Endocrinology




Disorders of Sex Differentiation (DSD)



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Definition




  • Congenital conditions in which there is discordance between anatomic sex, hormonal sex, and the sex chromosomes.




Pathophysiology



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Virilization of Females


(Female Pseudohermaphroditism)



  • Most commonly: enzymatic deficiencies in cortisol pathway → excessive ACTH, leading to congenital adrenal hyperplasia and excess androgen production
  • Most common is 21-hydroxylase deficiency
  • Other causes include virilizing tumors and maternal use of androgens (systemic or topical)

Inadequate Male Virilization


(Male Pseudohermaphroditism)


Three possible etiologies:



  • Decreased androgen production (nonvirilizing adrenal hyperplasia, inadequate Müllerian inhibiting substance)
  • Decreased end-organ response to androgen (testicular feminization—due to abnormal receptor)
  • 5α-reductase deficiency

Abnormal Gonadal Differentiation



  • True hermaphroditism (both testicular and ovarian tissue present in one individual)
  • Gonadal dysgenesis: partial (with one functional gonad, one streak) or total (two streak gonads; chance of neoplastic transformation high in Y-chromosome form)

Chromosomal Abnormalities or Associations



  • Trisomies 13 and 18
  • Triploidies
  • Smith–Lemli–Opitz syndrome
  • Rieger’s syndrome
  • CHARGE association
  • VACTERL association




Clinical Presentations




  • Overt genital ambiguity
  • Apparent female genitalia with an enlarged clitoris, posterior labial fusion, or an inguinal/ labial mass
  • Apparent male genitalia with bilateral descended testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testes
  • Family history of DSD, such as CAIS (Complete Androgen Insensitivity Syndrome)
  • Discordance between genital appearance and a prenatal karyotype




Diagnostic Evaluation




  • Karyotyping with X- and Y-specific probe
  • Abdominal US
  • Measurement of the following hormones:

    • 17-hydroxyprogesterone
    • Testosterone
    • Gonadotropin
    • Anti-Müllerian hormone

  • Serum electrolytes
  • Urinalysis




Adrenal and Pitutary Insufficiency in Neonates



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Primary Adrenal Insufficiency



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Inherited Causes Acquired Causes

Adrenocortical Dysgenesis


Impaired Steroid Responsiveness


Disorders of Steroid Biosynthesis



  • Caused by mutations in DAX1 and SF1 genes
  • These genes encode a nuclear transcription factor expressed in both gonads and the adrenal cortex
  • Results in deficiency of all adrenal steroids

Pseudohypoaldosteronism:



  • Mutation of aldosterone receptor gene or of epithelial sodium channel genes
  • Clinical presentation with salt wasting, hyperkalemia, shock, dehydration

Familial unresponsiveness to ACTH:



  • Results in normal mineralocorticoid activity, with diminished glucocorticoid activity
  • Clinical presentation with profound hypoglycemia and hypotension

StAR (acute steroid regulatory protein) deficiency:



  • Mediates transfer of cholesterol across mitochondrial membrane
  • Adrenals are large and lipid laden
  • Decreased levels of all adrenal steroids
  • 46 XY males appear female or only minimally virilized

3-β-Hydroxysteroid dehydrogenase deficiency:



  • Catalyzes the conversion of pregnenolone, 17-OH-pregnenolone, DHEA, and androstenedione
  • Clinical manifestations:

    • Salt-wasting adrenal crisis
    • 46, XX female may be mildly virilized
    • 46, XY male is undervirilized
    • Elevated substrates: DHEA and 17-OH-pregnenolone
    • Elevated 17-OH-progesterone

21-Hydroxylase deficiency:



  • Most common cause of CAH
  • Classic salt-wasting CAH:

    • Adrenal crisis with shock, hyperkalemia, and hyponatremia
    • Polyuria
    • Presentation at 1–4 wk of life
    • 46, XX infants are virilized

Exogenous glucocorticoid administration:



  • Infants receiving high-dose glucocorticoids for >10–14 d are at high risk
  • May require hydrocortisone for unexplained hypotension or hypoglycemia or in preparation for surgery

Bilateral adrenal hemorrhage:



  • Can be seen in LGA infants with difficult delivery/coagulopathy
  • Asymptomatic infants can have suprarenal calcifications on plain film of abdomen


  • 46, XY infants have large phallus and hyperpigmented scrotum
  • Markedly elevated levels of 17-OH-progesterone

Aldosterone synthase deficiency:



  • Rare condition
  • Hyponatremia and hyperkalemia




Diagnosis of Adrenal Insufficiency




  • ACTH or glucagon stimulation

    • Cortisol concentration should exceed 15–20 mcg/dL (413.8–551.8 nmol/L) 1 h after IV administration of cosyntropin (ACTH) 100 mcg/m2 or 2–3 h after IV administration of glucagon 50 mcg/kg

