Since the first case of 18q deletion syndrome was reported in 1964 , many scholars have tried to study the relationship between phenotype and deletion region or genotype. After years of research, it has been found that some common clinical phenotypes are related to the missing coding genes in those regions. For example, the regions related to short stature and growth hormone deficiency are 18q12.1q12.3, 18q21.1q21.33, and 18q22.3q23, and the possible main pathogenic gene is GALR1 [1, 13,14,15]. The region related to developmental delays and abnormal cerebral white matter development is 18q22.3q23, and the possible related pathogenic genes are ZNF236, ZNF516, MBP, GALR1 and lOC284276 [2, 16]. The region related to congenital heart disease is 18q22.3q23, and the possible main pathogenic gene is NFATC1 . The region related to cleft lip and cleft palate is 18q22.3q23, and the possible related pathogenic genes are SALL3 and TSHZ1 . The region related to IgA deficiency and renal dysplasia is 18q22.3q23, and the gene related to hearing impairment and abnormal ear development is ZNF407 [1, 4].
The patient in this case report had many phenotypes, including developmental delays, cleft palate, hypotonia, abnormal cerebral white matter development, hearing loss, vestibular dysplasia, strabismus, hypothyroidism, DDH and recurrent fever. The NGS results revealed that there was a 10.44 Mb deletion at 18q22.2q23. This deletion region contains genes related to developmental delays, short stature, cleft palate, hypotonia, abnormal cerebral white matter development, and hearing impairment. There was a previous case report of a patient with the same missing region as this case, and the phenotypes of this patient included developmental delays, hypotonia, hypothyroidism, recurrent fever, seizures, abnormal cerebral white matter development, dysplasia of corpus callosum, polydipsia, and polyuria . What they had in common was that the deletion region was 18q22.2q23, and both patients presented with developmental delays, hypotonia, hypothyroidism, recurrent fever, and abnormal cerebral white matter development. The differences were that the starting point of the deletion region in our case was 67,562,936, and the end point was 78,005,270. Our case also presented with a cleft palate, hearing loss, vestibular dysplasia, strabismus and DDH. Due to the presentation of these phenotypes combined with the analysis of previously reported cases, we highly suspect that most of the phenotypes in this patient were caused by the 18q22.2q23 deletion. The mother of the patient also had a cleft palate. According to CNV verification, her mother did not have 18q22.2q23 deletion. However, cleft palate is a kind of polygenic genetic disease, and its occurrence is related to many factors. According to the results, cleft palate of the mother may have nothing to do with 18q deletion syndrome, there may be some other chromosomal or genetic abnormalities related to this phenotype.
We did not find any mutations in genes that were related to the recurrent fever phenotype in this patient. Some researchers believe that recurrent fever may be related to the lack of IgA , but this child had no symptoms of infection, no growth of bacteria in the blood, normal concentrations of IgA and other immunoglobulins, and ineffective anti-infection treatment. Thus, we inferred that the fever was not associated with IgA deficiency or immune deficiency combined with infection in this case. The patient also had symptoms of low sweat secretion. Recurrent fever may be related to diseases that could cause this symptom, such as abnormal development of the cerebral cortex. Additionally, no pathogenic genes in the deletion region of this patient were found to be directly related to hypothyroidism. However, we found that the CD226 coding gene was in the deletion region, which encodes a glycoprotein that is expressed on the surface of NK cells, platelets, monocytes and T-cell subsets. This type of glycoprotein mediates the adhesion of platelets and megakaryocytes to vascular endothelial cells. It also plays a role in megakaryocyte maturation . Diseases related to CD226 mutations include a variety of autoimmune endocrine disorders, such as autoimmune thyroiditis (AITD) . However, the patient was too young to accurately assess autoimmune function. Whether this phenotype is related to this gene deletion needs further study in more cases. Some researchers consider that hypothyroidism is related to abnormal brain development or the thyroid itself ; in this case, we cannot exclude the possibility of temporary hypothyroidism.
The patient in this study also had a phenotype that had not been reported in patients with 18q deletion syndrome. The pathogenesis of DDH may be congenital or acquired. Acquired factors mainly include breech delivery. This patient was breech delivered, but she was born by cesarean section without birth injury factors. Therefore, DDH in this case was unlikely to be related to breech delivery. The underlying genetic mechanisms of DDH are not clear at present. The possible genetic mode may be autosomal dominant inheritance with incomplete penetrance, which may be related to variants of CX3CR1, UFSP2, HSPG2 and ATP2B4 [6, 21,22,23]. NGS analysis indicated that there was a heterozygous variant at the exon site and intron site of HSPG2 in this patient. The variant at the exon site, c.2244c > A, p.h748q, was a novel mutation from the father who had no clinical manifestation of DDH. The variation at the intron site, c.11671 + 154insa, was located in the deep intron region and was unlikely pathogenic. HSPG2 encodes for perlecan, a large proteoglycan that plays an important role in cartilage formation, cell adhesion, and basement membrane stability. The diseases related to HSPG2 mutations mainly include dyssegmental dysplasia Silverman-Handmaker type (DDHS) and Schwartz Jampel syndrome type 1, both of which are autosomal recessive diseases . The clinical features of DDHS include facial dysmorphisms, GU abnormalities, severe short stature, decreased joint mobility, cleft palate and club feet . Schwartz-Jampel syndrome type 1 is characterized by permanent myotonic myopathy and skeletal dysplasia, which result in short stature, dystrophy of epiphyseal cartilages, joint contractures, blepharophimosis, unusual pinnae, myopia and pigeon breasts [26, 27]. The clinical phenotypes of this case were quite different from those of these two diseases. Based on the genetic mode of inheritance, the possibility of these two diseases will not be considered for the time being. Previously, an experiment on HSPG2 mutant (C1532Yneo) mice  confirmed that HSPG2 mutant mice demonstrated weight loss and DDH. Considering that the genetic mode of inheritance of this disease may be autosomal dominant with incomplete penetrance, the possibility that the DDH in this case is caused by HSPG2 mutations has not yet been excluded. But, a replication analysis of 250 sporadic samples with Sanger sequencing by Xu et al.  indicated that HSPG2 variation was not associated with the susceptibility to DDH in the Chinese Han population. However, whether this phenotype is related to 18q deletion syndrome or other gene mutations needs to be further studied.