medwireNews: Study findings demonstrate the broad heterogeneous phenotypes found in children with 46,XY gonadal dysgenesis (GD), with insights into likelihood of spontaneous puberty and risk of gonadal malignancy.
Ajay Thankamony (Addenbrooke’s Hospital, Cambridge, UK) and co-workers compared the medical records of patients with partial GD assigned male (PGDm; n=103) or female (PGDf; n=107) with those of 100 patients with complete (C)GD.
The patients were identified from 34 countries via the I-DSD Registry and two Brazilian centres, and information was collated on karyotype, external masculinisation and external genital scores, hormone levels, pubertal status and gonadal histology. The patients were born between 1941 and 2020, and there was a family history of differences in sex development for 25.8%, 19.0% and 17.4% of the PGDm, PGDf and CGD groups, respectively.
The researchers defined CGD as a 46,XY karyotype and typical female genitalia with either Müllerian duct derivatives or no anti-Müllerian hormone (AMH), as well as elevated luteinising hormone (LH) and follicle-stimulating hormone (FSH) at puberty. The children in this comparator group presented at an average age of 15 years, with 62.5% having delayed puberty. A quarter of the CGD group had karyotype analysis at any earlier age following other symptoms – for example, 9.1% were investigated for abdominal pain found to be caused by gonadal tumours.
For the study, PGD was defined as a 46,XY karyotype and atypical genitalia, with GD demonstrated by histology or pathogenic mutations, or by human chorionic gonadotropin (hCG)-stimulated hormone levels less than twice the basal value, low basal testosterone with high gonadotropin levels in mini-puberty or puberty, below range levels of AMH or inhibin B or Müllerian duct derivatives.
Among the PGDm patients, 65% met the biochemistry or presence of Müllerian duct derivatives criteria, while 52% and 38% met the histology and pathogenic gene criteria, respectively, with respective rates among the PGDf patients of 74%, 60% and 46%.
The PGDm and PGDf individuals presented at an average age of 0.5 and 1.3 years, respectively, due to atypical genitalia in all of the PGDm patients and 62.1% of PGDf patients, while 17.9% and 8.4% of PGDf patients presented with delayed puberty and virilisation, respectively.
Among children who presented before 2 years of age, PGDm patients had a significantly more masculine genital appearance than their PGDf counterparts (external genitalia score 7.0 vs 4.0 points) and were less likely to have a uterus (31.3 vs 51.0%) or fallopian tubes (18.8 vs 35.5%). Ten patients without a uterus were assigned PDGf on the basis of typical female genitalia and gonadal dysfunction, the researchers say.
Genetic screening of 78.7% of the study participants identified a chromosomal or genetic alteration in 42.3%, including 48.3%, 50.0%, 59.0% and 48.3% of the PGDm, PGDf and CGD groups, respectively. Both PGDm and PGDf were most commonly associated with the NR5A1 alteration (25.6 and 42.2%, respectively), while SRY and WT1 alterations were the most common alterations in the CGD group (23.6 and 9.0%, respectively).
Thankamony and team found a high and comparable rate of comorbidity among the PGDm, PGDf and CGD groups (33.3, 33.0 and 38.0%, respectively). Neurodiversity disorders, such as developmental delay, autistic spectrum disorder and structural brain anomalies, were the most common type of comorbidity, occurring in 26.3%, 21.3% and 28.9%, respectively, followed by Wilm’s tumour, congenital proteinuria and other renal disorders, in 31.6%, 12.8% and 23.7%.
Analysis of available biochemical markers at mini-puberty (age 0–6 months) showed that the PGDm and PGDf groups had comparable levels of basal serum testosterone, FSH and LH. FSH levels were above the reference range in 64.7% and 67.9% of PGDm and PGDf patients, respectively, compared with all CGD patients, while LH levels were above the reference range in 17.6%, 7.1% and 16.7% of the groups, respectively.
Basal hormone levels were also comparable among the PGDm and PGDf patients who were diagnosed after the age of 13 years. PGDm and PGDf children were less likely than CGD children to have elevated serum LH (76.9 and 77.1 vs 93.8%), whereas there was a broader range of above reference levels of FSH (100, 95.4 and 80.0%).
The PGDm and PGDf patients had comparable testosterone levels after hCG stimulation at any age, and similar rates of low AMH (58.1 vs 48.0%) or inhibin B (69.2 vs 66.7%) levels.
The researchers also reviewed pubertal development. Overall, 18.5% of women with CGD who were diagnosed aged 13 years or older had spontaneous breast development. Puberty was induced at a median age of 16 years and menarche was achieved in 72.3% at a median age of 17.3 years.
Of the 45 PGDm patients diagnosed aged 13 years or older, 55.6% had at least one gonad. Spontaneous onset of puberty occurred in 80.0% at a median age of 12 years and, although 30.3% completed puberty with testosterone treatment, 59.3% achieved Tanner G5 by age 18 years without testosterone. And after completion of puberty without testosterone no replacement therapy was required.
Thankamony et al observe that spontaneous rather than induced puberty was significantly more common in patients with at least one labioscrotal gonad (62.9 vs 12.5%), and there was a trend towards a higher rate among those with an hCG testosterone response at least double the basal level (88 vs 33%). Of note, all the PGDm patients with an NR5A1 mutation and at least one gonad experienced spontaneous puberty compared with just 50% of those with other genetic alterations.
Among the PGDf patients who presented at age 13 years or later, 43.2% of 26 with at least one labioscrotal gonad experienced hirsutism or clitoral enlargement and had male testosterone levels. Almost a third (30.8%) of these patients had spontaneous breast development including six patients who simultaneously had virilisation. Puberty induction was initiated at median age of 13 years and 30% achieved menarche after the age of 15 years.
Turning to surgical intervention, the team reports that PGDm patients commonly underwent orchidopexy (50%) and hypospadias repair (73.6%), while 47.1% of PGDf patients underwent clitoral reduction and 44.9% vaginoplasty.
Male to female sex reassignment was performed during infancy, childhood or adolescence in 5.3% of 94 PGDm patients, while 16.1% of 93 PGDf patients were reassigned male during infancy, childhood, adolescence or adulthood.
Gonadal biopsy and subsequent gonadectomy was required for a respective 43.5% and 22.5% of PGDm patients, and 22.9% and 52.6% of PGDf patients, compared with 26.0% and 100.0% of CGD patients.
Histology revealed that dysgenetic testis was the most common gonadal feature in PGD patients versus streak gonad in those with CGD.
Of concern, gonadal malignancy or germ cell neoplasia in situ occurred in 33.7% of CGD patients unilaterally (18.1%) or bilaterally (15.7%), with significantly lower rates in the PGDm (19.7%) and PGDf (8.8%) groups. The most common tumour types in all three groups were gondaoblastoma (47.8%), dysgerminoma/seminoma (28.4%), and germ cell neoplasia in situ (11.9%).
And 67% of patients with CGD and spontaneous breast development had gonadal tumours compared with just 26% of those without spontaneous breast development. A quarter of the eight PGDf patients with breast development had gonadal tumours but this was not significantly different to the 30% rate among the 13 PGDf patients who did not have breast development. Although there were only three tumour cases among the PGDm patients, the researchers note that only a third of these patients had histology assessment.
The team believes that the high incidence of gonadal tumours in CGD patients “highlights the importance of evaluating these patients” and says that large scale histology studies of patients with PGD “is the way forward for future prospective studies to determine the precise risk for germ cell neoplasia in later life, particularly in PGD assigned male and [those who retain] gonads post-pubertally.”
By Lynda Williams
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