Assoc. Professor Patricia Crock
Paediatric Endocrinologist, John Hunter Children's Hospital.
The term hypopituitarism means that the pituitary gland does not function normally. The term congenital hypopituitarism means that this has been from birth. Total loss of pituitary function is called panhypopituitarism. In cases of partial hypopituitarism, the loss may be restricted to one cell type.
The symptoms and signs of hypopituitarism are discussed below in relation to the age of the child.
Symptoms and signs in the newborn period
In the newborn period, babies with hypopituitarism usually have a normal birth weight and length because growth hormone is not essential for growth in the womb. Pituitary hormones are necessary for the normal maturation of other chemical systems in the body, particularly the liver enzyme system. Therefore, some babies may develop low blood sugar levels (hypoglycaemia) and become yellow (jaundice). Male babies may have smaller than normal genitalia.
Low Blood Sugar (Hypoglycaemia)
Definition: a blood sugar of 2.5 mmol/L or lower is abnormal.
The definition of a normal blood sugar level has varied over the years, partly because of technical problems in getting adequate samples in small babies and in having accurate machines to measure the result. Normally, when the blood sugar starts to fall below normal a baby will make extra growth hormone or cortisol, as these hormones help bring blood sugars back to normal. If a baby is unable to make enough growth hormone or cortisol at a time when the blood sugar is low, then this suggests that it may have hypopituitarism.
Symptoms of low blood sugar levels may include jitteriness, pallor and hunger. If the sugar levels are very low, the baby may go limp, floppy and blue or have a convulsion (epileptic seizure). Glucose may need to be given via a vein to quickly bring up the low glucose level. These babies are not able to go for long periods between feeds as their reserve of sugar is very limited, sometimes only two or three hours. Hypoglycemia is particularly associated with growth hormone and/or cortisol deficiency, but is also seen with thyroid hormone deficiency.
Definition: yellow discolouration of the skin and eyes due to accumulation of the pigment bilirubin from the liver.
Many normal babies have some jaundice in the newborn period. However, the jaundice associated with hormone deficiencies tends to last longer than usual and may need treatment under lights (ultraviolet treatment or “phototherapy”). The cause of the jaundice is related to slow maturation of liver enzymes. Other liver function may be abnormal.
Specialists in liver disease, gastroenterologists (or hepatologists in north America) may be consulted and find that the liver is inflamed with “giant cell hepatitis”. This inflammation is due to the lack of pituitary hormones, but the connection may only be made in retrospect. It may improve without treatment, but will improve more quickly with replacement of the relevant missing hormones – cortisol, thyroid hormone and/or growth hormone.
Jaundice is a particular feature of thyroid hormone deficiency in babies. Other signs include dry skin and lethargy, but these may be subtle and ascribed to other things.
Small Genitalia in Boys
In male babies, the growth of the penis is due to both growth hormone and sex hormones, so if either of these is missing, the penis may be smaller than normal. When sex hormone levels are low, the testes may not be descended (cryptorchidism = “hidden testicles”). The combination of a small penis, low blood sugar levels and prolonged jaundice should ring alarm bells for the diagnosis of hypopituitarism. Female babies do not have this extra clinical clue to help with the diagnosis of hypopituitarism.
Babies with cortisol deficiency may have particularly low blood sugar levels. This is the most potentially life-threatening of the hormone deficiencies. They may appear very tired, pale, lethargic and have little energy to feed. Vomiting, excessive drowsiness and high fevers (above 39 °C) can also be signs of low cortisol levels. As all these signs can be due to many other things, it is not easy to think of this diagnosis. Although theoretically cortisol deficiency causes low blood pressure, this is not always obvious in newborn babies who tend to compensate until the last minute. Cortisol deficiency may lead to collapse, loss of consciousness and seizures.
There are many developmental problems that can be associated with congenital hypopituitarism and these are loosely called “midline syndromes”. The pituitary is in the midline of the body and so problems in the development of other midline structures may affect it. Common associations are cleft palate (not just cleft lip alone), a single front tooth (“single central incisor syndrome”), underdeveloped optic nerves (optic nerve hypoplasia or de Morsier’s syndrome), absent septum pellucidum and/or agenesis of the corpus callosum (structural brain problems). The greater the severity of a midline brain developmental anomaly, then the greater the likelihood of pituitary involvement.
