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Human diseases can result from interrelated disorders at the levels of genes and chromosomes, the nervous system, cognition, emotions, behavior, and contextual influences [1]. In the present case study, analysis of the complex interplay of these factors has been applied to understand and treat the patient's complaints. This illustrates the added value of clinical neuropsychological examination along with clinical genetic testing in the medical treatment of severe, resistant hypertension and hypercortisolism.
CASE REPORT Patient presentationWe present the case of a 35-year-old Dutch, married female. She had a full time job as a supermarket employee and had been working for the same employer for 18.5 years. At 34 years of age she became ill and could no longer work. Because of substantially increased and generalized complaints of high stress and (mental and physical) fatigue, she visited the primary care practitioner. First examinations revealed hypertensive crisis Office Blood Pressure (OBP 260/160 mmHg) and hypercortisolism. She was subsequently referred to the specialized university medical center, department of internal medicine, where underlying pituitary and adrenal adenomas were ruled out as well as glucocorticoid receptor deficiency. Hypercortisolism was established by a Dexamethason suppression test. Later in this trajectory, cortisol had normalized, but oral contraceptives had also been stopped. Initial treatment included calcium antagonists, beta blockers, diuretics and angiotensin-converting enzyme-inhibitors (Nifedipine re 30 mg 1 dd, Doxazosin 4 mg 1 dd, Spironolactone 12.5 mg 1 dd, Perindopril/indapamide 5/1.25 mg 1 dd, Nebivolol 5 mg 1 dd), which, however, had little effect (24-h BP mean 142/95 mmHg, day time 146/95 mmHg, night 127/77 mmHg). After a 3-year treatment period in which the above medication was successively stopped and psychological treatment and social support were added simultaneously, blood pressure values were within the normal range (OBP 135/93 mmHg) without any medication. See Supplementary S1, https://links.lww.com/HJH/C292 for a combined Table and graphic of blood pressure values, medications and interventions.
Procedure and hypothesesIn 2018, the attending physician, who specialized in syndrome related endocrine dysfunction, presented the patient in her multidisciplinary outpatient clinic to a clinical neuropsychologist and clinical geneticist. The patient's history mentioned developmental problems, minor dysmorphic body features, and a life-long experience of fatigue and high stress levels. It was hypothesized that the hypertension could be the result of a combination of unmanaged cognitive and psychopathological disorders related to a genetic syndrome. For this reason, clinical neuropsychological examination and genetic testing were initiated.
Comprehensive clinical neuropsychological examination was performed, covering interviews, taking history from the first degree relatives, and analyses of the medical charts. The preliminary results endorsed the initial hypotheses of impaired (cognitive and affective) information processing and psychopathology. To further test these hypotheses, detailed neurocognitive testing was performed, comprising the following domains: intelligence, attention and executive functioning, memory, social cognition, psychopathology, and personality characteristics.
Copy number variation was performed by single nucleotide polymorphism (SNP) array. For this, genomic DNA was hybridized to an Illumina Infinium, GSA+MD-24 v1.0 BeadChip, which was used for genome wide array analysis with an average resolution of 0.15 Mb for the presence of copy number variations (CNVs). Panel sequencing of ciliopathy and inherited nephrological diseases was performed on an Illumina HiSeq after enrichment with Agilent SureSelectXT Human All Exon 50Mb Kit. After read alignment and variant calling with GATK en CoNIFER the data were annotated and analysed for pathogenicity.
The research has been performed according to the guidelines of the Vincent van Gogh Institutional Review Board. Ethical approval was not required. The patient provided written informed consent for publication and the first, fourth and fifth author were the treating psychologist, clinical geneticist, and endocrinologist of the patient, respectively.
RESULTS Developmental issues in childhoodAccording to her parents the patient was a stressed and restless baby. They noticed a comparatively slow psychomotor development (walking independently at 17 months and first words at 14 months) and behavioural abnormalities (little eye contact, frequent crying, clinging to her mother, difficulty with changes, difficulty understanding jokes, aggression toward her brother). At the age of six, a diagnostic classification of autism spectrum disorder (ASD) was established by a physician at a children's hospital. Because of learning difficulties, she followed special education until the age of 16 years.
