Forensically relevant challenging behaviors and the genetics domain.

Impulsive and aggressive behaviors along with intellectual disabilities often manifest in the context of genetic disorders and are a persisting challenge to professionals in the forensic psychiatric and psychological setting. The following chapter comprises an overview of relevant factors in the gene-context-behavior interaction such as monoamine oxidase A activity and specific epileptic phenomena. It presents several examples of monogenetic disorders with behaviors from the aggression spectrum and summarizes emerging strategies for treatment and clinical management thereof. The final part focuses on challenges and future developments in this field with relevance for the judicial and forensic systems. It is concluded that the relationship between a genetic syndrome and forensically relevant and/or violent behaviors should typically be addressed within a multidisciplinary framework that also includes the application of modern genetic techniques.

A Patient with Moderate Intellectual Disability and 49, XXXYY Karyotype.

Klinefelter syndrome is a chromosomal disorder in which one extra X chromosome is present (47,XXY). Several other numeric variants of this syndrome are described that comprise one or more additional sex chromosomes such as 48,XXXY, 48,XXYY and 49,XXXXY. These rare conditions are often associated with increased risk for congenital malformations, additional medical problems, and a more complex psychological phenotype. Since 1963, apart from two infants, only four adult patients with a XXXYY pentasomy have been published as case report. The present paper critically reviews the existing literature and provides detailed assessments of a 25-year-old male with intellectual disability and autism. For the first time, this very rare pentasomy is now recorded using all information about developmental history as well as findings from genetic, somatic, endocrinological and neuropsychological examination. It is concluded that children born with abnormalities of the external genitalia should always be evaluated for genetic abnormalities in order to avoid unwanted delay of appropriately designed multidisciplinary medical and psychological treatment.

Adult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene.

Histamine is involved in various physiological functions like sleep-wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep-wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement.

A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability.

The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27-51 years), while the majority was infant or adolescent (range: 0-20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.

Neurosyphilis Mimicking Autoimmune Encephalitis: A Case Report and Review of the Literature.

Neurosyphilis may imitate a wide range of neurological and psychiatric diseases, including autoimmune encephalitis. To avoid further cognitive decline and morbidity, early recognition and adequate treatment are of particular importance in both neurosyphilis and autoimmune encephalitis. In case of a strong clinical suspicion of a diagnosis of autoimmune encephalitis, guidelines recommend initiating immunotherapy even in the absence of immunological confirmation. Here, a case of neurosyphilis is reported in which the potential overlap in clinical presentation of autoimmune encephalitis and parenchymatous neurosyphilis is discussed. The here reported data suggest that, in cases presenting with new onset focal epilepsy, slowing of electroencephalographic activity over the temporal regions and magnetic resonance imaging suggestive of swelling of the amygdala, neurosyphilis should be excluded prior to initiation of immunotherapy for suspected autoimmune encephalitis.

A longitudinal perspective on the pharmacotherapy of 24 adult patients with Phelan McDermid syndrome.

Over the past years, 24 patients with Phelan-McDermid syndrome were carefully investigated with respect to history, somatic and neurologic antecedents, treatment history, behavioural issues, and psychiatric symptoms including possible catatonic features and regression phenomena. Patients were originally referred for specialized diagnosis and treatment advice because of recurrent challenging behaviours along with instable mood. In all, standardized neuropsychiatric examination was performed including assessment of intellectual and adaptive functioning as well as communication and behaviour concerns. Psychiatric diagnoses were actualized in interdisciplinary consultation meetings according to ICD-10 guidelines. The course of disease was periodically monitored with respect to treatment efficacy and psychopathology over a period varying from one to five years. In 18 patients, a deletion encompassing part of or the entire SHANK3 gene was found. All comprised two or more genes in addition to SHANK3. In six patients, a pathogenic variant in this gene was detected. The psychopathological profile of all patients (nine were published before) was characterized by symptoms from the autism and schizoaffective spectrum while in five, periodic catatonic symptoms were also established. In their third decade, four patients with the deletion subtype developed a regression-like gradual decline of functioning. Based on actual psychiatric classification, in 18 patients, a diagnosis of atypical bipolar disorder was established of which symptoms typically started from late adolescence onward. In most patients, treatment with mood stabilizing agents in combination with individually designed contextual measures, and if indicated with the addition of an atypical antipsychotic, resulted in gradual stabilization of mood and behaviour.

Clinical Presentation of Laboratory Confirmed Neurosyphilis in a Recent Cases Series.

