Case Presentation
The patient is the second child of healthy nonconsanguineous parents of mixed Belgian, Hungarian, English, and Scottish descent. The patient was born at 37.5 weeks by induction due to maternal migraines following an uncomplicated pregnancy. She had some mild respiratory distress at birth which quickly improved. Her birth weight was 3.03 kg (54th percentile). As an infant, she had feeding difficulties with ineffective latching but gained weight appropriately with bottle feeding. There is a history of torticollis at 4 months of age.
She met motor milestones until 9 months of age, after which time significant motor delays were observed. She walked at the age of 18 months with a crouched stance. Currently, at 16 years of age, she can walk independently for short distances, with an unusual gait and a kyphotic stance; she requires constant supervision. Her fine motor skills never progressed beyond childhood and are limited. She had a few words which she then lost, and she remains nonverbal. As an infant she had startle behaviours, which were spasm-like; however, the electroencephalograms (EEGs) did not suggest infantile spasms. At the age of 6, she began to have absence episodes and partial and generalized tonic-clonic seizures, which have continued since. Her epilepsy has been classified as treatment resistant, due to failure of several antiepileptic agents and she is currently controlled with a vagal nerve stimulator. The patient was also diagnosed with celiac disease at 7 years of age due to persistent diarrhea leading to hypernatremia and hospitalizations, and clinical response to a gluten-free diet (no biopsy performed).
Genetic testing between 4 and 10 years of age was normal, including chromosomal microarray analysis, Angelman, Rett syndrome testing, comprehensive epilepsy panel and Mitochondrial DNA testing. Subsequently, a clinical trio WES was arranged which did not identify causative variants in genes to explain the patient’s presentation; however, a paternal secondary finding of a pathogenic variant in theBRCA2 gene (c.475+1G>T) was identified. Three years later, exome data reanalysis was offered to the patient’s family to help provide a genetic diagnosis, given the rapid accrual of knowledge in genomic medicine with new genes available for analysis. The exome reanalysis identified biallelic variants (one on each copy) in a candidate gene NHLRC2 . One of the variants was reported as pathogenic (c.1750delC) and was inherited from her mother. The other variant was reported as a variant of uncertain significance (c.2074 G>T) and was inherited from her father. The reanalysis of the exome sequencing confirmed the previously identified BRCA2pathogenic variant and found a new pathogenic variant in theBRCA1 gene (c.5096G>A), which was again inherited from the patient’s father. This c.5096G>A BRCA1variant was initially classified as a variant of uncertain significance (5). However, in 2018, an analysis of a large cohort of 129 families, using several analytical approaches, confirmed that c.5096G>A BRCA1 variant is associated with intermediate cancer risks (compared with the average BRCA1truncating variant) and thus was identified in our probands WES reanalysis. Interestingly, this variant was found to have a lower associated cancer risk (20% for risk for breast cancer and 6% for ovarian cancer by age 70 for a female) than typical BRCA1pathogenic variants (5).
On family history, paternal grandmother had breast cancer in her 40s. Maternal grandmother had colon cancer at age 64. There is no family history of other malignancy. The patient’s mother has migraines. Her father and paternal grandmother have Crohn’s disease. There are no individuals with seizures, intellectual disability, or other neurological issues in the family.
Gynecology consult was undertaken to review the genetics and other clinical challenges. This initially focused on the patient’s functionality, menstrual and hygiene challenges with her developmental delay, with further discussions to focus on response to therapeutic options in the patient and family context (6). One of the significant challenges with decision-making for the family will be morbidity and life expectancy with respect to surgery versus more conservative or medical options.