Turner syndrome is a chromosomal disorder, characterized by the partial or total deletion of one X chromosome, resulting in various karyotypes that presumably lead to different phenotypes. However, most studies find it difficult to predict phenotypes from karyotypes due to the presence of mosaicism. The purpose of this study is to clarify the relationship between karyotype and phenotype in Turner syndrome with non-mosaic X chromosome structural rearrangements. A systematic literature search was conducted using Medline and Embase classics plus Embase between 1947 and September 2023. A total of 487 Turner women with non-mosaic X chromosome structural rearrangements were included from the 69 studies. The prevalence of short stature was 72.4% in Turner syndrome with non-mosaic X chromosome structural rearrangements, 80.1% in the short arm deletion group (del (Xp)), 75% in the del(X)(p22.3) group, 65.8% in the del(X)(p21) and del(X)(p22) group, and 37.5% (20%-66.7%) in the long arm deletion group (del(Xq)). The prevalence of ovarian dysfunction was 78.8% in Turner syndrome with non-mosaic X chromosome structural rearrangements, 72.5% in the del (Xp) group, 27.6% in the del (X)(p22.3) group, 33.3% in the del (X)(p21) and del(X)(p22) group, and 94.6% in the del (Xq) group. The recognition of X chromosome breakpoints is useful in the management of Turner syndrome complications, since some phenotypes are unique depending on the deletion region. Ovarian dysfunction is significantly related to karyotype, so the identification of karyotypes in Turner syndrome is important for managing ovarian dysfunction and predicting future fertility. The Kell blood group system is vast, with 38 blood group antigens. The Kell system is notorious for its immunogenicity, which is third after ABO and Rhesus D. This system is involved in severe forms of hemolytic disease of the fetus and newborn and hemolytic transfusion reactions. Further, this blood group system is associated with chronic granulomatous diseases and a multisystem syndrome involving neurological, cardiovascular, and hematologic symptoms called McLeod syndrome. The symbol of the Kell blood group system as per "International Society of Blood Transfusion" (ISBT) is KEL; ISBT number: 006. History: The Kell blood group system was described in 1946 and named after Mrs Kelleher, whose newborn child died of hemolytic disease of fetus and newborn (HDFN) due to an antibody against his red blood cells (RBCs). This antibody also reacted with her daughter's and husband's RBCs and was named anti-K. Later, its antithetical antigen k was discovered in 1949, and the null phenotype (K0) in 1957. Genetics: The KEL gene encodes the Kell antigens and is located at chromosome 7q34, comprising 20 exons spanning 21.25 kb of genomic DNA. This gene is also known as Kell metallo-endopeptidase, ECE3, or CD238. Single nucleotide polymorphisms are responsible for multiple Kell antigens. Another important XK gene required for the expression of Kell antigen is present on the short arm of chromosome X (Xp21.1) and is responsible for forming the Kx antigen. Structure of Kell glycoprotein: The KEL gene encodes the polymorphic Kell and para-Kell glycoproteins, structurally single-pass RBC membrane proteins, or type II glycoproteins. The N terminal is intracytoplasmic, and the C terminal is multi-folded, bound by disulfide bonds, and extracytoplasmic. They constitute around 732 amino acids; mutations in these lead to the formation of a multitude of Kell antigens. The Kell glycoprotein is covalently linked to the Kx protein via a single disulfide bond. This