OBJECTIVE: The worldwide increase in the incidence of syphilis necessitates alertness to the occurrence of neurosyphilis. Early recognition of neurosyphilis allows for timely treatment, leading to a better treatment outcome. This retrospective study aims to describe the clinical presentation of neurosyphilis in a recent series of neurosyphilis patients. METHOD: All patients were included with a new, laboratory confirmed, diagnosis of neurosyphilis in the period 2004-2018. The clinical data were analysed. RESULTS: 34 neurosyphilis patients (1 woman and 33 men) were identified. Age varied from 31-84 years (median age: 44 years). A history of syphilis infection was known for 11 (32%) patients; 12 (35%) patients were HIV seropositive. The distribution of the clinical syndromes was as follows: 16 patients with early neurosyphilis (acute meningitis, meningovasculitis and/or uveitis), 9 patients with late neurosyphilis (General Paralysis of the Insane and/or Tabes Dorsalis), 2 patients with symptoms of both early and late neurosyphilis, 6 patients with asymptomatic neurosyphilis and in 1 patient insufficient data were available to determine a clinical syndrome. Early neurosyphilis was seen in all age categories, late neurosyphilis only occurred in patients > 40 years. CONCLUSIONS: Neurosyphilis occurs in adults in all age groups, in men more frequent than in women, often in HIV-infected patients, and can present with a wide range of clinical syndromes. Usually no previous infection with syphilis is known.

Phelan-McDermid syndrome due to SHANK3 mutation in an intellectually disabled adult male: successful treatment with lithium.

For 30 years, Phelan and co-workers described a syndrome characterised by neonatal hypotonia, global developmental delay, strongly impaired speech, sleep disturbances and hyperreactivity to sensory stimuli. This Phelan-McDermid syndrome (PMS), also presenting with symptoms from the autism spectrum and a higher risk of developing seizure disorders, may be caused by a deletion of chromosome 22q13 or by a mutation in the SHANK3 gene. Its core psychopathological phenotype comprises symptoms from the bipolar spectrum for which generally treatment with a mood-stabilising anticonvulsant in combination with an atypical antipsychotic seems to be most effective. In addition to two elsewhere published adolescent patients, we here describe in detail the history of an adult male patient with PMS caused by a SHANK3 mutation in whom successive treatment regimens with antipsychotics and mood-stabilising anticonvulsants were all ineffective. Ultimately, addition of lithium to existing olanzapine therapy led to enduring stabilisation of mood and behaviour.

Malaria Fever Therapy for General Paralysis of the Insane: A Historical Cohort Study.

BACKGROUND/AIMS: This year marks the 100th anniversary of the first malaria fever treatment (MFT) given to patients with general paralysis of the insane (GPI) by the Austrian psychiatrist and later Nobel laureate, Julius Wagner-Jauregg. In 1921 Wagner-Jauregg reported an impressive therapeutic success of MFT and it became the standard treatment for GPI worldwide. In this study, MFT practice in the Dutch Vincent van Gogh psychiatric hospital in GPI patients who had been admitted in the period 1924-1954 is explored. METHODS: To identify patients with GPI, cause-of-death statistics was used. Data on MFT were retrieved from annual hospital reports and individual patient records. RESULTS: Data on MFT were mentioned in the records of 43 out of 105 GPI patients. MFT was practiced in a wide range of patients with GPI, including those with disease duration of more than 1 year, up to 70 years of age, and those with a broad array of symptoms and comorbidities, such as (syphilitic) cardiac disease. Inoculation with malaria was done by patient-to-patient transmission of infected blood. CONCLUSIONS: MFT practice and mortality rates in MFT-treated patients correspond to similar findings worldwide. MFT was well tolerated and MFT-treated patients had a significantly longer survival.

Relationship between plasma homovanillic acid and outcome in patients with psychosis spectrum disorders.

