Clinical Case Reports Kabuki syndrome with ossification of the posterior longitudinal ligament requiring differentiation from Ehlers-Danlos syndrome: a case report with a literature review

Research Ethics Committee Approval (if necessary): We declare that the patient approved the study by signing an informed consent form and the study followed the ethical guidelines established by the Declaration of Helsinki. Abstract Kabuki syndrome (KS) comprises multiple congenital abnormalities and the main symptoms include characteristic facial features, skeletal and spinal abnormalities, and mental retardation. The estimated incidence of KS is 1 in 32000, and mutations in the KMT2D gene (also known as MLL2 ) are considered to be involved. The details of such mutations, including the mode of inheritance, are unclear. A 40-year-old woman visited our hospital with back pain and urinary incontinence. The patient had been diagnosed with Ehlers-Danlos syndrome (EDS) in childhood, on the basis of physical findings including hip subluxation. Because of her characteristic facial features, we suspected KS instead. Genetic testing revealed the presence of a rare missense mutation in KDM6A that was suggestive of KS. Computed tomography showed that she had ossification of the posterior longitudinal ligament (OPLL). On the basis of her clinical presentation and genetic mutation in KDM6A , we made a diagnosis of KS with OPLL. Hereditary diseases may share similar clinical characteristics, as in the case of our patient with Kabuki syndrome, who was misdiagnosed in childhood as having an Ehlers-Danlos syndrome involving disordered connective tissue. Physicians should undertake a comprehensive consideration of multiple clinical features when diagnosing a hereditary disease. 45 Kabuki

retardation. However, the most characteristic symptom of the syndrome is facial malformations. They are similar to the 'Kumadori' face painting used by actors of the Japanese classical art form ' Kabuki'. That is why Kabuki syndrome is so named (Figure 1) [2].
Mutation of the KMT2D gene (also known as MLL2) is found in approximately 70% of patients with a clinical diagnosis of KS. The KMT2D / MLL2 gene encodes a histone methylase (H3K4) that interacts with KMT2D [1].
KS is regarded as the result of an abnormality in histone methylation in patients with mutation of KDM6A. Our patient, who had previously been diagnosed with Ehlers-Danlos syndrome (EDS) in childhood, presented with unidentified weight loss, back pain and urinary incontinence in adulthood [reference].
Ultimately, we diagnosed her with KS with ossification of the posterior longitudinal ligament (OPLL) instead of EDS. This case provided us with a valuable learning opportunity and may prove meaningful for the future diagnosis and treatment of hereditary disease groups with overlapping clinical characteristics.

Chief complaints
A 40-year-old woman presented to our hospital with back pain and urinary incontinence.

History of present illness
The symptoms of back pain and urinary incontinence had been ongoing for 3 months.

History of past illness
Thirty-five years prior, at age 5, the patient had bilateral hip dislocations. She was diagnosed with EDS based on clinical findings including hip subluxation at the paediatrics department of another hospital and did not undergo genetic testing.
One year later, Suzuki-Binet Intelligence testing revealed an IQ of 42, and the patient was diagnosed with moderate mental retardation. Her family history included dementia in her mother and father, and uterine prolapse in her mother. Her sister had died in her 40s from a type of collagenases (details unknown).

Physical examination
The patient exhibited certain facial features indicative of KS; namely, long palpebral fissures with eversion of the lateral third of the lower eyelid, and arched and broad eyebrows, with the lateral third displaying notching or sparseness ( Figure 2).

Laboratory examinations
Genetic screening revealed one missense variant each in KMT2D/MLL2 (Online Mendelian Inheritance in Man: 147920) and KDM6A (Online Mendelian Inheritance in Man: 300867) in the patient. The variant found in KMT2D is a synonymous substitution with low pathological significance, i.e., no amino acid substitution.
However, the mutation found in KDM6A corresponds to the Jumonji C (JmjC) protein domain. This mutation is novel, highly pathogenic, and has not previously been registered in ClinVar, the Exome Aggregation Consortium, or the Human Gene Mutation Database. There were no abnormal findings on the patient's electroencephalogram or elec-trocardiogram. Blood cell analysis, and examinations of blood electrolytes, glucose and lipids, and liver and renal function, also showed no abnormalities.

Imaging examination
Computed tomography of the spine showed OPLL in the spinal canal (Figure 3), which was considered to be the cause of back pain and urinary incontinence.

Final diagnosis
The patient was diagnosed with KS with OPLL.

Treatment
She was prescribed corsets and acetaminophen (1800 mg/day) to alleviate the symptoms of OPLL for 3 months.

Outcome and follow-up
The patient's back pain improved slightly, but she later developed numbness, sensory and motor disturbances in both legs and became unable to walk well. If these neurological deficits persist, including the urinary incontinence, we may consider surgical treatment of the OPLL, because corsets and acetaminophen are not fundamental treatments for OPLL.

Discussion and Conclusion
The mutation found in KDM6A in our patient represents a new missense variant in KS. The sequence change replaces glycine with glutamate at codon 3419 in the KDM6A protein.
Glycine has a non-polar side chain, whereas glutamate has a polar uncharged side chain with moderate physicochemical differences. This variant is predicted to be highly pathogenic according to the SIFT and PolyPhen-2 prediction tools in InterVar, a bioinformatics software for clinical interpretation of genetic variants based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guideline. Because the phenotypic details of the parents and siblings of this case are unknown, the variant must be formally classified as having "Uncertain Significance" (clinical significance unknown). However, given that the phenotype of the patient is typical of KS, the pathogenic potential for the variant is high.
When our patient was diagnosed with EDS in childhood, gene therapy in this area was poorly developed. It was difficult to perform genetic screening tests, even in patients who were suspected of having a genetic disorder. The fact that her sister suffered from collagenosis also probably impacted her initial diagnosis. It is possible that her attending physician at the time made the diagnosis of EDS based on physical assessment alone.
The main clinical symptoms of KS are characteristic facial features, short stature, various organ malformations, and a variable degree of intellectual disability. We were unable to obtain a photograph of the patient in childhood, but her friends stated that she had always had distinctive facial features, supporting our own assessment of her physical features as being typical of KS.
Most KS patients have mutations in KMT2D/MLL2, but mutations in KDM6A are comparatively rare. Pathogenic variants in the genes encoding the chromatin modifiers KMT2D and KDM6A are responsible for Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), respectively. The patient had a mutation in both genes, therefore, it should be considered as KS1. [15].
A previous study showed that KDM6A is involved in the maternal inheritance of KS and that there is also an unidentified X-linked form of KS (type 2) [14]. In this case, the patient's sister died of an unspecified collagen disease. We considered the possibility that the patient's sister also had KS. This patient has a genetic mutation that is quite rare among patients with KS, making her KS diagnosis notable. If she has other living blood relatives besides her father and sister, they should also be tested for mutations in KDM6A. While there have been reports of skeletal abnormalities such as scoliosis in KS [2], to our knowledge this is the first reported case of KS with OPLL. Clinical symptoms related to OPLL include numbness of limbs, gait disturbance, back pain, and urination defecation disorder [16].
In this case, our patient was being cared for by helpers; therefore, she was not indicated for emergency surgery. However, there are no established guidelines for conservative therapy for OPLL. If her neurological symptoms worsen, she may be considered for surgery [1].
This case study highlighted three key messages. First, it is essential that we continue to consider other possible diagnoses in patients with heritable disease syndromes. Second, we should consider that patients with genetic disorders may exhibit complications that have never been reported. Third, genetic screening tests and physical assessments are both important in the diagnosis of genetic disorders.