  • Markedly elevated enzyme substrates

    • DHEA and 17-hydroxypregnenolone concentrations in 3-β-hydroxysteroid dehydrogenase deficiency
    • 17-Hydroxyprogesterone in 21-hydroxylase deficiency

  • All C19 and C21 steroids are low in StAR deficiency




Treatment of Acute Adrenal Insufficiency




  • IV glucose and normal saline for hypoglycemia and hypotension, respectively
  • IV hydrocortisone 50 mg/m2 to be given immediately, followed by maintenance dose of 50–100 mg/m2/day in four to six divided doses or by continuous infusion
  • Oral fludrocortisone 0.05–0.1 mg once daily for hyperkalemia or salt-wasting




Secondary Adrenal Insufficiency



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Etiologies


Clinical Presentation


Diagnosis


Treatment



  • Secondary to single gene mutations
  • Malformations or injury to the sella turcica or hypothalamus


  • Unexplained hypoglycemia after 4–5 postnatal days of age
  • Unexplained hypotension
  • Findings associated with hypopituitarism:

    • Lack of onset or abnormal progression of labor
    • Midline craniofacial or CNS deficit
    • Nystagmus, optic nerve hypoplasia, and other ocular abnormalities
    • Hypoplastic genitalia in boys
    • Prolonged jaundice; elevated hepatic transaminases


  • Random growth hormone is <5 ng/mL (nl is 8–15 ng/mL)
  • Low random and stimulated cortisol levels
  • Low random free T4 and TSH levels


  • Fluid resuscitation in acutely hypotensive infant
  • Hydrocortisone 50–100 mg/m2 IV as a single dose, then to 10 mg/m2/day in three divided doses daily
  • Growth hormone at 40 mcg/kg/day SQ once daily
  • Oral levothyroxine 15 mcg/kg/day


  • Hypernatremia, polyuria
  • Low TT4 and inappropriately normal TSH values on newborn screen
  • MRI findings: ectopic posterior pituitary “bright spot,” small anterior pituitary, and attenuated or interrupted pituitary stalk




Congenital Hypothyroidism



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Incidence




  • 1:3000–4000 of newborn infants (one of the most common potentially preventable causes of mental retardation)
  • 2:1 female:male ratio
  • Higher in Hispanic and Asian populations; lower in African-American population




Thyrogenesis




  • The fetus is entirely dependent on maternal thyroid hormone during the first half of pregnancy; hence, thyroid status of the mother greatly influences fetal thyroid status. Thyroid hormone is transferred to the fetus via the placenta. At term, fetal hypothalamic-pituitary axis reaches maturity.




Etiology



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Classification


Pathophysiology


Examples


Primary hypothyroidism


Defective development of thyroid gland (most common cause of hypothyroidism)


 


 


 


Dyshormonogenesis


Agenesis


Dysgenesis



  • Thyroid remnant in normal location (hypoplasia)
  • Maldescent or ectopic thyroid gland (ectopia)

Iodide-trapping defect


Iodide organification (oxidation) defect



  • Can occur with deafness (Pendred’s syndrome) or without deafness

Coupling defect of iodotyrosines


Deiodinization defect



  • Generalized or limited to thyroid gland and/or peripheral tissues

Thyroglobulin synthetic defects


Goiter with calcification


Peripheral tissue resistance to thyroid hormone


Unresponsiveness of thyroid to TSH


Goitrous cretinism caused by maternal ingestion of goitrogens


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


Iodine deficiency


Chemicals:



  • Sulfonamide antibiotics
  • Propylthiouracil
  • Iopanoic acid (contrast medium)

Foods:



  • Soybeans
  • Pine nuts
  • Peanuts
  • Millet
  • Strawberries
  • Pears
  • Peaches
  • Vegetables in the
  • genus Brassica
  • Spinach
  • Spinach
  • Bamboo shoots
  • Radishes
  • Horseradish

Endemic goiter


Central hypothyroidism (defects in either TSH or TRH production or response)


Genetic mutation


Isolated deficiency of TSH β subunit


Multiple pituitary hormone deficiencies


Midline congenital defects


Septo-optic dysplasia


Holoprosencephaly


Cleft lip/palate


Central single incisor


Acquired CNS injury


Hemorrhage


Hydrocephalus


Meningitis


Trauma


Nonaccidental injury





Clinical Features (May Not be Present at Birth)



