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A rare presentation of clinical short stature due to insensitivity of growth hormone (Loran syndrome).

INTRODUCTION: Growth is an inherent property of life and is mainly the result of the action of growth hormone (GH). GH is secreted from the anterior pituitary gland in the form of pulses throughout the day and night. These bursts of secretion increase the total daily GH secretion during the periods of maximal growth in adolescence. A substantial part (20-40%) of total 24h secretion of GH occurs during the first 90 minutes of nocturnal sleep (1). A genetic from of dwarfism having clinical and biochemical features of growth hormone deficiency (GHD) but abnormally high concentrations of immune reactive serum growth hormone, was first reported in 3 Yemenite siblings in 1966 (2). It has been reported from the Mediterranean, mid-eastern region and in Indian subcontinent (3).

CASE REPORT: A 12 year old male child was admitted to our hospital because of failure to thrive. According to his parents, both weight and length had remained unchanged since the age of 6 years. There is no history suggestive of any radiation exposure during the antenatal period. He was a product of full term, uneventful gestation and delivery. His birth weight, length and head circumference were normal. He was breast feed for a period of six months. He has elder brother and sister of 15 and 13 years of age respectively. Both of them show a growth along the 50th percentile. His parents are unrelated and are of Indian origin. Diabetes or other chronic illnesses were not reported in the family. He is a vegetarian with normal apatite. His bowel, bladder and sleeping habits are normal. He had complete routine immunization schedule in time. There is no history suggestive of any drug intake, known drug allergies, surgeries or any head injury.

Physical examination revealed an extremely short stature (104 cm) boy for his age. The normal expected height for his age is 154cm. He weighs about 13.5kg with normal intellectual function. The boy's parents are about 5'4" and 5'1" tall. Frontal bossing, hypoplastic nasal bridge were noted. He had a high pitched voice. Lungs, heart and abdomen (liver, spleen) examination revealed no pathological findings. A wide spectrum of diseases related to growth failure and seizures were excluded. Serum Growth hormone levels of about 105.29 ngm/ml (Normal range--07-ngm/ml) were noted. Growth hormone dynamic test (exercise) revealed fasting levels of 105.29, at 15 min--139.64 and at 30 min--140.25. Growth hormone dynamic test (clonidine) fasting--102.61, at 30min--132.69, at 60min--142.05, at 90 min--149.27 and at 120 min--129.81.

Supplementation of insulin like growth factor was the treatment option planned for the patient. Studies reveal the outcome of such treatment option is minimal.

DISCUSSION: Children with Laron syndrome clinically resemble isolated growth hormone deficiency Type 1A. Growth hormone receptor is encoded by a single gene located on the short arm of chromosome 5(5p 13-p12). Laron syndrome is due to a variety of homozygous point mutations in the growth hormone receptor gene (4). The growth hormone receptor has an extracellular growth hormone binding domain, a transmembrane domain and an intracellular signaling domain. Mutations in the extracellular domain interfere with binding of growth hormone resulting in Laron syndrome (5).

Clinically, patients with GHIS present in a manner virtually indistinguishable from those with severe GH deficiency. Birth weight and length are likely to be within the reference ranges, but postnatal linear growth is strikingly abnormal with a rapid decline in growth velocity soon after birth. In this condition IGF-1 and IGF-BP3 are markedly reduced despite normal or elevated serum levels of growth hormone and there is unresponsiveness to endogenous and exogenous GH. The natural history, without proper treatment, results in an extremely short adult stature ranging between 4 and 10 SDs below the median for normal height (6).

To date, nearly 300 patients have been identified worldwide, mostly from the Mediterranean, mid-eastern region and from Ecuador. Further, GHIS in these subjects is caused by a great variety of homozygous point mutations and about 30 different mutations (missense, nonsense or abnormal splicing) have been subsequently described (14-20). In contrast to this high number of patients suffering from GHIS caused by a wide variety of GHR gene mutations, there are only a few reports on patients with GHR gene deletions.

Relative obesity is present at birth and increases with age, with a relative excess of adipose tissue in the context of thin bones and diminished muscular mass. The upper-to-lower segment ratio is increased with regard to sex and chronologic age, denoting short limbs for trunk size. Congenital malformations, craniofacial abnormalities, and other physical features may be noted at birth. Facial bone growth is particularly retarded, and fontanel closure is delayed, leading to a disproportionate cephalofacial relationship because of the decreased vertical dimension of the face, with frontal bossing, a saddle nose, shallow orbits, and the setting sun sign of the eyes. Blue sclera may be noted, particularly in patients of Mediterranean or Middle Eastern origin. Hair growth is quite sparse in infancy and through early childhood. It is silky and forms temporal and frontal recessions. Tooth development is delayed, and the teeth may often be defective. The larynx is narrow, resulting in very high-pitched voice. The genitalia and gonads are small from birth.

Pubertal development is delayed, and the pubertal growth spurt is absent, but adult sexual maturation is eventually achieved. Walking and other gross motor developmental milestones are delayed because of the underdeveloped musculature. The hands and feet are small (acromicria). Hip dysplasia, notably avascular necrosis of the femoral head, has been reported in up to 25% of patients (7). The skin is thin and has a fine texture with wrinkles as in premature aging. Psychological evaluations suggest a great variability in intellectual development, ranging from normal intelligence to severe mental retardation.