BACKGROUND: Psychosis spectrum disorders, especially schizophrenia, have been linked to disturbed dopaminergic activity in the brain. Plasma homovanillic acid (pHVA) levels partly represent dopaminergic metabolism in the central nervous system. In the present study associations between (changes in) pHVA levels, symptom severity and symptomatic improvement in patients with psychoses were investigated. METHODS: From a total of 80 patients, 58 fulfilled all inclusion criteria and their symptom profile and severity were assessed by means of the Comprehensive Assessment of Symptoms and History (CASH), the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale for Severity and Improvement (CGI-S/CGI-I) at baseline and after 6 weeks of antipsychotic treatment. After inclusion, all patients were prescribed first- or second-generation antipsychotics by their treating psychiatrist. A total of 12 patients had first-episode psychosis (FEP). At both time points, pHVA levels were measured. Subsequently, pHVA levels were compared with an age-matched control sample and changes in pHVA levels (ΔpHVA) after treatment were associated with clinical parameters. RESULTS: Before analyses, data were scrutinized for possible confounders, particularly gender, smoking, medication status (including antipsychotic class), and recent drug use. The pHVA levels in patients were not different from those in controls. Treatment resulted in a significant decrease of all parameters. Symptomatic improvement as well as ΔpHVA was most pronounced in FEP patients. CONCLUSION: These findings show that patients with FEP have a more favourable outcome than non-FEP patients and that greater ΔpHVA also suggests that FEP patients still have the capacity to adjust dopaminergic neurotransmission.

Clinical Presentation of General Paralysis of the Insane in a Dutch Psychiatric Hospital, 1924-1954.

General paralysis of the insane (GPI) or dementia paralytica was once a fatal complication of syphilitic infection and a major reason for psychiatric hospitalization. Nowadays, physicians consider GPI to be exceptional. It should be noted, however, that syphilis re-emerged worldwide at the turn of the 20th to 21st century and a revival of GPI can, therefore, be expected. Advanced diagnosis is crucial in that treatment in the early, inflammatory phase is warranted before irreversible tissue damage occurs. Therefore, a renewed clinical awareness of the broad spectrum of psychiatric and neurologic signs and symptoms of GPI is needed. In this historical cohort study, comprising 105 patients with GPI admitted to the Dutch Vincent van Gogh Psychiatric Hospital in the period 1924-1954, the clinical presentation of this invalidating disorder is investigated and described in detail.

A 12q24.31 interstitial deletion in an adult male with MODY3: neuropsychiatric and neuropsychological characteristics.

A 39-year-old male patient with a disharmonic intelligence profile and juvenile diabetes mellitus is described. At 14 months of age, minor facial dysmorphisms were noticed. He had delayed motor development, obesity at early age, and a diagnosis of insulin-dependent diabetes at the age of 10 years. He successfully completed secondary education and has been engaged in unskilled work activities, living independently. Upon examination, no psychiatric symptoms were present and his neuropsychological profile showed normal, although disharmonic, intellectual capacities and suboptimal social cognition. Genome wide array analysis identified an interstitial 12q24.31 deletion of 1.67 Mb encompassing hepatocyte nuclear factor-1-alpha gene (HNF1A), supporting a diagnosis of maturity-onset diabetes of the young. Results are discussed in relation to the few identified or published overlapping deletions. This is the first patient with normal intelligence in whom the presence of subtle facial dysmorphisms were decisive for introducing genetic analysis that, in turn, disclosed a rare form of diabetes necessitating modifications in treatment regimen. Clinicians, including those involved in psychiatry, should be aware of the diagnostic and prognostic value of atypical physical features in patients with a long history of complicated glucose regulation.

Neurosyphilis in the mixed urban-rural community of the Netherlands.

OBJECTIVE: Neurosyphilis is caused by dissemination into the central nervous system of Treponema pallidum. Although the incidence of syphilis in the Netherlands has declined since the mid-1980s, syphilis has re-emerged, mainly in the urban centres. It is not known whether this also holds true for neurosyphilis. METHODS: The epidemiology of neurosyphilis in Dutch general hospitals in the period 1999-2010 was studied in a retrospective cohort study. Data from the Dutch sexually transmitted infection (STI) clinics were used to analyse the number of patients diagnosed with syphilis in this period. RESULTS: An incidence of neurosyphilis of 0.47 per 100 000 adults was calculated, corresponding with about 60 new cases per year. This incidence was higher in the western (urbanised) part of the Netherlands, as compared with the more rural areas (0.6 and 0.4, respectively). The number of patients diagnosed with syphilis in STI clinics increased from 150 to 700 cases in 2004 and decreased to 500 new cases in 2010. The sex ratio was in favour of men, yielding a percentage of 90% of the syphilis cases and of 75% of the neurosyphilitic cases. The incidence of neurosyphilis was highest in men aged 35-65 years, and in women aged 75 years and above. The most frequently reported clinical manifestation of neurosyphilis was tabes dorsalis. In this study, 15% of the patients were HIV seropositive. CONCLUSION: The incidence of neurosyphilis in a mixed urban-rural community such as the Netherlands is comparable to that in other European countries. Most patients are young, urban and men, and given the frequent atypical manifestations of the disease reintroduction of screening for neurosyphilis has to be considered.

