Neonatal presentation of COG6‐CDG with prominent skin phenotype

Abstract

Many of the genetic childhood disorders leading to death in the perinatal period follow autosomal recessive inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Often, affected children die before a genetic diagnosis can be established, thereby precluding targeted carrier testing in parents and prenatal or preimplantation genetic diagnosis in further pregnancies. The clinical phenotype of congenital disorders of glycosylation (CDG) is very heterogeneous and ranges from relatively mild symptoms to severe multisystem dysfunction and even a fatal course. A very rare subtype, COG6‐CDG, is caused by deficiency of subunit 6 of the conserved oligomeric Golgi complex and is usually characterized by growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. It has been proposed that a distinctive feature of COG6‐CDG can be ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies. In a Greek family, who had lost two children in the neonatal period, with prominent skin features initially resembling restrictive dermopathy, severe arthrogryposis, respiratory insufficiency and a rapid fatal course trio whole‐exome sequencing revealed the homozygous nonsense mutation c.511C>T, p.(Arg171*) in the COG6 gene. Skin manifestations such as dry skin and hyperkeratosis have been reported in only five out of the 21 reported COG6‐CDG cases so far, including two patients with the c.511C>T variant in COG6 but with milder ectodermal symptoms. Our case adds to the phenotypic spectrum of COG6‐CDG with prominent ectodermal manifestations at birth and underlines the importance of considering CDG among the possible causes for congenital syndromic genodermatoses.

Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6‐CDG

“…Sequencing analysis of the COG6‐cDNA revealed a homozygous variant (c. 1646G > T), leading to amino acid exchange p.Gly549Val in the COG6 protein (Lubbehusen et al, 2010). At the best of our knowledge, since Lubbehusen and colleagues described the first COG6‐CDG patient in 2010, only 23 patients with COG6‐gene mutation have been described so far worldwide (Alsubhi et al, 2017; Althonaian et al, 2018; Huybrechts et al, 2012; Komlosi et al, 2020; Li et al, 2019; Lubbehusen et al, 2010; Mandel et al, 2020; Rymen et al, 2015; Shaheen et al, 2013). The clinical phenotype related to mutation of COG6 gene (MIM *606977) is named COG6‐CDG (OMIM #614576), except in the case of the deep intronic splice site mutation (c.1167‐24A > G), which results in Shaheen syndrome (OMIM #615328), a milder phenotype than severe COG6‐CDG (Alsubhi et al, 2017; Althonaian et al, 2018; Shaheen et al, 2013).…”

“…To better understand the genotype–phenotype correlation, our patient was compared with 16 previously described patients with COG6‐CDG (OMIM #614576) (Alsubhi et al, 2017; Althonaian et al, 2018; Huybrechts et al, 2012; Komlosi et al, 2020; Li et al, 2019; Lubbehusen et al, 2010; Mandel et al, 2020; Rymen et al, 2015; Shaheen et al, 2013) (Table 1), excluding patients with Shaheen syndrome (OMIM #615328) (Alsubhi et al, 2017; Althonaian et al, 2018; Shaheen et al, 2013). To date, only 13 pathogenetic variants have been reported in the COG6 gene (HGMD professional udate 2020.3, https://portal.biobase-international.com/hgmd/pro/start.php), including five missense variants, two nonsense variants, four splicing variants, one insertion, and one deletion.…”

“…Usually these patients present with multi‐systemic disease and involvement of central nervous system (Arora et al, 2019). Among the defects of the COG complex, COG6‐CDG is a very rare disease which counts less than 25 patients reported worldwide (Althonaian, Abdulrahman Alsultan, Morava, & Alfadhel, 2018; Alsubhi et al, 2017; Huybrechts et al, 2012; Komlosi et al, 2020; Li et al, 2019; Lubbehusen et al, 2010; Mandel et al, 2020; Rymen et al, 2015). The most common clinical features of COG6‐CDG are growth retardation, microcephaly, developmental disability, liver or gastrointestinal disease, hepatosplenomegaly, recurrent infections, hypohidrosis/hyperthermia and hyperkeratosis (Li et al, 2019; Rymen et al, 2015).…”

Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis

“…We recently described a family with two affected children with COG6-CDG in whom very dry, tight, and rigid skin with hyperkeratosis and scaling was the prominent skin feature at birth (Komlosi et al, 2020).…”

“…The spectrum of clinical manifestations comprises psychomotor delay and intellectual disability, muscle hypotonia, seizures, endocrine and coagulation abnormalities, ophthalmologic anomalies, failure to thrive, and variable dysmorphic features. Skin abnormalities are described in only about 20% of the different CDG forms ( Rymen et al, 2012 ; Haijes et al, 2020 ; Komlosi et al, 2020 ). Generally, the skin manifestations represent only a single feature within a much broader phenotype and include orange peel skin, ichthyosis, increased skin laxity, hypo/hyperpigmentation, tumoral calcinosis, aplasia cutis congenita, hypohidrosis, hyperthermia, lipodystrophy, and psoriasis ( Rymen et al, 2012 ; Kouwenberg et al, 2014 ; Alsubhi et al, 2017 ; Van Damme et al, 2017 ; Haijes et al, 2020 ; Komlosi et al, 2020 ).…”