Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome with a Novel Variant
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Heterozygous FGFR2 variants are associated with a spectrum of autosomal dominant craniosynostosis disorders, including Beare-Stevenson cutis gyrata syndrome (BSS). BSS is an ultrarare disorder with just over 30 cases worldwide, among which prenatal reports are limited. This multisystemic disorder is characterized by craniofacial abnormalities, respiratory/airway complications, genitourinary abnormalities, cutis gyrata, acanthosis nigricans, and intellectual disability. We report a prenatally diagnosed case of BSS with a novel variant.
Case Presentation
41-year-old G5P2022 referred at 25 weeks 2 days gestation for hydrops fetalis and multiple congenital anomalies. The pregnancy was conceived via IVF with PGT-A (euploid male). Illnesses and exposures were denied. Notable family history included a paternal uncle of the fetus with isolated cleft palate and another paternal uncle with isolated imperforate anus. First trimester ultrasound identified an increased nuchal translucency (7 mm).
Ultrasound at our center revealed anomalies of multiple systems including craniofacial (brachycephaly and focal regions of abnormal/absent calvarial ossifications, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism with proptosis and unopposed eyelids, and elongated/low set ears), skeletal (thoracolumbar segmentation anomalies and pectus excavatum), gastrointestinal (hepatomegaly and possible tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non-visualized perineum/anal region, hypospadias, and microphallus), and enlarged thymus. Fetal echocardiogram was normal. Ultrasound at 30 weeks 4 days identified an abnormal fetal skull shape with fullness posteriorly in the skin/nuchal fold and continued concern for abnormal genitalia (small shaft with unusual scrotal shape).
Diagnostic Workup
The patient underwent amniocentesis for genetic and infectious studies. Microarray and PCR for cytomegalovirus/toxoplasmosis were negative, thus trio genome sequencing (GS) was recommended.
GS resulted at 30 weeks 5 days and revealed a heterozygous, de novo, likely pathogenic FGFR2 variant (c.827T>G, p.Phe276Cys). Pathogenic FGFR2 variants are associated with multiple craniosynostosis syndromes, including Antley-Bixler, Crouzon, Saethre-Chotzen, Pfeiffer, Jackson-Weiss, and BSS. Ultrasound anomalies were felt to be most consistent with BSS.
Treatment and Management
Given neonatal concern for airway compromise, delivery at our center was recommended. The patient presented in preterm labor at 35 weeks and delivered a male neonate (3.86 kg, >97%) via cesarean. Infant required immediate intubation and mechanical ventilation and was noted to be a difficult airway with significant macroglossia and micrognathia. Postnatal Genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, lower extremity 2-3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, and facial hemangioma. Postnatal phenotype was felt to be consistent with the BSS diagnosis.
Outcome and Follow-Up
Plastic Surgery, ENT, Neurosurgery, Oral and Maxillofacial Surgery, and Ophthalmology evaluated the neonate and confirmed likely metopic craniosynostosis, possible choanal atresia, and multiple ocular anomalies. Following confirmation of these anomalies, parents desired ongoing comfort care, but no withdrawal of life-sustaining technology due to faith-based preferences. He ultimately expired on DOL 50.
Discussion
Specific gain-of-function FGFR2 variants (p.Ser372Cys and p.Tyr375Cys) have been previously reported to cause BSS. This is the first report of a variant at this position (p.Phe276Cys) in association with BSS. Importantly, this variant has been reported in other unrelated individuals who presented with craniosynostosis without features of BSS. This highlights the value of detailed imaging to provide robust prenatal phenotyping and facilitate appropriate genetic counseling and anticipatory guidance. In this case, the prenatal phenotype was suggestive of BSS.
Conclusion
This case expands the genotype-phenotype correlation of BSS and demonstrates the clinical utility of prenatal GS given that the genetic diagnosis had direct implications for delivery planning. The diagnostic work-up of this fetus emphasizes potential limitations of prenatal phenotyping as concern for craniosynostosis did not arise until late in gestation. Lastly, our experience illustrates challenges that may arise when the pathways of care offered must also meet a family’s faith-based goals for care.
