A novel UBA2 variant causing Aplasia Cutis Congenita with Ectrodactyly Skeletal (ACCES) syndrome in a family with variable expressivity
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Aplasia cutis congenita with ectrodactyly skeletal (ACCES) syndrome is an autosomal dominant disorder caused by pathogenic variants in UBA2. ACCES syndrome is associated with cutis aplasia, limb abnormalities, developmental delays, dysmorphic facies, as well as ocular, cardiac, genital, and renal defects with highly variable expressivity. Here we report a novel UBA2 variant in two siblings with clinical diagnoses of ACCES syndrome.
Case Presentation
Patient 1 was born at term to a 26-year-old G1P1 mother and 26-year-old father after an uncomplicated pregnancy. Dysmorphology examination at 20 months of age revealed a tall and broad forehead, hypertelorism with a broad nasal bridge, epicanthal folds, mildly bulbous nasal tip, bilateral ear tags, small left cheek pit, conical teeth, multiple hemangiomas, and gluteal cleft asymmetry. She had mild developmental delay for which she received early intervention services with resolution of delays by the age of 3 years.
Patient 2 is the full brother of Patient 1. He was born at term after a pregnancy complicated by omphalocele. At birth there was visible bowel in the umbilical cord that was corrected surgically. He had hypospadias and Meckel’s diverticulum that also required surgical repair. He had a small patent ductus arteriosus and mild bilateral pelviectasis. Dysmorphology examination at age 2 years revealed a tall and broad forehead, deep set eyes, mild hypertelorism, down-slanting palpebral fissures, bulbous nasal tip, small and widely spaced teeth, some conical teeth, rounded nails, and bilateral overriding toes. He had hypertonia and global developmental delay.
Diagnostic Workup
Molecular testing of Patient 1 revealed a normal chromosomal microarray and a heterozygous variant, UBA2 c.175 A>G p.Arg59Gly, identified by exome sequencing. This variant was also identified by exome analysis of Patient 2, utilizing both parents and Patient 1 as comparators. The variant was inherited from her father, who is known to have had hypospadias and autism. Review of the family history additionally demonstrated paternal grandfather with hypospadias and paternal great-grandfather with ectrodactyly. The UBA2 variant was classified as a Variant of Uncertain Significance as it has not been previously reported, is absent from the general population, and computational predictors indicate that it has a damaging effect on protein function. In support of this prediction, the variant occurs in the ATP binding site and alteration of the arginine at codon 59 to alanine is known to result in defective adenylation which would theoretically cause loss of function. Another pathogenic variant in this region, p.Asn56Thr, has been previously described.
Discussion
This family exemplifies the highly variable expressivity known in this condition and expands the phenotypic spectrum. Patient 1 displays characteristic facial features and dental anomalies. She has a focal cheek pit that we now recognize to be consistent with aplasia cutis spectrum. She had multiple infantile hemangiomas and is the second individual with ACCES syndrome known to have this congenital skin anomaly. Patient 2 displays characteristic facial features, and dental and urogenital anomalies. He was born with omphalocele, which is not previously known to be associated with ACCES syndrome. Subsequent review of the literature identified a previously reported individual born with omphalocele and focal dermal hypoplasia. While molecular diagnostics were not available for this individual, the reported phenotype combines features seen in Patient 1, focal dermal hypoplasia, and Patient 2, omphalocele. This is further compelling evidence for expanding the phenotypic spectrum of ACCES syndrome to include omphalocele.
Conclusion
ACCES syndrome is an autosomal dominant multisystem disorder with highly variable expressivity. We report a new family with two siblings affected by ACCES syndrome due to a novel UBA2 variant. These cases support a broadening of our understanding of the phenotypic spectrum to include focal dermal hypoplasia, multiple infantile hemangiomas, and omphalocele.
Aplasia cutis congenita with ectrodactyly skeletal (ACCES) syndrome is an autosomal dominant disorder caused by pathogenic variants in UBA2. ACCES syndrome is associated with cutis aplasia, limb abnormalities, developmental delays, dysmorphic facies, as well as ocular, cardiac, genital, and renal defects with highly variable expressivity. Here we report a novel UBA2 variant in two siblings with clinical diagnoses of ACCES syndrome.
Case Presentation
Patient 1 was born at term to a 26-year-old G1P1 mother and 26-year-old father after an uncomplicated pregnancy. Dysmorphology examination at 20 months of age revealed a tall and broad forehead, hypertelorism with a broad nasal bridge, epicanthal folds, mildly bulbous nasal tip, bilateral ear tags, small left cheek pit, conical teeth, multiple hemangiomas, and gluteal cleft asymmetry. She had mild developmental delay for which she received early intervention services with resolution of delays by the age of 3 years.
Patient 2 is the full brother of Patient 1. He was born at term after a pregnancy complicated by omphalocele. At birth there was visible bowel in the umbilical cord that was corrected surgically. He had hypospadias and Meckel’s diverticulum that also required surgical repair. He had a small patent ductus arteriosus and mild bilateral pelviectasis. Dysmorphology examination at age 2 years revealed a tall and broad forehead, deep set eyes, mild hypertelorism, down-slanting palpebral fissures, bulbous nasal tip, small and widely spaced teeth, some conical teeth, rounded nails, and bilateral overriding toes. He had hypertonia and global developmental delay.
Diagnostic Workup
Molecular testing of Patient 1 revealed a normal chromosomal microarray and a heterozygous variant, UBA2 c.175 A>G p.Arg59Gly, identified by exome sequencing. This variant was also identified by exome analysis of Patient 2, utilizing both parents and Patient 1 as comparators. The variant was inherited from her father, who is known to have had hypospadias and autism. Review of the family history additionally demonstrated paternal grandfather with hypospadias and paternal great-grandfather with ectrodactyly. The UBA2 variant was classified as a Variant of Uncertain Significance as it has not been previously reported, is absent from the general population, and computational predictors indicate that it has a damaging effect on protein function. In support of this prediction, the variant occurs in the ATP binding site and alteration of the arginine at codon 59 to alanine is known to result in defective adenylation which would theoretically cause loss of function. Another pathogenic variant in this region, p.Asn56Thr, has been previously described.
Discussion
This family exemplifies the highly variable expressivity known in this condition and expands the phenotypic spectrum. Patient 1 displays characteristic facial features and dental anomalies. She has a focal cheek pit that we now recognize to be consistent with aplasia cutis spectrum. She had multiple infantile hemangiomas and is the second individual with ACCES syndrome known to have this congenital skin anomaly. Patient 2 displays characteristic facial features, and dental and urogenital anomalies. He was born with omphalocele, which is not previously known to be associated with ACCES syndrome. Subsequent review of the literature identified a previously reported individual born with omphalocele and focal dermal hypoplasia. While molecular diagnostics were not available for this individual, the reported phenotype combines features seen in Patient 1, focal dermal hypoplasia, and Patient 2, omphalocele. This is further compelling evidence for expanding the phenotypic spectrum of ACCES syndrome to include omphalocele.
Conclusion
ACCES syndrome is an autosomal dominant multisystem disorder with highly variable expressivity. We report a new family with two siblings affected by ACCES syndrome due to a novel UBA2 variant. These cases support a broadening of our understanding of the phenotypic spectrum to include focal dermal hypoplasia, multiple infantile hemangiomas, and omphalocele.