome and β-thalassemia very rarely occur together in an individual.
Case presentation
An Indonesian adolescent, 18 years old, complained is fatigue a week ago. She has a medical history of β-thalassemia for age 6 months and Turner syndrome identification for age 16 years. Meanwhile, she regular consumes deferasirox 500 mg every day. Physical examination showed pale conjunctiva and pale face. Body view similar children aged 13 years old. Laboratories investigation values included Hb of 7.7 gr/dL, MCV of 79.5 fL, MCH of 25.9 pg, MCHC of 28.6%, WBC of 6780/mm³, PLT of 242,000/mm³, AST of 15 U/L, ALT of 20 U/L, Ferritin of 1692.32 ng/mL, growth hormone of 0.468 ng/mL, Estradiol of <11.80 pg/mL, luteinizing hormone of 53.50 mIU/mL, and follicle-stimulating hormone of 115.19 mIU/mL. Chromosomal analysis showed Turner syndrome. The patient received a packed red cell transfusion of up Hb of 10 gr/dL, deferasirox 500 mg daily, and a contraceptive tablet. Due to financial issue in Indonesia, patient with Turner syndrome does not get proper hormonal therapy such as growth hormone, vitamin D supplementation, and other hormone replacement therapy.
Discussion
Turner syndrome and thalassemia in low-resource settings are challenges in themselves, so in their implementation, only thalassemia can be controlled, but for therapy, it does not show an improvement in prognosis.
Conclusion
Turner syndrome and thalassemia both worsen the patient's condition.
... It was postulated that dual diagnosis may be caused by the same meiotic error. [9] Diagnosis of those patients is clinically challenging, as the overlapping features and additive effect result in a blended phenotype. Some may initially diagnose as an apparent atypical presentation of one of the diseases. ...
... Recent studies suggest that multiple genetic conditions are involved in TS, including single gene variations, rare copy number variants, genetic polymorphisms, and epigenetics [1,[11][12][13]. Although there are many different types of genetic tests, there is no single test that can detect all the different genetic conditions. ...
The molecular genetic mechanism of Turner syndrome (TS) still leaves much to be discovered. Methods: TS (45X0) patients and age-matched controls (46XX and 46XY) were selected. The nanopore sequencing combined with trio-whole exome sequencing (trio-WES) were used for the first time to investigate TS. Results: Thirteen TS (45X0) patients and eight controls were enrolled. Trio-WES analysis did not find any pathogenetic or likely pathogenic variants except X chromosome (chrX) deletion. The average methylation levels and patterns of chrX in 45X0 and 46XY were similar, and significantly higher than in 46XX (p = 2.22 × 10−16). Both hyper-methylation and hypo-methylation were detected in the CpG island (CGI), CGI_shore, promoter, genebody, and PAR1-region, while in the transposon element inactivation regions of the chrX and hypermethylation were predominant. A total of 125 differentially methylated genes were identified in 45X0 compared to 46XX, including 8 and 117 hypermethylated and hypomethylated genes, respectively, with the enrichment terms of mitophagy, regulation of DNA-binding transcription factor activity, etc. Conclusions: The results suggest that the methylation profile in patients with TS might be determined by the number of X chromosomes; the patterns of methylation in TS were precisely associated with the maintenance of genomic stability and improvement of gene expression. Differentially methylated genes/pathways might reveal the potential epigenetic modulation and lead to better understanding of TS.
... Zarrouk-Mahjoub, 2016;Hodapp et al., 2006;Jones, McNamara, Longoni, et al., 2018;Katiyar, Davies, & Goel, 2020;Martin et al., 2014;Masciullo et al., 2013;Murakami, Kimura, Enomoto, et al., 2019;Polavarapu et al., 2019;Posey et al., 2016;Retterer et al., 2016;Ricci et al., 2012;Scarlato et al., 2015;Schreiber et al., 2013;Smith et al., 2019;Splinter et al., 2018;Trujillano et al., 2017;Vona et al., 2018). Complete diagnosis of these cases can pose a challenge as it can be difficult to ascertain if an atypical clinical feature could represent a novel phenotype of the primary condition or are due to a second genetic or acquired disease. ...
Reports of patients with concomitant diagnoses of two inherited genetic disorders, sometimes referred to as “double trouble,” have appeared intermittently in the medical literature. We report eight additional cases with dual diagnoses of two genetic conditions. All cases had a phenotype atypical for their primary diagnosis, leading to the search for a second genetic diagnosis. These cases highlight the importance of the history, physical examination and continued work‐up if the phenotype of the patient falls drastically outside what has been reported with their primary diagnosis. Some of the diagnoses of the patients presented here (e.g., Myotonic Dystrophy Type 1, fascioscapulohumeral muscular dystrophy) would not have been identified by genetic testing done on a next generation sequencing backbone (e.g., panel or exome sequencing). When the clinical picture is atypical or more severe than expected the possibility of a dual diagnosis (double trouble) should be considered. Identification of a second genetic condition can impact management and genetic counseling.
... Surveillance includes checking LFTs annually beginning at age 10 years, which is younger than previously suggested Alexiou et al., 2014;Hanaei, Habibi, Nejat, Sayarifard, & Vasei, 2015;Jones et al., 2018;Pier et al., 2014), case series (Larizza et al., 2016), and epidemiologic studies (Ji et al., 2016) provide support for an increase in certain types of cancer occurrence (showing a difference in pattern), the overall risk does not appear to be increased (see also Section 4.2). Thus, surveillance for cancer is not indicated. ...
Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.
Objective
Girls with Turner syndrome (TS) often have features that have been associated with obstructive sleep‐disordered breathing (oSDB). However, little is known about oSDB in TS. Herein, we aimed to characterize oSDB in young patients with TS and identify associated risk factors.
Study Design
Retrospective cross‐sectional study.
Setting
Tertiary care pediatric hospital.
Methods
We reviewed medical records for patients diagnosed with TS seen at our institution between October 1, 2007 and December 31, 2019 with the first outpatient visit before age 6 years. The prevalence of oSDB was compared to the general pediatric population with 1‐sample binomial proportion tests. Clinical characteristics were compared between those diagnosed with oSDB and those without oSDB, and risk factors for oSDB were identified.
Results
Of 151 patients with TS, 73 (48%) were diagnosed with oSDB which is 4‐fold higher than the general pediatric population (12%, P < 0.0001). In the multivariable model, adenoid, tonsillar, and inferior turbinate hypertrophy, birthweight, failure to thrive, and older age at the last clinic visit were all associated with increased odds for oSDB.
Conclusion
Young children with TS have a high prevalence of oSDB and thus should be screened for oSDB. Polysomnography should be performed in those with associated risk factors and symptoms oSDB. Treatment of oSDB is imperative as individuals with TS are already at increased risk of behavioral problems, neurocognitive deficits, and growth impairment that may be worsened with oSDB.
Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co-occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA-a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co-occur in individuals with Turner syndrome.
Background:
Retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR) are two distinct pathologies of retinal angiogenesis with overlapping clinical features.
Methods:
Examination, multimodal imaging, and genetic testing were used to guide diagnosis and treatment.
Results:
We report a combined phenotype of X-linked FEVR and ROP in a 4-month-old girl with mosaic Turner syndrome with ring X chromosome born at 26 weeks gestational age. She was initially diagnosed with atypical ROP with a vitreous band causing a localized traction retinal detachment, inferotemporal to the macula in the right eye, vessels to posterior zone 2 with no clear ridge temporally in the left eye, and fluorescein leakage in both eyes. Due to the suspicion of concurrent FEVR, genetic testing using a vitreoretinopathy panel was performed which revealed a mosaic Turner syndrome associated with 45,X/46,X,r(X), subsequently confirmed by chromosome analysis. The deleted region in the ring X chromosome included the NDP and RS1 genes. The patient was treated with laser photocoagulation of the peripheral avascular retina and sub-Tenon's triamcinolone injection in both eyes, intravitreal injection of bevacizumab in the left eye, and pars plicata vitrectomy in the right eye.
Conclusions:
In premature neonates with atypical ROP, a clinical suspicion of concurrent FEVR or similar vasculopathy is important and genetic testing may elucidate a genetic etiology, which could influence management and prognosis. Turner syndrome can be connected with co-occurring Mendelian gene disorders, particularly in individuals with mosaicism. The concurrence of FEVR and ROP appears to result in atypical and possibly more severe phenotypes.
We present an 18‐month‐old male with Tetralogy of Fallot, retrognathia, short stature, global developmental delay, and dysmorphic features who was found to have dual diagnoses of both Williams syndrome and 22q11.2 deletion syndrome (22q11.2DS). To our knowledge, this is the second case of such a co‐occurrence documented in the medical literature. Our patient presents with a blended physical phenotype of these two conditions and a behavioral phenotype that is distinct from what is typically observed in either disorder alone. We compare our patient's phenotype to the previously reported case and to the typical phenotypes for each individual condition. Additionally, we discuss why the occurrence of these two disorders together seems to be so rare, and the benefit of a genetics evaluation to an inpatient service team and the patient.
Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies and sensorineural hearing loss when compared to loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.
There are currently no published cases that report concomitant Turner syndrome (TS), 2q37 deletion syndrome and X-linked hypophosphatemic rickets (XLH). Interestingly, since the clinical phenotypes of TS and 2q37 deletion syndrome overlap, the correct diagnosis may be missed without a standardized approach to genetic testing consisting of both karyotype and microarray. Both chromosome anomalies have been associated with short stature and a variety of skeletal abnormalities however to date no reports have associated these syndromes in association with a phosphate regulating endopeptidase homolog, X-linked (PHEX) gene deletion resulting in XLH. We report a 3-year-old female with 3 concurrent genetic disorders including a 9.98 Mb terminal deletion of chromosome 2: del(2)(q37.1;q37.3), XLH secondary to a small microdeletion of part of the PHEX gene, and mosaic TS (mos 45,X[32]/46,X[18]). This is the first case report of a patient with 2q37 deletion syndrome and mosaic TS (mos 45,X[32]/46,X[18]) found to have XLH secondary to an interstitial constitutional PHEX gene deletion. Her severe phenotype and multiple genotypic findings reinforce the importance of thorough genetic testing in the setting of complicated phenotypic presentations.
Objective:
17α-Hydroxylase deficiency (P450c17D) is characterized by hypogonadism and mineralocorticoid hypertension. We aimed to estimate the relative incidence and spectrum of preliminary misdiagnoses in Brazilian P450c17D patients.