Kx antigen protein traverses the RBC membrane 10 times. The absence of Kx protein leads to McLeod syndrome. The Kell glycoproteins have been found to have a similar sequence as the neprilysin (M13) family of zinc endopeptidases and, hence, act like proteolytic enzymes. They share a pentameric sequence HEXXH, which is needed to add zinc and proteolytic activity. Kell preferentially cleaves big endothelin-3, converting it to the bioactive peptide endothelin-3. This potent vasoconstrictor peptide leads to vascular endothelial growth factor formation. Antigens: The Kell system is highly polymorphic, consisting of 38 different blood group antigens. The Kell antigens are found on erythroid cells and progenitor myeloid cells and are also present in skeletal muscles and testes. Common Kell Antigens K antigen: ISBT symbol: KEL1. ISBT number: 006.001. Low prevalence antigen. Antithetical antigen: k (KEL 2). Cord RBCs: Expressed. The K antigen is detected on fetal RBCs as early as the tenth gestational week and is well-developed at birth. The KEL1 antigen is strongly immunogenic after the Rh blood group system. Study results have reported that every 1 out of 10 Kell antigen-negative individuals transfused with Kell antigen-positive donor red cells can develop anti-K antibodies after transfusion. The K antigen is not denatured by the enzymes ficin and papain but is destroyed by combined trypsin and chymotrypsin. Additionally, dithiothreitol (DTT), 2-mercaptoethanol, 2-aminoethylisothiouronium bromide, and ZZAP (mixture of a sulfhydryl reagent [dithiothreitol] and a proteolytic enzyme [papain or ficin]) can also destroy the Kell antigen. DTT, a reducing agent, interferes with the disulfide bonds between amino acids essential for the structural integrity of specific proteins and maintaining the pentameric structure of immunoglobulin (Ig) M molecules. Treating RBCs with DTT can denature other blood group antigens, including Kell, Lutheran, Yt, John Milton Hagen (JMH), Landsteiner-Wiener (LW), Cromer, Indian, Dombrock, and Knops systems—potentially impacting the recognition of these antigens by their specific antibodies. k (Cellano) antigen: ISBT symbol: KEL2. Formerly termed as Cellano. ISBT number: 006.002. High prevalence antigen. Antithetical antigen: K (KEL1). Cord RBCs: Expressed. Detected as early as seven weeks of gestation. Resistance and sensitivity to enzymes and chemicals are the same as those of KEL1. Kpa antigen: ISBT symbol: KEL3. ISBT number: 006.003. Low prevalence antigen. Antithetical antigen: Kpb (KEL4) Kpc (KEL21). Cord RBCs: Expressed. Resistant to enzymes (ficin, papain, chymotrypsin). Kpb antigen: ISBT symbol: KEL4. ISBT number: 006.004. High prevalence antigen. Antithetical antigen: Kpa (KEL3) Kpc (KEL21). Cord RBC's: Expressed. Resistant to enzymes (ficin, papain, chymotrypsin). Jsa antigen: ISBT symbol: KEL6. ISBT number: 006.006. Low prevalence antigen. Antithetical antigen: Jsb (KEL7). Cord RBCs: Expressed. Resistant to enzymes (ficin, papain, chymotrypsin). Jsb antigen: ISBT symbol: KEL7. ISBT number: 006.007. High prevalence antigen. Antithetical antigen: Jsa (KEL6). Cord RBC: Expressed. Resistant to enzymes (ficin, papain, chymotrypsin). Other rare Kell antigens These are further divided as high and low-prevalence antigens: High prevalence antigens: Ku (KEL5), KEL11, KEL12, KEL13, KEL14, KEL16, KEL18, KEL19, Km (KEL20), KEL22, TOU (KEL26), RAZ (KEL27), KALT (KEL29), KTIM (KEL30), KUCI (KEL32), KANT (KEL33), KASH (KEL34), KELP (KEL35), KETI (KEL36), KHUL(KEL37), KYOR(KEL38), KEL40 Low prevalence antigens: Ula (KEL10), Wka (KEL17), KEL21, KEL23, KEL24, VLAN (KEL25), VONG (KEL28), KYO (KEL31), KEAL (KEL39), KEL41 Antibodies of the Kell Blood Group System Anti-K antibodies, commonly IgG antibodies, do not bind complement and mostly react at 37 °C with the anti-human globulin (AHG) phase. Anti-K antibodies can also react at room temperature in the saline phase if they are IgM-type; they are usually formed in response to exposure following pregnancy or transfusion, but some examples of naturally occurring anti-K can also be seen. These IgM antibodies have been found in patients with Escherichia coli infections, which disappear after recovery. Anti-K antibodies may show depressed reactivity with some low–ionic-strength solution reagents, so an AHG phase is required to detect these antibodies. Anti-K has been implicated in severe hemolytic transfusion reactions and HDFN. If a patient develops antibodies to high-prevalence Kell antigens like k, it is challenging to find compatible units due to the low percentage of antigen-negative donors; antibody formation is rare due to its high prevalence. Identifying antibodies against low-prevalence antigens is difficult as their corresponding antigens are not included in antibody identification panels, which can rarely present as unexpected HDFN or transfusion reactions (see Table. Kell Blood Group Frequencies in Different Populations by Percentage). Anti-K will react well with K+k+ and K+k− red cells in antibody panels, showing no dosage phenomena. A rare case report of anti-Jsb was found in the Nigerian population, where this antibody was associated with decreased red cell survival.  Uncommon Kell Phenotypes K0 phenotype and anti-Ku antibody: K0 or Kell null phenotype was identified by Chown et al in 1957, and it lacks all Kell antigens on the RBCs. The Kell null phenotype shows a prevalence of 0.001% except in populations of Finland and Japan. These individuals show the inheritance of 2 recessive K0 genes in homozygotes (K0 K0). The absent antigens do not cause any functional abnormality in these RBCs. The alloantibody in K0 individuals post-transfusion has been called anti-Ku (anti-KEL5), which is clinically significant. These recipients should only be transfused with the K0 red cell type. One case report shows that anti-Ku specificity and anti-H were also identified in co-trimoxazole (trimethoprim and sulfamethoxazole) dependent antibodies. If there is a diminished presence of Kell antigens in place of complete absence, the phenotype is called Kmod. This is due to multiple missense mutations in the glycoprotein. Both K0 and Kmod show increased Kx protein. Kmod individuals may also form anti-Ku-type antibodies, but neither are similar.  McLeod phenotype: This rare phenotype occurs due to the absence of the Kx protein. Kell glycoprotein is covalently linked to Kx protein by a single disulfide bond, and hence, in its absence, it lacks a high prevalence Kell antigen and has depression of the rest. Individuals with this phenotype develop a neuromuscular syndrome, McLeod syndrome. This condition is an X-linked recessive disorder where females are carriers and males are affected. At the molecular level, it can be due to a hemizygous XK pathogenic variant (90%) or a hemizygous deletion of Xp21.1 (10%). The Kell blood group system antigens are expressed weakly in individuals with McLeod syndrome, except for the Km antigen (KEL20), which is absent. The XK gene encodes a protein that helps properly express antigens of the Kell blood group system on the RBC surface. When this gene is mutated, it leads to the functional ineffectiveness of the Kell antigens. Depressed Kell antigen (Cellano) in Gerbich-negative phenotypes: Both Muller and Debien reported reduced expression of 'k' antigens in RBCs of Gerbich group-negative phenotype (Ge:-2,-3) in individuals using monoclonal anti-k. This may be due to conformational changes in epitopes of the Kell blood group system, which shift the protein 4.1 complex to proteins like glycophorin C in the RBC membrane.  