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Pituitary Dwarfism

Dwarfism (Pituitary)

Dwarfism describes limited growth, resulting in a short but proportionate stature. It may emerge from different pathological conditions, one of them being a reduced production of growth hormone by the pituitary gland. People affected by this disease suffer from pituitary dwarfism.


Presentation

Congenital GH deficiency and PD may be noted in infancy or childhood. The growth rate of an affected child will be significantly slower than that of healthy children, but this may not be recognized until the child is two or three years old. If the growth rate has not been analyzed in infancy, parents may consult the pediatrician with older children or even adolescents. The main symptoms are retarded but proportional growth and small stature. Due to limited lipolysis, the child may be chubby. With regards to adolescents, puberty may be delayed. About 5% of PD patients suffer from hypoglycemic episodes. Mental retardation is not characteristic for GH deficiency and PD.

Adults suffering from untreated congenital GH deficiency and PD or from acquired GH deficiency present with excess body fat, smaller muscle mass, reduced tolerance to exercise and altered blood lipids. X-rays may reveal diminished bone mineralization.

Short Stature in Children
  • Although it is uncommon, growth hormone deficiency may also be diagnosed in adults. [1] Too little growth hormone can cause short stature in children, and changes in muscle mass, cholesterol levels, and bone strength in adults. [2] Most of the time, no[rarediseases.info.nih.gov]
Eruptions
  • Marked delay in eruption of the permanent teeth. 4. Retention of permanent teeth in the maxillary and mandibular shafts. 5.[ncbi.nlm.nih.gov]
  • Later, children with GHD may present with delayed rates of development of facial bones, slow tooth eruption, delayed lengthening of long bones, fine hair, and poor nail growth.[rarediseases.org]
Responsiveness Decreasing
  • RESULTS: At mean age of 19.2 /- 0.7 yr, the mean peak GH response decreased significantly after ITT (P 0.00001) and GHRH plus arginine (P 0.0001).[ncbi.nlm.nih.gov]
Nocturnal Enuresis
  • We suggest that the ectopic posterior lobe is one cause of nocturnal enuresis.[ncbi.nlm.nih.gov]

Workup

Medical history and clinical examination form the basis of GH deficiency and PD diagnostics. Body height, weight and proportions should be registered, ideally over the course of time. This way, a growth curve can be established and compared with normal growth curves.

If limited growth has been diagnosed, its cause has to be identified. Serum concentrations of insulinlike growth factor-1 may be evaluated. Also, GH stimulation tests may be of great value to identify reduced GH release by the pituitary gland. The insulin tolerance test, the GHRH-arginine test and the glucagon stimulation test are reliable alternatives. While the insulin tolerance test consists in evaluating the body's response to hypoglycemia, the GHRH-arginine test assesses its direct response to stimulating GHRH. It is not yet clear how glucagon stimulates GH release. In all cases, GH levels should rise considerably during the course of the test.

Diagnostic imaging can be applied to confirm the diagnosis. Radiographic imaging of the hand enables the physician to estimate the child's bone age. Magnetic resonance imaging of the head allows visualization of pituitary gland and hypothalamus and may be of help to identify the disease's cause.

Delayed Bone Age

Treatment

Treatment of GH deficiency and PD is based on GH replacement. GH therapy should take place before closure of the epiphyseal plates and PD can rarely be reversed afterwards. Adults suffering from GH deficiency and PD may still benefit from GH therapy to resolve metabolic and cardiovascular abnormalities. Hypoglycemic episodes do usually resolve under GH therapy.

While decades ago GH was collected from deceased bodies, nowadays recombinant human GH is administered. It is generally well tolerated. Recombinant human GH has rarely been associated to adverse effects, most of them being injection site reactions. Nausea, headache and fever have been observed. Adults under GH therapy may suffer from edema, because GH exerts an antidiuretic effect. Furthermore, gynecomastia and idiopathic intracranial hypertension have been reported, whereby the latter requires a break in therapy and a restart at lower doses. Acromegaly is not an adverse effect of GH therapy but rather a sign for overdosage. Some studies reported possibly dose-dependent increased risks for cancer and cardiovascular diseases, and therefore recommend the GH dose not to be higher than necessary [9]. Other studies did, however, not confirm these risks [10].

Generalized hypopituitarism is very challenging, from the pharmacologist's point of view. All hormone deficiencies have to be compensated.

Prognosis

Isolated GH deficiency can be treated with GH in order to avoid PD and the prognosis is good if the disorder is detected early. With respect to body height, prognosis is poor when PD is diagnosed after the epiphyseal plates have closed. Adult patients may nevertheless benefit from GH therapy due to the great variety of functions this hormone does fulfill in the human body.