Design:
Cross-sectional study.
Methods:
We reviewed, updated, and analyzed data of 40 P450c17D patients (21 XY, 19 XX).
Results:
Complete data were unavailable for two patients. Seven patients were relatives of an index case. Of the 31 index cases, 29 (94%) received a total of 16 misdiagnoses (1 to 4 per patient) before confirmation of P450c17D. Essential hypertension (55%), pure gonadal dysgenesis (35%), and androgen resistance syndrome (21%) were the most frequent misdiagnoses. Median ages at initial and final diagnosis were 13.2 and 16.5 years, respectively, with an average interval to diagnosis of 3.2 years. Initially, 38 patients (95%) had hypertension, and 75% had hypokalemia. Primary amenorrhea and sexual infantilism were present in 95% patients, and 73% were at Tanner stage I. All had low-to-undetectable estrogens and androgens with elevated gonadotropins and progesterone (580±53 ng/dL). Several had recurrent infections in childhood and neurological issues prior to final diagnosis, and/or had siblings who died of infectious diseases or unknown causes before puberty.
Conclusions:
The high percentage of prior misdiagnoses in P450c17D patients may be attributable to the rarity of and relative unfamiliarity with the disease, its varied clinical presentation, and the limited access to critical steroid dosages and genotyping. Reduced sex steroids, and elevated gonadotropins and progesterone levels, in addition to mineralocorticoid hypertension, are pathognomonic of P450c17D. CYP17A1 gene mutations provide a definitive diagnosis.
Abbreviations:
P450c17D = 17α - Hydroxylase deficiency; CAH = Congenital Adrenal Hiperplasia; CYP17A1 = 17 α - Hidroxylase enzyme; HH = Hipergonadotropic Hypogonadism; ACTH = Adrenocorticotropic hormone; DOC = Deoxycorticosterone; 18OHDOC = 18-Hidroxydeoxycorticosterone; TS = Tanner stage; 17OHD = 17α - Hydroxylase deficiency; Pt = Patients; Dx = Diagnosis; CN = Chromatin-negative; CDP = Constitutional delay of puberty; CT = Computed tomography; Dx RO = Diagnosis ruled out; defc = deficiency; GNT = Gonadotropins; MC = Mineralocorticoid; NL = normal; POF = premature ovarian failure; PRA = plasma renin activity; RVH = renovascular hypertension; Turner Sd = Turner syndrome; US = ultrasonography.
Introduction:
Turner syndrome is a relatively common chromosomal disorder which affects about one in 2000 live born females. Duchenne muscular dystrophy is an X-linked recessive disorder affecting 1:3600 live born males. Considering the above, the coexistence of these two diseases may occur only anecdotally.
Case presentation:
Here, we report a 4 ½ year-old female with classical 45,X Turner syndrome who also had Duchenne muscular dystrophy caused by a point mutation in the dystrophin gene (c.9055delG). The patient showed the typical phenotype of Turner syndrome including distinctive dysmorphic features (short neck, low posterior hairline, wide position of nipples), aortic coarctation and feet lymphedema. Besides, she presented with an unusually early beginning of muscular dystrophy symptoms with infantile-onset motor developmental delay, intellectual disability and early calf muscular hypertrophy.
Conclusion:
The coexistence of an X-linked recessive disorder should be considered in women affected by Turner syndrome presenting with additional atypical clinical features.
Turner syndrome affects 25–50 per 100,000 females and can involve multiple organs through all stages of life,
necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important
advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with
TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the
USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five
groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during
childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other
comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four
pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and
Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy
and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines
project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with
The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and
Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology.
The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society,
the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in
pre-meeting discussions and in the consensus meeting.
Neurofibromatosis type 1 (NF1) is classically defined by the presence of multiple c afé-au-lait macules as one of the diagnostic criteria. Turner syndrome (TS) can also present with café-au-lait macules along with short stature. Our patient is the fifth reported with both NF1 and TS and the first who has been on growth hormone for short stature associated with TS.
Most cases of Van der Woude syndrome are caused by a mutation to interferon regulatory factor 6 on chromosome 1. Turner syndrome is caused by complete or partial absence of the second sex chromosome in girls. We describe a unique case of the two syndromes occurring concurrently though apparently independently in a girl with Van der Woude syndrome diagnosed at birth and Turner syndrome at 14 years 9 months. Short stature was initially misattributed to Van der Woude syndrome and pituitary insufficiency associated with clefts before correctly diagnosing Turner syndrome. We discuss the prevalence of delayed diagnosis of Turner syndrome, the rarity of reports of concurrent autosomal chromosome mutation and sex chromosome deletion, as well as the need to consider the diagnosis of Turner syndrome in all girls with short stature regardless of prior medical history.
Introduction . The coexistence of Down and Turner syndromes due to double chromosome aneuploidy is very rare; it is even more rare to find the presence of a double monoclonal chromosomal abnormality. Objective . To report a unique case of double monoclonal chromosomal abnormality with trisomy of chromosome 21 and an X ring chromosome in all cells studied; no previous report has been found. Case Report . Female, 28 months old, with pathological short stature from birth, with the following dysmorphic features: tilted upward palpebral fissures, short neck, brachycephaly, and low-set ears. During the neonatal period, the infant presented generalized hypotonia and lymphedema of hands and feet. Karyotype showed 47,X,r(X),+21 [30]. Conclusion . Clinical features of both Down and Turner syndromes were found, highlighting short stature that has remained below 3 z score from birth to the present, associated with delayed psychomotor development. G-banded karyotype analysis in peripheral blood is essential for a definitive diagnosis.