Cognitive deficitsA below average to low average IQ level [Full Scale IQ (FSIQ) 79–89] was obtained, with an unequal distribution of indices. The perceptual reasoning index (average to high average) was significantly higher than the verbal comprehension index (below average to low average), working memory index (below average to average), and information processing speed index (exceptionally low to low average). Scores on additional tests measuring processing speed were exceptionally low to below average; confirming mental slowness. Regarding affective information processing, the patient presented difficulty recognizing emotions in facial expressions, as well as problems in recognizing and verbalizing her own emotions (alexithymia).
PsychopathologyAssessment of psychopathology and personality traits revealed internalizing mental health issues, expressed by a high level of depressive complaints, many somatic problems, severe fatigue, and insomnia. In addition, self-reported psychiatric symptoms and personality traits revealed a predominantly lowered and notably flat profile, consistent with alexithymic traits. The patient considered herself a nonassertive person, although she enjoyed the company of others. Furthermore, she reported an excessive trust in others. The patient's coping style was characterized by a tendency to engage in emotion-focused coping (blaming herself, getting angry, getting tensed) rather than task-focused coping (making purposeful attempts to solve problems) in response to stress. Moreover, questionnaires showed that she had a limited range of stress management strategies. These findings are consistent with impaired affective information processing.
Results of all clinical neuropsychological tests are displayed in Table 1 and Figure 1 (see Table S2, Supplemental Digital content, https://links.lww.com/HJH/C292 for the list of applied neuropsychological tests and references).
TABLE 1 - Clinical neuropsychological test results The patient's intelligence quotient (IQ) Domain Test Wechsler intelligence quotientsa Score labels b Intelligence WAIS-IV-NL FSIQ 79–89 Below average score − low average score VCI 76–88 Below average score − low average score PRI c 100–115 Average score – high average score WMI 79–94 Below average score – average score PSI 67–86 Exceptionally low score − low average score Test results on the patient's cognitive functioning, psychopathology and personality Domain Test Domain of measurement Score labelsd Scores Reference Percentiles Attention TMT Processing speed, divided attention and mental flexibility Below average scores 3–8 Schmand et al. (2012) D2 Visual selective attention, processing speed and concentration Low average score 14 Brickenkamp & Oosterveld (2014) Executive functioning D-KEFS CWIT Processing speed Exceptionally low scores <1–2 Delis et al. (2001) Inhibition and switching High average scores 79-88 Fluency (GIT-2) Semantic memory, working memory, inhibition Below average score-low average score 8-14 Schmand et al. (2012) BADS Planning, organizing, attention, initiating, monitoring Average score 54 Krabbendam & Kalff (1997) DEX Proxy-evaluation of problems in planning and organization Average score 50-75 Krabbendam & Kalff (1997) BRIEF Self-reported number of executive problems Average score 69 Scholte & Noens (2011) Proxy-reported number of executive problems Exceptionally high score 98 Memory 15-WT Auditory-verbal learning, memory, and recognition Average scores 34−38−73 Schmand et al. (2012) LLT Visual spatial learning and memory Average scores 25−50 Kessels et al. (2012) Visual processing ROCF test Visual copying Average scores 25−30 Bouma et al. (2012) Visual direct reproduction Average score 60 Social cognition ERT Perception of morphed facial expressions Below average score 5 Kessels et al. (2014) TAS-20 self Self-reported difficulties in perceiving and naming own emotions, and tendency to external oriented thinking High average score 79 Bagby et al. (1994) TAS-20 proxy Proxy-reported patient's difficulties in perceiving and naming own emotions, and tendency to external oriented thinking Exceptionally high score >99 Coping CISS Task oriented coping Low average score 10 De Ridder & Van Heck (2004) Emotion oriented coping Average score 46 Avoidance oriented coping Average score 54 Score labels e Uniform T-scores Psychopathology and personality MMPI-2-RF Demoralization Normal range 59 Ben-Porath & Tellegen (2008/2011) Somatic complaints Normal range 52 Low positive emotions Clinically significant 45 Cynism Clinically significant 31 Antisocial behavior Clinically significant 49 Persecutory ideation Normal range 61 Dysfunctional negative emotions Clinically significant 40 Aberrant experiences Normal range 54 Hypomanic activation Clinically significant 44 FSIQ, Full Scale Intelligence Quotient; PRI, Perceptual Reasoning Index; PSI, Processing Speed Index; VCI, Verbal Comprehension Index; WAIS-IV-NL [2], Wechsler Adult Intelligence Score-IV Dutch translation; WMI, Working Memory Index.aM= 100, SD = 15.
