Case 2: A premature infant with ambiguous genitalia

An infant born at 30 weeks' gestation to a 39-year-old G2P0A1 mother presented with ambiguous genitalia. The infant's mother was a smoker, but was otherwise healthy. She was not on any medication and had received routine prenatal care. A maternal serum screen predicted low risk for Down syndrome and spina bifida. Amniocentesis for advanced maternal age demonstrated a 46XY fetus. Ultrasounds during the pregnancy demonstrated severe intrauterine growth restriction (IUGR), decreased amniotic fluid and abnormal genitalia. Birth weight was 630 g, length was 30.7 cm and head circumference was 24 cm (all <<3rd percentile). Physical examination revealed a wasted infant with severe hypospadias and micropenis. The penile length was 7 mm, more than 2 SD below the mean for 30 weeks' gestation (–2 SD = 17mm). The testicles were palpable within both inguinal canals. The baby did not exhibit dysmorphic features. The patient's electrolytes and glucose levels were normal. Testosterone (T) and dihydrotestosterone (DHT) levels, measured two days after birth, were both normal for the infant's age. An ultrasound showed no evidence of female reproductive organs. Further diagnostic tests at two months of age suggested a probable diagnosis. Disorders of sex development are defined as atypical development of chromosomal, gonadal or anatomical sex, and are addressed in the recent consensus guidelines published in Pediatrics (1). The differential diagnosis for ambiguous genitalia is extensive. Categorization of patients based on karyotype is helpful in determining the cause, but is often not available at birth. Possibilities include an XX infant with virilization, an XY infant with undervirilization or sex chromosome mosaicism with mixed gonadal dysgenesis. In practice, an infant with an unknown karyotype and ambiguous genitalia should have their electrolytes monitored and their 17-alpha-hydroxyprogesterone level measured to rule out classical congenital adrenal hyperplasia (CAH). In most cases, CAH is caused by a deficiency in 21-hydroxylase resulting in adrenal insufficiency, with or without salt wasting, and ambiguous genitalia in XX infants. This would not apply to our case of an XY infant with bilateral palpable gonads, hypospadias and micropenis, which is consistent with an undervirilized male. However, very rare forms of CAH, such as 3-beta-hydroxysteroid dehydrogenase deficiency, may result in the undervirilization of an XY infant and a salt-wasting crisis, due to inadequate synthesis of testosterone, cortisol and aldosterone. Male sexual development requires an XY chromosome complement, normal testicular development and function, and normal response to androgen. The SRY gene located on the Y chromosome triggers the differentiation of gonads into testes. Placental chorionic gonadotropin stimulates fetal Leydig cells to secrete T. T is converted to DHT by 5-alpha reductase in peripheral tissue and is critical for the development of male external genitalia. Immediately following birth, the level of luteinizing hormone (LH) rises, resulting in an elevation of T in male infants; there is a window from 12 h to 48 h of life to obtain T levels. Following this short window, there is another physiological postnatal surge of gonadotropins and sex steroids. In males, this ‘mini-puberty’ typically peaks between one and two months and wanes by six months to prepubertal levels. Measuring gonadotropins, T and DHT during this narrow window is often critical in determining the cause of undervirilization. Normal levels of mullerian inhibiting substance (MIS) indicate the presence of testes. Abnormal testicular development may cause undervirilization. A number of transcription factors are important in testicular development, as well as steroid hormone production in the gonads and adrenal glands. Deficiency of steroidogenic factor-1 or duplication of DAX-1 in males may cause ambiguous or female genitalia and adrenal insufficiency. Mutations in the Wilm's tumour gene may lead to syndromes with ambiguous genitalia. Abnormal androgen synthesis may be caused by enzyme defects in the steroidogenic pathway or may be a result of resistance to LH. Both enzymatic defects and LH resistance result in low levels of T and elevated LH, due to lack of feedback inhibition. 5-alpha-reductase deficiency is an autosomal recessive disorder resulting in impaired synthesis of DHT from T, resulting in a markedly elevated T:DHT ratio. Reduced T production may also be of central origin due to either a lack of hypothalamic gonadotropin-releasing hormone, as in Kallman's syndrome, mutations in genes for the gonadotrope subunits or related to congenital hypopituitarism. These central disorders may be associated with midline defects such as septo-optic dysplasia. Androgen resistance is associated with elevated androgen levels. Complete androgen insensitivity results in female external genitalia in an XY infant, whereas partial androgen insensitivity results in undervirilization. Recently, concerns have been raised that endocrine disruptor chemicals may interfere with normal virilization, but the evidence is not conclusive. If testicular tissue is present on examination or imaging and MIS levels are normal, a human chorionic gonadotropin stimulation test can be performed to differentiate infants with disorders of androgen synthesis from those with abnormal response to androgen. Finally, in approximately one-half of undervirilized males there is no specific diagnosis made. These infants have been found to have lower birth weights compared with undervirilized males with an identifiable cause (2,3). Hypospadias is also associated with IUGR (4). Table 1 provides a brief summary of an approach for the evaluation of an undervirilized XY infant. In our case, the infant had palpable testes and normal MIS, indicating the presence of testicular tissue. Fluorescence in situ hybridization for the SRY gene was normal. T, DHT, gonadotropin and electrolyte levels were normal, indicating normal quantity and quality of androgen production. At two months chronological age, LH, follicle-stimulating hormone, and T were normal. Normal levels of growth and thyroid hormones and absence of hypoglycaemia provided further evidence for normal pituitary function. Given the normal