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NeoQuest January 2023: Neonate with Hypoglycemia and Hyperbilirubinemia

January 11, 2023

A term male infant born by cesarean section is admitted to the NICU at 12 hours of age for a temperature of 36oC (96.8oF) and a point-of-care glucose level of <20 mg/dL. His birth weight is appropriate for gestational age. He is placed in an isolette, given a glucose bolus, started on intravenous glucose, and given antibiotics after a sepsis evaluation. At seven days of age, he continues to require intravenous glucose for hypoglycemia and multiple rounds of phototherapy for persistent indirect hyperbilirubinemia. His physical exam is reassuring, without any significant findings. He receives an extensive work-up, which includes non-contrast brain magnetic resonance imaging (MRI) (Figure 1A).

Which of the following genetic mutations is most consistent with this infant’s underlying diagnosis?


Figure 1A. Non-contrast brain MRI of the neonate in the vignette. Image adapted from: Balasundaram P, Lucena MH,  Nafday S. A neonate with a rare presentation of persistent hypoglycemia and prolonged jaundice. Neoreviews. 2023;24(1):e39–42. 10.1542/neo.24-1-e39

Which of the following genetic mutations is most consistent with this infant’s underlying diagnosis?

  1. ABCC8 mutation
  2. GH1gene mutation
  3. IGSF1 gene deficiency
  4. PROP1 mutation
  5. TBX19 mutation

 

Answer: D. PROP1 mutation

Explanation:

The infant in this vignette presents with hypothermia, persistent hypoglycemia, hyperbilirubinemia, and an abnormal brain MRI (Figure 1A), a constellation of findings that raise suspicion for multiple pituitary hormone deficiencies and a diagnosis of central hypopituitarism (CH).1–3 While the etiology of CH is unknown in the majority of cases, familial or sporadic congenital CH is most commonly due to mutations in PROP1 (Option D), a pituitary-specific transcription factor.3,4 CH in the neonatal period is characterized by one or more pituitary hormone deficiencies. The anterior pituitary, regulated by the hypothalamic neurosecretory system, has a central role in the secretion of six hormones (Figure 2).2,3 Brain MRI is the preferred modality for assessing pituitary abnormalities in patients with CH, which may include a hypoplastic pituitary gland with an ectopic posterior pituitary or an interrupted or hypoplastic pituitary stalk (Figures 1B and 3).4


Figure 1B: Non-contrast brain MRI of the neonate in the vignette reveals a hypoplastic anterior pituitary (yellow arrow), an ectopic posterior pituitary bright spot (blue arrow), and an absent infundibular stalk (white arrow). Image adapted from Balasundaram P, Lucena MH, Nafday S. A neonate with a rare presentation of persistent hypoglycemia and prolonged jaundice. Neoreviews. 2023;24(1):e39–42. 10.1542/neo.24-1-e39


Figure 2. Overview of organ targets for hypothalamic and anterior pituitary hormones. Abbreviations: ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotropin-releasing hormone; IGF = insulin-like growth factor; LH = luteinizing hormone; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine. Image adapted from: Bautista G. Overview of congenital hypopituitarism for the neonatologist. Neoreviews. 2022;23(5):e300–e310


Figure 3. Comparative neonatal brain MRIs demonstrating differences in pituitary anatomy. (A) Brain MRI of a healthy infant showing the normal anatomical presence of the anterior pituitary, pituitary stalk, and the posterior pituitary bright spot. (B) Brain MRI of an infant with congenital hypopituitarism showing a flattened anterior pituitary, an ectopic posterior pituitary bright spot, and an absent infundibulum. Image adapted from: Cherella CE, Cohen LE. Congenital hypopituitarism in neonates. Neoreviews. 2018;19(12):e742–e752

Growth hormone (GH) and adrenocorticotropic hormone (ACTH) from the anterior pituitary stabilize glucose and stimulate the release of free fatty acids during stress and fasting states.2,3 In patients with CH, low levels of GH and ACTH can cause persistent hypoglycemia with ketosis, though CH in the neonatal period often presents with hypoketotic hypoglycemia with inappropriately increased insulin levels.1,2,5 As fetal growth is independent of GH, neonates with CH are typically of normal size at birth, such as the infant in this vignette.1,4 The deficiency of ACTH can cause secondary adrenal insufficiency, which can present with hyponatremia without hypokalemia due to mild cortisol insufficiency.2 Thyroid stimulating hormone (TSH) deficiency can result in secondary hypothyroidism, which presents with low thyroxine (T4) and TSH levels.2 Hyperbilirubinemia in patients with CH can be due to GH deficiency, hypothyroidism, or adrenal insufficiency, resulting in impaired bilirubin conjugation, cholestasis, and prolonged indirect hyperbilirubinemia.1,6  In CH, gonadotropin deficiency in males can present as micropenis, with or without undescended testes, due to luteinizing hormone deficiency. Females with gonadotropin deficiency are often asymptomatic at birth.1,2

