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 identified to be related to the missing coding genes in those region. For example, the regions related to short stature and growth hormone deficiency are 18q12.1q12. 3, 18q21. 1q21. 33, 18q22.3q23, the possible main pathogenic gene is GALR1[1, 13–15]. The region related to developmental delays and abnormal cerebral white matter development is 18q22.3q23, the possible related pathogenic genes are ZNF236, ZNF516, MBP, GALR1 and lOC284276[2, 16, 17]. The region related to congenital heart disease is 18q22.3q23, the possible main pathogenic gene is NFATC1. The region related to cleft lip and cleft palate is 18q22.3q23, the possible related pathogenic genes are SALL3 and TSHZ1. The region related to IgA deficiency and renal dysplasia is 18q22.3q23, the gene related to hearing impairment and abnormal ear development is ZNF407 [1, 4].
The case in this 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 10.44Mb deletion at 18q22.2q23. The deletion region contained genotypes related to developmental delays, short stature, cleft palate, hypotonia, abnormal cerebral white matter development, hearing impairment. There was a case report with the same missing region as this case in the past, whose phenotypes included developmental delays, hypotonia, hypothyroidism, recurrent fever, seizures, abnormal cerebral white matter development, dysplasia of corpus callosum, polydipsia, polyuria. What they had in common was the deletion region was 18q22 2q23, both appeared developmental delays, hypotonia, hypothyroidism, recurrent fever, abnormal cerebral white matter development. The differences were that the starting point of the deletion region in our case was 67562936, the end point was 78005270. Our case appeared cleft palate, hearing loss, vestibular dysplasia, strabismus and DDH. Combined with the analysis of previously reported cases, we highly suspect that most of the phenotypes in this child were caused by 18q22 2q23 deletion.
For the recurrent fever phenotype in this child, we did not find any related mutant genes. Some researchers believed that recurrent fever may be related to the lack of IgA , but this child had no infected symptoms, no growth of blood bacterias, normal contents of IgA and other immunoglobulins, and anti-infection treatment was ineffective. This inferred that the fever was not associated with IgA deficiency or immune deficiency combined with infection in this case. The child also had the symptom of less sweat secretion. Recurrent fever may be related to the diseases that could cause this symptom, such as abnormal development of cerebral cortex. As for hypothyroidism, no pathogenic genes were found that directly related to hypothyroidism in the deletion region of this child. But we found CD226 coding gene in deletion region, which encodes a kind of glycoprotein expressed on the surface of NK cells, platelets, monocytes and T cell subsets. This kind 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 mutation include a variety of autoimmune endocrine disorders, such as autoimmune thyroiditis (AITD). However, the child 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 thyroid itself , in this case we can not exclude the possibility of temporary hypothyroidism as well.
The child 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 case was breech delivered, but he was born by cesarean section smoothly without birth injury factors. Therefore, DDH in this case was unlikely to be related to breech delivered. The genetic mode and mechanism of DDH are not clear at present, the possible genetic mode may be autosomal dominant inheritance with incomplete penetrance, which may be related to the variation of CX3CR1, UFSP2, HSPG2 and ATP2B4 [6, 22–24]. After NGS detection, there was heterozygous variation at exon site and intron site of HSPG2 of this child. The variation at exon site, c.2244c > A (p.H748Q), was a new mutation comed from the father who had no clinical manifestation of DDH. Variation at intron site, c.11671 + 154insa, was located in the deep intron region, and was unlikely pathogenic. The diseases related to HSPG2 mutation mainly include Dyssegmental dysplasia Silverman-Handmaker type (DDHS) and Schwartz Jampel syndrome type 1, both of which are autosomal recessive diseases.Clinical features of DDHS include a flat midface, narrow thorax, abnormal ears, short neck, severe short stature, short and bowed limbs, as well as decreased joint mobility, cleft palate and club feet. Schwartz-Jampel syndrome type 1 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 breast, ect. The clinical phenotypes of this case were quite different from these two diseases. Combined with the genetic mode, the possibility of these two diseases will not be considered for the time being. Previously, in a experiment on HSPG2 mutant (C1532Yneo) mice, it confirmed that HSPG2 mutant mice would have weight loss and DDH. Considering that the genetic mode of this disease may be autosomal dominant inheritance with incomplete penetrance, the possibility of DDH in this case caused by HSPG2 variation was still not excluded. However, whether this phenotype was related to 18q deletion syndrome or other genes mutation need to be further studied.