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Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.

ABSTRACT: BACKGROUND:Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant. METHODS:Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis. RESULTS:On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans. CONCLUSIONS:This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.

SUBMITTER: Rymer K

PROVIDER: S-EPMC6565579 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.

Rymer Karen K Shiang Rita R Hsiung Anting A Pandya Arti A Bigdeli Tim T Webb Bradley T BT Rhodes Jennifer J

Molecular genetics & genomic medicine 20190423 6

<h4>Background</h4>Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and sh ...[more]

PMID: 31016899

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Project description:BackgroundPURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems.MethodsAmplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient.ResultsClinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome.ConclusionsOur data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation.

Dataset Information

Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.

Publications

Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.

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