BDNF and S100B in psychotic disorders: evidence for an association with treatment responsiveness.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and S100B are involved in brain plasticity processes and their serum levels have been demonstrated to be altered in patients with psychoses. This study aimed to identify subgroups of patients with psychotic disorders across diagnostic boundaries that show a specific symptom profile or response to treatment with antipsychotics, by measuring serum levels of BDNF and S100B. METHODS: The study sample consisted of 58 patients with DSM-IV psychotic disorders. Comprehensive Assessment of Symptoms and History (CASH), Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression scale for severity and improvement (CGI-S/CGI-I) were applied at baseline and after 6 weeks of antipsychotic treatment. At both time points, serum levels of BDNF and S100B were measured and compared with a matched control sample. RESULTS: Baseline BDNF and S100B levels were significantly lower in patients as compared with controls and did not change significantly during treatment. Dividing the patient sample according to baseline biochemical parameters (low and high 25% and middle 50%), no differences in symptom profiles or outcome were found with respect to BDNF. However, the subgroups with low and high S100B levels had higher PANSS scores than the middle subgroup. In addition, the high subgroup still showed significantly more negative symptoms after treatment, whereas the low subgroup showed more positive symptoms compared with the other subgroups. CONCLUSION: Serum levels of BDNF and S100B are lowered in patients with psychotic disorders across diagnostic boundaries. The differences between high and low S100B subgroups suggest a relationship between S100B, symptom dimensions and treatment response, irrespective of diagnostic categories.

Neuropsychological phenotype of a patient with a de novo 970 kb interstitial deletion in the distal 16p11.2 region.

The 16p11.2 microdeletion syndrome is characterized by a wide range of phenotypic expressions and is frequently associated with developmental delay, symptoms from the autism spectrum, epilepsy, congenital anomalies, and obesity. These phenotypes are often related to a proximal 16p11.2 deletion of approximately 600 kb (BP4-BP5) that includes the SH2B1 gene that is reported to be causative for morbid obesity. This more centromeric deletion is most strongly related to autism spectrum susceptibility and is functionally different from the more distal 16p12.2p11.2 region, which includes the so-called atypical 16p11.2 BP2-BP3 deletion (approximately 220 kb) presenting with developmental delay, behavioral problems and mild facial dysmorphisms. Here, an adult male with a long history of maladaptive behaviors is described who was referred for diagnostic assessment of his amotivational features. Extensive neuropsychological examination demonstrated rigid thinking, anxious beliefs, and ideas of reference in the presence of normal intelligence. Microarray analysis demonstrated a de novo 970 kb 16p11.2 BP1-BP4 microdeletion that can be regarded as explanatory for his behavioral profile. It is concluded that microdeletion syndromes are not exclusively related to intellectual disabilities and genetic testing is of putative relevance for the understanding of neuropsychiatric and neuropsychological phenomena.

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare neuropsychiatric syndromes characterized by iron accumulation in the basal ganglia. The pantothenate kinase-associated neurodegeneration (PKAN) was the first NBIA form to be genetically identified almost 15 years ago. Nowadays, eight types can be genetically distinguished. More recently, a novel NBIA was delineated and termed Static Encephalopathy of childhood with Neurodegeneration in Adulthood (SENDA), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with an onset in the second to third decade. Very recently, mutations in the WD repeat-containing protein 45 (WDR45) gene located on Xp11.23 were shown to be the causal factor. The protein encoded by WDR45 propels protein interaction important for autophagy. This form was therefore retermed Beta-propeller Protein Associated Neurodegeneration (BPAN). Here, the first three Dutch patients with genetically proven BPAN are comprehensively described with respect to course and neurological as well as neuropsychiatric phenotypes. All three showed a characteristic delayed progression of neurological symptoms with parkinsonism and prominent dystonia. Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease. The specific course and prognosis should implicate restrained psychopharmacological interventions. The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder. However, the identification of a WDR45 mutation is needed for a definite diagnosis of BPAN.

Behavioural phenotype of a patient with a de novo 1.2 Mb chromosome 4q25 microdeletion.

