Definition

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

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

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

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.

Clinical Features (May Not be Present at Birth)

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

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.

• 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.

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)

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.