Growth Hormone Resistance Clinical Presentation

  • Author: Arlan L Rosenbloom, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Apr 18, 2012
 

History

The clinical features of GHRD are not different than those of severe GH deficiency. Postreceptor abnormalities differ from GHRD in not having hypoglycemia, because the counter-regulatory effects of GH are not impaired. As noted above, IGF-I mutations differ from GHRD with severe mental retardation, sensorineural deafness, micrognathia, microcephaly, and intrauterine growth retardation. Heterozygous IGF-I receptor mutations have no or mild-moderate effect on brain development, but they do result in intrauterine growth retardation.

Next

Physical

The clinical features with GHRD and STAT5b mutation are not distinguishable from those of severe GH deficiency.

15 Ecuadorian children with GHRD due to homozygosi15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for 11-year-old boy, 4th from the left and his 8-year-old brother holding the ball who is almost the same height.

ALS deficiency has modest, at most, effect on growth, without any other phenotypic features. IGF-I mutations result in severe intrauterine and postnatal growth failure, deficient brain development in utero and severe mental retardation, deafness, and micrognathia.[4, 5, 6] Heterozygous IGF 1 receptor mutations result in varying degrees of intrauterine and postnatal growth retardation, microcephaly, and normal to moderately retarded cognitive development.[7, 19, 20, 21, 22, 23]

Clinical characteristics of GHRD:

Growth

  • Birth weight - normal; birth length - usually normal
  • Growth failure, from birth, with velocity ½ normal
  • Height deviation correlates with (low) serum levels of IGF-I and IGFBP-321-year-old woman and her 23-year-old brother with21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, and his IGF-I level is 4 times hers and his IGFBP3 level twice hers.
  • Adult stature -4 to -12 standard deviations below normal mean
  • Delayed bone age, but advanced for height age
  • Small hands or feet

Craniofacial characteristics

  • Sparse hair before age 7; frontotemporal hairline recession all ages
  • Prominent forehead (bossing)
  • Head size more normal than stature with impression of large head
  • "Setting sun sign" (sclera visible above iris at rest) 25% < 10 years of age (together with the craniofacial disproportion can lead to impression of hydrocephalus and unnecessary workup)
  • Hypoplastic nasal bridge, shallow orbits
  • Decreased vertical dimension of face
  • Blue scleras
  • Prolonged retention of primary dentition with decay; normal permanent teeth, may be crowded; absent 3rd molars
  • Sculpted chin
  • Unilateral ptosis, facial asymmetry (15%); (only reported in GHRD])

Musculoskeletal/body composition

  • Hypomuscularity with delay in walking
  • Avascular necrosis of femoral head (25% of GHRD)
  • High-pitched voices in all children, most adults
  • Thin, prematurely aged skin
  • Limited elbow extensibility after 5 years of age
  • Children underweight to normal for height, most adults overweight for height; marked decrease of ratio of lean mass to fat mass, compared to normal, at all ages

Metabolic

  • Hypoglycemia (fasting)
  • Increased cholesterol and LDL-C levels
  • Decreased sweating

Sexual development

  • Small penis in childhood; normal growth with adolescence
  • Delayed puberty
  • Normal reproduction
Previous
Next

Causes

More than 50 mutations in the GHR gene have been described in the approximately 250 known patients with GHRD. The report of the characterization of the GHR gene included the first description of a genetic defect of the GHR, a deletion of exons 3, 5, and 6; recognition that the exon 3 deletion represented an alternatively spliced variant without functional significance resolved the dilemma of explaining deletion of nonconsecutive exons.