The cardinal biochemical features of GHIS are low levels of all GH-dependent proteins, including very low or even undetectable serum IGF-1 levels, IGF binding protein 3, and acid labile subunit in association with normal or increased GH levels. The regulation of GH secretion and feedback mechanisms is normal. The most important functional test for the diagnosis is the IGF-1 generation test because serum IGF-1 levels are low and do not increase with the administration of exogenous rGH for days or weeks, demonstrating the state of GH resistance in these patients (8). Metabolic abnormalities include fasting hypoglycemia and hypercholesterolemia.

The underlying metabolic defect lies in the lack of responsiveness of the target organs to endogenous GH. In 1984, it was proven by liver biopsy that GH does not bind to its receptors and therefore is unable to generate IGF-1 [8]. This explains why patients with primary GHIS typically have low to undetectable serum levels of IGF-1, even though serum GH levels are normal or high. In addition, exogenous rGH fails to accelerate growth or to stimulate serum IGF-1 levels or IGF binding protein 3. The only effective treatment is the daily administration of rIGF-1 starting from early childhood and probably throughout life. The rIGF-1 treatment accelerates linear growth velocity, and appropriate dose titrating results in tripling of the baseline growth rate during the first year of treatment (9). Even if these patients may never experience sufficient catch-up growth to bring their height within the normal range, they do achieve an adult height significantly greater than expected in the absence of therapy. The main reasons could be, on the one hand, the inability to replicate physiological IGF-1 distribution and action and, on the other hand, the inability to restore GH defects, because animal studies indicate that GH has growth-promoting effects apart from the IGFs (10). Evidence exists that rIGF-1 therapy also reduces body fat, stimulates kidney function, and maintains left ventricle dimension and function within the normal range of age-matched control subjects.

CONCLUSION: Primary GH resistance or GHIS, also known as Laron syndrome, is a hereditary disease caused by deletions or mutations in the GHR gene or the post-receptor mechanisms. These polymorphic defects lead to the inability to generate IGF-1, which is the anabolic effector of GH. The early and continuous IGF-1 deficiency causes dwarfism as well as skeletal and muscular underdevelopment. Daily administration of rIGF-1 is effective in promoting catch-up growth and is safe. However, no data are available concerning treatment throughout life. An early correct diagnosis of this syndrome is crucial for appropriate preventive care and therapy.

REFERENCE:

(1.) Martin JB. Neural Regulation of Growth Hormone Secretion. N Eng J Med 1973; 188: 13841393.

(2.) Laron Z, Pertzelan A, Mannheimer S, 1966 Genetic pituitary hormone dwarfism with high serum concentration of growth hormone -a new inborn error of metabolism? Isr J Med Sci 2: 152-155.

(3.) Chakrabothy PP. Basu AK. Mandal SK. Dipanjan B. Laron's syndrome in two siblings. Indian Journal of Pediatrics. 2007; 74: 870-1.

(4.) Lopez-Bermejo A, Buckway CK, Rosenfeld RG. Genetic defects of the growth ormone insulin-like growth factor axis.Trends in Endocrinology and Metabolism 2000;11: 39-49.

(5.) Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Growth hormone insensitivity. Nelson's Textbook of Pediatrics, 18th edition, 2: 2296-7.

(6.) Laron Z, Lilos P, Klinger B: Growth curves for Laron syndrome. Arch Dis Child 1993, 68:768-770.

(7.) Ben-Dov I, Gaides M, Scheinowitz M, Wagner R, Laron Z: Reduced exercise capacity in untreated adults with primary growth hormone resistance (Laron syndrome). Clin Endocrinol (Oxf) 2003, 59:763-767.

(8.) Laron Z: Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab 2004, 89:1031-1044.

(9.) Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, GH Insensitivity Syndrome Collaborative Group: Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab 2007, 3:902-910.

(10.) Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A: Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 2001, 229:141-162.

AUTHORS:

[1.] C. Sugunakar

[2.] N. NarsimhaRao

[3.] M.B.R. Sarma

PARTICULARS OF CONTRIBUTORS:

[1.] Associate Professor, Department of General Medicine, KIMS & RF.

[2.] Assistant Professor, Department of General Medicine, KIMS & RF.

[3.] Professor & HOD, Department of General Medicine, KIMS & RF.

NAME ADDRESS EMAIL ID OF THE CORRESPONDING AUTHOR:

Dr. C. Sugunakar, Department of General Medicine, KIMS & RF, Amalapuram.

Email--drsugunakar@yahoo.co.in

Date of Submission: 26/11/2013.

Date of Peer Review: 27/11/2013.

Date of Acceptance: 10/12/2013.

Date of Publishing: 19/12/2013.
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Article Details
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Title Annotation:CASE REPORT
Author:Sugunakar, C.; Rao, N. Narsimha; Sarma, M.B.R.
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Case study
Geographic Code:9INDI
Date:Dec 23, 2013
Words:1733
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