gonadotropins and T:DHT ratio, androgen insensitivity was unlikely. The most likely diagnosis was micropenis associated with IUGR – a diagnosis of exclusion. As the infant grew, his penis almost tripled in length (2 cm), but remained more than two SD below the mean. He was treated with four monthly injections of T enanthate 25 mg, both for the micropenis and to facilitate easier hypospadias repair. This therapy resulted in fair response (penile length 2.4 cm). The cause of micropenis/hypospadias associated with IUGR is not known. Placental factors and the possibility of a role for endocrine disruptor chemicals have been postulated. Further surveillance of this patient into puberty will be important to monitor growth and genital development. Approach to evaluation of an undervirilized XY infant Assess for palpable testes Karyotype: normal testicular development is dependent on normal XY chromosomes Fluorescence in situ hybridization for SRY gene: SRY triggers testicular differentiation MIS: Normal levels of MIS indicate presence of testes Secondary to abnormal enzyme activity in steroidogenic pathway or LH resistance Testosterone: low and responds poorly to stimulation LH: levels are elevated due to lack of feedback T:DHT ratio: elevated in setting of 5-alpha reductase deficiency Electrolytes and glucose: to assess for aldosterone/cortisol insufficiency Central: lack of hypothalamic GnRH, mutations in LH/FSH genes or congenital hypopituitarism LH: low Evaluate pituitary function: Glucose, cortisol, growth hormone and thyroid hormone: evaluate Basal androgen levels: normal or elevated hCG stimulation test: differentiates between disorders of androgen synthesis and abnormal response to androgen If the above evaluation does not yield a diagnosis consider an association with IUGR, a diagnosis of exclusion Follow-up with growth and genital development Assess for palpable testes Karyotype: normal testicular development is dependent on normal XY chromosomes Fluorescence in situ hybridization for SRY gene: SRY triggers testicular differentiation MIS: Normal levels of MIS indicate presence of testes Secondary to abnormal enzyme activity in steroidogenic pathway or LH resistance Testosterone: low and responds poorly to stimulation LH: levels are elevated due to lack of feedback T:DHT ratio: elevated in setting of 5-alpha reductase deficiency Electrolytes and glucose: to assess for aldosterone/cortisol insufficiency Central: lack of hypothalamic GnRH, mutations in LH/FSH genes or congenital hypopituitarism LH: low Evaluate pituitary function: Glucose, cortisol, growth hormone and thyroid hormone: evaluate Basal androgen levels: normal or elevated hCG stimulation test: differentiates between disorders of androgen synthesis and abnormal response to androgen If the above evaluation does not yield a diagnosis consider an association with IUGR, a diagnosis of exclusion Follow-up with growth and genital development FSH Follicle-stimulating hormone; GnRH Gonadotropin-releasing hormone; hCG human chorionic gonadotropin; IUGR Intrauterine growth restrictions; LH Luteinizing hormone; MIS Mullerian inhibiting substance; T:DHT Testosterone:Dihydrotestosterone Approach to evaluation of an undervirilized XY infant Assess for palpable testes Karyotype: normal testicular development is dependent on normal XY chromosomes Fluorescence in situ hybridization for SRY gene: SRY triggers testicular differentiation MIS: Normal levels of MIS indicate presence of testes Secondary to abnormal enzyme activity in steroidogenic pathway or LH resistance Testosterone: low and responds poorly to stimulation LH: levels are elevated due to lack of feedback T:DHT ratio: elevated in setting of 5-alpha reductase deficiency Electrolytes and glucose: to assess for aldosterone/cortisol insufficiency Central: lack of hypothalamic GnRH, mutations in LH/FSH genes or congenital hypopituitarism LH: low Evaluate pituitary function: Glucose, cortisol, growth hormone and thyroid hormone: evaluate Basal androgen levels: normal or elevated hCG stimulation test: differentiates between disorders of androgen synthesis and abnormal response to androgen If the above evaluation does not yield a diagnosis consider an association with IUGR, a diagnosis of exclusion Follow-up with growth and genital development Assess for palpable testes Karyotype: normal testicular development is dependent on normal XY chromosomes Fluorescence in situ hybridization for SRY gene: SRY triggers testicular differentiation MIS: Normal levels of MIS indicate presence of testes Secondary to abnormal enzyme activity in steroidogenic pathway or LH resistance Testosterone: low and responds poorly to stimulation LH: levels are elevated due to lack of feedback T:DHT ratio: elevated in setting of 5-alpha reductase deficiency Electrolytes and glucose: to assess for aldosterone/cortisol insufficiency Central: lack of hypothalamic GnRH, mutations in LH/FSH genes or congenital hypopituitarism LH: low Evaluate pituitary function: Glucose, cortisol, growth hormone and thyroid hormone: evaluate Basal androgen levels: normal or elevated hCG stimulation test: differentiates between disorders of androgen synthesis and abnormal response to androgen If the above evaluation does not yield a diagnosis consider an association with IUGR, a diagnosis of exclusion Follow-up with growth and genital development FSH Follicle-stimulating hormone; GnRH Gonadotropin-releasing hormone; hCG human chorionic gonadotropin; IUGR Intrauterine growth restrictions; LH Luteinizing hormone; MIS Mullerian inhibiting substance; T:DHT Testosterone:Dihydrotestosterone Karyotyping can help classify infants with ambiguous genitalia into one of three categories: XY infants with undervirilization, XX infant with virilization or an infant with sex chromosome mosaicism Undervirilized XY infants should undergo investigations to assess for abnormal testicular tissue, abnormal androgen synthesis and abnormal response to androgens (androgen insensitivity) Postnatal surges of gonadotropins and sex steroids occur at one to two months, and wane by six months to the low levels of a prepubertal child; therefore, adequate assessment requires measurement during this narrow window IUGR-associated micropenis is a diagnosis of exclusion

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.