A female patient, 20 years of age, is reported with a history characterized by developmental and psychomotor delay, and during grammar-school period increasing learning problems, ritualistic behaviours and social withdrawal. Subsequently, challenging and autistic-like behaviours became prominent. The patient showed mild facial dysmorphisms, long thin fingers with bilateral mild short V metacarpals, and hyperlaxity of the joints. Neuropsychiatric examination disclosed obsessive, ritualistic behaviours and vague ideas of reference. Neuropsychological assessment demonstrated mild intellectual disability, mental inflexibility and incongruent affect. MRI-scanning of the brain showed no relevant abnormalities. Genome wide SNP array analysis revealed a 1.2 Mb de novo interstitial microdeletion in 4q25 comprising 11 genes, that was considered to be causative for the developmental delay, perseverative cognitive phenotype and dysmorphisms. To the authors knowledge, this is the first report of a de novo 4q25 microdeletion that presents with a specific behavioural phenotype.

Cardiometabolic comorbidity in antipsychotic treated patients: need for systematic evaluation and treatment.

OBJECTIVE: The aim of the study was to determine the prevalence of cardiometabolic dysregulations and their somatic treatment regimens in a group of psychiatric patients treated with antipsychotics. METHODS: In a naturalistic cohort study, baseline cardiometabolic parameters were measured in 543 outpatients. After one year, a second assessment was performed in 220 patients out of the total sample. In addition, it was investigated whether in patients with somatic comorbidities adequate treatment was prescribed. RESULTS: In this cohort, about half of the patients fulfilled the criteria for metabolic syndrome. Only a limited number of patients, however, received pharmacologic treatment for individual risk factors: About 19% for hypercholesterolemia, 26% for hypertension, and 52% for diabetes. Non-treated patients were significantly younger than treated patients. Follow-up data show that the course of the cardiometabolic parameters can be dynamic. CONCLUSIONS: Cardiometabolic risk factors are highly prevalent in psychiatric patients treated with antipsychotic drugs. Unfortunately, adequate treatment of cardiometabolic comorbidity in these relatively young patients is seriously hampered. Thus, specific guidelines for psychiatric patients have to be developed taking into account the high cardiovascular risk at a relatively young age and potential pharmacokinetic interactions between psychotropics and somatic compounds. Moreover, integration of psychiatric and physical health care systems for patients with mental disorders is urgently needed.

Neuropsychiatric adverse events of varenicline: a systematic review of published reports.

INTRODUCTION: Over the past years, the impact of varenicline in patients with mental illness has been debated as serious neuropsychiatric adverse events (AEs) have been reported with varenicline use. AIM: To identify and summarize published case reports of neuropsychiatric AEs ascribed to varenicline and to determine potential risk factors for these AEs. METHODS: A literature search of MEDLINE, the Cochrane Library, EMBASE, and PsychInfo database was conducted for case reports concerning the neuropsychiatric AEs of varenicline published in English from 2006 (approval year by the US Food and Drug Administration and the Dutch Medicines Evaluation Board) to January 1, 2012. RESULTS: We identified 25 published cases. In most reports, patients had been admitted to psychiatric hospitals with serious neuropsychiatric AEs due to varenicline. The average patient age was 46.4 years, and 56% were men; 68% of patients had a psychiatric history. The onset of symptoms started 2 days to 3 months after the initiation of varenicline. One report described completed suicide in a man with no psychiatric history. In most cases (84%), the neuropsychiatric symptoms resolved after the discontinuation of varenicline. Analysis of all reports using the Naranjo causality scale, a method for estimating the probability of adverse drug reactions, indicated probable causality in 76% of the cases and definite causality in 12% of cases. CONCLUSION: Varenicline is associated with an increased risk of serious neuropsychiatric AEs, especially in patients with a psychiatric illness. It is strongly recommended that varenicline be administered only to mentally stable patients and under close monitoring.

Kallmann syndrome and paranoid schizophrenia: a rare combination.

Kallmann syndrome (KS) is a genetically heterogeneous and rare disorder characterised by the combination of hypothalamic hypogonadism and anosmia/hyposmia, a variable degree of intellectual disability and several somatic anomalies. In about one-third of the patients, mutations have been identified in at least seven different genes. Virtually no data are available about possible neuropsychiatric symptoms in KS. Here, a young adult male is described with a previous clinical diagnosis of KS and recent paranoid schizophrenia of which positive, but not negative symptoms, fully remitted upon treatment with antipsychotics. Neither genome-wide array analysis nor mutation analyses disclosed imbalances or mutations in any of presently known KS disease genes. This is the first report on a patient with KS and paranoid schizophrenia in whom extensive genetic analyses were performed. It is concluded that further studies are warranted in order to elucidate a possible increased risk for psychiatric symptoms in patients with KS.