A 6-month-old girl was referred by an ophthalmologist because of postoperative bleeding. She was scheduled for operation because of persistent hyperplastic primary vitreous. Workups were done and prolonged partial thromboplastin time with normal platelet count, normal bleeding time, and prothrombin time were detected. There was negative family history of bleeding tendency in both maternal and paternal family, so at the first step, Factor XI assay was requested which was normal. Then, von Willebrand factor and factor VIII were assayed which was 127% and less than 1%, respectively. Severe factor VIII deficiency was not suspected in a girl unless in siblings of a hemophilic patient who gets married with her carrier cousin. Chromosomal study and genetic testing were requested and mosaic Turner syndrome (45 XO) with ring X (p22, 2q13) along with inversion 22 (hemizygote) was detected. Abdominal and pelvic sonography showed absence of both ovaries with presence of infantile uterus. Maternal genetic study was in favor of carrier of hemophilia (heterozygote inversion 22). To the best of our knowledge, this is the first case of association of Turner syndrome with severe hemophilia A and persistent hyperplastic primary vitreous.
In the present paper we report an extremely rare case of mosaicism of 45,X/47,XX,+13 in a 28-year-old women. The patient was referred for cytogenetic evaluation for secondary amenorrhoea. The patient was found to have some mild characteristic features of Turner syndrome such as wide carrying angle and short stature. Ultrasound examination revealed the presence of a small sized uterus and bilateral streak ovaries. G-banded chromosome analysis revealed a mosaic female karyotype involving two different cell lines. One cell line (72% of analysed metaphases) presented monosomy of X while the remaining 28% of cells showed trisomy of chromosome 13. Fluorescence in situ hybridization (FISH) with locus specific probe for trisomy 13 and CEP X for monosomy X substantiated the results obtained from karyotyping.
QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc) over time and relate the findings to the Turner syndrome phenotype.
Adult women with Turner syndrome (n = 88) were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett's (bQTc) and Hodges's formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done.
The mean hQTc in women with Turner syndrome (414.0±25.5 ms) compared to controls (390.4±17.8 ms) was prolonged (p<0.001) and did not change over time (416.9±22.6 vs. 415.6±25.5 ms; p = 0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other Turner syndrome karyotypes (418.2±24.8 vs. 407.6±25.5 ms; p = 0.055). In women with Turner syndrome and a bQTc >432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2) and one in a minor Long QT syndrome gene (KCNE2).
There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women.
NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.
Cornelia de Lange syndrome (CdLS) is a dominantly inherited disorder characterized by facial dysmorphism, growth and cognitive impairment, limb malformations and multiple organ involvement. Mutations in NIPBL gene account for about 60% of patients with CdLS. This gene encodes a key regulator of the Cohesin complex, which controls sister chromatid segregation during both mitosis and meiosis. Turner syndrome (TS) results from the partial or complete absence of one of the X chromosomes, usually associated with congenital lymphedema, short stature, and gonadal dysgenesis.
Here we report a four-year-old female with CdLS due to a frameshift mutation in the NIPBL gene (c.1445_1448delGAGA), who also had a tissue-specific mosaic 45,X/46,XX karyotype. The patient showed a severe form of CdLS with craniofacial dysmorphism, pre- and post-natal growth delay, cardiovascular abnormalities, hirsutism and severe psychomotor retardation with behavioural problems. She also presented with minor clinical features consistent with TS, including peripheral lymphedema and webbed neck. The NIPBL mutation was present in the two tissues analysed from different embryonic origins (peripheral blood lymphocytes and oral mucosa epithelial cells). However, the percentage of cells with monosomy X was low and variable in tissues. These findings indicate that, ontogenically, the NIPBL mutation may have appeared before the mosaic monosomy X.
The coexistence in several patients of these two rare disorders raises the issue of whether there is indeed a cause-effect association. The detailed clinical descriptions indicate predominant CdLS phenotype, although additional TS manifestations may appear in adolescence.
Marfan syndrome is an autosomal dominant heritable disorder of the connective tissue that involves primarily the skeletal, ocular, and cardiovascular systems. Turner syndrome is a genetic disorder resulting from partial or complete X chromosome monosomy. We report the anesthetic management of a case of Marfan-Turner syndrome, which is the first such case to appear in the literature to our knowledge. A 3 year old ASA III girl was scheduled to undergo minor plastic surgery. She had a short webbed neck, prognathism, micrognathia, low-set ears, and a high palate. Her anterior and posterior facial heights were long. She had growth retardation, pectus excavatum, and joint laxity. She also had high-degree mitral insufficiency, mitral valve prolapse, and an atrial septal defect. After sevoflurane induction, the airway was secured using a size 2 LMA without any difficulty in the spontaneously breathing patient. Her blood pressure was within normal limits, no arrthymia occurred, and anesthesia was uneventful. Special care should be given to syndromic patients. Prior medical evaluations and any prior anesthetic history can help to focus preoperative evaluations and planning. Preoperatively targeting relevant organ systems, any anatomic or laboratory abnormalities that can be optimized, and perioperative airway management are all key to a successful outcome.
