MAP2K2 mutation as a cause of cardio‐facio‐cutaneous syndrome in an infant with a severe and fatal course of the disease

Abstract

Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

“… k Armour & Allanson, 2007; Croonen et al, 2013; Dentici et al, 2009; Digilio et al, 2011; Gos et al, 2018; Narumi et al, 2007; Nava et al, 2007; Pierpont et al, 2017; Rauen et al, 2010. …”

“…Regarding CFC syndrome, BRAF seems to be the most commonly associated mutation to cardiac anomalies, both PVS and/or HCM (Chen et al, 2019; Croonen et al, 2013; Digilio et al, 2011; Lee et al, 2011; Narumi et al, 2007; Nava et al, 2007; Sarkozy et al, 2009; Ueda et al, 2017), whereas heart defects are less frequent or milder in patients with MAP2K1 and MAP2K2 mutations (Armour & Allanson, 2007; Croonen et al, 2013; Dentici et al, 2009; Digilio et al, 2011; Gos et al, 2018; Narumi et al, 2007; Nava et al, 2007; Pierpont et al, 2014; Pierpont et al, 2017; Rauen et al, 2010). In the present CFCS subcohort with BRAF mutations, a higher prevalence of HCM (most frequently asymmetric form of mild degree) compared to pulmonary stenosis (PVS or SVPS) was recorded.…”

Cancer-associated genodermatoses

“…В большинстве случаев мутации возникают de novo и пациенты не имеют родственников с КФКС. Чаще всего в вышеупомянутых генах выявляют точечные мутации, однако описаны отдельные случаи крупных перестроек в генах BRAF и MAP2K2 [38][39][40][41].…”

Cardio-facio-cutaneous syndrome and gastrointestinal defects: report on a newborn with 19p13.3 deletion including the MAP 2 K2 gene

“…Cardio-facio-cutaneous syndrome (CFCS) belongs to RASopathies, a group of conditions caused by germline mutations in genes encoding components or regulators of the rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathway [ 1 ], main mechanism regulating cell growth and differentiation, proliferation, migration, and apoptosis [ 2 ]. It is a rare condition, with about 300 reported patients.…”