https://orcid.org/0000-0002-6690-5297
Weiss–Kruszka syndrome is a rare congenital syndrome that could be associated with systemic lupus syndrome.
Dear Editor, Weiss–Kruszka syndrome (WSKA) is an autosomal dominant (AD) congenital syndrome due to mutations in the ZNF462 gene and manifests with developmental delay and multiple craniofacial abnormalities with variable expressivity [1]. It is also characterized by cognitive impairment, whilst about a third of the affected individuals belong to the autism spectrum. Although the disease is inherited in the AD manner, most of the described subjects (95%) had de novo variants with no affected family members [1]. WSKA has been recently described and only 26 (including our patient) affected individuals have been classified to date [2]. SLE is a systemic autoimmune disease characterized by the presence of autoantibodies and multi-organ inflammation. Genetic factors play an important role in disease pathogenesis, particularly in patients with childhood-onset SLE.
The objective of this case report is to describe the case of an SLE patient who was found to have WSKA related to a novel pathogenic AD variant in the ZNF462 gene and inform clinicians of a possible association between the two conditions.
A 25-year-old Caucasian female with a history of SLE, diagnosed at the age of 14, manifested with malar rash, Raynaud’s phenomenon, polyarthritis, thrombocytopenia, positive ANA, ds-DNA antibody and hypocomplementemia. At the age of 17, she was hospitalized with lower extremity oedema due to acute renal injury, and kidney biopsy was consistent with lupus nephritis class IV. The patient was successfully treated with glucocorticoids, hydroxychloroquine and cyclophosphamide, and subsequently was switched to mycophenolate. Recently, she was admitted to our hospital for fatigue and easy bruising, due to haemolytic anaemia, thrombocytopenia and acute renal injury. Schistocytes were present on peripheral smear and ADAMTS-13 activity was <5%. The working diagnosis was thrombotic thrombocytopenic purpura due to SLE exacerbation and the patient was aggressively managed with high-dose glucocorticoids, plasma exchange and rituximab resulting in symptom resolution. During her hospitalization, the presence of various clinical features raised the suspicion of a genetic syndrome. First, on physical examination the patient exhibited dysmorphic features such as hypertelorism, prognathism, arched eyebrows, flattened nasal bridge, small upper lip, mild intellectual disability and a history of childhood-onset SLE (Fig. 1). Whole exome sequencing (WES) by next-generation sequencing was used for the genetic investigation of the patient.
Patient’s dysmorphic features. (A and B) Front and lateral clinical photographs illustrating hypertelorism, prognathism, arched eyebrows, flattened nasal bridge and small upper lip
The patient underwent genetic evaluation with WES and the novel heterozygous AD pathogenic variant c.4142delT (p.lle1381ThrfsTer16) in ZNF462 gene was identified. Confirmation of the identified variant was also verified by Sanger sequencing. Pathogenic variants in the ZNF462 gene were previously described in patients with the recently reported WSKA of which several characteristics are compatible with our patient’s features. ZFN462 encodes a zinc-finger transcription factor that plays a role in embryonic development, transcriptional regulation and chromatin remodelling. Given that chromatin remodelling has been implicated in the pathogenesis of SLE, the association of this novel ZNF462 variant in the development of SLE needs to be determined [3, 4].
This is the first report of a patient with coexisting SLE and WSKA due to a novel variant. This case illustrates the need for further research in order to elucidate any possible pathophysiologic link between the two conditions. Informed consent has been received.
Funding
No specific funding was received from any funding bodies in the public, commercial or non-profit sectors to carry out the work described in this manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
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