To report the presence of Axenfeld-Rieger spectrum in a case of 45,X Turner syndrome. Design: Non-interventional case report.
A 13-year-old girl underwent complete genetic clinical evaluation comprising detailed family history taking with pedigree construction in addition to a thorough clinical examination and a number of investigations. A cytogenetic study, molecular testing for hidden Y-chromosome material, and a full ophthalmological assessment including slit lamp examination were also performed.
Physical examination revealed typical features of Turner syndrome: short stature, webbing of the neck with low posterior hairline, widely spaced nipples and lack of development of secondary sexual characteristics. Abdominal and pelvic ultrasound showed a horse-shoe kidney with double ureter, a hypoplastic uterus and bilateral streak ovaries. Mitral regurgitation was diagnosed on echocardiography. Chromosomal analysis revealed a 45,X Turner syndrome karyotype while the molecular study failed to demonstrate any occult Y chromosome derivative. The ophthalmological assessment revealed sclerocornea and Axenfeld anomaly with synechia.
Few reported cases in the literature describe the coexistence of Axenfeld-Rieger spectrum and Turner syndrome. Our study adds to the evidence that ocular problems occur frequently in Turner syndrome. A routine ophthalmologic examination is recommended early in Turner syndrome to diagnose and treat confirmed abnormalities. Conversely, general examination and chromosomal analysis should be indicated in patients presenting with anterior chamber dysgenesis.
Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR.
Turner syndrome; Duchenne Muscular Dystrophy; Deflazacort; 6MWT; Female DMD; Short stature
Background
Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.
Methods
We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.
Results
A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10⁻⁷).
Conclusions
In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.)
Mosaic Turner syndrome (TSM) commonly occurs in the form of 45,X/46,XX and 45,X/46,X,i(X)(q10). Mosaicism for a Y chromosome, 45,X/46,XY, has been well documented and is associated with increased risk of gonadoblastoma (GB). To date, there are only six reported cases of TSM with a trisomy 18 karyotype, and only two of these were phenotypically female with 45,X/47,XY,+18 karyotype. We present the case of a phenotypically female infant born with dysmorphic features. G-banded karyotype and interphase FISH of blood showed 45,X in 95% and 47,XY,+18 (trisomy 18) in 5% of cells analysed. However, interphase FISH of buccal cells showed only the presence of the 45,X cell line. Due to the presence of Y chromosome material, elective gonadectomy was performed at 13 months of age. There were bilateral streak ovaries with early evidence of GB bilaterally, a rudimentary uterus and bilateral fallopian tubes with unilateral ectopic adrenal tissue identified histologically. Interphase FISH of the gonadal tissue was similar to the blood findings with 45,X in 86% of cells and 47,XY,+18 in 14% of cells analysed. This case highlights a rare karyotype of TSM and trisomy 18 in the same patient and is the first reporting the associated finding of bilateral GB.
One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.
Cornelia de Lange Syndrome (CdLS) is an autosomal dominant (NIPBL, SMC3, and RAD21) or X-linked (SMC1A and HDAC8) disorder, characterized by distinctive craniofacial appearance, growth retardation, intellectual disability, and limb anomalies. In 2005, the Spanish CdLS Reference Center was started and now we have more than 270 cases in our database. In this special issue, we describe some of the unique or atypical patients studied by our group, whose clinical features have contributed to the expansion of the CdLS classical phenotype, helping clinicians to diagnose it. We include the case of a male with unilateral tibial hypoplasia and peroneal agenesis who had a mutation in NIPBL; we also describe one patient with a mutation in NIPBL and somatic mosaicism identified by new generation sequencing techniques; we also include one patient with CdLS and Turner syndrome; and last, an interesting patient with a duplication of the SMC1A gene. Finally, we make a short review of the splicing mutations we have found in NIPBL regarding the new knowledge on the physiological variants of the gene. © 2016 Wiley Periodicals, Inc.
Pseudohypohyperparathyroidism (PHHP) is a rare type of pseudohypoparathyroidism (PHP), which seems to have a normal skeletal response to parathyroid hormone but shows renal resistance. Almost all patients with PHHP have PHP Ib, a subtype of PHP that is usually caused by GNAS methylation defects, often in exon 1A. Some features of Albright hereditary osteodystrophy can occasionally be found in patients with PHHP, but these features are also common in Turner syndrome. The authors report on an extremely rare case of a patient with PHHP and Turner syndrome, a 47-year-old woman who sought medical attention for hypocalcemia and elevated parathyroid hormone. She had no family history of hypocalcemia and no STX16 gene deletions. She had a mosaic karyotype of 46, X, del(X)(p11.4)/45, XO. Pyrosequencing was performed to determine the GNAS exon 1A methylation. The degree of methylation found in exon 1A of the patient was lower than her unaffected relatives.
