Perinatal presentation of Klinefelter syndrome and variants: take-home lessons for the urologist (2024)

Background

Klinefelter syndrome (KS) is a sex chromosome disorder usually diagnosed in adulthood during work-up for infertility or hypogonadism. Perinatal diagnoses are uncommon.

Case presentation

We report two newborn cases of KS with associated hypospadias and bilateral cryptorchidism suspected on prenatal genetic testing triggered by ambiguous genital appearance on prenatal ultrasound. Management is presented and the relevant literature on the prenatal and prepubertal presentation and management of KS is summarized.

Conclusions

Klinefelter syndrome can be suspected prenatally in patients with increased nuchal translucency or ambiguous genitalia. Cell-free DNA can establish prenatal diagnosis with good sensitivity and specificity. Early diagnosis allows for early initiation of multidisciplinary care, focused counseling, lifestyle modification, early androgen replacement, and cryopreservation during late puberty or early adulthood. Testosterone treatment during infancy was linked to improved phenotypic features of KS and better cognitive and behavioral outcomes.

2.1 Case 1

A second-trimester ultrasound of a healthy 29-year-old 2nd gravida primipara without significant perinatal drug exposure, demonstrated fetal growth restriction, ventricular septal defect, and ambiguous genitalia. Cell-free DNA (cfDNA) testing was positive for KS. The patient was born at 38weeks of gestation via uncomplicated vaginal delivery and had a birth weight of 2580 g. On genital examination, he had micropenis, proximal penile hypospadias, ventral chordee, hypoplastic scrotum, and bilateral non-palpable gonads (Fig.1). Associated anomalies included preauricular skin tags (Fig.1), pulmonary valve stenosis, and VSD. Renal ultrasound was normal and the patient had a karyotype of 48, XXYY. The patient received 3 monthly testosterone injections starting at 3months of age. He underwent diagnostic laparoscopy at the age of 6months. Both testes were intra-abdominal. Bilateral one-stage laparoscopic orchiopexy was successfully performed at 6months of age. The patient is currently awaiting hypospadias repair.

2.2 Case 2

Abnormal genital appearance and fetal growth restriction on prenatal ultrasound in a 21-year-old primigravida triggered prenatal genetic testing. Cell-free DNA was positive for KS. No other anomalies were seen on prenatal ultrasound. The patient was delivered at 37weeks via C-section. The newborn assessment showed bilateral non-palpable cryptorchidism, male external genitalia with coronal hypospadias without significant chordee, and no other associated anomalies. Postnatal karyotyping was 47, XXY. Bilateral one-stage laparoscopic orchiopexy was successfully carried out at 6months of age. The patient received 3-monthly testosterone injections starting at the age of 3months based on the current data showing possible favorable effect on the long-term cognitive function. Testosterone treatment resulted in increased penile length and glans width. Tubularized incised plate repair of hypospadias was performed at the age of 9months. At 3month postoperative follow-up, the patient had an apical slit-like meatus with excellent cosmetic outcome with no evidence of complications. Genital exam findings at birth, at the time of hypospadias repair, and 3months postoperatively are shown in Fig.2.

An increasing number of genetic and congenital conditions are diagnosed in utero. Prenatal diagnosis of KS is associated with a less severe phenotype than cases diagnosed postnatally. Prenatally diagnosed cases can benefit from early developmental and speech interventions and subsequently have less severe phenotypes. It has also been postulated that parents of prenatally diagnosed cases are older, more educated and of better socio-economic classes. They have made a conscious decision to maintain pregnancy and are more supportive of their children. These factors favor the outcome of prenatally diagnosed cases [4, 5] Nevertheless, only 10–13% of KS patients are diagnosed prenatally due to the lack of knowledge of the prenatal ultrasound features characteristic of KS. In a report of 51 cases with KS diagnosed prenatally, increased nuchal translucency ≥ 3mm was the most commonly observed prenatal ultrasound abnormality in 23.1% and 29.2% of fetuses had other associated anomalies on second-trimester anatomical ultrasound [6]. Increased nuchal translucency has a low sensitivity and specificity for KS and can be seen with other chromosomal abnormalities. Neither patient in the current report had increased nuchal translucency on prenatal ultrasound. Prenatal genetic testing with cfDNA was rather triggered by fetal growth restriction and ambiguous genitalia on prenatal ultrasound. cfDNA has acceptable sensitivity and specificity for diagnosing KS with a positive predictive value ranging from 71 to 91%. [6] Definitive prenatal diagnosis of KS requires amniocentesis or chorionic villous sampling which are more invasive and were declined in both of our patients.

