Congenital knee and hip dislocations with brain malformation in an infant with a supernumerary chromosome +der(9)t(5;9)
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Congenital knee and hip dislocations are a rare congenital malformation. FLNB-related disorders represent a spectrum of allelic disorders that are characterized by congenital dislocation of the hips, knees, and elbows; skeletal malformations; and distinct craniofacial features, which may overlap with the skeletal presentation seen in trisomy 9p. Here we present a patient with congenital hip and knee dislocation who was initially suspected to have FLNB-related Larsen syndrome, but negative FLNB sequencing and deletion/duplication analysis triggered further genetic workup.
Case Presentation
Genetics was consulted on a 16-hour-old male infant born to a G2P1 27-year-old mother. Fetal ultrasound showed concern for agenesis of the corpus callosum, mild ventriculomegaly, and intrauterine growth restriction. Patient was born small for gestational age with congenital dislocation of bilateral hips and knees, persistent flexion or extension of multiple proximal and distal interphalangeal joints with clinodactyly of the 5th digit on both hands, microcephaly, short stature, a unilateral single transverse palmar crease, overlapping toes, and a bulbous nasal tip. Echocardiogram showed a bicuspid aortic valve and mildly dilated aortic sinus and ascending aorta. Postnatal brain MRI was notable for inferior cerebellar vermis hypoplasia, small acute infarct within the right periventricular white matter, choroid plexus cyst, mild dilation of bilateral lateral ventricles, global supratentorial cerebral volume loss, and concern for possible Dandy-Walker spectrum disorder.
Diagnostic Workup
Single gene sequencing and deletion/duplication analysis of FLNB demonstrated no pathogenic variants. Given negative testing and concern for brain MRI changes observed after the initial genetics assessment, chromosome and chromosomal microarray analyses were ordered. These studies showed an abnormal chromosome complement [47,XY,+der(9)t(5;9)(q35.1;q21.31)], most likely the result of a meiotic 3:1 malsegregation event in the setting of a parental balanced translocation.
Treatment and Management
Congenital joint dislocations were managed with splinting by orthopedic surgery, with the plan for serial casting as the patient grows.
Outcome and Follow-Up
Knee and hip alignment have not significantly changed by 3 weeks of life. The patient remains admitted to the neonatal intensive care unit to monitor his ability to feed independently and to monitor for apnea and bradycardia events. Parental chromosomal studies are in process.
Discussion
Congenital knee and hip dislocation are a rare congenital anomaly which can be related to monogenic disorders or chromosomal anomalies. Here we describe a patient for whom we initially suspected the diagnosis of Larsen syndrome but who was found instead to have a supernumerary chromosome, consisting of the short arm and centromere of chromosome 9 with a small portion of proximal 9q and a small portion of 5q35, resulting in trisomy 9p and trisomy of the most terminal 8.5 Mb of 5q. Trisomy 9p has a variable phenotype and has been associated with growth restriction, short stature, cerebral and cerebellar hypoplasia, congenital heart disease, agenesis or hypoplasia of the corpus callosum, skeletal anomalies, clinodactyly, single palmar crease, hypoplasia of phalanges, hip dislocations, a bulbous nasal tip, and joint hypermobility. Large duplications of 9p have been associated with Dandy-Walker malformation including hypoplasia of the cerebellar vermis and mild dilation of the lateral ventricles. A few patients with trisomy 9 or mosaic trisomy 9 have been reported to have congenital dislocation of the hips and knees. The duplication of 5q35 includes NSD1 which is triplosensitive, and reported to have a "reverse" Sotos syndrome-like presentation characterized by short stature, microcephaly, delayed bone maturation, digital anomalies, and abnormalities of internal organs.
Conclusion
Trisomy 9p can present with a Larsen syndrome-like phenotype. Careful evaluation of features such as brain malformations and feeding difficulties, however, should raise concern for a broader differential beyond Larsen syndrome for patients who present with congenital knee and hip dislocations.
