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PTEN and WDR19 Variants in a Neonate with Brain and Cutaneous Anomalies

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
PTEN is a well-studied gene associated with several health conditions. Individuals with variants in PTEN have been identified as having a spectrum of conditions, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and PTEN-related Proteus-like syndrome. Variants in WDR19 are associated with cranioectodermal dysplasia 4, a ciliopathy that can involve several systems throughout the body.  

 

The proband in this case presented with several features of both conditions, and genetic testing identified variants in both PTEN and WDR19. These results, as well as the presentation, support that either one or both of the VUS in WDR19 could be a new pathogenic variant.  

Case Presentation
The Medical Genetics team was initially consulted on the proband’s first day of life for cutaneous lesions of unknown etiology. These lesions were thick white plaques covering most of the left skull and satellite lesions involving the left ocular region, left ear, and midline neck. Follicles in a normal hair pattern could be seen underneath the lesion. There was a prenatal history of late and scant care, though no abnormalities were identified on ultrasound. Additional significant findings on proband’s clinical exam included low-set ears with posterior rotation, a short and broad nose with flattened nasal bridge and bulbous tip, midface hypoplasia, dysplastic toenails, long fingers, and congenital dermal melanocytosis at the sacrum. She was large for gestational age in weight, length, and head circumference.  

Diagnostic Workup
Brain MRI identified significant cortical dysplasia and cortical thickening with absence of normal sulcation of left hemisphere. EEG revealed status epilepticus on multiple occasions. Biochemical labs included plasma amino acids, urine organic acids, and an acylcarnitine profile. All were non-diagnostic. Newborn screening #1 was normal, though #2 was positive for congenital adrenal hyperplasia and congenital hypothyroidism.  

 

Genetic testing included a rapid proband-only genome sequence analysis. Positive results include a pathogenic variant in PTEN (c.388C>T), a likely pathogenic variant in WDR19 (c.3652dup) and 2 VUS in WDR19 (c.2365G>A and c.2671C>T). Secondary findings were declined by the family.  

Treatment and Management
The proband was treated with supportive measures to control status epilepticus. Multiple antiepileptic drugs were used in continuous drips were initiated, though the seizures did not respond.  

Outcome and Follow-Up
Unfortunately, the proband passed away at about 3 weeks old due to suspected complications of polyethylene glycol exposure (one of the additives in pentobarbital drips). Parental testing was not obtained.  

 

Discussion
This case is significant for exploring a dual diagnosis in a patient with features of both conditions, PTEN and WDR19. Neonatal presentation is not a common feature for PTEN, but patients with biallelic pathogenic variants in WDR19 can present with hair and skin findings in infancy.  

 

At this time, the proband’s WDR19 variants are of uncertain significance. However, cranioectodermal dysplasia 4 demonstrates an autosomal recessive inheritance pattern. Therefore, either VUS could be investigated further and reclassified as pathogenic.  

Conclusion
The proband’s genetic testing revealed variants in 2 genes that are consistent with her presentation. The most significant feature includes hemimegancephaly, consistent with neuronal migration anomalies. Cutaneous lesions can also be seen in individuals with PTEN variants (typically associated with Cowden and Bannayan-Riley-Ruvalcaba syndromes). While conditions involving PTEN variants demonstrate autosomal dominance inheritance, those involving WDR19 are typically autosomal recessive. Therefore, this proband’s genetic testing results both revealed a pathogenic PTEN variant and potentially a previously unknown WDR19 variant. Such a strong presentation so early in life is rare and supports the pathogenicity of the VUS.  

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