Expanding the fetal phenotype of USP7-related conditions
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability and behavioral abnormalities. HAFOUS is caused by heterozygous loss-of function variants in USP7. To date there are approximately 60 cases reported describing postnatal phenotype. Information about prenatal phenotype is significantly limited with a single case of fetal cystic hygroma reported. Other congenital anomalies described include heart defects and contractures. However, the fetal phenotype of HAFOUS largely remains unknown. We present 3 cases with fetal hydrops in combination with USP7 variants including a novel splice site variant and two copy number variants.
Case Presentation
Case1: A 35yo (G5P2022) was noted to have non-immune hydrops fetalis (NIHF) including cystic hygroma, pleural effusion and mild ascites at 12w6d, which progressed to generalized ascites with pleural and pericardial effusion at 15w3d. Diagnostic testing was declined. Fetal demise was noted at 17w4d. Chromosomal microarray on products of conception showed a male fetus with a pathogenic 734kb deletion of 16p13.2. The deletion includes 7 OMIM genes, including USP7. Parental karyotypes and qPCR for the deletion were negative. Autopsy was not performed.
Case 2: A 36yo (G8P6016) was noted to have NIHF including large cystic hygroma, abdominal ascites, pleural effusion, and generalized edema at 15w3d. A single umbilical artery, oligohydramnios and abnormal position of the fetal legs was also identified. Chromosomal microarray on placental biopsy was normal female. Maternal TORCH titers were non-contributory. Subsequently, trio exome sequencing identified a de novo heterozygous pathogenic variant in USP7 [c.383+1G>C p.?]. Pregnancy was terminated and autopsy was not performed.
Case 3: A 33yo (G7P3033) was noted to have NIHF with skin edema, bilateral pleural effusion, and ascites at 16w6d. Additional findings included bilateral loculated cystic structure on the fetal neck, armpits and groin, as well as an anechoic cystic fluid collection within the fetal buttocks. Growth restriction (<1%) and echogenic bowel were also seen. Fetal demise was noted at 17w6d. Cytomegalovirus, parvovirus and toxoplasmosis PCRs on amniotic fluid were negative. Chromosomal microarray on amniotic fluid showed a female fetus with a 358 kb duplication of 16p13.2, including partial duplication of USP7, classified as a variant of uncertain significance. Proband only exome sequencing was negative; however, CNV analysis was not performed due to suboptimal data. Parental testing for the duplication was declined. Autopsy confirmed the ultrasound findings and noted low set ears; and short, broad nasal root with transverse skin crease. No internal malformations were identified.
Diagnostic Workup
N/A
Treatment and Management
N/A
Outcome and Follow-Up
N/A
Discussion
HAFOUS is a recently described neurodevelopmental disorder with limited data on presentation, especially in the prenatal period. We present 3 cases of fetal hydrops, which likely represents the most severe end of the HAFOUS clinical spectrum. While the exact disease mechanism is not known, USP7 is involved in critical cellular pathways which are essential for normal fetal development. Expression of USP7 is essential for normal MAGEL2 protein function and loss of function variants in MAGEL2 lead to Schaaf-Yang syndrome (SYS), which has overlapping neurodevelopmental phenotype. Both HAFOUS and SYS involve hypotonia, which can impair fetal movement and potentially lead to fetal akinesia or fetal hydrops. While we noted abnormal foot positioning in one fetus, the full description of prenatal phenotype was limited by the nature of the cases.
Conclusion
This report contributes to the mutational spectrum of USP7-related conditions. We present 3 fetal cases with the most severe end of the HAFOUS clinical spectrum reported to date. Variants affecting USP7 noted on both exome and microarray should be considered in the differential diagnosis when fetal hydrops is diagnosed.
Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability and behavioral abnormalities. HAFOUS is caused by heterozygous loss-of function variants in USP7. To date there are approximately 60 cases reported describing postnatal phenotype. Information about prenatal phenotype is significantly limited with a single case of fetal cystic hygroma reported. Other congenital anomalies described include heart defects and contractures. However, the fetal phenotype of HAFOUS largely remains unknown. We present 3 cases with fetal hydrops in combination with USP7 variants including a novel splice site variant and two copy number variants.
Case Presentation
Case1: A 35yo (G5P2022) was noted to have non-immune hydrops fetalis (NIHF) including cystic hygroma, pleural effusion and mild ascites at 12w6d, which progressed to generalized ascites with pleural and pericardial effusion at 15w3d. Diagnostic testing was declined. Fetal demise was noted at 17w4d. Chromosomal microarray on products of conception showed a male fetus with a pathogenic 734kb deletion of 16p13.2. The deletion includes 7 OMIM genes, including USP7. Parental karyotypes and qPCR for the deletion were negative. Autopsy was not performed.
Case 2: A 36yo (G8P6016) was noted to have NIHF including large cystic hygroma, abdominal ascites, pleural effusion, and generalized edema at 15w3d. A single umbilical artery, oligohydramnios and abnormal position of the fetal legs was also identified. Chromosomal microarray on placental biopsy was normal female. Maternal TORCH titers were non-contributory. Subsequently, trio exome sequencing identified a de novo heterozygous pathogenic variant in USP7 [c.383+1G>C p.?]. Pregnancy was terminated and autopsy was not performed.
Case 3: A 33yo (G7P3033) was noted to have NIHF with skin edema, bilateral pleural effusion, and ascites at 16w6d. Additional findings included bilateral loculated cystic structure on the fetal neck, armpits and groin, as well as an anechoic cystic fluid collection within the fetal buttocks. Growth restriction (<1%) and echogenic bowel were also seen. Fetal demise was noted at 17w6d. Cytomegalovirus, parvovirus and toxoplasmosis PCRs on amniotic fluid were negative. Chromosomal microarray on amniotic fluid showed a female fetus with a 358 kb duplication of 16p13.2, including partial duplication of USP7, classified as a variant of uncertain significance. Proband only exome sequencing was negative; however, CNV analysis was not performed due to suboptimal data. Parental testing for the duplication was declined. Autopsy confirmed the ultrasound findings and noted low set ears; and short, broad nasal root with transverse skin crease. No internal malformations were identified.
Diagnostic Workup
N/A
Treatment and Management
N/A
Outcome and Follow-Up
N/A
Discussion
HAFOUS is a recently described neurodevelopmental disorder with limited data on presentation, especially in the prenatal period. We present 3 cases of fetal hydrops, which likely represents the most severe end of the HAFOUS clinical spectrum. While the exact disease mechanism is not known, USP7 is involved in critical cellular pathways which are essential for normal fetal development. Expression of USP7 is essential for normal MAGEL2 protein function and loss of function variants in MAGEL2 lead to Schaaf-Yang syndrome (SYS), which has overlapping neurodevelopmental phenotype. Both HAFOUS and SYS involve hypotonia, which can impair fetal movement and potentially lead to fetal akinesia or fetal hydrops. While we noted abnormal foot positioning in one fetus, the full description of prenatal phenotype was limited by the nature of the cases.
Conclusion
This report contributes to the mutational spectrum of USP7-related conditions. We present 3 fetal cases with the most severe end of the HAFOUS clinical spectrum reported to date. Variants affecting USP7 noted on both exome and microarray should be considered in the differential diagnosis when fetal hydrops is diagnosed.
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