CCDC47 gene and trichohepatoneurodevelopmental syndrome: Report of the fifth and sixth cases from Saudi Arabia.

Trichohepatoneurodevelopmental syndrome (THNS) is an ultra-rare and complex disorder affecting multiple organ systems. It is characterized by liver dysfunction, hypotonia, global developmental delay, coarse hair, and dysmorphic features. We describe two cases of THNS of Saudi origin, the fifth and sixth cases in the medical literature. Both cases presented with multiple dysmorphic features, generalized hypotonia, global developmental delay, and high liver enzyme level. Exome sequencing of Case 1 identified a pathogenic homozygous variant within the CCDC47: NM_020198.2:c.567_570del, p.(Glu190Profs*7). Genome sequencing of Case 2 identified two likely pathogenic heterozygous variants within the CCDC47: NM_020198.2:c.1327C>T, p.(Arg443*) and NM_020198.2:c.422dup, p.(Leu141Phefs*19). The trans phase of the detected variants has been confirmed by the parental testing. Furthermore, we evaluated the gene-disease association as per ClinGen guidelines and reached a strong level of association after inclusion of the new patients/variants. The findings from these cases will help to delineate the clinical phenotype and the mutational spectrum of this complex disorder.

Case Report: Clinical delineation of CACNA1D mutation: New cases and literature review.

Background: Calcium ions are involved in several human cellular processes; nevertheless, the relationship between calcium channelopathies (CCs) and autism spectrum disorder (ASD) or intellectual disability (ID) has been previously investigated. We delineate the spectrum of clinical phenotypes and the symptoms associated with a syndrome caused by an inherited gain-of-function mutation in CACNA1D in a family with a history of neuropsychiatric disorders. We also review the clinical and molecular phenotype of previously reported variants of CACNA1D. Case presentation: We report the case of a 9-year-old female patient, diagnosed with ASD, severe ID, hyperactivity, and aggressive impulsive behaviors. The father, who was a 65-year-old at the time of his death, had ID and developed major depressive disorder with catatonic features and nihilistic delusion, followed by rapidly progressive dementia. He died after experiencing prolonged seizures followed by post-cardiac arrest. The patient's sister was a 30-year-old woman, known to have a severe ID with aggressive behaviors and sleep disorders. The sister has been diagnosed with bipolar disorder and psychosis. Through whole exome sequencing, a heterozygous previously identified and functionally characterized missense likely pathogenic variant was identified in the CACNA1D gene NM_001128840.3: c.2015C > T (p.Ser672Leu). These findings are consistent with the genetic diagnosis of autosomal dominant primary aldosteronism, seizures, and neurological abnormalities. This variant was found in the heterozygous status in the patient, her father, and her affected sister. Conclusion: This case report will help to determine the key clinical features of this syndrome, which exhibits variable clinical presentations.

Coexistence of Polyarteritis Nodosa of the Vulva and Retina in a Behçet's Disease Patient: A Case Report.

Polyarteritis nodosa (PAN) is a multisystem disease that may affect the vessels of multiple organ systems. It has clinical variants including single-organ disease and cutaneous-only PAN. To our knowledge, this is a unique case report describing the coexistence of PAN of the vulva and retina in a Behçet's disease (BD) patient.  We report a case of a 31-year-old Lebanese woman with painful genital ulcers and multiple oral aphthae associated with arthralgia, light flashes, blurry vision, and photosensitivity. There were well-defined, punched-out erosions over the buccal and gingival mucosa; specifically, multiple punched-out, deep ulcers with unremarkable borders and black eschar involving two-thirds of both labia majora and minora sparing the clitoris with bilateral inguinal lymphadenopathy. Dilated fundus examination showed a few cotton wool spots and intraretinal hemorrhage. Fundus fluorescein angiography showed multiple arteriolar infarctions involving the macula in both eyes, more so in the right eye. Vulvar biopsy was consistent with PAN due to the involvement of a medium-sized subcutaneous artery and showed neutrophilic infiltration of its wall. Stain for elastic lamina showed medium-sized subcutaneous artery involvement. After ruling out infectious aetiologies, she was managed by intravenous pulse methylprednisolone 1,000 mg for three days, followed by oral prednisolone 50 mg with a slow taper, oral colchicine 0.5 mg twice daily, and adalimumab 40 mg once every two weeks to stop the progression of the ocular insult and genital mutilation. There was significant improvement of the ulcer with no new cutaneous or systemic manifestations. This case report highlights the importance of considering PAN-like lesions in cases of Behçet's disease. We emphasized the addition of cutaneous PAN as one of the cutaneous manifestations of BD.