key: cord-0706547-bk77hcfz authors: Verhoeven, Willem M A; Egger, Jos I M; Mergler, Sandra; Meijer, Ton A A; Pfundt, Rolph; Willemsen, Marjolein H title: A Patient with Moderate Intellectual Disability and 49, XXXYY Karyotype date: 2022-03-10 journal: Int J Gen Med DOI: 10.2147/ijgm.s348844 sha: 64868646c87d28625bc7390b5b5ce49835a838eb doc_id: 706547 cord_uid: bk77hcfz 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. Introduction respect to symptoms from the autism spectrum as well as developmental and speech delays, particularly in expressive language. 8 Also, other domains are reported to be more affected, especially social-emotional functioning. 9 Apart from the above-mentioned numeric sex chromosome anomalies, from 1986 until present, six case reports on the 49,XXXYY chromosome anomaly have been published, ie, four male adults and two children. All were diagnosed with intellectual disability (Table 1) . This chromosomal condition is extremely rare and its prevalence is estimated to be <1/ 1.000.000. 10 Here, we describe in detail the developmental history and findings at genetic, somatic, endocrinological and neuropsychological examination of the fifth intellectually disabled adult male with this very rare pentasomy. The patient is 25 year-old. Written informed consent for the present case report was provided by both parents. Institutional approval was not required; the patient has never been institutionalized and still lives at his parents' home. Pregnancy and delivery were uncomplicated. His birth weight was about 3500 grams. He has one older brother and two younger sisters, all healthy and well educated. His father had completed professional higher education (teacher) and his mother intermediate vocational education (nurse). His birth weight was about 3500 grams. He has one older brother and two younger sisters, all healthy and well educated. With respect to family history, his mother uses levothyroxine for primary hypothyroidism. Neonatally, minor facial dysmorphisms, general hypotonia and excessive sleep were noticed. His psychomotor and speech/language development were delayed and his behaviour was characterized by some mild head banging and detailed interest for turning objects and toys. At the age of five years, he was referred to a child psychiatrist for evaluation of his significantly delayed development, chronic lack of energy and disinhibited behaviours. Apart from mild intellectual disability, a diagnosis of autism was made. Karyotyping showed a 49, XXXYY karyogram. He followed elementary school for a couple of days only and switched directly to a school for special education until the age of 19 years. Aged 10 years, he was referred again to a child psychiatrist because of panic attacks and aggressive outburst with self-biting, hitting and screaming at sudden contextual changes, especially during school time and when staying one day weekly in his guest house. At examination, the patient then displayed rigid thinking, nearly absence of eye contact and emotionally reciprocity, as well as high distractibility and weak impulse control especially when disturbed in his activities. A diagnosis of autism was reaffirmed and the parents were advised to maintain a structured and supportive approach and to continue logopedic training and physiotherapeutic support in order to stimulate language and motor development. In addition, a low dose of risperidone was started for behavioural control. Aged fifteen years, he attended again an outpatient department for child and adolescent psychiatry. At that time his developmental age was estimated to correspond with that of a five-year-old child. Once more a diagnosis of autism was made and his socialemotional developmental age was considered to be 18 months with a total IQ of maximally 45 with a high risk of overestimation. Because of substantial weight gain, one year later, symptomatic treatment with risperidone was replaced by 5mg aripiprazole. Aged 21 years, subclinical hypothyroidism was established and subsequently, treatment with levothyroxine was started in a daily dose of 25µgr. Despite symptomatic treatment with 5mg aripiprazole per day, his disinhibited behaviours with temper tantrums increasingly disturbed the family situation at home. Therefore, he was gradually admitted to a care farm where he was occupied during the day in a subgroup with simple work (ie, feeding animals, cleaning, sorting, carrying supplies), maintaining structured personal guidance aimed among others to increase his self-esteem. During his daytime activities, however, unexpected environmental changes frequently evoked temper tantrums with aggressive incidents and screaming which he regretted afterwards. Ultimately, however, these could no longer be corrected by the staff members and as a consequence, at the age of 23 years, he had to return to his parental home. Subsequently, he followed five days weekly elementary daytime activities at a wood and metal company (cleaning and sorting of second-hand materials) with individual guidance that, unfortunately, had to be temporarily stopped after eight months due to the COVID-19 restrictions. After restart, because of accumulation of challenging behaviours necessitating permanent individualized care, the patient was referred for expert consultation. At referral, the patient had recently restarted his daytime activities at the wood and metal company. In addition to symptomatic treatment with 5mg aripiprazole daily, 25µgr levothyroxine was still prescribed. Because of lack of symptomatic effect, aripiprazole was tapered off gradually. Relevant hematological and biochemical parameters as well as vitamin status were all normal. His hormonal panel revealed normal values for TSH, FT4, FT3, prolactin, and estradiol but increased values for FSH (16 U/l; normal range: 1-9 U/l) and LH (14 U/l; normal range: 1.7-9 U/l) and a significant lower value for testosterone (1.12 nmol/l; normal range: 5.70-26.10 nmol/l). Etiological analysis demonstrated again the pentasomy with karyotype 49, XXXYY ( Figure 1 ). To exclude other genetic abnormalities, whole exome sequencing was performed which showed no pathogenic sequence variants or copy number variants associated with intellectual disability. At examination, height, weight and head circumference were 182,5cm, 99,8kg (BMI: 29, 8) and 53,5cm (−2,5 SDS), respectively ( Table 2 ). Somatic and neurological examination disclosed no abnormalities. Minor facial dysmorphisms were noticed ie, broad nasal tip, full lips, small simple shaped ears, brachycephaly, mild prognathism and slightly flat midface. In addition, he had small shoulders and marked truncal overweight. With respect to his extremities, he had relatively small hands and feet, four finger line, strikingly lateral position of the patella at his left knee and marked flexible flatfeet. His penis was short with minor scrotum and descended testes with a diameter of 3cm as well as nearly absent pubic hair-growth. Behaviour was characterized by lack of energy and initiative as well as short periods with temper tantrums. 