• Double aneuploidy involving Down and Turner syndromes is a rare occurrence. Of the six patients reported to have combined Down and Turner syndromes, four fundamentally different forms of chromosome mosaicism have been noted and all have been mosaic with respect to monosomy X. Reported here is the first example of a Turner-Down patient in whom there is no X mosaicism. The different forms of the double aneuploidy cannot be explained by any single combination of nondisjunctional errors. The clinical findings in these patients and the several mechanisms of nondisjunctional error that may account for the observed forms of aneuploidy are reviewed and discussed.
(Am J Dis Child 129:1062-1065, 1975)
17α-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia. It leads to a reduced production of cortisol and sex steroids and thus an increase in adrenocorticotrophic hormone and gonadotrophins levels. High adrenocorticotrophic hormone levels result in an accumulation of 17-deoxysteroids, such as deoxycorticosterone and corticosterone. Deoxycorticosterone and corticosterone have an important mineralocorticoid activity. We report the case of a 66-year-old woman who presented with hypertension and symptomatic hypokalaemia. Primary hyperaldosteronism was suspected and a right adrenal mass was removed. After surgery, the patient was referred to the endocrinology department for persistant hypokalaemia. Actually, she presented some signs of hypogonadism (impuberism, primary amenorrhea, infertility). Cortisol and 17OH-progesterone serum levels were low. Deoxycorticosterone and corticosterone were markedly elevated. The hypothesis of 17α-hydroxylase deficiency was considered and confirmed by genetic exploration. A non-sense mutation c.938G>A (p.Trp313X) in exon 5 of the CYP17 gene was found that had never been reported so far to our knowledge. Moreover, the patient's karyotype found a mosaic Turner syndrome. This case is particularly interesting because of the delay of diagnosis. The 17α-hydroxylase deficiency diagnosis is to be considered when hypertension is associated with hypokalaemia and hypogonadism, even in adult patients.
Chromosomal aneuploidy is considerably frequent and may involve either autosomes or sex chromosomes. While double aneuploidy involving both autosomal and sex chromosomes is rare, several reports described the cases of sex chromosomal aneuploidies in combination with trisomy 21, such as Down-Klinefelter and Down-Turner syndrome. However, trisomy 8-Turner syndrome has been rarely described to date. Here we report a case of a 28-year-old female with mosaic trisomy 8-Turner syndrome. The patient was referred to our hospital for aortic dissection. On physical evaluation, features of her phenotype, which included short stature, webbed neck and cubitus valgus, suggested congenital anomalies such as Turner syndrome. Chest CT revealed aortic dissection with bicuspid aortic valve and coarctation. G-banding cytogenetic analysis of peripheral blood showed mosaicism with two cell lines (45,X[17]/47,XX,+8[33]). FISH analysis indicated that 15% of the cells were of monosomy X karyotype and 85% of the cells were with XX karyotype and trisomy 8 was detected only in XX cells. Though the patient exhibited clinical features of Turner syndrome, somatic stigmas present were not clearly distinguishable from those of trisomy 8, such as short stature, skeletal and cardiac abnormalities. Observations from most of the double aneuploidy cases indicated that the patient's phenotype was not necessarily in correlation to the ratio of autosomal and sex chromosomal aberrations. Mosaicism in trisomy 8-Turner syndrome was rarely documented and we believe this is the first reported case of mosaicism in trisomy 8-Turner syndrome presenting with aortic dissection and surviving into adulthood.
A 21-year-old woman with a short stature presented with primary amenorrhoea and a 45X karyotype, and comparative genomic hybridization revealed 1p36 deletion and abnormal genes in multiple chromosomes to support the diagnosis of Turner syndrome and monosomy 1p36 deletion syndrome. The main clinical features of this condition include microsomia, poor sexual development, menoschesis, gigantorectum, absence of internal genitalia, sometimes with thyropenia and low intelligence. This disease can be easily diagnosed for its heterogeneous clinical manifestations.
X-linked congenital nystagmus is a rare disorder in which affected males manifest binocular uniplanar nystagmus with associated head oscillation. In the families previously reported, affected females have been described. We report on a multigeneration family with X-linked congenital nystagmus with an affected woman. She was a (46,XX/45,X) mosaic. Magnetic resonance images of the brain of affected individuals were normal.
A 14-year-old girl with Turner phenotype is described, whose lymphocyte and skin fibroblast cultures both revealed a 45,X/47,XY,+18 chromosomal mosaicism. In blood cultures one third and in fibroblasts 7% of the cells had 47 chromosomes. The identity of the Y and the supernumerary 18 were determined by fluorescence and Giemsa banding patterns. The patient is of normal intelligence and does not exhibit any signs of masculinization or stigmata of trisomy 18.
The present report describes a child with Down's syndrome and male pseudohermaphroditism in whom we found a 47, XY,+21/46, X,+21 mosaic chromosome complement. Necropsy revealed both Mullerian and Wolffian structures and bilateral testes.
I HAVE already reported a longitudinal cytogenetic study of eleven infant Down's syndrome mosaics1, and now have further data on most of the eleven subjects and similar data on seven more.
