NeoQuest February 2022: A Term Infant with Refractory Hypoglycemia and Jaundice

A term infant admitted to the NICU with refractory hypoglycemia and prolonged jaundice has an exam notable for a measured stretch penile length of 1 cm and bilateral undescended testes (Figure 1 [left]). Chromosomal analysis confirmed a 46,XY karyotype. A brain magnetic resonance imaging was obtained that showed 3 abnormal findings (Figure 2, A–C [right]).

Figure 1 (left). Physical examination findings of genital area. Image from: Singh N, Ankur K, Chetry S, et al. A case of persistent hypoglycemia with disorder of sex development. Neoreviews. 2022;23(2):e125–e127. doi: 10.1542/neo.23-2-e125¹

Figure 2 (right). Sagittal T1 brain magnetic resonance imaging findings (A–C). Image from: Cherella C, Cohen L. Neoreviews. 2018;19(12):e742–e752²

Which of the following diagnostic evaluations corroborates this infant’s underlying diagnosis?

1. Elevated 17-hydroxyprogesterone level
2. Increased serum testosterone-to-dihydrotestosterone ratio
3. Low cortisol, luteinizing hormone, follicle-stimulating hormone, and total testosterone levels
4. Normal-to-high testosterone and dihydrotestosterone levels in the setting of high anti-müllerian hormone

Answer: C. Low cortisol, luteinizing hormone, follicle-stimulating hormone, and total testosterone levels

Explanation: This infant is an undervirilized genotypic male presenting with symptoms of congenital hypopituitarism in the setting of A) an ectopic posterior pituitary, B) abnormal/absent pituitary stalk, and C) anterior pituitary hypoplasia confirmed on brain magnetic resonance imaging (MRI) (Figure 2, A–C). This constellation of findings is consistent with Pituitary Stalk Interruption Syndrome (PSIS). Although the pathogenesis is not clearly understood, the abnormal pituitary in PSIS is speculated to be an outcome of maldevelopment and/or perinatal ischemic/traumatic damage, resulting in midline defects (eg, cleft palate and mid-face hypoplasia) and anterior pituitary hormone deficiencies.^3–4

The anterior pituitary is responsible for the production and release of adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), growth hormone (GH), luteinizing hormone (LH), prolactin, and thyroid stimulating hormone (TSH), regulating one’s growth, metabolism, and reproduction. PSIS classically presents with either isolated GH deficiency or multiple pituitary hormone deficiencies, resulting in a large range of clinical signs and symptoms (Table 1).⁵ The most common neonatal presentation of PSIS includes refractory hypoglycemia, prolonged jaundice, cryptorchidism, and micropenis.⁵ In the setting of refractory hypoglycemia, a low cortisol level from a critical sample and a low serum ACTH would suggest central adrenal insufficiency. Prolonged jaundice is well associated with hypothyroidism as well as congenital hypopituitarism.² Additionally, low levels of LH, FSH, and total testosterone in a patient with bilateral cryptorchidism and micropenis are indicative of central hypogonadotropic hypogonadism and can further support the diagnosis of PSIS (Option C).^4,5 This diagnosis is confirmed based on the hallmark triad of MRI findings: A) absent or ectopic posterior pituitary, B) absent or thin pituitary stalk, and C) aplasia or hypoplasia of the anterior pituitary (Figure 3B, A–C).²

Table 1. Hormone abnormalities and resulting clinical signs associated with anterior pituitary deficiencies.⁵

Figure 3. A. T1 sagittal brain MRI scan of an infant with a normal pituitary gland (A and C) with intact pituitary stalk (B). B. T1 sagittal brain MRI scan of an infant with classic features of PSIS: A) ectopic posterior pituitary, B) abnormal/absent pituitary stalk, and C) anterior pituitary hypoplasia. Image from: Cherella C, Cohen L. Congenital hypopituitarism in neonates. Neoreviews. 2018;19(12): e742–e752.³

Like the abnormal pituitary in PSIS, enzyme defects involved in adrenal biosynthesis can also decrease male androgen production, resulting in ambiguous genitalia or a female phenotype in a 46,XY neonate. In the adrenal biosynthesis pathway (Figure 4), there are multiple enzymes involved in testosterone and dihydrotestosterone (DHT) synthesis that are required for normal male sexual differentiation.⁶ A deficiency in any one of these enzymes is generally characterized as a form of congenital adrenal hyperplasia (CAH) and can exhibit varying presentations associated with an excess and/or deficiency of adrenal hormones. Table 2 summarizes the different forms of CAH and their hallmark clinical, laboratory and genetic features. (7)  Specifically, enzymatic defects of 3-beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase/17,20 lyase, and 17-beta-hydroxysteroid dehydrogenase can present with failure of virilization of a 46,XY newborn. (7) A predominantly elevated 17-hydroxyprogesterone level is classically indicative of CAH due to 21-hydroxylase deficiency (Option A). In this common cause of CAH, the external genitalia are ambiguous and virilized in 46,XX individuals, whereas the external male genitalia are phenotypically normal in 46,XY.

