Lethal COG6‐CDG in neonatal patient with arachnodactyly, joint contractures, and skin manifestations: Founder mutation in the Southeastern European population?

Abstract

Herein, we report a lethal case of the ultra-rare COG6congenital disorder of glycosylation (CDG) presenting with skin manifestations (scaling and erosions) and joint contractures in a neonate of Albanian origin. The patient was homozygous for a COG6 pathogenic variant, previously reported in another three individuals of Greek, Bulgarian and Turkish descent. The presence of a founder mutation in the geographical area is possible. The index case emphasizes the need to consider CDGs in neonatal patients with skin manifestations and joint contractures, particularly patients of Southeastern European or West Asian origin. Herein, we report a case of the ultra-rare conserved oligomeric Golgi complex (COG6)-congenital disorder of glycosylation (CDG) presenting with arachnodactyly, multiple contractures, and skin manifestations. The index individual was the first child of nonconsanguineous parents of Albanian origin with no family history of note. The patient was a girl born at 32 weeks with a birth weight Pediatric Dermatology VERVERI Et al.

The SwedishCOG6‐CDGexperience and a comprehensive literature review

“… Note : Features of the two COG6‐CDG patients in our cohort (P1 and P2) and the previously published cases (R1:1, Cirnigliaro et al 6 ; R2:1, Ververi et al 7 ; R3:1, Zhao et al 8 ; R4:1, Lugli et al 10 ; R5:1, Lugli et al 9 ; R6:1, R6:2, Komlosi et al 11 ; R7:1, R7:2, Mandel et al 12 ; R8:1, Li et al 13 ; R9:1, Althonaian et al 14 ; R10:1, Wu et al 15 ; R11:1‐R11:7, Alsubhi et al 16 ; R12:1; Pérez‐Cerdá et al 17 ; R13:1‐R13:7, Rymen et al 18 ; R14:1, Shaheen et al 19 ; R15:1, Huybrechts et al 20 ; R16:1, Lubbehusen et al 21 In Shaheen et al, 19 11 more patients are mentioned but not individually clinically described). …”

“… Note : Features of the two COG6‐CDG patients in our cohort (P1 and P2) and the previously published cases (R1:1, Cirnigliaro et al 6 ; R2:1, Ververi et al 7 ; R3:1, Zhao et al 8 ; R4:1, Lugli et al 10 ; R5:1, Lugli et al 9 ; R6:1, R6:2, Komlosi et al 11 ; R7:1, R7:2, Mandel et al 12 ; R8:1, Li et al 13 ; R9:1, Althonaian et al 14 ; R10:1, Wu et al 15 ; R11:1‐R11:7, Alsubhi et al 16 ; R12:1; Pérez‐Cerdá et al 17 ; R13:1‐R13:7, Rymen et al 18 ; R14:1, Shaheen et al 19 ; R15:1, Huybrechts et al 20 ; R16:1, Lubbehusen et al 21 In Shaheen et al, 19 11 more patients are mentioned but not individually clinically described). Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; ASD, atrial septal defect; AST, aspartate aminotransferase; AV, aortic valve; BRP, birth‐related problems; CK, creatine kinase; DD, developmental delay; ep, epicanthal; F, female; FTT, failure to thrive; FXI, factor 11; HLH, hemophagocytic lymphohistiocytosis; ID, intellectual disability; IN, inverted nipples; LSE, low‐set ears; M, male; P, percentile; PDA, persistent ductus arteriosus; PFO, persistent foramen ovale; PT, prothrombin time; PVL, periventricular leukomalacia; SD, standard deviation; trc, thrombocytes; US, ultrasound; VSD, ventricular septal defect; WM, white matter; ‐, not present; +, present, N/R, not reported.…”

“…The mutations divide in seven missense, eight nonsense, and five splice variants (Figure 2 ). Homozygosity for p.Arg141* causes a particularly severe phenotype where the four published cases died within 40 days of age, 7 , 11 , 18 whereas Gly390Phefs*6 has a much milder clinical presentation (also known as Shaheen syndrome 19 ). Homozygous variants, suggesting consanguinity, were found in 32/43 patients.…”

“… 5 There are 16 publications totaling 41 patients with COG6‐CDG, of which 30 have clinical descriptions and 16 derive from two families (12 + 4). 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 Of the 41, only 9 presented with compound heterozygous variants, whereas the others were homozygous. The phenotype of COG6‐CDG varies between subjects, but is severe in a significant proportion with growth retardation, microcephaly, DD or ID, hypohidrosis, arthrogryposis, and 17/41 fatalities during the first 15 months of life.…”

“…The COG complex contains eight subunits, of which deficiencies in seven (all but COG3) have been described to cause a CDG 5 . There are 16 publications totaling 41 patients with COG6‐CDG, of which 30 have clinical descriptions and 16 derive from two families (12 + 4) 6–21 . Of the 41, only 9 presented with compound heterozygous variants, whereas the others were homozygous.…”