The prognosis may be less favorable in cases of generalized hypopituitarism or severe underlying diseases.

Etiology

PD results from a GH deficiency that may be congenital or acquired and this hormone deficiency may be an isolated finding or occur in association with generalized hypopituitarism.

Congenital forms of GH deficiency may be due to generalized CNS malformations or genetic defects that affect any protein involved in the cascade of binding GH-releasing hormone (GHRH), signal processing, GH synthesis and GH release. Of note, the hormonal network might be disturbed further upstream, i.e. at hypothalamus level, or further downstream, e.g. due to non-functional GH receptors. Disorders resulting in such conditions will not, however, result in PD but otherwise classified hormonal disturbances.

Acquired GH deficiency may result from brain traumas, inflammation due to toxoplasmosis or CNS tuberculosis, neoplasias and irradiation of the CNS, among others.

Most cases of PD are termed idiopathic, an exact cause can only be identified in about 25% of all cases. The most common triggers for GH deficiency are neoplasias, septo-optic dysplasia and other, not classified CNS malformations. For further data regarding less common causes for GH deficiency please refer to [1] [2] [3].

Epidemiology

GH deficiency and PD is more common in children, but can possibly affect people of any age. Indeed, in most cases, GH deficiency is present at birth. Retarded growth may, however, not be diagnosed until years later. Most diagnoses are made when children enter school - and are compared to their classmates - and in puberty, when the growth spurt does not occur appropriate to age.

Surprisingly, men seem to be affected more often than women. This finding may be due to gender bias, since boys may be diagnosed with a small stature more easily than girls [4]. However, at least with regards to acquired GH deficiency, the observed gender ratio may also be explained by disparities regarding gender distribution of underlying diseases. No racial predilection has been proven.

The incidence of congenital isolated GH deficiency has often been estimated to range between 1 and 3 cases per 10,000 births [5]. In single studies, values ranging from 1 in 30,000 to 1 in 2,000 births have been proposed. In order to be able to compare values reported by different authors, the application of a clear definition of the term GH deficiency would be required.

Studies have also been conducted to assess the incidence of dwarfism among school children, but they are difficult to evaluate because there is no clear cut-off value regarding limited and normal growth. GH deficiency cannot be determined by measuring body height alone. Notwithstanding, children, particularly boys, may receive GH therapy when falling below a certain growth rate [6]. The average adult height in untreated PD patients is 130 cm in women and 143 cm in men.

GH deficiency and PD are not lethal conditions. Infant and child mortality may nevertheless be increased among patients suffering from these diseases because they are often accompanied by other pituitary hormone deficiencies that may indeed have life-threatening consequences [7]. Life expectancy may be reduced in PD patients due to metabolic alterations and dyslipidemia.

Sex distribution
Age distribution

Pathophysiology

Pituitary GH release is regulated by serum levels of GHRH, a hypothalamic liberin also called somatoliberin. Upon GH release, negative feedback triggers reduction of GHRH release. If GH levels decrease below a certain value, GHRH will once again be released by the hypothalamus.

For GHRH to effectively stimulate GH release, GHRH needs to bind to a G protein-coupled receptor expressed in the pituitary gland. Subsequent intracellular signaling cascades trigger GH synthesis and release into the blood stream. Here, GH binds to a soluble carrier protein and is transported to its target tissues. Binding of GH to its receptor on the surface of target cells increases expression of specific growth factors that, in turn, mediate the effects of GH in their target tissues. Such growth factors may be the insulinlike growth factor, the epidermal growth factor or the fibroblast growth factor.

Any interruption of this signaling cascade may lead to GH deficiency and PD. Many genetic defects contributing to this phenotype have been identified. For instance, more than ten different mutations affecting the gene encoding for the pituitary-specific positive transcription factor 1 have been described. All these genetic disorders lead to familial GH deficiency, a disease that may be accompanied by symptoms associated with prolactin and thyroid-stimulating hormone deficiencies since cells producing these hormones also depend on the mutated transcription factor [8]. Similarly, development of different types of pituitary cells is hindered by missense mutations affecting the PROP1 gene. Patients suffering from this kind of genetic defect develop deficiencies in GH, prolactin and glandotropic pituitary hormones.

Gene defects may contribute to certain developmental disorders and CNS malformations, as is the case in septo-optic dysplasia. In patients suffering from this kind of disease, GH deficiency and PD do not occur in an isolated form.

Direct damage to GH-producing pituitary cells is responsible for acquired GH deficiencies and may result from trauma, inflammation and irradiation. Neoplasias may originate from the pituitary gland or may invade the endocrine gland from the surrounding tissue.