Lab method for Kell blood group determination Determining the Kell blood group involves various methodologies, each with advantages and limitations. These methods can be broadly categorized into serological and molecular techniques. In serological methods, hemagglutination tests such as forward typing are commonly used to detect the presence of Kell antigens on RBCs by utilizing specific antibodies like anti-K. Agglutination indicates the presence of the K antigen, while a lack of agglutination suggests its absence. Although this method is rapid and straightforward, it may lack sensitivity for weakly expressed antigens, particularly in partial or weak Kell phenotypes. Reverse typing involves testing the serum for anti-K antibodies to confirm the results of forward typing, which is crucial for ensuring accurate blood typing before transfusions. This step helps identify any unexpected antibodies that could lead to transfusion reactions. Another technique, gel centrifugation, employs a gel medium to separate agglutinated from non-agglutinated cells, thereby improving sensitivity and specificity. This method is particularly beneficial in reducing false-negative results and is often used in blood banks for routine testing. In molecular methods, polymerase chain reaction (PCR)-based techniques are highly sensitive and detect specific genotypes associated with Kell antigens. This approach is particularly useful in cases where serological methods may fail, such as in patients with autoimmune hemolytic anemia or those who have been recently transfused, as these conditions can obscure antigen expression. PCR with sequence-specific primers (PCR-SSP) enables the determination of specific alleles associated with Kell antigens; this is both cost-effective and reliable, making it suitable for routine testing in blood banks. This method can also identify rare phenotypes that may not be detected through serological means. PCR with restriction fragment length polymorphism (PCR-RFLP) analyzes variations in DNA sequences corresponding to different Kell antigens, providing detailed genetic information about blood group polymorphisms. This level of detail can be crucial for understanding compatibility in transfusions and organ transplants. Microarray technology, which can simultaneously analyze multiple blood group antigens, including Kell, is highly efficient for large-scale screenings and provides comprehensive data on various blood group systems. This method allows for rapid screening of donors and patients alike, facilitating better matching processes.

Objective: To investigate the clinical characteristics and management status of children with Turner syndrome (TS) in China. Methods: As a cross-sectional study, 1 089 TS patients were included in the database of the National Collaborative Alliance for the Diagnosis and Treatment of Turner Syndrome from August 2019 to November 2023. Clinical characteristics (growth development, sexual development, organ anomalies, etc.), karyotypes, auxiliary examinations, and treatments were collected and analyzed. Results: Among the 1 089 TS cases, 809 were recorded karyotypes. The karyotype distribution was as follows: 45, X in 317 cases (39.2%), X