Expanding the phenotype of 16p11.2 Microduplication Syndrome: Different presentation in three family members with new clinical findings
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
The 16p11.2 duplication syndrome is an autosomal dominant genetic condition that has a wide variable phenotype usually with minor dysmorphic features, developmental delay, and motor compromise. Few minor congenital anomalies affecting different body systems have been described in the past. We describe three related patients with 16p11.2 duplication with additional medical findings.
Case Presentation
The proband is a boy who was referred due to penoscrotal hypospadias and developmental delays. On initial physical exam was found to have short stature, hypotonia, minor distinctive facial features, and a sacral dimple. Brain imaging evidenced a blake pouch cyst and vermian hypoplasia. Spinal US showed a conus medullaris at L2-L3 intervertebral disc level.
The proband's older sister had developmental delay, and a normal cognitive development. Recently diagnosed with ADHD and depression.
The proband’s father developed blepharospasm and dystonia at age 13, then became wheelchair bound and required DBS surgery. Has a history of urinary blockage and multiple UTIs that required surgery.
Diagnostic Workup
The three patients have a 523 kb 16p11.2 duplication. The father has a negative WES.
Discussion
These three patients highlights the importance to categorize the 16p11.2 duplication syndrome as a multisystemic genetic condition and to not only to classify it as a neurodevelopmental disorder. Hypospadias have not been described as part of the syndrome. The 16p11.2 region contains KCTD13 gene which is robustly expressed in the developing and adult GU tract, including urethra, corpus cavernosum and preputial glans. Furthermore, KTCD13 CNVs are frequent in penile and testicular abnormalities. It encodes a substrate that regulates the BCR E3 ubiquitin protein ligase complex, which is essential for the regulation of microtubular cytoskeleton that is required for the nuclear androgen receptor activation and degradation. In fact, a loss of KCTD13 might decrease these receptors hindering the differentiation and development of male genitalia. In addition, gene dosage changes influence on SOX9, MAP3K1, and RHOA complex that participate in sexual differentiation.
PRRT2 located in 16p11.2 has been described in patients with paroxysmal disorders such as benign infantile epilepsy, paroxysmal kinesigenic dyskinesia and generalized dystonia. It is expressed in the cerebral cortex, basal ganglia, and cerebellum. It encodes a proline-rich transmembrane protein that mediates Ca2+-mediated neurotransmitter release in presynaptic glutaminergic neurons and interacts with glutamate receptors. Silencing PRRT2 increases susceptibility for movement disorders and epilepsy. Additional research is needed to confirm phenotype in the setting of a 16p11.2 duplication.
Conclusion
Herein we describe related patients with 16p11.2 duplication syndrome with unusual neurologic and unreported genitourinary malformations. This is the first report of dystonia, and hypospadia with fetal ambiguous genitalia. Herein, we hypothesize co-occurring KCTD13 and PPRT2 in a 16p11.2 duplication as a possible cause of lower tract genitourinary malformations and paroxysmal disorders, respectively. Further investigation about the gene interactions and dosage effects in the 16p11.2 locus to modulate brain and urinary development. In order to shorten the diagnostic odyssey, we encourage the inclusion of hypospadia and dystonia into the16p11.2 duplication syndrome.
The 16p11.2 duplication syndrome is an autosomal dominant genetic condition that has a wide variable phenotype usually with minor dysmorphic features, developmental delay, and motor compromise. Few minor congenital anomalies affecting different body systems have been described in the past. We describe three related patients with 16p11.2 duplication with additional medical findings.
Case Presentation
The proband is a boy who was referred due to penoscrotal hypospadias and developmental delays. On initial physical exam was found to have short stature, hypotonia, minor distinctive facial features, and a sacral dimple. Brain imaging evidenced a blake pouch cyst and vermian hypoplasia. Spinal US showed a conus medullaris at L2-L3 intervertebral disc level.
The proband's older sister had developmental delay, and a normal cognitive development. Recently diagnosed with ADHD and depression.
The proband’s father developed blepharospasm and dystonia at age 13, then became wheelchair bound and required DBS surgery. Has a history of urinary blockage and multiple UTIs that required surgery.
Diagnostic Workup
The three patients have a 523 kb 16p11.2 duplication. The father has a negative WES.
Discussion
These three patients highlights the importance to categorize the 16p11.2 duplication syndrome as a multisystemic genetic condition and to not only to classify it as a neurodevelopmental disorder. Hypospadias have not been described as part of the syndrome. The 16p11.2 region contains KCTD13 gene which is robustly expressed in the developing and adult GU tract, including urethra, corpus cavernosum and preputial glans. Furthermore, KTCD13 CNVs are frequent in penile and testicular abnormalities. It encodes a substrate that regulates the BCR E3 ubiquitin protein ligase complex, which is essential for the regulation of microtubular cytoskeleton that is required for the nuclear androgen receptor activation and degradation. In fact, a loss of KCTD13 might decrease these receptors hindering the differentiation and development of male genitalia. In addition, gene dosage changes influence on SOX9, MAP3K1, and RHOA complex that participate in sexual differentiation.
PRRT2 located in 16p11.2 has been described in patients with paroxysmal disorders such as benign infantile epilepsy, paroxysmal kinesigenic dyskinesia and generalized dystonia. It is expressed in the cerebral cortex, basal ganglia, and cerebellum. It encodes a proline-rich transmembrane protein that mediates Ca2+-mediated neurotransmitter release in presynaptic glutaminergic neurons and interacts with glutamate receptors. Silencing PRRT2 increases susceptibility for movement disorders and epilepsy. Additional research is needed to confirm phenotype in the setting of a 16p11.2 duplication.
Conclusion
Herein we describe related patients with 16p11.2 duplication syndrome with unusual neurologic and unreported genitourinary malformations. This is the first report of dystonia, and hypospadia with fetal ambiguous genitalia. Herein, we hypothesize co-occurring KCTD13 and PPRT2 in a 16p11.2 duplication as a possible cause of lower tract genitourinary malformations and paroxysmal disorders, respectively. Further investigation about the gene interactions and dosage effects in the 16p11.2 locus to modulate brain and urinary development. In order to shorten the diagnostic odyssey, we encourage the inclusion of hypospadia and dystonia into the16p11.2 duplication syndrome.