Congenital knee and hip dislocations are a rare congenital malformation. FLNB-related disorders represent a spectrum of allelic disorders that are characterized by congenital dislocation of the hips, knees, and elbows; skeletal malformations; and distinct craniofacial features, which may overlap with the skeletal presentation seen in trisomy 9p. Here we present a patient with congenital hip and knee dislocation who was initially suspected to have FLNB-related Larsen syndrome, but negative FLNB sequencing and deletion/duplication analysis triggered further genetic workup.
Case Presentation
Genetics was consulted on a 16-hour-old male infant born to a G2P1 27-year-old mother. Fetal ultrasound showed concern for agenesis of the corpus callosum, mild ventriculomegaly, and intrauterine growth restriction. Patient was born small for gestational age with congenital dislocation of bilateral hips and knees, persistent flexion or extension of multiple proximal and distal interphalangeal joints with clinodactyly of the 5th digit on both hands, microcephaly, short stature, a unilateral single transverse palmar crease, overlapping toes, and a bulbous nasal tip. Echocardiogram showed a bicuspid aortic valve and mildly dilated aortic sinus and ascending aorta. Postnatal brain MRI was notable for inferior cerebellar vermis hypoplasia, small acute infarct within the right periventricular white matter, choroid plexus cyst, mild dilation of bilateral lateral ventricles, global supratentorial cerebral volume loss, and concern for possible Dandy-Walker spectrum disorder.
Diagnostic Workup
Single gene sequencing and deletion/duplication analysis of FLNB demonstrated no pathogenic variants. Given negative testing and concern for brain MRI changes observed after the initial genetics assessment, chromosome and chromosomal microarray analyses were ordered. These studies showed an abnormal chromosome complement [47,XY,+der(9)t(5;9)(q35.1;q21.31)], most likely the result of a meiotic 3:1 malsegregation event in the setting of a parental balanced translocation.
Treatment and Management
Congenital joint dislocations were managed with splinting by orthopedic surgery, with the plan for serial casting as the patient grows.
Outcome and Follow-Up
Knee and hip alignment have not significantly changed by 3 weeks of life. The patient remains admitted to the neonatal intensive care unit to monitor his ability to feed independently and to monitor for apnea and bradycardia events. Parental chromosomal studies are in process.
Discussion
Congenital knee and hip dislocation are a rare congenital anomaly which can be related to monogenic disorders or chromosomal anomalies. Here we describe a patient for whom we initially suspected the diagnosis of Larsen syndrome but who was found instead to have a supernumerary chromosome, consisting of the short arm and centromere of chromosome 9 with a small portion of proximal 9q and a small portion of 5q35, resulting in trisomy 9p and trisomy of the most terminal 8.5 Mb of 5q. Trisomy 9p has a variable phenotype and has been associated with growth restriction, short stature, cerebral and cerebellar hypoplasia, congenital heart disease, agenesis or hypoplasia of the corpus callosum, skeletal anomalies, clinodactyly, single palmar crease, hypoplasia of phalanges, hip dislocations, a bulbous nasal tip, and joint hypermobility. Large duplications of 9p have been associated with Dandy-Walker malformation including hypoplasia of the cerebellar vermis and mild dilation of the lateral ventricles. A few patients with trisomy 9 or mosaic trisomy 9 have been reported to have congenital dislocation of the hips and knees. The duplication of 5q35 includes NSD1 which is triplosensitive, and reported to have a "reverse" Sotos syndrome-like presentation characterized by short stature, microcephaly, delayed bone maturation, digital anomalies, and abnormalities of internal organs.
Conclusion
Trisomy 9p can present with a Larsen syndrome-like phenotype. Careful evaluation of features such as brain malformations and feeding difficulties, however, should raise concern for a broader differential beyond Larsen syndrome for patients who present with congenital knee and hip dislocations.