chromosome structural variants (including partial deletions of p or q arm, ring chromosome, and marker chromosome) in 89 cases (11.0%), 45, X/46, XX mosaicism in 158 cases (19.5%), mosaicism with X chromosome structural variants in 209 cases (25.8%), and presence of Y chromosome material in 36 cases (4.4%). Among the 824 TS cases, the age of diagnosis was 9.7(6.4, 12.2) years, with a height standard deviation score (HtSDS) of -3.1±1.2. Five hundred and fifty three cases underwent growth hormone (GH) stimulation test, and 352 cases (63.7%) had GH peak values <10 μg/L and 75.9% (577/760) had low IGF1 levels, with IGF1 SDS ≤-2 accounting for 38.2% (290 cases). Among 471 cases aged ≥8 years, 132 cases (28.0%) showed spontaneous sexual development (mean bone age (11.0±1.7) years), 10 cases had spontaneous menarche (mean bone age (12.0±2.2) years), and 2 cases had regular menstrual cycles. Common physical features included cubitus valgus (311 cases (28.5%)), neck webbing (188 cases (17.2%)), low posterior hairline (185 cases (17.0%)), shield chest (153 cases (14.0%)), high arched palate (127 cases (11.6%)), short fourth metacarpal (43 cases (3.9%)), and spinal abnormalities (38 cases (3.5%)). Congenital cardiovascular and urogenital anomalies occurred in 91 cases (19.4%) and 66 cases (12.0%)respectively. Abdominal ultrasound in 33 cases (7.2%) indicated fatty liver, hepatomegaly, intrahepatic bile duct stones, and splenomegaly. Among 23 cases undergoing oral glucose tolerance test (OGTT) test, 2 were diagnosed with diabetes mellitus and 4 with impaired glucose tolerance. Following diagnosis, 669 cases (80.7%) received rhGH treatment at a chronological age of (9±4) years and bone age of (8.3±3.2) years. Additionally, 112 cases (19.4%) received sex hormone replacement therapy starting at the age of (14±4) years and bone age of (12.6±1.2) years. Conclusions: The karyotypes of 45, X and mosaicism were most common in Chinese children with TS. The clinical manifestations were mainly short stature and gonadal dysplasia. However, a few TS children could be in the normal range of height, and some cases among those aged of ≥8 years old had spontaneous sexual development. Some exhibited physical features, congenital cardiovascular and urogenital anomalies, and dysfunction of the hypothalamic-pituitary-IGF1 axis. Moreover, a few of them developed impaired glucose tolerance and diabetes mellitus. Following diagnosis, most of the patients received rhGH treatment, and a few of them received sex hormone replacement therapy. 目的： 了解中国儿童特纳综合征（TS）的临床特征及诊疗情况。 方法： 横断面研究。选择2019年8月至2023年11月全国特纳综合征诊疗协作联盟数据平台录入的1 089例TS患儿为研究对象，对其临床特征（生长发育情况、性发育情况、系统器官畸形等）、核型分布、实验室检查及治疗现状等进行回顾性分析。 结果： 1 089例TS患儿中809例详细记录了核型，其中45，X 317例（39.2%），X染色体结构变异89例（11.0%），45，X/46，XX嵌合体158例（19.5%），伴X染色体结构变异的嵌合体209例（25.8%），含有Y染色体物质36例（4.4%）。824例患儿的确诊年龄为9.7（6.4，12.2）岁。确诊时患儿的身高标准差积分为-3.1±1.2，553例患儿行生长激素激发试验，其中352例（63.7%）生长激素峰值<10 μg/L；760例患儿行胰岛素样生长因子1（IGF1）检测，577例（75.9%）IGF1水平低于正常，290例（38.2%）IGF1 标准差积分≤-2。471例年龄≥8岁的患儿中，132例（28.0%）出现自发性性发育，10例出现自发性月经，2例有规律的月经周期。自发性性发育和自发性月经初潮的患儿骨龄分别为（11.0±1.7）、（12.0±2.2）岁。患儿相对常见的躯体特征为肘外翻311例（28.5%）、颈蹼188例（17.2%）、后发际低185例（17.0%）、盾状胸153例（14.0%）、腭弓高窄127例（11.6%）、第4掌骨短43例（3.9%）、脊柱异常38例（3.5%）等。合并先天性心血管异常和泌尿系异常的患儿分别为91例（19.4%）和66例（12.0%）。33例（7.2%）患儿肝脏超声提示存在脂肪肝、肝大、肝内胆管结石、合并脾大等。23例行糖耐量试验的患儿中，有2例诊断糖尿病、4例存在糖耐量异常。669例（80.7%）患儿确诊后应用了重组人生长激素（rhGH）治疗，起始治疗年龄为（9±4）岁，骨龄（8.3±3.2）岁。112例（19.4%）患儿进行了性激素替代治疗，起始治疗年龄为（14±4）岁，骨龄（12.6±1.2）岁。 结论： 中国儿童TS的核型以45，X单体和嵌合体为主，临床主要表现为身材矮小（呈矮胖体型）和性腺发育不良。少数患儿身高可在正常范围；部分年龄≥8岁的患儿可出现自发性性发育。部分患儿合并躯体特征，先天性心血管、泌尿系统异常，下丘脑-垂体-IGF1轴功能异常，少数出现糖耐量受损和糖尿病。大多数患儿确诊后应用了rhGH治疗，少数患儿开始了性激素替代治疗。.