15 ), a total score of 17 (cut-off score = 10) corroborated a diagnosis of autism. Based on the results of these combined assessments (see Table 2 for an overview), a diagnosis of autism was definitively confirmed as well as moderate intellectual disability. Two weeks after discontinuation of aripiprazole, the behavioural repertoire, lack of initiative and general well-being of the patient were significantly improved whereas temper tantrums occurred incidentally only. However, few weeks later, challenging behaviours intensified again upon which the physician for intellectual Disabilities decided to restart treatment with aripiprazole 5mg daily. Re-evaluation of his hormonal status revealed for LH, FSH and testosterone values of 13 U/l (1.7-9 U/L; range: 1.7-9 U/l)), 16 U/l (range: 1-9 U/L) and 1.11 nmol/l (range: 5.70-26.10 nmol/l) respectively, and normal values for prolactin as well as for TSH and FT4. Based on these hormonal results, the endocrinologist originally planned to start with transdermal testosterone gel once daily 12.5mg but instead decided to start with 5mg daily for two weeks and a more gradual dose increasing of 5mg each two weeks up to 20mg. This resulted in more stable behavioural and emotional functioning and a better sleep pattern. A further increase of testosterone dosage to the standard dose of 40-60mg daily will be contingent upon stability and course in relation to testosterone blood level. In the present paper we described in detail the developmental history and the findings obtained from genetic, endocrinological and neuropsychological examination in a 25-year-old intellectually disabled adult male with a 49,XXXYY chromosome anomaly. In addition to two young children, this is until now the fifth adult male individual worldwide in whom such a pentasomy is demonstrated ( Table 1) . As far as can be reconstructed from earlier documents, surprisingly, measurement of hormonal parameters, except TSH, FT4 and prolactin, has previously never been done. As can be inferred from Table 2 , somatic examination disclosed minor dysmorphic features, especially regarding head circumference. His hormonal panel was characterized by a significantly decreased level of testosterone and enhanced values for LH and FSH corresponding with a diagnosis of primary hypogonadism. Extensive neuropsychological evaluation of the patient with objective testing confirmed a diagnosis of autism. His behavioural profile differed not essentially from that described in patients with other numeric sex chromosomal disorders albeit that in the presented case, autism, level of intellectual disability, and contextually determined disinhibited behaviours alternated by apathy seemed to be more pronounced. As to treatment, since some atypical antipsychotics (risperidone and paliperidone, but as far as known not aripiprazole) are identified to have a decreasing effect on the testosterone level due to elevated prolactin levels, 16, 17 the endocrinologist decided to start suppletion with testosterone after aripiprazole was fully discontinued for at least two weeks in order to adjust the correct dosage. The facial dysmorphisms and the severity of cognitive and psychiatric dysfunctions in the present patient are in accordance with results from other studies that found supernumerary sex chromosomes to be associated with further reduction of skull surface area, [18] [19] [20] higher frequency of brain structure abnormalities, 21 and increased vulnerability toward psychiatric and psychosocial disturbances. 7, 22 In general, individuals with sex chromosome aneuploidies have a higher risk to develop metabolic and cardiovascular disorders. 23 Since the scientific information on syndromes with multiple additional sex chromosomes is rather limited, for those disorders it seems best to follow the recently published guidelines on Klinefelter syndrome of the European Academy of Andrology in collaboration with the European Society of Endocrinology. 24, 25 This report is an addition to the existing limited data on the very rare 49,XXXYY pentasomy. It demonstrates that children born with any abnormality of the external genitalia have to be always evaluated for chromosomal abnormalities, results of which can also guide the timely detection of intellectual and cognitive disabilities, somatic anomalies, and androgen deficiency. This approach will help avoiding underdiagnosis of delayed development of language and speech as well as of autistic disorder which are all crucial for the prompt deployment of specific pedagogical measures and medical interventions. 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The journal is characterized by the rapid reporting of reviews, original research and clinical studies across all disease areas. The manuscript management system is completely online and includes a very quick and fair peer-review system The authors are indebted to the parents of the patient for their kind cooperation and their written informed consent for publication of the developmental history of their son. We thank Mr. Leo van Mil, coordinator Centre for Consultation and Expertise region West, who referred the patient for expert consultation. Psychological tests were performed by Mrs. Aleika Jansen and Mrs. Tara Bonekamp from the Regional Team Diagnostics and Treatment of ASVZ in Sliedrecht. The authors report no conflicts of interest in this work.