Unlabelled:
Very few cases of mosaic trisomy 13 combined with a monosomy X have been reported. It can be assumed that most likely the zygote was 47,XX,+13 and 2 chromosomes (13 and X) were lost simultaneously during an early postzygotic division. Here, we reported a 3-year-old girl with mosaicism of trisomy 13 and monosomy X. The child had a short neck, hypertelorism, depressed nasal ridge, epicanthal fold, mid-facial hypoplasia, thin upper lip, long philtrum, ear anomalies, postaxial polydactyly, atrial septal defect, hydronephrosis, and sensorineural hearing loss. Her weight and length were consistently below the fifth centile. She demonstrated global developmental delay when evaluated at 10 and 16 months. The range of developmental quotients (DQs) was from 0.6 to 1.1; the personal-social part was the best, and gross motor development was the worst. When evaluated at 31 months, the DQs of motor development were from 0.52 to 0.69, the object manipulation subscale was 0.52, the visual-motor integration subscale was 0.59 and the mental DQ was 0.52. Her social-behavior part was the best, language was the worst and the DQs had dropped with growth.
Conclusion:
This is a case report of global development in a girl with mosaicism of trisomy 13 and monosomy X. The majority of physical anomalies observed tend to be mild and non-life threatening. Her DQs dropped with growth, and the language and mental development were significantly delayed after 30 months.
Recessive X-linked dystonia-parkinsonism almost exclusively affects men. We investigated the genetic mechanisms causing this disorder in a female patient.
We confirmed the presence of an X-linked dystonia-parkinsonism–specific change in our patient by sequencing. In addition, we employed quantitative real-time PCR and array comparative genomic hybridization to determine the patient's X-chromosome copy number.
The patient's sequence electropherogram suggested a higher amount of the mutated allele compared with the wild-type allele. Subsequently, extensive gene dosage analyses revealed a copy number of the X chromosomes between 1 and 2, indicating loss of 1 X chromosome in a subset of cells. Phenotypic reevaluation of the patient showed several clinical features of Turner syndrome.
Our female X-linked dystonia-parkinsonism patient suffered from an undiagnosed X-chromosome monosomy in a subset of cells (45,X/46,XX), suggesting an atypical Turner syndrome and contributing the first molecular explanation for the manifestation of an X-linked dystonia-parkinsonism phenotype in women.
We report on an individual with developmental delays, short stature, skeletal abnormalities, normal pubertal development, expansion of the fragile X triplet repeat, as well as an isodicentric X chromosome. S is a 19-year-old woman who presented for evaluation of developmental delay. Pregnancy was complicated by a threatened miscarriage. She was a healthy child with intellectual impairment noted in infancy. Although she had global delays, speech was noted to be disproportionately delayed with few words until age 3.5 years. Facial appearance was consistent with fragile X syndrome. Age of onset of menses was 11 years with normal breast development. A maternal male second cousin had been identified with fragile X syndrome based on DNA studies. The mother of this child (S's maternal first cousin) and the grandfather (S's maternal uncle) were both intellectually normal but were identified as carrying triplet expansions in the premutation range. S's mother had some school difficulties but was not identified as having global delays. Molecular analysis of S's fragile X alleles noted an expansion of more than 400 CGG repeats in one allele. Routine cytogenetic studies of peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored. Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from peripheral blood showed that the structurally normal chromosome had the fragile site in approximately 16% of the cells. Analysis of maternal fragile X alleles identified an allele with an expansion to ∼110 repeats. FMRP studies detected the expression of the protein in 24% of cells studied. To our knowledge, this is the first patient reported with an isodicentric X and fragile X syndrome. Whereas her clinical phenotype is suggestive of fragile X syndrome, her skeletal abnormalities may represent the presence of the isodicentric X. Treatment of S with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol, this individual reinforces the recommendation of obtaining chromosomes on individuals with developmental delay even with a family history of fragile X syndrome. Am. J. Med. Genet. 85:197–201, 1999. © 1999 Wiley-Liss, Inc.
There is a well-known association between neurofibromatosis-1 (NF1) and Noonan syndrome-like manifestations, including short stature, short broad neck, and hypertelorism. These anomalies are thought to be due to variable expression of the NF1 gene. We report on two girls with NF1 who were found to have the Ullrich-Turner syndrome. Case 1, a 12-year-old white girl, was followed in a Neurofibromatosis Clinic because of multiple café-au-lait spots and a family history of NF1 in her mother and sister. On examination, she had short stature, hypertelorism, and short neck with low posterior hairline. Karyotype was 86% 46,XY/14% 45,X. Case 2, the first child of a woman with NF1, presented at birth with lymphedema of hands and feet and a short broad neck. Karyotype was 45,X. At age 23 months she was short, had epicanthic folds, hypertelorism, narrow palate, right simian crease, 19 café-au-lait spots, and axillary freckling. We conclude that chromosome studies should be performed in girls with NF1 who have short stature and Noonan- or Ullrich-Turner-like findings. Dilemmas raised by the dual diagnoses of NF1 and Ullrich-Turner syndrome include potential risks of growth hormone therapy and estrogen replacement therapy. © 1996 Wiley-Liss, Inc.
Double aneuploidy involving Down syndrome and Turner syndrome is a rare chromosomal abnormality presumed to occur with a frequency of about 1 in 2 million births. Twenty-one cases of this combined anomaly have been reported and two infants were born with this anomaly after a mistake in prenatal diagnosis. We report the first prenatal diagnosis of Down syndrome combined with Turner mosaicism and suggest that this polysyndrome may be more common than previously estimated. We, therefore, wish to alert cytogenetic laboratories performing prenatal diagnoses of the potential risks of misdiagnosis of this polysyndrome if banding is not performed and if a sufficient number of mitotic cells are not analysed.
