Rare 48, XXYY Syndrome with Primary Infertility and Behavioural Disorder: A Case Report

Abstract

The syndrome, 48, XXYY is a rare sex chromosome aneuploidy in males. These individuals have unique clinical features such as male infertility, testicular agenesis, tall stature, gynaecomastia, tremors and variable phenotypes of neurodevelopment and psychiatric disorders. We report a case of a 32-year-old infertile male patient with tall stature and atrophied testes. The seminal analysis showed azoospermia. Hormone analysis and ultrasonographic evaluation confirmed the diagnosis as non-obstructive azoospermia. Clinically, he was diagnosed with Klinefelter syndrome (KS). Cytogenetic investigation confirmed an abnormal male karyotype with sex chromosome aneuploidy, with a 48, XXYY genotype. He had more complex physical, medical and psychological phenotypes which made him distinct from males with 47, XXY KS. Although hypergonadotropic hypogonadism features are shared in both syndromes, the 48, XXYY patients have more psychological disorders, with moderate intellectual disability and attention-deficit/hyperactivity disorders (ADHD). This patient had the rare 48, XXYY chromosomal constitution, which is considered a variant of KS but manifests with more complex clinical and psychological features. Most 48, XXYY males are diagnosed due to infertility. In addition to cognitive impairment and developmental delay, behavioural dysfunction and difficulties in occupational skills are the main complications. Early detection, clinical assessment, genetic counselling, hormonal therapy and infertility management are essential for better long-term outcomes for these patients.

INTRODUCTION

The 48, XXYY, a sex chromosomal aneuploidy, is characterised by the presence of an additional homologous pair of X and Y chromosomes, distinct from the 46, XY male karyotype. It is considered a variant of classic 47, XXY Klinefelter syndrome (KS) because of the similarities and well-recognised clinical features found in both syndromes. These may include: seminiferous tubule dysgenesis, androgen deficiency, thromboembolic disease, movement disorders, cognitive and behavioural dysfunction and susceptibility to autoimmune disorders.[1] Previous reports have shown that the 48, XXYY condition is more severe and distinct in comparison to classic KS. It is rare with global incidence of 1: 18,000–1: 40,000 males and leads to testicular dysgenesis and hypergonadotropic hypogonadism with non-obstructive azoospermia.[2,3] Reports from India are scarce. However, the reported incidence in India is quoted to be between 1: 17,000 and 1: 50,000 live male births (https://genetic.org/xxyy-project-india/). Recently, Resim et al. from Turkey have reported mosaic karyotype 48, XXYY/47, XYY in a male presenting with infertility, along with various congenital abnormalities and the presence of renal-malrotation and psychiatric problems.[4] Endocrine abnormalities in 48, XXYY males cause reduced testosterone levels, increased follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels along with hypogonadism.[5] Changes in physical characteristics include dysmorphic facial features, elbow abnormalities and poor muscle development. In addition to the above, commonly associated medical problems include asthma, peripheral vascular disease, diabetes and intention tremors.[6,7]

Some specific clinical features, including intellectual disability (formerly mental retardation) and psychiatric problems, have been described in 48, XXYY males. Neurodevelopment and psychological disorders are also more common and significant in 48, XXYY, and developmental dyspraxia may enhance early language and motor deficits.[8] Attention-deficit/hyperactivity disorders (ADHD) is present in over 70% of 48, XXYY males, with symptoms of inattention, distractibility, poor organisational skills, hyperactivity, and/or impulsivity which affect daily functioning.[1] This is significantly higher than the 35%–45% rate of ADHD in 47, XXY. In addition to ADHD, autism spectrum disorders are much more common in individuals with 48, XXYY syndrome accounting for a rate of 28%–50%.[9]

Here, we report a rare case of 48, XXYY patients with non-obstructive azoospermia infertility with intellectual impairment and behavioural disorder. We also present a systematic review on the wide spectrum of clinical abnormalities associated with this rare syndrome in males.

CASE REPORT

This study was approved by the Institutional Ethics Committee, Mahatma Gandhi Institute of Medical Sciences, Sevagram (Approval no. IEC/164/2016). This process is in accordance with the Declaration of Helsinki.

