OCA is an autosomal recessive rare genetic disease . Patients with OCA have reduced or even lack melanin biosynthesis due to genetic defects . Clinical reports suggest eye color of the OCA patients as gray, light brown, or reddish-brown, with a defect in visual acuity, and often accompanied by vision loss . According to the clinical phenotype of the patient gene profile studies that cause disease etiology, OCA is categorized into seven different types; OCA1 through OCA7. Among them, OCA1 is further sub-categorized into OCA2, caused by a mutation in the OCA2 gene . Patients carrying OCA2 mutations are reported to have a subtle change in the pigmentation, which progresses with age, and hence it is also called incomplete albinism or the classical tyrosinase-positive albinism. OCA2 mutation is most prevalent in African populations . It is clinically characterized by hypopigmentation of the skin, hair and involves unique eye changes of all types of albinism: including nystagmus, the translucency of iris, and reduction of iris pigmentation, reduction of retinal pigmentation and clearness of choroidal vessels in fundus examination. It has been reported that the foveal dysplasia and misrepresentation of optic fiber radiation in the optic chiasma lead to strabismus, reduced stereo vision, and changes in the power generation position .
The OCA2 gene is located on chromosome 15 and encodes for transporter protein P on the melanosome membrane. The P protein is an 838-aminoacid long polypeptide chain foldeand modified, and its three-dimensional structure contains 12 transmembrane helixes . These transmembrane helices together form transport support, which transports tyrosine across the membrane to melanocytes and provides a substrate for melanin catalysis by tyrosinase in the melanin body . Currently, more than 300 cases have been recorded in the HGMD database depicting the pathogenic mutation of the OCA2 gene. Besides, patients with a heterozygous deletion mutation of OCA2 experience a minimal or reduced synthesis of the transporter. OCA2 carries a semi-synthetic missense mutation c.2056G>A (guanine>adenine) on the remaining allele .This mutation substitutes alanine with threonine at 686th position of the 9th transmembrane helix, which results in the extension of the amino acid R group carbon chain . This change significantly affects the spatial structure of the transporters, reduce or even prevent the transmembrane transport of tyrosine, and influence the synthesis of melanin. All these changes eventually lead to OCA phenotype . Previous reports suggest that a small number of OCA2 gene mutations lead to brown hair or blue eyes . However, this observation is limited to missense mutations in non-coding regions or non-transmembrane helix regions of the coding regions. The mutations carried by the children, in this case, are located in the transmembrane helix regions, which may lead to OCA, and is consistent with our observation . In this study, the mother, grandmother, and brother of the proband were heterozygous, and all three had yellow hair. We speculate that although the melanin was expressed in all three immediate relatives, the content was significantly less. This observation may explain the pathogenicity of the missense mutation.
PWS and Angelman syndrome (AS) are examples of imprinting defects which may be caused by a deletion, UPD, or imprinting failures. Clinical manifestations of AS include severe growth retardation, mental retardation, typical craniofacial appearance (round face and flat nasal bridge, up-slanted palpebral, epicanthic folds, etc), seizures, ataxia, language disorder, and mental retardation. If the 15q11-q13 deletion mutation affects the expression of paternally imprinted genes, it leads to PWS. The world's first PWS case was discovered in 1887, and was subsequently defined and named by Prader et al. in 1956 [20, 21]. Hundreds of PWS patients have been reported worldwide, and clinical features include: fetal movement decreases before birth; neonatal hypotonia, weakened reflect, difficulty feeding, and genital hypoplasia. Limb development occurs within 1 year of age, but eventually leads to uncontrolled food intake and centripetal obesity. PWS, also accompanied by growth retardation, and mental retardation, characteristic facial features (narrow long face, almond eyes, squint eyes, large chin, etc.), and reduced motion activities due to weak musculature. By the 6 years of age, patients develop itching and scratching, leave marks, abdominal olfactory lines, thick saliva in the corners of the mouth, insensitive to pain, diabetes, poor puberty development, and poor prognosis .