Neonates with hyperinsulinemia, hypoketosis, and hypoglycemia should raise suspicion for congenital hyperinsulinism, most commonly caused by mutations in the ABCC8 (Option A) and KCNJ11 genes, which encode KATP channels.7 Clinical findings indicative of congenital hyperinsulinism include a high glucose infusion requirement, a detectable insulin level higher than anticipated for the glucose level, increased C-peptide levels, low free fatty acid levels, low serum ketone levels, and absence of ketonuria.7 Persistent hyperbilirubinemia and abnormal brain MRI findings are not commonly associated with congenital hyperinsulinism.7

Congenital hypopituitarism can be associated with isolated central pituitary hormone deficiency, the most common being isolated GH deficiency (IGHD). IGHD has four different types of genetic forms. Type 1A is associated with GH1 gene mutation (Option B), which is characterized by complete absence of GH.4 Male neonates typically present with hypoglycemia and/or micropenis.2,4 Hypothermia, as seen in this patient, is typically not associated with GH deficiency. Thus, the presence of hypothermia raises the concern for multiple central pituitary hormone deficiencies.

Immunoglobulin superfamily member 1 (IGSF1) gene mutations (Option C) are associated with isolated central congenital hypothyroidism.4 Hypothermia and prolonged indirect hyperbilirubinemia in the newborn period are often suggestive of central hypothyroidism, characterized by low T4 and inappropriately low-to-normal TSH levels with normal levels of other pituitary hormones.2,8 Infants with isolated central hypothyroidism may have abnormal physical exam findings, including macroglossia, coarse facies, a wide anterior fontanelle, a persistent posterior fontanelle, an umbilical hernia, and an abnormal neurologic exam, including hypotonia and delayed deep tendon reflexes,2,8 characteristics which were not observed in the neonate in this vignette. In addition, hypoglycemia in central hypothyroidism, if present, is more likely to occur with combined pituitary hormone deficiencies, most commonly due to ACTH or GH deficiencies.8

Isolated ACTH deficiency, associated with TBX19 mutations (Option E), is a rare cause of severe hypoglycemia, prolonged jaundice, and adrenal insufficiency.4 Infants with isolated ACTH deficiency demonstrate low ACTH and cortisol levels, normal levels of other pituitary hormones, and a normal brain MRI, which was not observed in the infant in this case.9

Did you know?

  • In neonates with congenital isolated TSH deficiency, it is important to first assess for the presence of central adrenal insufficiency, as thyroid hormone replacement can enhance cortisol clearance and precipitate adrenal crisis.2

What is the differential diagnosis for a newborn with persistent hypoglycemia? For a comprehensive overview of the causes of transient and persistent hypoglycemia in the neonatal period, refer to Table 1 in: Tas E, et al. Glucose homeostasis in newborns: an endocrinology perspective. Neoreviews. 2020;21(1):e14-e2910

What are the most common embryologic mutations associated with congenital hypopituitarism?

For an overview of clinical presentations of pituitary hormone deficits associated with select gene mutations, refer to the Table in: Bautista G. Overview of congenital hypopituitarism for the neonatologist. Neoreviews. 2022;23(5):e300–e310 2

NeoQuest January Authors
Srirupa Hari Gopal, MBBS, Baylor College of Medicine
Lila S. Nolan, MD, Washington University School of Medicine

References:

  1. Balasundaram P, Lucena MH, Nafday S. A neonate with a rare presentation of persistent hypoglycemia and prolonged jaundice. Neoreviews. 2023;24(1):e39–42. 10.1542/neo.24-1-e39
  2. Bautista G. Overview of congenital hypopituitarism for the neonatologistNeoreviews. 2022;23(5):e300–e310
  3. Ara LBI, Katugampola H, Dattani MT. Congenital hypopituitarism during the neonatal period: epidemiology, pathogenesis, therapeutic options, and outcome. Front Pediatr. 2021;8:600962
  4. Cherella CE, Cohen LE. Congenital hypopituitarism in neonates. Neoreviews. 2018;19(12):e742–e752
  5. Gandhi K. Approach to hypoglycemia in infants and children. Transl Pediatr. 2017;6(4):408–420
  6. Bhattacharya D, Kumar R, Dayal D. Prolonged neonatal hyperbilirubinaemia in a case of congenital hypopituitarism. BMJ Case Rep. 2019;12(2):e228793
  7. Sims K. Congenital hyperinsulinism. Neoreviews. 2021;22(4):e230–e240
  8. Weiner A, Oberfield S, Vuguin P. The laboratory features of congenital hypothyroidism and approach to therapy. Neoreviews. 2020;21(1):e37–e44
  9. Kardelen Al AD, Poyrazoğlu Ş, Aslanger A, et al. A rare cause of adrenal insufficiency - isolated ACTH deficiency due to TBX19 mutation: long-term follow-up of two cases and review of the literature. Horm Res Paediatr. 2019;92(6):395–403
  10. Tas E, Garibaldi L, Muzumdar R. Glucose homeostasis in newborns: an endocrinology perspective. Neoreviews. 2020;21(1):e14–e29
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