A couple was referred for cytogenetic analysis from the department of obstetrics and gynaecology of a tertiary care hospital. The couple was married for 7 years and had a strong desire for raising a family but till date had not conceived. On clinical examination, it was found that the husband had atrophied testes and semen analysis showed azoospermia. On the other hand, the wife was regularly menstruating and her gynaecological examination was normal. On general examination, the husband was a 34-year-old illiterate male employed at a textile factory. His physical examination revealed him to be a tall-statured man with 182 cm height, 89 kg weight and body mass index of 26.9 kg m – 2 with a normal blood pressure of 125/75 mmHg. The secondary sexual characteristics of the patient were poorly developed, and he had some feminine characteristics, such as no facial hair and bilateral gynaecomastia. In addition, he presented with forward head posture, long face, orbital hypertelorism, eunuchoid skeleton, reduced muscle mass, poor dentition, elongated arms and legs, small atrophied testes and small penis. He had mild tremors and reported a history of peripheral vascular disease, signs typically reported to be associated with this condition. He also reported a history of repeated deep vein thrombosis (DVT). He had experienced learning difficulties at school and had needed support and help with reading and writing. On interview, he was found to be an anxious personality. He had substantial psychiatric complaints including bipolar disorder with nervousness, impulsive behaviour and auditory hallucinations. He expressed irritable moods with learning and mild intellectual disability, attention-deficit/hyperactivity disorders (ADHD) and poor social interactions.

We performed semen analysis, hormonal studies, cytogenetic analysis and molecular assessment for Y chromosome microdeletions to diagnose the cause of infertility. Repeated semen analysis showed azoospermia (pellet negative). Hormonal measurements were made by radioimmunoassay. The patient had increased FSH level: 34.6 mUI/mL (normal range: 0.7–11.1 mUI/mL), increased LH level: 14.72 mUI/mL (normal range: 0.8–7.6 mUI/mL) and low Testosterone level: 2.1 ng/mL (normal range: 2.45–8.36 ng/mL). The ultrasonography and hormonal studies confirmed the diagnosis of non-obstructive azoospermia. Chromosomal analysis was performed on phytohemagglutinin-M stimulated whole peripheral blood lymphocytes for 72 h. The lymphocyte culture was harvested and Geimsa-Trypsin-Geimsa banding was performed following standard laboratory protocol. The karyotype was prepared from the metaphase chromosome according to the International System for Human Cytogenomic Nomenclature. At least 30 metaphases were counted in cytogenetic analysis (320–400 G-banding) to rule out sex chromosome mosaicism in the patient. The cytogenetic analysis showed the constitutional sex chromosome numerical aberration with 48, XXYY karyotype in the male [Figure 1]. His wife’s karyotype was found to be normal. The Y chromosome microdeletions multiplex polymerase chain reaction assay did not show any deletions of SRY gene and of the 18 sequences-tag sites covering AZFa, AZFb and AZFc region suggesting that the AZF region was intact. A written informed consent was obtained from the patient. This case report was a part of our extramural research project, which was approved by the Institutional Ethics Committee under the research project titled ‘Genetics of Infertility’ (IEC/164/2016).

Figure 1.

The Geimsa-Trypsin-Geimsa-banded 48, XXYY metaphase and karyotype of the patient, (a) 48, XXYY metaphase with two X (black arrow) and two Y (dotted arrow) chromosomes and (b) 48, XXYY karyotype prepared from the above metaphase sex chromosome aneuploidy

DISCUSSION

The syndrome 48, XXYY is a sex chromosome aneuploidy in males that causes primary infertility due to non-obstructive azoospermia. This syndrome is caused by two consecutive non-disjunctions during meiosis I and meiosis II at the time of spermatogenesis in the father, and thus the extra sex chromosomes are usually from the father. It is also possible that non-disjunction of sex chromosomes at the second meiotic division in both parents may result in the fusion between a 24, XX ovum and a 24, YY sperm.[10] This syndrome was initially considered as a variant of 47, XXY KS because both the syndromic males share common clinical features including craniofacial dysmorphism, skeletal anomalies, lower cognitive function, congenital cardiac anomalies, hypergonadotropic hypogonadism, micro-orchidism, primary infertility and tall stature.[2,11] However, 48, XXYY syndrome male has additional clinical phenotypes such as eunuchoid body shape, peripheral vascular disease, varicose vein at skin surface, especially below the keen, asthma, respiratory infections, immunological dysfunctions, neurodevelopmental and behavioural problems.[12,13,14] The presence of extra copies of sex chromosomes in 48, XXYY patients influences male sexual development leading to atrophied testis and low testosterone levels. With each addition of X chromosome, there is a progressive divergence from typical development with an increased frequency of phenotypic, endocrinological and structural abnormalities; while the addition of an extra Y chromosome provides cognitive and behavioural abnormalities in these males. The affected males with increased numbers of X or Y sex chromosomes are at risk of speech impairment, partial hearing loss or auditory processing problems which increases their risk of learning deficits, emotional issues, cognitive problems and social adjustment difficulties.[11] The comparison of key features between the KS and 48, XXYY syndrome are depicted in Table 1.

Table 1.