Chromosome analysis of amniotic fluid cells from a 17-week-old fetus with a nuchal cystic hygroma showed a 45,X/47,XX,+21 karyotype. Analyses of cord blood lymphocytes, skin fibroblasts, amniotic membrane, and chorionic villi demonstrated both cell lines in various proportions. We studied the origin and mechanism of formation of the double mosaic aneuploid using Q-banded chromosomal heteromorphisms, and one RFLP, two VNTRs, one tetranucleotide repeat, 28 CA repeat markers, mapped to every member of chromosomes. The heteromorphic markers examined showed no discordant patterns in parent-to-child transmission or between the two cell lines except for those in chromosomes 21 and X. Fetal DNA was extracted from its established monoclonal fibroblast cell lines with 45,X or 47,XX,+21 karyotypes. Genotyping with the DNA markers showed that each cell line was identical at every locus, except for chromosome 21 or X loci, indicating that the fetus was not a chimera but a mosaic. The 21-trisomic cells had one paternal allele and two maternal heterozygous alleles at the D21S270 locus, and the 45,X (21-disomic) cells had two biparental alleles. Alleles at two X chromosomal loci, DXS991 and DXS8057, were biparental in the 47,XX,+21 cells, whereas only the paternal allele was retained in the 45,X cells. Based on these findings, we concluded that the fetus started as a 47,XX,+21 zygote that had resulted from nondisjunction at the maternal first meiotic division and that one each of the maternally derived chromosomes 21 and X was lost during an early mitotic division, leading to the mosaicism. Am. J. Med. Genet. 75:432-437, 1998. © 1998 Wiley-Liss, Inc.
Es wird ber ein 7jhriges Mdchen berichtet, bei dem im Mosaik Zellen mit Trisomie 21, Monosomie X und normalem weiblichem Karyotyp gefunden wurden. Klinisch bot die Patientin das abgeschwchte Erscheinungsbild des Mongolismus. Die fr das Turner-Syndrom typischen ueren Vernderungen traten demgegenber zurck.A 7 year old girl is found to have a chromosome mosaic of trisomy 21, monosomy X, and normal female karyotype. The patient showed some clinical symptoms of mongolism, whereas Turner-stigmata were less obvious.
A case of female hemophilia with a 46,XXr/45,X karyotype and signs of Turner syndrome, has been followed for the past 10 years. One of her brothers also has hemophilia A. A study with polymorphic DNA probes located in the Xq27-qter region has enabled us to demonstrate that the ring chromosome is of paternal origin and that the factor VIII gene region is deleted. The hemizygous state allowed expression of the hemophilia A mutation, present on the morphologically normal X chromosome, inherited from her carrier mother.
This paper summarizes previous chromosomal studies in patients with the Cornelia de Lange syndrome showing abnormal karyotypes. We report on 45 cases of the Cornelia de Lange syndrome clinically examined by one of us (B. B.) and chromosomally studied using several different methods. Two abnormal karyotypes were found: a girl with a 45,X karyotype and a boy with a (13q14q) translocation which was also found in his phenotypically normal mother and maternal grandmother. Because of recent reports of the duplication 3q syndrome and Comelia de Lange-like phenotypes, prometaphase chromosomes were studied in 31 patients. All karyotypes were normal. As there was an excess of boys among the younger patients, special examination for the fragile site on X(q28) was carried out. This abnormality was not found. Even though no patients with the dup(3q) syndrome were found among the Cornelia de Lange patients, chromosome studies are recommended especially in connection with genetic counselling. A recurrence rate of 2–5% must still be considered for the Cornelia de Lange syndrome.
Cornelia de Lange Syndrome (CdLS) is a genetically heterogeneous disorder characterized by dysmorphic facial features, cleft palate, limb defects, growth retardation, and developmental delay. Approximately 60% of patients with CdLS have an identifiable mutation in the NIPBL gene at 5p13.2. Recently, an X-linked form of CdLS with a generally milder phenotype was attributed to mutation of the structural maintenance of chromosomes 1A gene (SMC1A) at Xp11.22. Relatively few CdLS patients with mutations in SMC1A are known; female carriers have minor facial dysmorphism and cognitive deficiency without major structural abnormalities. To date, all mutations identified in SMC1A are missense or small in-frame deletions that preserve the open reading frame of the gene and likely have a dominant-negative effect. We report on a female with monosomy X mosaicism and a phenotype suggestive of a severe form of CdLS who presented with growth and mental retardation, multiple congenital anomalies, and facial dysmorphism. Array CGH confirmed mosaic monosomy X and identified a novel deletion of SMC1A spanning multiple exons, suggesting a possible loss-of-function effect. Sequencing of both genomic and cDNA demonstrated an 8,152 bp deletion of genomic DNA from exon 13 to intron 16. Although a loss-of-function effect cannot be excluded, the resulting mRNA remains in-frame and is expressed in peripheral blood lymphocytes, suggesting a dominant-negative effect. We hypothesize that the size of this deletion compared to previously reported mutations may account for this patient's severe CdLS phenotype. The presence of mosaic monosomy X may also modify the phenotype. © 2011 Wiley Periodicals, Inc.