KS could be diagnosed before puberty during work-up for genital abnormalities or learning disabilities. Both of our patients had bilateral intra-abdominal testes with concomitant hypospadias. Cryptorchidism is not uncommon in KS with a reported incidence of 55.5–69% among patients diagnosed before puberty. KS is the most prevalent genetic abnormality associated with cryptorchidism diagnosed in 1–2% of patients [7]. Penile anomalies including hypospadias, chordee, and penoscrotal transposition were sporadically reported in patients with KS. Lee et al. reported on four patients with hypospadias and concomitant cryptorchidism among six patients with KS and associated genital anomalies [3]. A 2015 literature review identified reports of 15 patients with prepubertal diagnosis of KS and associated penoscrotal anomalies. Hypospadias and chordee were the commonest abnormalities and 6 patients had concomitant cryptorchidism. All these cases were diagnosed postnatally during workup for genital anomalies [8]. Following the recommendations of the Chicago Consensus Conference on Disorders of Sexual Differentiation by offering karyotyping in patients with bilateral cryptorchidism and patients with cryptorchidism and associated hypospadias or micropenis can improve the early diagnosis and management of KS and other chromosomal abnormalities. [9]

Several explanations were proposed to explain the genital abnormalities associated with KS including diminished androgen production. Both subnormal and normal testosterone levels were reported in fetuses with KS [10, 11]. Androgen insensitivity is another plausible explanation however, normal androgen binding characteristics were demonstrated in some patients with KS and genital abnormalities [3]. Other possible explanations include CAGn polymorphism and skewed X chromosome inactivation. The presence of two or more copies of DAX-1 on the X chromosomes may result in a dose-dependent suppression of the SRY gene in utero and explain the higher prevalence of anomalies in patients with KS variants [3]. The variable phenotype of the external genitalia of KS patients may result from the interplay of these potential causes.

Early diagnosis of KS represents an opportunity for parental education, focused counseling, early characterization of the neuropsychological and developmental profile, establishment of multidisciplinary care, and hopefully ameliorating some of the known complications [12]. Patients with KS are at an increased risk of insulin resistance, cardiovascular diseases, and other features of metabolic syndrome. Patients diagnosed at an early age can be counseled regarding a healthy diet, regular exercise, screening of lipid profile, and other risk factors in early adolescence or sooner. Furthermore, patients with KS may benefit from early testosterone treatment. KS patients may have a blunted testosterone surge during the mini-puberty of infancy and some retrospective studies demonstrated cognitive and behavioral benefits with testosterone administration during the first few months of life [13]. In a randomized controlled trial, testosterone treatment during infancy was associated with less risk of adiposity and a greater increase in total body mass, fat-free mass, length z-score, stretched penile length, and growth velocity [14]. Finally, patients with prepubertal KS have preserved seminiferous tubules but with reduced germ cell numbers. Prepubertal diagnosis of KS represents an opportunity for cryopreservation and early initiation of androgen replacement therapy during late puberty and early adulthood before patients have extensive hyalinization and fibrosis of the seminiferous tubules and develop symptoms and signs of hypogonadism [14].

cfDNA:

Cell-free DNA

KS:

Klinefelter syndrome

Authors and Affiliations

1. West Virginia University School of Medicine, Morgantown, WV, 26506, USA

   Matthew Frownfelter

2. Department of Urology, West Virginia University, Morgantown, WV, 26506, USA

   David Zekan,Osama Al-Omar&Ahmed Abdelhalim

3. Department of Urology, Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt

   Ahmed Abdelhalim

Contributions

All authors have made substantial contributions to the manuscript. They have read and approved its final version. They have no direct or indirect commercial financial incentive associated with publishing the article.

Corresponding author

Correspondence to Ahmed Abdelhalim.

Ethics approval and consent to participate

IRB approval was deemed unnecessary according to the institution policy.

Consent for publication

Written informed consent was obtained from the patient's guardians for the publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.

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