There are also numerous chromosomal changes that have been reported in association with hypopituitarism including deletions of 1q, 4q, 18p, 22q amongst others.
Symptoms and signs in infancy and childhood
If hypopituitarism is not diagnosed in the newborn period, then the most common reason to suspect it is poor growth.
Children with growth hormone deficiency grow abnormally slowly and so they progressively lose height relative to their peers. At the time of diagnosis they are usually under the 3rd centile (the lowest line on the growth charts used to track growth) - unless they have tall parents. Hair may be thin and wispy and grow slowly.
The second feature is a relative excess of weight for height. It is often not appreciated that growth hormone has many metabolic effects on body fat distribution and blood fats (lipids). The excess weight is carried as abdominal fat that may look like cellulite (called “fat dimpling”). This type of body fat is associated with a higher risk (long-term) of heart disease and unhealthy blood lipid profiles, which is why growth hormone should be continued into adulthood in patients who have a severe deficiency.
Note however, that in children who also have cortisol deficiency, excess abdominal fat may not be a feature. Also, some children may continue to be at risk of hypoglycemia beyond the neonatal period, especially if they are fasting or have cortisol deficiency as well.
As the skeletal growth is retarded, the child’s body proportions resemble those of a younger child. Their facial growth is also slowed and so their facial appearance is often described as “cherubic” – meaning that it is “angelic” or “baby-like”. The forehead is prominent, the bridge of the nose may be depressed and the voice can be high-pitched. The anterior fontanelle, the soft spot on the baby’s skull, may be slow to close over. Baby teeth may be slow to appear which is termed delayed dental eruption. There may be irregular development and setting of permanent teeth. The strength of their bones is also affected.
Growth hormone also has significant effects on muscle mass or lean body mass and bone mass. Children with severe growth hormone deficiency often have poor muscle tone (hypotonia) which improves with therapy. For example they may become more confident and coordinated in the playground.
The signs of thyroid hormone deficiency due to TRH or TSH deficiency are similar to, but more subtle than those related to primary failure of the thyroid gland. Poor growth, poor energy levels, dry skin and hair (with “cradle cap”), and constipation are the main symptoms. Mood changes are also common.
Although cortisol deficiency may be present at birth, it may also develop over time. It is not understood exactly why the pituitary gland can progressively fail with age, even as late as into the teenage years or beyond, but it is more likely in patients with abnormalities of the pituitary stalk on MRI scan. Therefore, long term follow-up of patients on growth hormone in childhood is essential and repeated testing of pituitary function may be necessary.
Although a cleft palate is usually diagnosed at birth, there are some more subtle forms that may not be obvious until the child starts to speak. Children with a sub-mucous cleft of the soft palate may have symptoms such as “nasal” speech and regurgitation of liquids out their nose (for example when they vomit). Any child with a cleft palate and short stature should be referred for assessment of GH deficiency and possibly TSH deficiency.
Symptoms and signs in adolescence
The two issues in this age group are the onset of puberty and the development of further pituitary hormone deficiencies.
It is not always possible during the pre-pubertal years to predict if a child with partial hypopituitarism will go into puberty spontaneously. It is less likely in someone who had signs of sex hormone deficiency in the neonatal period (as outlined above) or in patients with panhypopituitarism. Thus, a boy with small genitalia and undescended testes at birth is less likely to go into puberty by himself. In addition, there is no hormonal stimulation test which is 100% reliable at predicting the likelihood of going into puberty.
This second issue is even more important. In children with certain genetic causes of hypopituitarism such as Prop 1 defects, there is the potential for the progressive loss of pituitary cells – particularly corticotrophs. Repeated hormone testing in the same individual over a number of years has shown that corticotroph function is lost over time. Patients who have previously coped well with intercurrent illness (for example a bad flu or cough has not troubled them), will start to get sicker than other family members with the same illness. If they start vomiting, get high fevers (over 39 degrees Celsius) and are lethargic, then one must think that these could be symptoms of cortisol deficiency. These symptoms may mimic a bad gastroenteritis.