[Causes of ambiguous external genitalia in neonates].Srp Arh Celok Lek. 2001 Mar-Apr; 129(3-4):57-60.SA
The classification of disorders such as ambiguous genitalia in newborns is difficult because similar or identical phenotypes could have several different aetiologies. In most cases it was impossible to correlate the aetiology of the disorder and the appearance of the external genitalia [1-3]. A newborn with ambiguous genitalia needs prompt evaluation that will permit gender assignment and detection of life-threatening conditions (salt-losing crisis due to congenital adrenal hyperplasia or Wilms' tumour). We studied the causes and characteristics of ambiguous genitalia in newborn infants over the period from 1990 to 1999.
PATIENTS AND METHODS
The following genital phenotypes are considered as ambiguous: 1. Hypospadias with no palpable gonads; 2. Hypospadias with micropenis and no palpable gonads or one palpable gonad; 3. Newborn with female external genitalia and a gonadal mass in labia or labial fusion and/or clitoral enlargement [1, 4]. The diagnostic evaluation of newborns with ambiguous genitalia consisted of history and physical examination, determination of serum electrolytes, plasma 17-hydroxyprogesterone (17-OHP), chromosome analysis on cultured lymphocytes, sonogram of the abdomen in connection with a genitogram; and whenever it was necessary, basal plasma concentrations of testosterone and, after the stimulation with human chorionic gonadotropin (hCG), laparotomy for definitive determination of gonadal histology. All disorders with ambiguous genitalia have been classified in four groups: : 1. Female pseudohermaphroditism (FPH); 2. Male pseudoherma phroditism (MPH); 3. True hermaphroditism (TH); 4. Asymmetrical gonadal dysgenesis (ASGD).
The causes of sexual differentiation disorders in a group of 38 newborns with ambiguous genitalia are presented in Table 1. Main criteria for the diagnosis of FPH were normal female karyotype 46, XX, masculinization of external genitalia and no palpable gonads. Genitography revealed urogenital sinus and vagina, and ultrasound examination the uterus. During initial examination seven of 15 newborns with congenital adrenal hyperplasia (CAH) (Table 2) due to 21-hydroxylase (P450c21) deficiency (21-OHD) had clinical or laboratory signs of adrenal crisis. Two children had a simple virilizing form of 21-OHD. The female gender was chosen for these children. In other three patients with FPH isolated clitoral hyperplasia or labial fusion was the main reason for the studies. The common characteristics of newborns with MPH were as follows: normal male karyotype 46,XY with normally developed or dysgenetic testes, and/or good response to hCG stimulation. The complete androgen insensitivity (testicular feminization) was detected in two children (Table 3) with female external genitalia and palpable gonads in the labial folds, and female gender was chosen. The Denys-Drash syndrome was detected in one newborn with ambiguous genitalia, no palpable gonads, and normal response to hCG, and ultrasound findings of multiple bilateral renal tumours were identified as Wilms' tumour. In other newborns with MPH incomplete masculinization consisted of hypospadias, mostly of perineoscrotal type and of micropenis (penile size less than 2 cm) and/or bilateral or unilateral cryptorchidism (Table 3). In all children male sex was chosen. Asymmetrical gonadal dysgenesis was detected in two newborn infants. Both children had 46,XY/46,XX karyotype, testes on one side of the abdomen, and streak gonad on the other, developed vagina, uterus and unilateral Fallopian tube, and were raised as females. True hermaphroditism was established in one newborn with 46,XX karyotype, with a testis on one side of the abdomen and an ovotestis on the other side. The parents decided for male gender. The aetiology of ambiguous genitalia was not established in five children; in two children with 46,XY and one with 46,XX karyotype (with palpable gonads) the diagnostic study was not completed.
The most common cause of ambiguous genitalia in our newborn patients was CAH due to 21-OH deficiency [2, 4, 6, 7]; 87 percent of patients had salt wasting form of the disease. In the majority of patients the appearance of the external genitalia made possible the detection of the disease immediately after the birth. So, the relative high incidence of adrenal crisis in our patients with CAH (38%) seems unreasonable. The decision for gender assignment was possible after the appropriate study of the nature of the disorder. The causes of MPH are numerous and heterogeneous [1, 3, 8]. With the exception of two patients with complete form of androgen insensitivity, in all newborns with MPH the male gender predominated. The appearance of external genitalia with severe perineoscrotal hypospadia and/or micropenis suggested the possibility of incomplete androgen resistance. If a male assignment is being considered, the response of the phallic size to treatment with testosterone was recommended. If penile size did not reach the 2.5 cm range or above, a male sex assignment was not advisable . It is important for the paediatric surgeon to be involved in the diagnostic evaluation of these infants to plan the timing and techniques of the surgical reconstruction . The decision to raise a patient with sex chromosome mosaicism, true hermaphroditism, or mixed gonadal dysgenesis as either a male or a female was based on the appearance of the external genitalia and possible fertility [1, 9]. The parental decision of male sex in our patients with true hermaphroditism could not be considered as optimal.