bScore labels according to Guilmette et al.[3].cSignificant higher than VCI, WMI, and PSI with a base rate of 4.2%, 5.5%, and 0.8%, respectively.15-WT, 15 Word Test; BADS, Behavioural Assessment of the Dysexecutive Syndrome; BRIEF, Behavior Rating Inventory of Executive Function questionnaire; CISS, Coping Inventory for Stressful situations – questionnaire; CWIT, Color Word Interference Test; D2, sustained attention test; DEX, Dysexecutive Questionnaire; D-KEFS, Delis-Kaplan Executive Function System; ERT, Emotion Recognition Task; GIT-2, Groninger Intelligence Test-version 2; LLT, Location Learning Test; MMPI-2-RF, Minnesota Multiphasic Personality Inventory-2 Restructured Form; ROCF test, Rey-Osterrieth Complex Figure test; TAS-20, Toronto Alexithymia Scale - questionnaire; TMT, Trail Making Test.
dScore labels according to Guilmette et al.[3].eScore labels uniform T-scores MMPI-2-RF: T >65 or T <50 = clinically significant.
FIGURE 1: Illustration of the relationships between stress symptoms/behavior, genetics, brain development and cognitive functioning, including neuropsychological findings.
Genetic analysisPhysical examination revealed overweight (BMI 30.7), normal height (−0.8 SD) and head circumference (0.3 SD). There were mild dysmorphic features such as low-set small ears, slightly hypoplastic nostrils and flat feet. Overweight developed slowly from early age on. There was no apparent eating disorder. Family history showed mild hypertension in her mother. Ultrasound evaluation of kidneys revealed no structural abnormalities or other pathological findings.
The SNP array results showed a loss of approximately 572 kb in band 16p11.2 ((arr[hg19] 16p11.2(29627349–30199713)x1). The established 16p11.2 loss fully covers the critical region of the recurrent 16p11.2 proximal microdeletion (BP4-BP5) (OMIM #611913). In patients with a loss in this region, a variable phenotype, including global developmental delay, intellectual disability, autism, neuropsychiatric disorders, epilepsy, dysmorphism, macrocephaly and obesity, has been described extensively [4–8]. No mutations were found in genes involved in inherited nephrological diseases or ciliopathy by targeted exome sequencing.
Genotype–phenotype relationshipsPost hoc, the results of neuropsychological examination were compared with literature on cognitive phenotyping in 16p11.2 microdeletion (Table 2). The patients’ developmental delay, below average FSIQ, weaker verbal comprehension as compared to perceptual reasoning abilities, impaired emotion recognition, autism spectrum symptoms are in accordance with the literature on group level. Not previously reported in the literature on 16p11.2 and ASD is the slow information processing speed and alexithymia found in this patient. Moreover, the cognitive profile can be linked to the life-long experienced and gradually intensified fatigue and stress, ending up in severe hypertension. As a result of early developmental delay and the cognitive and affective deficits associated with the 16p11.2 microdeletion, the patient struggled to meet expectations from an early age on. This made her susceptible to stress. As she got older, expectations increased, while she took on adult life tasks (work, living with partner), thereby increasing stress. She relied on her parents, who provided necessary support, while she was unable to regulate her stress levels. In addition, her chronic stress condition was masked by her adequate presentation, partner relationship and employment, and was hidden from view by the active help of her family. Since the hypertensive crisis required referral to a medical specialist, her chronic stress condition eventually came to light. Figure 1 illustrates the relationships between stress symptoms/behavior, genetics, brain development and cognitive functioning.
TABLE 2 - Cognitive phenotyping of the 16p11.2 deletion syndrome: literature overviewa Author Year of publication N b (age range in years) Size and position deletion Applied intelligence tests Mean intelligence quotientc Specific cognitive function characteristics, developmental and mental health issues, and other clinical observations Egger et al.[9] 2014 1 (33) ∼970 kb (28.5–29.4) KAIT FSIQ 112 - no developmental delayDAS-II, Differential Ability Scales-II; FSIQ, Full Scale Intelligence Quotient; KAIT, Kaufman Adolescent and Adult Intelligence Test; MSEL, Mullen Scales of Early Learning; PIQ, Performance Intelligence Quotient; VIQ, Verbal Intelligence Quotient; WAIS-III, Wechsler Adult Intelligence Score-III; WASI, Wechsler Abbreviated Scale of Intelligence; WISCIV, Wechsler Intelligence Scale for Children-IV; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence-III.
aAdapted from Barge-Schaapveld et al.[15] and Egger et al.[9].bN= number of patients.
cM= 100; SD= 15.
