The clinical presentation spectrum and diagnostic yield in children with gender development disorder: a single-center experience

Haslak Gokce Velioglu; Elvan Bayramoglu; Ilayda Altun; Mert Ucar; Hande Turan; Olcay Evliyaoglu

doi:10.1530/endoabs.118.PO75

Background: Disorders of sex development (DSD) are a heterogeneous group characterized by variations in chromosomal, gonadal, and anatomical sex development. Clinical presentation varies widely, and phenotypic findings during the initial evaluation play an important role in guiding the diagnostic approach. This study aimed to describe the clinical and phenotypic characteristics of DSD cases evaluated at our center and to analyze their distribution according to karyotype. A secondary objective was to evaluate differences between cases with and without an identifiable genetic etiology.

Methods: The clinical data of patients diagnosed with CGB were retrospectively reviewed. Demographic characteristics, clinical findings, and external genital scores (EGS) were recorded. Cases were classified according to karyotype as 46,XY, 46,XX, or chromosomal abnormalities. The distribution of demographic, clinical, and laboratory findings among these groups was evaluated. Final diagnoses were determined based on clinical, biochemical, and genetic assessments. Among cases who underwent genetic testing, differences between patients with identifiable genetic etiologies and those without (idiopathic) were analyzed.

Results: A total of 220 cases were included, with a median age at presentation of 1.8 (0.15–19) years and a median EGS of 9.5. Most patients had a 46,XY karyotype (n = 186, 84.5%), followed by 46,XX (n = 24, 11%) and chromosomal abnormalities (n = 10, 4.5%). The clinical and phenotypic characteristics according to karyotype groups are summarized in Table 1. Genetic testing results were available for 96 cases. Among them, 71 had an identifiable genetic diagnosis and 25 were classified as idiopathic. The median EGS was significantly lower in the genetic diagnosis group (7 vs. 10; P <0.001), and consanguinity was more frequent (49.3% vs. 20%; P =0.020). The presence of Müllerian structures (40.8%) and ovarian detection on ultrasound (23.9%) were also more common in this group (P <0.05). In contrast, isolated hypospadias (52%), complete scrotal fusion (88%), and chordee (68%) were more frequently observed in cases without a genetic diagnosis (P <0.05). Detailed comparisons between groups are presented in Table 2. The overall diagnostic yield of genetic testing was 64%, reaching 69.2% among 46,XY cases.

Table 1. Distribution of patients’ general characteristics according to their karyotype
	Group 46, XY (n = 186)	Group 46, XX (n = 24)	Group Chromosomal abnormality(n = 10)
Age at presentation (Years) (Median (Min.-Max.)	1.7 (0.15–19)	2.8 (0.6–17)	1.82 (0.25–12)
Consanguineous marriage (n, %)	43 (23.1%)	13 (54.2%)	1 (10%)
Maternal virilization during pregnancy (n, %)	2 (1.1%)	-	-
Reason for referral to our clinic
Suspected genital abnormalities (n, %)	51 (27.4%)	19 (79.2%)	7 (70%)
Isolated hypospadias (n, %)	61 (32.8%)	-	1 (10%)
Undescended testis (n, %)	56 (30.1%)	-	2 (20%)
Primary amenorrhea (n, %)	8 (4.3%)	3 (12.5%)	-
Inguinal hernia (n, %)	7 (3.8%)	-	-
Underdeveloped breasts (n, %)	1 (0.5%)	1 (4.2%)	-
Precocious puberty (n, %)	1 (0.5%)	-	-
Microlithiasis (n, %)	1 (0.5%)	-	-
Absence of the uterus (n, %)	-	1 (4.2%)	-
Dominant phenotype
Male (n, %)	161 (86.6%)	10 (41.7%)	10 (100%)
Female (n, %)	25 (13.4%)	14 (58.3%)	-
External genital score (Median (Min.-Max.))	10 (0–12)	3.5 (0–8.5)	8.25 (5–10.5)
Penis
<10 mm (n, %)	13 (7%)	6 (25%)	-
10–20 mm (n, %)	17 (9.1%)	6 (25%)	1 (10%)
21–25 mm (n, %)	20 (10.8%)	5 (20.8%)	2 (20%)
26–30 mm (n, %)	20 (10.8%)	6 (25%)	2 (20%)
>30 mm (n, %)	116 (62.4%)	1 (4.2%)	5 (50%)
Scrotal fusion
None (n, %)	23 (12.4%)	10 (41.7%)	-
Posterior fusion (n, %)	4 (2.2%)	5 (20.8%)	4 (40%)
Total fusion (n, %)	159 (85.5%)	9 (37.5%)	6 (60%)
Bifid scrotum (n, %)	51 (27.4%)	8 (33.3%)	5 (50%)
Cardiac (n, %)	70 (37.6%)	2 (8.3%)	5 (50%)
Presence of Müllerian structures (n, %)	18 (9.7%)	20 (83.3%)	6 (60%)
Presence of gonads on ultrasound
Absent (n, %)	7 (3.8%)	-	-
Ovaries (n, %)	2 (1.1%)	23 (95.8%)	-
Testis (n, %)	175 (94.1%)	-	9 (90%)
Ovotestis (n, %)	-	1 (4.2%)	1 (10%)
Dysgenetic (n, %)	2 (1.1%)	-	-
Diagnosis	Gonadal Development Disorders • Gonadal dysgenesis (n = 10) Testosterone Synthesis-Action Defect • 17-beta-hydroxysteroid dehydrogenase (n = 5) • Antley-Bixley Syndrome (n = 1) • 5-alpha reductase deficiency (n = 13) • Complete/Partial Androgen Resistance (n = 6) Persistent Müllerian Duct Syndrome (n = 7) Noonan syndrome (n = 2) Prader-Willi Syndrome (n = 2) Down syndrome (n = 4) Idiopathic (n = 136)	Gonadal Development Disorders • 46 XX Ovotestis (n = 1) Androgen Excess • 21-Hydroxylase Deficiency (n = 15) • 11 Beta-hydroxysteroid dehydrogenase deficiency (n = 1) Rokitansky-Küster-Hauser-Mayer Syndrome (n = 3) Idiopathic (n = 7)	• 45 X, 46 XY: mosaic (n = 2) • mos45,X/46,X+mar SRY+ (n = 1) • 47 XXY (n = 2) • mos45/46,XY (n = 1) • mos45,X-Y/46,X,del(Y)(q11.23)/46,Xi(Y)(q11.23) (n = 1) • 46,X, Yqh (n = 1) • 46,XX (74%)/47,XXY (26%) (n = 1) • 8q21.3q22.1x1, Yq11.223q11.23x2 (n = 1)
LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; USG: Ultrasonography.