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  • Periorbital edema


  • Mottled skin


  • Poor/hoarse cry


  • Lethargy


  • Feeding difficulty


  • Constipation


  • Inactivity


  • Pallor


  • Hypothermia


  • Hypotonia


  • Prolonged icterus


  • Respiratory distress


  • Large anterior/posterior fontanelles


  • Perioral cyanosis




Screening Methods for Congenital Hypothyroidism



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Method


Limitations


Combined primary TSH and T4 measurements



  • Ideal screening approach

Primary TSH with backup T4 measurement



  • May not detect delayed TSH elevation in infants with TBG deficiency, central hypothyroidism, and hypothyroxinemia
  • Delayed TSH elevation common among LBW and VLBW neonates

Primary T4 with backup TSH measurement



  • Detects primary hypothyroidism and infants with TBG deficiency and central hypothyroidism
  • May miss infants with delayed TSH elevation with initial normal T4




The Specimen




  • Ideally obtained 48 h–4 d of age

    • Specimen collected in the first 24–48 h may lead to false-positive TSH elevations when using any of the screening methods
    • False-negative results may occur in critically ill newborns or after transfusions




Laboratory Studies



Low T4 and Elevated TSH




  • Low T4 with TSH >40 mU/L

    • Primary hypothyroidism

  • Low T4 with elevated TSH but <40 mU/L

    • Obtain a second newborn screen
    • 10% of infants with congenital hypothyroidism have TSH values of 20-40 mU/L 20 and 40 mU/L
    • Reference range between 2 and 6 wk of age is 1.7–9.1 mU/L



Normal T4 and Elevated TSH




  • Persistent basal TSH >10 mU/L (after 2 wk of life)

    • Abnormal

  • TSH level between 6–10 mU/L that persists after the first month of life

    • Treatment is controversial



Low T4 and Normal TSH




  • Low T4 is defined as 2 SD below the mean (10 μg/dL in newborns)

    • Hypothalamic immaturity

      • Preterm infants

    • Primary hypothyroidism and delayed elevation of TSH

      • During illness: Dopamine infusion and administration of high-dose glucocorticoids may result in inhibition of TSH and therefore low T4
      • Preterm infants

    • TBG deficiency
    • Central hypothyroidism



Low T4 and Delayed TSH Increase




  • Seen mostly in LBW, VLBW, or critically ill infants

    • Obtain second newborn screen at 2–6 wk of life or
    • Obtain serum sample for any infant with two successive T4 values below the third percentile



Transient TSH Elevation




  • Confirmatory test result in normal T4 and TSH

    • Intrauterine exposure to maternal antithyroid drugs
    • Maternal thyroid receptor antibodies
    • Heterozygous thyroid oxidase 2 deficiency
    • Germline mutation in the TSH-receptor
    • Endemic iodine deficiency
    • Prenatal or postnatal exposure to excess iodides




Management




  • L-thyroxine should be initiated as soon as hypothyroidism is confirmed.

    • Initial dosage is 10–15 μg/kg.
    • Goal of therapy is to normalize T4 within 2 wk and TSH within 1 mo.
    • Only T4 tablets should be used.
    • Avoid concomitant administration of soy, iron, or fiber.
    • T4 value is used to titrate dose.

      • Serum T4 and TSH are measured at 2 and 4 wk after treatment
      • Every 1–6 mo during the first 6 mo
      • Every 3–4 mo between 6 mo and 3 yr
      • Every 6–12 mo until growth is completed
      • At more frequent intervals if:

        • Compliance is an issue
        • Abnormal values
        • Dose has been changed
        • Source of medication has been changed

      • Optional diagnostic studies

        • Thyroid US
        • Iodine-123 thyroid uptake
        • Sodium technetium-99m pertechnetate thyroid uptake




Hypothyroxinemia and Prematurity



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Embryology




  • Thyroid gland is the first endocrine gland to develop at 3–4 wk gestation.

    • Thyroglobulin synthesis starts from the first month of gestation.
    • Iodine trapping by 8–10 wk of gestation.

      • Iodine is transferred from the mother to the fetus via the placenta.

    • T3 and T4 synthesis and secretion by 12 wk of gestation.

      • Fetal T4 rise from 2 mcg/dL at 12 wk to 10 mcg/dL at term.
      • Free T4 values parallel total T4 values.

        • 0.1 ng/dL at 12 wk to 1.5 ng/dL at term.
        • Upsurge is secondary to TSH secretion and the thyroid gland’s developing responsiveness to TSH.

          • Cord blood concentration of TSH and T4 are directly proportional to gestational age.

  • Hypothalamic–pituitary–thyroid axis.

    • Develops in the first trimester.
    • Maturation occurs during the second half of gestation.
    • Negative feedback is underdeveloped until 1–2 mo postnatal life.

      • Hypothalamic neurons generate TRH by 6–8 wk.
      • Pituitary portal vessel by 8–10 wk.
      • TSH is secreted by 12 wk.