The PWS pathogenesis is categorized into five sub-types, 5-6Mb deletion of paternal alleles, which accounts for about 65% to 75% of all patients being the most common. PWS, then further sub categorized into type I and type II according to the location of the deletion. However, is no significant difference in the clinical outcome. PWS maybe the result of maternal uniparental disomy (UPD), with a relatively mild symptom, and accounting for 20% to 30% of the imprinted deletion, accounting for 2% to 5%; very few (<1%) are chromosomal imbalance shifts and single-gene mutations . Studies have found that the loss of the imprinted gene NDN or SNRPN gene expression on chromosome 15 causes PWS the main reason [10, 11], but still does not rule out the possibility of other pathogenic genes in the 15q11-q13 interval. The NDN gene expresses the growth inhibitory protein Necdin, which is used in the nucleus to regulate the cell cycle, cell differentiation, and apoptosis. The expression of this protein is reduced or deletion can lead to unregulated cell growth regulation and cause disease . The SNRPN gene can express two RNA-related proteins: the gene can express small nuclear ribonucleoprotein associated protein N (SNRPN protein) alone. Also known as SmN splicing factor), a type of Sm protein, is involved in the process of small ribonucleoproteins (snRNPs) shear modification of mRNA; at the same time, it can also be linked to a specific upstream section to express SNRPN protein and SNRPN protein upstream reading frame protein through a bicistronic transcript. (SNRPN upstream reading frame protein) . Decreased or deleted expression of this gene is likely to affect the splicing and modification of mRNA, and then cause a series of neuroendocrine diseases. The chromosomal mutations carried by the children in this case also include the parent source of SNRPN Allele deletions have a high probability of causing PWS disease. Although the father of the child carries a mutation, the clinical phenotype is normal, it can be speculated that the chromosome deletion is a new mutation or inherited from the grandmother of the child, but the specific source of this mutation still needs to be further investigation and research.
There is a paternal deletion of the SNRPN gene in children with this study, which is in line with the genetic pattern of human genome imprinting disease PWS; the OCA2 gene. The gene deletion represents a compound heterozygous mutation of missense mutation and gene deletion, which is inconsistent with the autosomal recessive type 2 autosomal genetic method. Combined with phenotypes such as OCA and feeding difficulties, the diagnosis is OCA2 with PWS. Previously, 5 cases of children with PWS and other diseases have been reported in China. By analyzing the clinical and genotype statistics of these children, combined with the analysis of the children, in this case, we found that the compound diseases reported in children in China were all PWS-related complications. For example, diabetes, fatty liver, thyroid dysfunction, diabetic ketoacidosis, acute severe pancreatitis and other metabolic syndromes due to endocrine disorders in children, and acquired diseases such as scoliosis due to the obesity of children (Table 1), The child, in this case is the only child in China that has PWS and other diseases caused by congenital pathogenic genotypes, and the symptoms are more serious, and the child died during infancy.
The current work provides clinical insights into OCA2 and PWS and guidance for subsequent genetic counseling. Because albinism refers to a group of autosomal recessive genetic diseases, PWS is caused by the deletion of candidate gene expression on the parent chromosome at chromosome 15 (15q11.2-q13.1), the father is carriers of multiple genes deletions and the mother is a carrier of the OCA2 mutation, so the patient is a 2nd child of his/her parents, it is most likely that the 3rd child will significantly be impacted. The probability occurrence of OCA2 and PWS is 1/8th, the probability occurrence of OCA2 alone is 1/8th, the probability occurrence of PWS alone is 3/8th. Genomic tests using either NGS or MLPA technology is highly recommended for any upcoming child if the parents are planning for a second child to avoid any possible malignant diseases.
This article uses NGS and MLPA technology to validate the genomic study and report the first domestic child with OCA2 combined with PWS. OCA2 and PWS are sporadic malignant diseases, and easy to misdiagnose. This case report not only provides clinical insights into OCA2 and PWS diseases, but also preventive clues of complex diseases. For example, PWS combined with Hashimoto's thyroiditis, PWS combined with Metabolic syndrome, PWS combined with Diabetic ketoacidosis, PWS combined with Diabetes, PWS combined with Scoliosis. Besides, this study demonstrates the significance of genetic counseling and genetic testing in reducing the incidence of malign genetic diseases in children. Therefore, in the case of children with unclear diagnosis and suspected ocular and skin albinism and/or PWS, it is necessary to complete the genetic testing as soon as possible to make a clear diagnosis, achieve early diagnosis and treatment, and improve the prognosis of the children. At the same time, genetic counseling can be provided to parents, to prevent the occurrence of disease, to provide a guarantee for the birth of healthy children.
OCA2 combined with PWS due to OCA2 gene missense mutation combined with large fragment deletion of 15q11-13 region was first reported in this study, of which the clinical signs can be subtle and symptoms can be more severe. This case report not only provides clinical insights into OCA2 and PWS diseases, but also the understanding of the clinical phenotype and pathogenesis of OCA2 and PWS was strengthened. Also, this study demonstrates the significance of genetic counseling and genetic testing in reducing the incidence of malign genetic diseases. therefore, early genetic testing is crucial for those patients to yield an accurate diagnosis and initiate aggressive interventions to optimize the outcomes.