Results of the patient's neuropsychological assessment, genetic testing and her developmental history indicated the need for psychological treatment of her stress symptoms (heightened emotional behaviors, severe fatigue, hypertension). Therefore, the patient underwent the following psychological treatment.
Individual psychological treatment. Aimed to lower high stress levels and improve emotion regulation and coping skills. Considering her cognitive limitations, i.e. relatively low verbal comprehension abilities, low information processing speed and problems in affective information processing, this treatment was given in a setting equipped for people with lower intellectual abilities. The patient successfully underwent individual training of copings skills (based on dialectical behavioral therapy), although certain difficulties remained in recognizing the role of autism spectrum disorder in her susceptibility for the experience of elevated stress levels. In addition, the patient's (work) environment was also adjusted, especially by implementing working part-time.
Home counselling and support. In addition to the psychological treatment, taking into account the patient's (cognitive) difficulties to transfer and generalize knowledge and skills, home counselling proved to be necessary, initially weekly and later bi-weekly. Home counselling supported the actual application of newly acquired coping skills at home, and also focused on adding more structure in daily life (e.g. calendar management, balancing strenuous and relaxing activities).
Psychoeducation for the patient and her family. The strengths and weakness in cognitive and emotional information processing based on the neuropsychological findings were explained. Also, relations between the patient's individual profile of information processing, exposure to environmental stressors and experience of anxiety were explained and educated. Combined with the establishment of the 16p11.2 deletion syndrome and psychoeducation on its features, uncertainty about the patient's diagnosis was reduced and the clinical assessment results clarified her lifelong (developmental and somatic) issues. The 16p11.2 deletion syndrome also provided a diagnosis that helped communicating her difficulties with other healthcare providers and occupational doctor, thereby strengthening self-support.
All interventions (assessment, psycho-education, treatment, and home support) had a beneficial effect on the patients’ experienced stress levels and subsequently on her hypertension. Vice-versa, hypertension immediately re-occurred with increasing stress after interim termination of home support services. Therefore, she was indicated for long-term, frequent support at home to help her with stress management in her daily life.
DISCUSSIONIn cases of resistant hypertension and polypharmacy, social and psychological factors should be included in HTN-anamnesis and multidisciplinary analyses should be considered, consisting of comprehensive neuropsychological testing combined with clinical genetic analysis.
In this case, chronic contextual stress as a cause of the medical condition did not surface earlier, probably because the patient had a regular and permanent job, she met age-appropriate expectations (living independently with partner), had limited social contacts, and supportive proxies. Therefore the hypertension remained unrecognized for a long time.
Underdiagnosis can further increase the experienced levels of stress/burden in patients (and their support system) due to multiple, inconclusive or conflicting results of consultations and unsuccessful treatment. This may also contribute negatively to the trust placed in doctors, in turn heightening stress levels in patients.
Hypertension in this patient was related to unmanaged mental health issues, particularly underlying cognitive deficits (slightly lowered intelligence, slow mental speed, problems in mentalizing) and social and emotional deficits (alexithymia, mood and sleep problems, autism spectrum disorder – and matching problems in coping with stress). Exposure to psychosocial chronic stress and nonadaptive affective response to stress may cause hypertension [16]. Also, alexithymia has been found more often in people with hypertension as compared to people without hypertension, possibly suggesting an association between alexithymia and hypertension [17]. Furthermore, the cognitive and behavioral profile of this patient was in accordance with findings of previous studies of patients with a 16p11.2 microdeletion on a group level.
This case illustrates how multidisciplinary collaboration, in particular the contribution of clinical neuropsychology, increases the opportunities to explore hidden causes of resistant hypertension. Relatively mild phenotypic presentation and multiple subtle cognitive deficits may indicate underlying neurodevelopmental and genetic pathology [18]. Therefore, physicians should consider neuropsychological and genetic factors, in addition to medical analysis. Clinical neuropsychological diagnosis can provide clarification and treatment options.
ACKNOWLEDGEMENTSSources of any support for the writing of the paper: None.
Disclosure: No funding has been received for this work from National Institutes of Health (NIH); Wellcome Trust; Howard Hughes Medical Institute (HHMI); and others.
Author disclosure statement: A.G.B.R., E.W., M.G., R.K., L.dG.H., and J.I.M.E. have nothing to declare.
Conflicts of interestThere are no conflicts of interest.
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