Discussion

We report a case of CHP with a unique presentation. Diagnosing and identifying the aetiology of CHP can be challenging. CHP is usually suspected when there is a combination of signs, including hypoglycaemia, prolonged jaundice, temperature dysregulation, electrolyte abnormalities and haemodynamic instability. However, we suspected CHP based on refractory shock and hypothyroxinaemia.

Persistent cutis marmorata can be a feature of congenital hypothyroidism.2 Hypothyroidism should be investigated in cases of unexplained cutis after ruling out sepsis, temperature and electrolyte instability. In our neonate, mottling persisted for a long time even after resolution of sepsis. No evaluation for vasculitis was performed.

The diagnosis of CHP is difficult, especially in preterm babies due to the hypothalamic–pituitary axis immaturity and lack of normative values for pituitary function tests.1 We attributed the low fT₄ at 72 hours of life to transient hypothyroxinaemia of prematurity (THOP). THOP is usually considered as the first possibility in any preterm with low fT₄ and normal TSH. It is self-limiting and commonly seen in very preterm neonates (50% in less than 28 weeks).3 It is attributed to immaturity of the hypothalamic–pituitary–thyroid axis along with loss of placental transfer of T₄, reduced iodine stores or low Thyroid-binding globulin levels. Sick euthyroid syndrome is the derangement of thyroid function test during any critical illness and also has a biochemical presentation similar to THOP. In our baby, serum-free T₄ levels were low even at 72 hours of life when she was otherwise clinically stable. Medications like dopamine, glucocorticoids, diuretics and aminophylline have also been known to cause abnormalities in the thyroid function tests.3 Dopamine was used only for 12 hours in our patient and this cannot be considered a cause for the abnormal values due to its very short half-life. Moreover, the presence of refractory shock, hypocortisolism and hypoplastic anterior pituitary in MRI of our child cannot be explained by THOP or sick euthyroid syndrome.

The report in our baby also highlights that TSH-based screening, which is followed widely4 can miss the diagnosis of central hypothyroidism. In our unit, fT₄ and TSH levels are routinely done to screen hypothyroidism in preterm neonates <32 weeks,5 which gave us a clue to the early diagnosis of the condition. ACTH stimulation test is usually done when there is low cortisol at the time of hypoglycaemia to confirm adrenal insufficiency.6 We did not perform the test as hypocortisolism was secondary to hypopituitarism.

Since the random levels of growth hormone are high in the neonatal period, no provocative tests are required.7 There is usually a postnatal surge in gonadotrophins (Follicle-stimulating harmone and Luteinizing harmone) and this lasts for a few months to 2–3 years. Hence, measuring levels of these hormones for checking the integrity of hypothalamic–pituitary–gonadal axis would be more appropriate when done at a later date.3 High prolactin levels can be seen in neonates up to 6 weeks of age, making the interpretation of values difficult.3 After discussion with the paediatric endocrinologist, measurement of these pituitary hormone levels was planned at a later age.

Another interesting clinical sign observed in this case was that there was no variability or increase in heart rate despite refractory hypotension and high inotrope doses. Though β1 adrenergic receptors are less at birth when compared with the α1 receptors in preterm neonates,8 tachycardia is one of the early signs of sepsis and shock.9 Even dopamine at a dose of 2–5 µg/kg/min and norepinephrine even at 0.05 µg/kg/min is known to cause tachycardia in preterm neonates.10

Adrenergic receptor downregulation secondary to adrenal insufficiency (absolute/relative) is implicated in the causation of vasopressor-resistant hypotension. In addition to upregulating the cardiovascular adrenergic receptors, steroids also exert non-genomic actions, which rapidly increase catecholamines’ responsiveness.11 The Cochrane review,12 which included only two Randomized controlled trials, concluded that steroids effectively treat refractory hypotension in preterm infants without an increase in short-term adverse consequences.

MRI of the brain and the pituitary gland is recommended in all patients with suspected or confirmed CHP to identify a structural abnormality.1 An isolated ectopic posterior pituitary is usually considered a normal variant. The triad of an ectopic posterior pituitary, abnormal pituitary stalk and anterior pituitary hypoplasia is known as ‘pituitary stalk interruption syndrome’.13 This finding was present in our baby.

In a systematic review of 144 Italian patients, the overall frequency of mutations was 2.9% in sporadic cases of Combined pituitary harmone deficiency and 12.5% in familial cases. It was concluded that in sporadic cases, mutations are only likely to be identified in patients from countries with a high prevalence of mutations and patients who present with extrapituitary manifestations.14 Genes associated with pituitary thin stalk, small adenohypophysis and ectopic neurohypophysis include SHH, GIF and SIX3, and we found no significant variants in these genes.14

Management involves timely diagnosis and physiological replacement of the deficient hormones. It is recommended to start hydrocortisone before levothyroxine in CHP to prevent worsening of the adrenal crisis.1 Problems that could arise in future due to other endocrinopathies like short stature requiring Growth harmone therapy, diabetes insipidus, gonadotrophin deficiency and decreased bone mineral density need to be appropriately managed. Follow-up with multidisciplinary team involving the neonatologist, endocrinologist, developmental specialist and geneticist is vital in CHP to address other hormonal dysfunctions and growth disturbance.