Comparison of clinical features between 47, XXY and 48, XXYY males

Clinical features		47, XXY[15]		48, XXYY
Parent of origin of extra chromosome		50% maternal and 50% paternal		100% paternal[10]
Prevalence		1 in 600 male births		Much rarer, estimated 1 in 18,000 to 1 in 50,000[11]
Primary clinical features		Mild developmental delay, infertility, reduced testosterone, tall stature, learning difficulties		More severe developmental and intellectual delays, lower IQ, delayed speech and motor skills[1,11]
Physical features		Taller than average, less muscle mass, gynaecomastia, small testes		Similar physical features to 47, XXY but may have more pronounced movement disorder, neurological and developmental challenges[1]
Infertility		Hypergonadotropic hypogonadism		Severe Hypergonadotropic hypogonadism[3]
Congenital malformation		Clinodactyly and common congenital malformations (inguinal hernia, cleft palate - occult, submucous) in 18%		Clinodactyly and congenital malformations (inguinal hernia, cardiac, radioulnar synostosis, cleft palate, clubfoot, renal dysplasia) in 70% and 56%, respectively[2,15]
Cognitive problem		Mild learning disabilities, difficulty with language and executive function		More significant intellectual disabilities, especially in language and delayed motor skills[1]
Behavioural issues		Risk of social challenges, mild behavioural issues		More pronounced behavioural challenges, including impulsivity and social difficulties[1,11]
Developmental and cognition		Speech and motor delays (40%–75%); 50%–75% learning disabilities		Speech and motor delays (75%–92%); 100% learning disabilities[1,11]
Tremor		Mild tremor		Severe Intention and postural tremors[11,15]
Diagnosis		Typically diagnosed during adolescence or adulthood due to symptoms or infertility		Often diagnosed earlier due to more obvious developmental issues[1,8]

IQ=Intelligence quotient

It is reported that males with KS variant 48, XXXY have decreased cognitive functions compared to those with 48, XXYY. It seems that the addition of extra copy of X chromosome decreases the overall intelligence quotient by 15–16 points. However, in both disorders, it is always difficult to state precisely whether these specific clinical features have occurred due to extra X chromosome or the extra Y chromosome.[15] An extra copy of the X or Y chromosome in males causes hypergonadotropic hypogonadism, primary infertility and a wide range of psychological and medical problems. This patient presented with mild tremors and type 2 diabetes mellitus, which are more common among 48, XXYY syndrome patients.[6,16] It is also observed that intention tremors are common clinical manifestation in 50% individuals with sex chromosome aneuploidy such as 47, XXY and 47, XYY syndrome males.[15,16] It is assumed that overexpression of pseudoautosomal region genes which are homologous on the X and Y chromosomes cause tremors in these individuals. However, an additional X alone may be less tremorgenic due to the formation of Barr’s body of the extra X chromosome.[14]

Neurodevelopment and psychological disorders are common but variable in severity in 48, XXYY syndrome.[4,9] Seventy per cent of these males have attention-deficit/hyperactivity disorders (ADHD), while others may manifest mood abnormalities such as impulsivity, aggression, mood instability, autistic-like behaviours and poor social function. In classic KS, the typical cognitive pattern shows deficits in specific domains of cognition including language and frontal-executive functions rather than a general decline in intellectual ability.[11,15] As a result, 48, XXYY males have significantly lower language-associated disabilities and adaptive functioning than typical 47, XXY males. Our patient had DVT at a very early age of 16 with multiple recurrences. An increased incidence of DVT in 48, XXYY syndrome is reported in more than 20% of cases over the age of 20 years.[13] The pathophysiology in these patients has not been elucidated but could be due to oestrogen-testosterone imbalance.

CONCLUSION

Sex chromosome aneuploidies represent a spectrum of syndromic features in males and females that may not be recognised at birth. In these patients, a few peculiar clinical phenotypes along with neurodevelopmental features appear during childhood. Early diagnosis and systematic evaluations are necessary for better clinical management of syndromic features such as various skeletal, cardiac and renal anomalies, infertility and neurodevelopmental problems. Cytogenetic evaluation should be performed in all non-obstructive azoospermia patients. Patients should receive counselling regarding the nature of the presenting condition and the available treatment options.

Author contributions

PA performed a genetic investigation and genetic counselling of the patient. SJ and JE were involved in clinical diagnosis and management. PA and PN wrote, reviewed and edited the manuscript. All authors read and approved the manuscript.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Data availability statement

Data related to this study and what is available in the published material can be obtained in digitalised form from the corresponding author.

Funding Statement

This work was supported by the Department of Health Research, Ministry of Health and Family Welfare, New Delhi (Grant award no. V.25011/318-HRD/2016-HR).