Heterozygous FGFR2 variants are associated with a spectrum of autosomal dominant craniosynostosis disorders, including Beare-Stevenson cutis gyrata syndrome (BSS). BSS is an ultrarare disorder with just over 30 cases worldwide, among which prenatal reports are limited. This multisystemic disorder is characterized by craniofacial abnormalities, respiratory/airway complications, genitourinary abnormalities, cutis gyrata, acanthosis nigricans, and intellectual disability. We report a prenatally diagnosed case of BSS with a novel variant.
Case Presentation
41-year-old G5P2022 referred at 25 weeks 2 days gestation for hydrops fetalis and multiple congenital anomalies. The pregnancy was conceived via IVF with PGT-A (euploid male). Illnesses and exposures were denied. Notable family history included a paternal uncle of the fetus with isolated cleft palate and another paternal uncle with isolated imperforate anus. First trimester ultrasound identified an increased nuchal translucency (7 mm).
Ultrasound at our center revealed anomalies of multiple systems including craniofacial (brachycephaly and focal regions of abnormal/absent calvarial ossifications, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism with proptosis and unopposed eyelids, and elongated/low set ears), skeletal (thoracolumbar segmentation anomalies and pectus excavatum), gastrointestinal (hepatomegaly and possible tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non-visualized perineum/anal region, hypospadias, and microphallus), and enlarged thymus. Fetal echocardiogram was normal. Ultrasound at 30 weeks 4 days identified an abnormal fetal skull shape with fullness posteriorly in the skin/nuchal fold and continued concern for abnormal genitalia (small shaft with unusual scrotal shape).
Diagnostic Workup
The patient underwent amniocentesis for genetic and infectious studies. Microarray and PCR for cytomegalovirus/toxoplasmosis were negative, thus trio genome sequencing (GS) was recommended.
GS resulted at 30 weeks 5 days and revealed a heterozygous, de novo, likely pathogenic FGFR2 variant (c.827T>G, p.Phe276Cys). Pathogenic FGFR2 variants are associated with multiple craniosynostosis syndromes, including Antley-Bixler, Crouzon, Saethre-Chotzen, Pfeiffer, Jackson-Weiss, and BSS. Ultrasound anomalies were felt to be most consistent with BSS.
Treatment and Management
Given neonatal concern for airway compromise, delivery at our center was recommended. The patient presented in preterm labor at 35 weeks and delivered a male neonate (3.86 kg, >97%) via cesarean. Infant required immediate intubation and mechanical ventilation and was noted to be a difficult airway with significant macroglossia and micrognathia. Postnatal Genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, lower extremity 2-3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, and facial hemangioma. Postnatal phenotype was felt to be consistent with the BSS diagnosis.
Outcome and Follow-Up
Plastic Surgery, ENT, Neurosurgery, Oral and Maxillofacial Surgery, and Ophthalmology evaluated the neonate and confirmed likely metopic craniosynostosis, possible choanal atresia, and multiple ocular anomalies. Following confirmation of these anomalies, parents desired ongoing comfort care, but no withdrawal of life-sustaining technology due to faith-based preferences. He ultimately expired on DOL 50.
Discussion
Specific gain-of-function FGFR2 variants (p.Ser372Cys and p.Tyr375Cys) have been previously reported to cause BSS. This is the first report of a variant at this position (p.Phe276Cys) in association with BSS. Importantly, this variant has been reported in other unrelated individuals who presented with craniosynostosis without features of BSS. This highlights the value of detailed imaging to provide robust prenatal phenotyping and facilitate appropriate genetic counseling and anticipatory guidance. In this case, the prenatal phenotype was suggestive of BSS.
Conclusion
This case expands the genotype-phenotype correlation of BSS and demonstrates the clinical utility of prenatal GS given that the genetic diagnosis had direct implications for delivery planning. The diagnostic work-up of this fetus emphasizes potential limitations of prenatal phenotyping as concern for craniosynostosis did not arise until late in gestation. Lastly, our experience illustrates challenges that may arise when the pathways of care offered must also meet a family’s faith-based goals for care.
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