Anal atresia is a congenital anorectal malformation. The anus is not perforated and the distal enteric component ends blindly. Hamartoma is defined as a benign tumor-like nodule composed of an overgrowth. The etiology of such malformations remain unclear and it is multifactorial . Perineal masses are divided into three categories: lipomas, vascular anomalies, and hamartomas. Association of a perineal hamartoma with anorectal anomaly is extremely rare. In a review with 2000 cases of anorectal malformations there were presented only eight cases with hamartoma. The all patients were female . The coexistence of perineal hamartoma and anal atresia was documented in the literature in only one child. Yamaçake et al., reported the association of perineal hamartoma with anorectal malformations in a neonate male. The karyotype of their case was 46, XY. They did not perform any molecular genetic test . The karyotype of our proband was 46,XX. We also studied molecular genetic tests (microarray and whole exome sequencing) in our patient.
Array comparative genomic hybridization or comparative genomic hybridization, is a high-resolution genome-wide screening testing to detect a majority of chromosomal imbalance and microdeletion and microduplication . Our patient had anorectal malformations due to 7p12.3 duplication of 551 kb, this duplication involves the four OMIM genes TNS3, PKD1L1, HUSI, UPP1. The whole exome sequencing did not reveal pathogenic or VUS (variant of uncertain significance) variants in genes possibly associated with this clinical picture. There are only a few patients with “pure” 7p12 microduplication at public databases (DECIPHER). One male case was described before. He had 23.19 kb deletion at 7p12.3 chromosome (position 47,829,924–47,853,114/GRCh38). His clinical features showed intestinal malrotation, polydactyly, and renal abnormalities. This overlapped region included the PKD1L1 gene like our patient’s. The other case reported in the literature was female. She had disproportionate short stature, hypoglycemia and microcephaly. Her cytogenetic duplication was at 7p12.3 chromosome (568.84 kb) including PKDILI, HUSI, UPP1, ABCA13 and SUN3 genes. The duplicated coordinate was between 48,106,082–48,595,326 regions. To our knowledge the duplication at 7p12.3 chromosome is seen very rare. Therefore, its clinical impact remains uncertain and the associated phenotypes poorly characterized.
Polycysiın 1-Like 1 (PKD1L1) is a gene associates with ciliary calcium signaling and embryonic laterality determination in humans and mice. Heterozygous PKD1L1 variants were found in patients with biliary atresia . Rodriguez et al. described a patient with a homozygous PKD1L1 mutation with situs inversus, atrial septal defect, pulmonary artery stenosis and bicytopenia . In 2019, Le Fevre et al. reported bi-allelic variants in the PKD1L1 gene associated with heterotaxy (abnormal organ arrangement) and congenital heart defects in four individuals from three unrelated families . Heterotaxy of splenic, hepatic anomalies and bilobed lungs were described in the literature .
Human seminal inhibitor I (HUSI) gene encodes an inhibitor, which protects epithelial tissues from serine proteases. This gene is associated with renal osteodystrophy . UPP1 (Uridine phosphorylase 1) gene encodes a uridine phosphorylase that functions in the degradation and salvage of pyrimidine ribonucleotides. Gene ontology analysis shows immune and inflammatory response . Tensin 3 (TNS3) gene is encoding an intracellular protein. TNS3 may play an important role in actin remodeling and the dissociation of the integrin-tensin-actin complex. Downregulation of this gene contributes to metastasis in renal cell carcinoma . In a study rs3750163 polymorphism of TNS3 gene was not associated with Immunoglobulin A nephropathy susceptibility in a Chinese Han population . Duplication of chromosome 7p12.3 (including OMİM genes: TNS3, PKD1L1, HUSI, UPP1) can cause a spectrum of phenotypic features as seen in our patient with minor dysmorphic findings and anorectal malformations. The microduplication of our patient was not clearly associated with the clinical traits reported before. According to our knowledge, the duplication at 7p12.3 chromosome are rarely seen to date. It is expected that our case will contribute to the literature. Different phenotypic features may accompany the 7p12.3 microduplications. More detailed genetic and/or functional studies, or patients with point mutations/CNVs (copy number variants) affecting only one or a few of these genes, are needed to elucidate this possibility.
To date, this present case is the second case concerning the special coexisting of hamartoma, imperforate anus, and cystic lesion with a diameter of 4 mm at the filum terminale (L2 vertebra) on lumbar magnetic resonance imaging. Characteristics and pathogenesis of such patients have yet to be discussed and revealed. Genome-wide CNV analysis of our patient with perineal hamartoma and anal atresia was identified microduplication at 7p12.3. This case showed that association of duplication of 7p12.3 chromosome with the rare clinical entity with hypotonia, cystic lesion observed at the level of the filum terminale. Our case may help identify more cases with duplications in this region. Further studies are needed to describe anorectal malformations.