Table 2. Comparison of cases with and without an identified genetic etiological cause of sexual development disorder among those who underwent genetic testing.
	Genetic CGB (n=71)	Idiopathic CGB (<>	<>
<Age at presentation (Years) (Median (Min.-Max.))	1.7 (0.5ߝ19)	1.6 (0.25ߝ15.25)	0.207
Consanguineous marriage (n, %)	35 (49.3%)	5 (20%)	0.020
Reason for referral to our clinic			C;0.001*
Suspected genital (n, %)	38 (53.5%)	8 (32%)
Isolated hypospadias (n, %)	3 (4.2%)	13 (52%)
Undescended testis (n, %)	19 (26.8%)	4 (16%)
Primary amenorrhea (n, %)	5 (7%)	0 (0%)
Inguinal hernia (n, %)	6 (8.5%)	0 (0%)
Underdeveloped breasts (n, %)	-	-
Precocious puberty (n, %)	-	-
Microlithiasis (n, %)	-	-
Absence of the uterus (n, %)	-	-
Dominant phenotype			0.002
Male (n, %)	47 (66.2%)	25 (100%)
Female (n, %)	24 (33.8%)	0 (0%)
External genital score (Median (Min.-Max.))	7 (0ߝ11)	10 (5ߝ11.5)	C;0.001
Phallus			0.267
C;10 mm (n, %)	8 (11.3%)	1 (4%)
10ߝ20 mm (n, %)	13 (18.3%)	1 (4%)
21ߝ25 mm (n, %)	11 (15.5%)	6 (24%)
26ߝ30 mm (n, %)	10 (14.1%)	3 (12%)
E;30 mm (n, %)	29 (40.8%)	14 (56%)
Scrotal fusion			0.012**
None (n, %)	20 (28.2%)	0 (0%)
Posterior fusion (n, %)	6 (8.5%)	3 (12%)
Total fusion (n, %)	45 (63.4%)	22 (88%)
Bifid scrotum (n, %)	23 (32.4%)	10 (40%)	0.657
Cord (n, %)	14 (19.7%)	17 (68%)	C;0.001
Presence of M&#FC;llerian structures (n, %)	29 (40.8%)	4 (16%)	0.045
Presence of gonads on ultrasound			0.008***
Absent (n, %)	3 (4.2%)	0 (0%)
Ovaries (n, %)	17 (23.9%)	0 (0%)
Testis (n, %)	50 (70.4%)	25 (100%)
Ovotestis (n, %)	1 (1.4%)	0 (0%)
Disgenetic (n, %)	-	-
Testosterone response a			0.379
Insufficient response (n, %)	14 (31.87%)	4 (18.2%)
Adequate response (n, %)	30 (68.2%)	18 (81.8%)
CGB: Sexual development disorder; LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; USG: Ultrasonography.
^aCases in which the testosterone response was not evaluated were excluded from this analysis.
*Isolated hypospadias was significantly more common in the ÉC;Idiopathic CGBÉD; group.
**Complete scrotal fusion was significantly more common in the ÉC;Genetic CGBÉD; group, while the absence of fusion was significantly more common in the ÉC;Idiopathic CGBÉD; group
***On ultrasound, the gonads were assessed as ovaries significantly more frequently in the ÉC;Genetic CGBÉD; group and as testes in the ÉC;Idiopathic CGBÉD; group.

Conclusions: CGB cases exhibit a broad clinical spectrum. Phenotypic evaluation, particularly the external genital score, may provide important clues regarding the likelihood of identifying a genetic etiology and help guide the diagnostic approach.

Endocrine Abstracts

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