Figure 4. Adrenal steroidogenesis pathways. Image from: McCann-Crosby, B. Ambiguous genitalia: evaluation and management in the newborn. Neoreviews. 2016;19(12):e742–e752.⁶

Table 2. Different forms of CAH and their hallmark features. 17-OHP, 17-hydroxyprogesterone; DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone; HCG, human chorionic gonadotropin; StAR, steroidogenic acute regulatory protein. Image from: Antal Z, Zhou P. Congenital adrenal hyperplasia: diagnosis, evaluation, and management. Pediatr Rev. 2009;30(7):e49–e57.⁸

Failure of virilization can also be seen in 5-alpha reductase deficiency in which testosterone does not convert into DHT, leading to an increased serum testosterone-to-DHT ratio (Option B).⁶ This distinguishing feature highlights the different roles that testosterone and DHT play in the development of male reproductive organs. Testosterone stimulates the development of the internal male genitalia (epididymis, vas deferens, and seminal vesicles), while DHT influences the development of external male genitalia.⁸ Without appropriate levels of DHT, the external male genitalia fail to virilize in utero despite high levels of testosterone, leading to ambiguous genitalia or a complete female phenotype.⁸

In comparison, androgen insensitivity syndrome results in defective androgen receptors due to a loss-of-function mutation in the AR gene on the X chromosome, leading to testosterone resistance and undervirilization of external genitalia. Unlike in 5-alpha reductase deficiency, the ability of the hypothalamic-pituitary-adrenal axis to produce appropriate gonadal steroids is intact, including normal production of testosterone and normal conversion to DHT.⁶ This is confirmed by normal-to-high testosterone and DHT levels and an elevated anti-müllerian hormone, a reliable marker that confirms the presence of testes and testicular function (Option D).⁶

Did you know?

• Individuals diagnosed with PSIS in the neonatal period tend to have a more severe phenotype (multiple pituitary deficiencies and absent anterior pituitary) compared to those diagnosed in childhood/adulthood.⁴
• Patients diagnosed with PSIS later in life during evaluation for growth restriction can have progressive endocrine hormone derangement over time, warranting close follow-up to screen for other hormone deficiencies.⁴

Prophylactic nephrectomy and gonadectomy are recommended in a 46,XY infant with undervirilization, electrolyte derangement, elevated serum creatinine, and significant proteinuria. What potential complications could these procedures help prevent?

To learn more about this and review other etiologies of ambiguous genitalia, read the following articles:

• Viehl L, Gaut J, Dandamudi R, Davis T. Case 3: ambiguous genitalia in a newborn. Neoreviews. 2018;19(8):e485–e489⁹
• Lee B, Strobel K, Chu A. The neonate with ambiguous genitalia. Neoreviews. 2021;22(4):e241–e249¹⁰

NeoQuest February Authors
Neena Jube-Desai, MD, MBA FAAP, University of Maryland
Shanmukha Mukthapuram, MD FAAP, University of Cincinnati College of Medicine

References:

1. Singh N, Ankur K, Chetry S, et al. A case of persistent hypoglycemia with disorder of sex development. Neoreviews. 2022;2(2):e125–e127
2. Cherella C, Cohen L. Congenital hypopituitarism in neonates. Neoreviews. 2018;19(12): e742–e752
3. Parks JS. Congenital hypopituitarism. Clin Perinatol. 2018;45(1):75–91
4. Bar C, Zadro C, Diene G, et al. Pituitary stalk interruption syndrome from infancy to adulthood: clinical, hormonal, and radiological assessment according to the initial presentation. PloS One. 2015;10(11):e0142354
5. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms.Eur J Endocrinol. 2011;164(4):457–465 
6. McCann-Crosby, B. Ambiguous genitalia: evaluation and management in the newborn. Neoreviews. 2016;19(12):e742–e752
7. Antal Z, Zhou P. Congenital adrenal hyperplasia: diagnosis, evaluation, and management. Pediatr Rev. 2009;30(7):e49–e57
8. Evaluation of the newborn with developmental anomalies of the external genitalia. American Academy of Pediatrics. Committee on Genetics.Pediatrics. 2000;106(1 Pt 1):138–142
9. Viehl L, Gaut J, Dandamudi R, Davis T. Case 3: ambiguous genitalia in a newborn. Neoreviews. 2018;19(8):e485–e489
10. Lee B, Strobel K, Chu A. The neonate with ambiguous genitalia. Neoreviews. 2021;22(4):e241–e249