Endocrine System

Diagnosis and reasoning

This 10-year-old child has a history of inadequate weight gain and short stature, as per her mother.

The first step in such a case is to measure the patient's body parameters and plot them on the relevant growth curves. These are below the 3rd percentile for her age and gender, indicating true growth failure. Additionally, the weight-for-height ratio is between the 25th and 50th centile, further supporting this diagnosis.

The next step is determination of the appropriate proportions. The upper-to-lower body ratio in this case suggests proportional short stature, excluding skeletal dysplasias such as achondroplasia and osteogenesis imperfecta. A normal skeletal survey supports these findings.

Note also that our patient's growth velocity is below the expected range for her age and her height is less than the calculated mid-parental height, ruling out familial or constitutional short stature.

A thorough medical history and physical examination help assess for chronic diseases, recurre

nt infections, malabsorption disorders, and childhood malignancies as potential causes of growth delay. Our patient's history, physical findings and initial laboratory work all indicate that the above etiologies are unlikely.

There was also no history of the use of long-term medications such as steroids, which are known to inhibit growth. An uneventful birth history and a normal birth weight rule out intrauterine causes of growth failure.

Certain chromosomal disorders such as Turner's and Down's syndromes are associated with short stature, with characteristic dysmorphic features; the absence of such features makes these conditions less likely. However, karyotyping should be performed in all patients presenting with short stature, in order to definitively exclude these etiologies.

At this point, the most important clue to arriving at the diagnosis is the delayed bone age. While endocrine disorders are an uncommon cause of short stature, these should now be considered, as the other, more common etiologies have been eliminated.

In this regard, the key endocrinopathies to exclude are hypothyroidism, and growth hormone (GH) deficiency (GHD); thus, a thyroid profile and assessment of IGF-1 levels should follow.

Note that GH is secreted in a pulsatile manner, and has a very short half-life. Thus, estimation of serum GH levels is of limited value; a negative result does not imply GHD. IGF-I levels are reflective of circulating GH, and vary less throughout the day, and are thus a better screening test.

In this patient, IGF-I levels are significantly diminished; follow-up provocative testing via the insulin tolerance test (ITT) reveals an inadequate GH response, confirming the presence of GHD.

Recall that the mother gave a history of delayed dentition, and the physical examination revealed a prominent forehead with immature facies and increased fat around the trunk. These clues, together with the findings on the endocrine profile, suggest that the GHD is congenital in origin.

The diagnosis of GHD mandates an MRI of the brain, as these children sometimes present with midline cerebral defects. However, our patient's MRI reveals normal brain development, indicating that this is likely a sporadic case of congenital GHD.

Management options for isolated GHD consist of supplementation of GH until the appropriate height is achieved. Evidence suggests that adding calcium and Vitamin D to this regimen may help increase bone mass.

Since there is no coexisting thyroid hormone deficiency, levothyroxine is not indicated. Protein supplementation is not required either, as she appears well nourished and shows no signs of nutritional deficiencies.


Growth hormone deficiency (GHD) is a rare disorder characterized by the inadequate secretion of growth hormone (GH) from the anterior pituitary; it may occur in both children and adults.

Note that the remainder of this monograph pertains to GHD in the pediatric age group alone; in industrialized countries, this has been estimated to occur in 1/30,000 people per year; males are affected more frequently.

Considering the underlying pathophysiology, GH is an anabolic hormone which plays a key role in protein, lipid, and carbohydrate metabolism; it is also responsible for postnatal longitudinal growth.

Normally, growth hormone releasing hormone (GnRH) is secreted from the hypothalamus, stimulating release of GH into the systemic circulation, where it then mediates insulin-like growth factor 1 (IGF-1) release from the liver. Note that IGF-1 is the main effector of GH activity

Thus, any disturbances in the hypothalamic-pituitary axis (HPA), IGF-1 production, or receptor-signal transduction from either a congenital or acquired pathology can result in GHD.

Childhood GHD is most often secondary to genetic mutations or structural abnormalities of the pituitary gland; this is as opposed to the adult form, which is mainly acquired in origin.

The key genetic mutations involved are grouped into four classes: Types IA and IB are autosomal recessive, IIB is autosomal dominant, and III is X-linked. Laron's syndrome is another known cause. Chromosomal abnormalities that cause GHD include Turner's, Down's, and Prader-Willi syndromes.

