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CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations. We performed whole exome and Sanger sequencing to identify the underlying molecular cause in five patients with CDAGS syndrome from four distinct families. Whole exome sequencing revealed biallelic rare variants that disrupt highly conserved nucleotides within the RNU12 gene. RNU12 encodes a small nuclear RNA that is a component of the minor spliceosome and is essential for minor intron splicing. Targeted sequencing confirmed allele segregation within the four families. All five patients shared the same rare mutation NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide within the precursor U12 snRNA 3' extension. Each of them also carried a rare variant on the other allele that either disrupts the secondary structure or the Sm binding site of the RNU12 snRNA. Whole transcriptome sequencing analysis of lymphoblastoid cells identified 120 differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events in the patient. These findings provide evidence of the involvement of RNU12 in craniosynostosis, anal and genitourinary patterning, and cutaneous disease., (© 2021 Wiley Periodicals LLC.)

Introduction: Craniosynostosis and clavicular hypoplasia, delayed closure of the fontanelle, cranial defects, anal and genitourinary abnormalities, and skin (CDAGS), is an infrequent autosomal recessive entity with only 10 cases reported; no associated gene has been identified so far., Case Report: The proband is a 2-year-old Mexican female with brachycephaly, cleft palate, anal malformation with rectovestibular fistula, and clinodactyly of the third toe overlapping the second. At 4 months of age, she developed a disseminated dermatosis with erythematous scaly nummular plaques, elevated keratotic sharp borders with thin to broad flaking, hematic crusts, and keratotic surface in others. The lesions were slightly pruritic and began at the lower limbs with posterior dissemination to the upper limbs, head, and trunk; palms and soles were unaffected. A skin biopsy showed hyperkeratosis, parakeratosis, acanthosis, and perivascular inflammatory infiltration in the upper reticular dermis among other alterations. She also presented mild bilateral neurosensory hypoacusia and enamel dysplasia. Her karyotype was normal. Treatment with topical hydrating creams partially improved the skin lesions at their center, while the sharply keratotic borders remained, giving a clinical resemblance to porokeratosis., Discussion: The patient suffers from CDAGS syndrome but has normal development, and feet abnormality was described in only one other patient. The treatment with topical hydrating creams improved the skin lesions at their center, while porokeratotic characteristics persisted. CDAGS remains a diagnostic challenge; a comparison with previously reported cases is discussed. The timely detection of the syndrome will allow early treatment that may improve the condition of the patients., (© 2017 The International Society of Dermatology.)