Prevention

There is no preventive measure to avoid congenital GH deficiency. PD, however, may be evaded by early diagnosis of GH deficiency and adequate treatment. Acquired GH deficiencies may be avoided preventing head traumas and causal diseases, but this may not always be possible.

Summary

Pituitary dwarfism (PD) results from a hormonal disorder affecting the pituitary gland.

The pituitary gland is an endocrine organ located close to the hypothalamus inside the skull. Several endocrine glands throughout the body, e.g. the thyroid gland, the gonads and the adrenal glands, are regulated by glandotropic hormones released by the pituitary gland. Furthermore, the pituitary gland produces non-glandotropic hormones that directly affect their target organs. One of these non-glandotropic hormones is the growth hormone (GH), also called somatotropine, which binds to somatotropine receptors expressed in liver, muscle, bones and other tissues. GH has an anabolic effect and stimulates growth, glykogenolysis and lypolysis, among other processes. If any pathological condition affects the pituitary gland in such a way that a GH deficiency is triggered, the aforementioned processes are impaired. PD results from limited growth due to a GH deficiency.

Patient Information

The pituitary gland is a hormone producing gland located close to the brain. It produces a wide variety of hormones, one of them being the growth hormone (GH). Its main function is to stimulate growth during infancy, childhood and puberty. In adults, it affects many metabolic processes. If not enough GH is synthesized, released or otherwise available, normal growth is hindered. This condition results in pituitary dwarfism (PD).

Causes

The regulatory network around the pituitary gland and its GH is a rather complex system. Its complexity makes it susceptible to several gene defects, to infection and inflammation as well as to other diseases. If gene defects cause GH deficiency, the disorder is termed congenital GH deficiency because it's already present at birth. Of note, gene defects may cause other developmental and hormonal disturbances at the same time. Injury, infection, inflammation and other diseases such as brain tumors may cause acquired GH deficiencies.

Symptoms

Congenital GH deficiency may be noticed in infancy, childhood or puberty. The main symptoms are retarded growth, small stature and maybe chubbiness. In adolescents, puberty may be delayed. If parents suspect their child not to grow normally, a pediatrician should be consulted. He or she will compare the child's growth with that of his or her peers. Usually, retarded growth is not recognized until the child is two or three years old.

Treatment

Treatment should be started as early as possible in order to avoid PD. Therapy consists in replacing the deficient GH with recombinant GH, i.e. GH produced in a laboratory. GH is usually injected once a day. Treatment of GH deficiency and PD follows a long-term regimen and generally continues for several years. Regular follow-ups are necessary to monitor the child's development and growth. The therapy has very few side effects, the most frequent ones being nausea, headache, fluid retention and skeletal complications.

Prognosis

An early diagnosis is usually associated with a good prognosis. Many children grow considerably during the first year of treatment while their growth rate slows down afterwards. It is important to start GH therapy before the child's bones reach certain developmental stages, otherwise the patient may suffer from delayed puberty and PD in adulthood.

Prognosis is less favorable when GH deficiency is accompanied by several other hormone deficiencies or caused by severe underlying diseases.

References

Article

  1. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. 1996; 81(5):1704-1710.
  2. Frindik JP, Baptista J. Adult height in growth hormone deficiency: historical perspective and examples from the national cooperative growth study. Pediatrics. 1999; 104(4 Pt 2):1000-1004.
  3. Root AW, Kemp SF, Rundle AC, Dana K, Attie KM. Effect of long-term recombinant growth hormone therapy in children--the National Cooperative Growth Study, USA, 1985-1994. J Pediatr Endocrinol Metab. 1998; 11(3):403-412.
  4. Grimberg A, Stewart E, Wajnrajch MP. Gender of pediatric recombinant human growth hormone recipients in the United States and globally. J Clin Endocrinol Metab. 2008; 93(6):2050-2056.
  5. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah Growth Study: growth standards and the prevalence of growth hormone deficiency. J Pediatr. 1994; 125(1):29-35.
  6. Cuttler L, Silvers JB, Singh J, et al. Short stature and growth hormone therapy. A national study of physician recommendation patterns. Jama. 1996; 276(7):531-537.
  7. Mills JL, Schonberger LB, Wysowski DK, et al. Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients. J Pediatr. 2004; 144(4):430-436.
  8. Rainbow LA, Rees SA, Shaikh MG, et al. Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin Endocrinol (Oxf). 2005; 62(2):163-168.
  9. Carel JC, Ecosse E, Landier F, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab. 2012; 97(2):416-425.
  10. Sävendahl L, Maes M, Albertsson-Wikland K, et al. Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study. J Clin Endocrinol Metab. 2004; 97(2):E213-217.

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Last updated: 2018-06-22 05:36