        • TSH concentration increases to 15 mU/mL between 18 and 28 wk gestation.
        • Near term, the concentration decreases to 10 mU/mL.




Thyroid Function at Birth



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TSH Surge in First 24 h (reflecting acclimation to cold environment)


TSH Level after First Postnatal Week


TT4 Rise in First 24–36 h of Life


FT4 Rise in First 24–36 h of Life


Term infant


80 mU/L


<10 mU/L


17 mcg/dL


3.5 ng/dL


Preterm infant


40 mU/L


0.5–3.3 ng/dL (25–30 wk gestation)


1.3–4.7 ng/dL (31–36 wk gestation)


TT4, total T4; FT4, free T4






  • Surge at birth reflects acclimation to the new cold environment and to cord clamping.
  • FT4 and TSH are the most important parameters in the evaluation of thyroid function.
  • Serum TSH and T4 concentrations are reduced by:

    • Underdevelopment of the hypothalamic–pituitary–thyroid axis
    • Lower concentration of TBG levels
    • Severity of neonatal disease
    • Pharmacologic agents that inhibit TSH secretion (eg, glucocorticoids, dopamine)
    • Hypothyroxinemia of prematurity, with low T4 and inappropriately low TSH (common in infants <32 wk gestation)
    • Sick euthyroid syndrome reflects suppression of the pituitary’s response to TRH:

      • Inappropriately low TSH in the context of low T3
      • In severe cases, T4 concentration is also low

  • No consensus about normal thyroid values in preterm infants.
  • See below for an algorithm for further workup if the state newborn screen comes back abnormal for thyroid function.





eFigure 34-1.



Algorithm for workup of an infant with abnormal newborn thyroid screen.





Other Considerations




  • VLBW infants (<1500 g) have an eightfold risk of developing transient primary hypothyroidism.
  • The prevalence of primary or secondary hypothyroidism in preterm infants is similar to that seen in term infants (approximately 1:4000); there are no estimations on the prevalence of hypothyroxinemia of prematurity.
  • It is important, but very difficult, to distinguish central hypothyroidism from hypothyroxinemia of prematurity, and additional clinical findings should raise suspicion of central hypothyroidism:

    • Microphallus
    • Cleft lip/palate
    • Midline facial hypoplasia
    • Nystagmus
    • Hypoglycemia
    • Prolonged unconjugated hyperbilirubinemia
    • Cortisol, growth hormone, prolactin, or gonadotropin deficiency
    • Radiologic evidence of structural brain abnormalities (including intraventricular hemorrhage)




Neurodevelopmental Outcome and Hypothyroxinemia in the Preterm Infant




  • Neurologic dysfunction at 5 yo and school failure at 9 yo were significantly related to lower neonatal T4 values, even after adjustment for other perinatal factors.
  • Severe hypothyroxinemia had an 11-fold increased risk of disabling cerebral palsy compared with infants who did not have hypothyroxinemia.
  • However, no causal relationship has been established between neurodevelopmental outcome and hypothyroxinemia.




Thyroid Hormone Supplementation for Preterm Infants with Hypothyroxinemia




  • Cochrane systematic review concluded that available data do not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality or morbidity or to improve neurodevelopmental outcomes. (Cochrane Database of Systematic Reviews 2007(1), CD005948)




Corticosteroids in Neonates



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Bronchopulmonary Dysplasia (BPD)




  • Postnatal use of dexamethasone has been shown to have a short-term pulmonary benefit regardless of the time of initiation of use: <96 h after birth, at 7–14 DOL, or after 3 wk of age.

    • None of the strategies affected late mortality, incidence of retinopathy of prematurity, necrotizing enterocolitis, or pneumothorax. When used moderately early (7–14 d), a reduction in mortality at 28 d was observed.
    • Short-term benefits appear to be outweighed by the frequency of serious complications (see table below).

  • Use of corticosteroids should be avoided. However, it may be considered in those with life-threatening respiratory failure, but only after informed consent from the parents is obtained. If corticosteroids are required in critical situations of decompensating BPD, hydrocortisone appears to have less of an effect on neurodevelopmental outcome than the use of dexamethasone. Studied doses for hydrocortisone are 1.25 mg/kg/dose four times a day for 1 week followed by three doses a day for 1 week and then two doses and one dose per week and then discontinued.




Complications



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Acute


Intermediate


Late



  • Hyperglycemia
  • Hypertension
  • GI bleeding/ perforation


  • Infection
  • Growth failure
  • Cardiomyopathy
  • Adrenal suppression


  • Cerebral palsy (esp. with dexamethasone)
  • Impaired neurodevelopment

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Jan 9, 2019 | Posted by in PEDIATRICS | Comments Off on Endocrinology
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