Structural abnormalities include pituitary stalk interruption syndrome and agenesis of the corpus callosum. A familial history of such diseases or a history of consanguineous marriage poses an increased risk for these conditions. There is also a strong relationship with the presence of midline facial abnormalities, such as a cleft palate.

Acquired pathologies are less common in the pediatric age group; these include pituitary tumors, intracranial infections such as meningitis, traumatic brain injury, cranial radiotherapy, and pituitary infiltrative diseases.

That said, most of the time, childhood GHD is idiopathic, with no associated diseases.

The earliest clinical manifestation is a reduction in height velocity (normally 5-7cm/year) followed by a reduction in height below the mid-parental height. The child will have proportional short stature (i.e. a normal upper to lower body ratio).

Severe cases may demonstrate features of delayed teething, fine hair and poor nail growth. They may also demonstrate truncal obesity and midline facial hypoplasia.

Signs of genetic syndromes may be present, such as in Turner's syndrome (female with short stature, neck webbing and cardiac abnormalities) and Prader-Willi syndrome (short stature with obesity, mental retardation and renal abnormalities).

Children with congenital GHD may present with a neonatal history of jaundice, birth asphyxia, hypoglycemia and microphallus.

Note that as per the Consensus Guidelines for the Diagnosis and Treatment of GHD in Childhood and Adolescence, any child who presents with the following features must be investigated for GHD:

- Severe short stature (height >3 SD below the mean).

- Height >1.5 SD below mid-parental height.

- Height >2 SD below the mean AND a height velocity >1 SD below the mean over the past year OR decrease in height velocity >0.5 SD over the past year.

- In the absence of short stature, height velocity >2 SD below the mean over one year OR >1.5 SD below the mean over two years.

- Signs of intracranial lesions.

- Signs of multiple pituitary hormonal deficiencies.

- Neonatal signs of GHD (e.g. hypoglycemia and microphallus).

In patients with suspected GHD, random GH levels are of little value, as GH is secreted in a pulsatile manner with a very short half-life. However, serum levels of IGF-I are reflective of circulating GH, and vary less throughout the day, thus serving as a useful screening test. That said, a positive result is not specific for the condition.

Provocative GH testing with the insulin tolerance test (ITT) is diagnostic; in this, basal GH levels are first measured, following which insulin is administrated intravenously at a dose of 0.1 unit/kg to produce hypoglycemia. Glucose and GH levels are subsequently measured at 0, 15, 30, 60, 90 and 120 minutes. In children, a peak GH level <10μg/L is diagnostic of the condition.

Note that other provocative agents such as glucagon, clonidine, arginine, and L-dopa are less frequently used.

Karyotyping should be performed in every childhood case of GHD to rule out a congenital cause; genetic testing is not performed routinely, but can yield additional information regarding the underlying mutation.

A cranial MRI is extremely important to detect an underlying structural cause, such as a pituitary tumor. This will also help detect associated midline abnormalities such as abnormalities of the corpus callosum, absent olfactory bulbs, and septo-optic dysplasia.

All children diagnosed with GHD should be treated with recombinant human growth hormone as soon as possible. The aim of treatment is to normalize the height within the calculated target range for that child.

GH is administered once a day subcutaneously, usually in the evening. Levels of IGF-1 should be measured to establish the appropriate dose.

These children must be seen every three to six months for the assessment of height velocity and to detect any complications. Treatment should be continued until the child is post-pubertal and growth has been normalized.

In addition to GH replacement therapy, the underlying cause must be treated (e.g. estrogen replacement therapy in the case of Turner's syndrome, or surgical removal of pituitary tumors).

Psychosocial support and rehabilitation are very important in these cases, as starting GH replacement may cause low self-esteem and affect the quality of life due to anxiety, depression, social isolation and attention deficits, which may lead to low academic achievement.

Note that the earlier the diagnosis is made, and the sooner treatment is initiated, the more likely the child is to reach normal height.

Take home messages

1. Growth hormone deficiency (GHD) may present as two distinct clinical entities: childhood onset GHD (usually idiopathic), and adult onset GHD (usually acquired).

2. Growth increments are the most important criteria when making the diagnosis in children. If growth recorded during a six to twelve month period is within normal levels, it is unlikely that a growth disorder exists.

3. IGF-I levels, provocative testing, and cranial MRI remain the primary investigations when diagnosing pediatric GHD.

4. The response to GH replacement therapy is strongly correlated with the age at diagnosis; early detection and prompt initiation of treatment increases the likelihood that the child will achieve a normal height.


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