Chromosome 18p deletion syndrome is a disease caused by the complete or partial deletion of the short arm of chromosome 18, there were few cases reported about the prenatal diagnosis of 18p deletion syndrome. Noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy. However, the segmental deletions and duplications should also be concerned. Except that some cases had increased nuchal translucency or holoprosencephaly, most of the fetal phenotype of 18p deletion syndrome may not be evident during the pregnancy, 18p deletion syndrome was always accidentally discovered during the prenatal examination. In our case, we found a pure partial monosomy 18p deletion during the confirmation of the result of NIPT by copy number variation sequencing (CNV-Seq). The result of NIPT suggested that there was a partial or complete deletion of X chromosome. The amniotic fluid karyotype was normal, but result of CNV-Seq indicated a 7.56 Mb deletion on the short arm of chromosome 18 but not in the couple, which means the deletion was de novo deletion. Finally, the parents chose to terminate the pregnancy. To our knowledge, this is the first case of prenatal diagnosis of 18p deletion syndrome following NIPT.NIPT combined with ultrasound may be a relatively efficient method to screen chromosome microdeletions especially for the 18p deletion syndrome.

Wolf-Hirschhorn syndrome is a rare genetic syndrome caused by a heterozygous deletion on chromosome 4p16.3 and is characterized by a "Greek warrior helmet" facies, hypotonia, developmental delay, seizures, structural central nervous system defects, intrauterine growth restriction, sketelal anomalies, cardiac defects, abnormal tooth development, and hearing loss. A variety of ocular manifestations may occur in up to 40% of patients. We report the genetic testing results, systemic findings, and complete ophthalmologic examination findings in a patient with Wolf-Hirschhorn syndrome, including external photography, RetCam3 (Clarity Medical Systems, Pleasonton, CA) goniography, and fundus photography. In addition, we review the literature on ocular manifestations of Wolf-Hirschhorn syndrome. Microarray analysis revealed an unbalanced translocation between 4p16.3-15.3 and Xp22.33-p22.2. Systemic findings included "Greek warrior helmet" facies, hypotonia, cleft palate, neonatal tooth eruption, talipes equinovarus, bilateral clinodactyly, clitoromegaly, partial agenesis of the corpus callosum, bilateral renal hypoplasia, and two atrial septal defects. Ocular findings included normal intraocular pressures and corneal diameters, large-angle exotropia, downward slanting of the palpebral fissures, absent eyelid creases, upper and lower eyelid retraction with shortage of the anterior eyelid lamellae, euryblepharon, lagophthalmos with poor Bell's reflex and exposure keratopathy, hypertelorism, Axenfeld's anomaly, megalopapillae, and cavitary optic disc anomaly. We describe the ocular phenotype of a patient with Wolf-Hirschhorn syndrome, including the rare descriptions and photographs of Axenfeld's anomaly, megalopapilla, and cavitary optic disc anomaly in this condition.

Discordance between clinical phenotype and genotype has multiple causes, including mosaicism. Phenotypes can be modified due to tissue distribution, or the presence of multiple abnormal cell lines with different genomic contributions. We have studied a 20-month-old female whose main phenotypes were failure to thrive, developmental delay, and patchy skin pigmentation. Initial chromosome and SNP microarray analysis of her blood revealed a non-mosaic ∼24 Mb duplication of 15q25.1q26.3 resulting from the unbalanced translocation of terminal 15q to the short arm of chromosome 15. The most common feature associated with distal trisomy 15q is prenatal and postnatal overgrowth, which was not consistent with this patient's phenotype. The phenotypic discordance, in combination with the patchy skin pigmentation, suggested the presence of mosaicism. Further analysis of skin biopsies from both hyper- and hypopigmented regions confirmed the presence of an additional cell line with the short arm of chromosome X deleted and replaced by the entire long arm of chromosome 15. The Xp deletion, consistent with a variant Turner Syndrome diagnosis, better explained the patient's phenotype. Parental studies revealed that the alterations in both cell lines were de novo and the duplicated distal 15q and the deleted Xp were from different parental origins, suggesting a mitotic event. The possible mechanism for the occurrence of two mutually exclusive structural rearrangements with both involving the long arm of chromosome 15 is discussed.