In contrast to the alternatively spliced variant lacking exon 3, the first mutation of this exon has been described in a typical GHR-deficient patient with heterozygosity for a nonsense mutation in exon 4, and family studies indicate that heterozygosity for the exon 3 mutant has no effect. In addition to the original exon 5, 6 deletion, another deletion of exon 5 has been described, along with numerous nonsense mutations, missense mutations, frame shift mutations, splice mutations, and a unique intronic mutation resulting in insertion of a pseudo-exon. A number of other mutations have been described that are either polymorphisms or have not occurred in the homozygous or compound heterozygous state.[1, 26]

The point mutations that result in severe GH insensitivity when present in the homozygous state or as a compound heterozygote are all associated with the typical phenotype of severe GHD. All but a few of the defects result in absent or extremely low levels of GH binding protein (GHBP). Noteworthy is the D152H missense mutation that affects the dimerization site, thus permitting the production of the extracellular domain in normal quantities but failure of dimerization at the cell surface, which is necessary for signal transduction and IGF-I production. Two defects that are close to (G223G) or within (R274T) the transmembrane domain result in extremely high levels of GHBP. These defects interfere with the normal splicing of exon 8, which encodes the transmembrane domain, with the mature GHR transcript being translated into a truncated protein that retains GH binding activity but cannot be anchored to the cell surface.[26]

The intronic mutation present in the heterozygous state in a mother and daughter with relatively mild growth failure (both with standard deviation score (SDS) for height -3.6), and resulting in a dominant negative effect on GHR formation, is not associated with other phenotypic features of GH deficiency. This splice mutation preceding exon 9 results in an extensively attenuated, virtually absent intracellular domain.[27]

Japanese siblings and their mother have a similar heterozygous point mutation of the donor splice site in intron 9, also resulting in mild growth failure compared to GHRD but with definite, although mild, phenotypic features of GHD.[28] GHBP levels in the Caucasian patients were at the upper limit of normal with a radiolabeled GH binding assay and in Japanese patients the levels were twice the upper limit of normal using a ligand immunofunction assay. These heterozygous GHR mutants transfected into permanent cell lines have demonstrated increased affinity for GH compared to the wild-type full-length GHR, with markedly increased production of GHBP. When cotransfected with full-length GHR, a dominant negative effect results from overexpression of the mutant GHR and inhibition of GH-induced tyrosine phosphorylation and transcription activation. Naturally occurring truncated isoforms have also shown this dominant negative effect in vitro.

A novel intronic point mutation was discovered in a highly consanguineous family with 2 pairs of affected cousins with GHBP-positive GH insensitivity and severe short stature, but without the facial features of severe GHD or GHRD. This mutation resulted in a 108-bp insertion of a pseudo-exon between exons 6 and 7, predicting an in-frame, 36-residue amino acid sequence in a region critically involved in receptor dimerization.[29]

Five discrete homozygous mutations described in the 6 patients with STAT5b dysfunction have been associated with consanguinity.[8] Mutation of the ALS gene has been reported in 21 individuals from 16 families, with 16 discrete mutations noted, all resulting in absence of ALS and very low levels of IGF-I and IGFBP3 in the circulation, but modest, at worst, effects on rowth.[12, 13, 14, 15, 16, 17, 18] Seven discrete heterozygous mutations of the IGF-I receptor have been described, resulting in varying degrees of intrauterine and postnatal growth retardation, microcephaly, and mental retardation (from none to moderate).[7, 19, 20, 21, 22, 23] Thus far, only the 3 mutations previously noted for the IGF-I gene have been described.[2, 4, 5, 6]

Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Arlan L Rosenbloom, MD  Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Jaime Guevara-Aguirre, MD  Founder and General Director, The Institute of Endocrinology, Metabolism and Reproduction (IEMYR), Ecuador

Jaime Guevara-Aguirre, MD is a member of the following medical societies: Endocrine Society and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Phyllis W Speiser, MD  Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London)  Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References

  1. Rosenbloom AL. Genetic disorders of the hypothalamic-pituitary-GH/IGF-I axis. In: Preedy VR (ed). Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer-Verlag; p 2012:2723-2741.

  2. Rosenbloom AL. The physiology of human growth: a review. Reviews in Endocrinology. July 2008;36-48.

  3. Rosenbloom AL. Recombinant insulin growth factor I in growth therapy. In: Preedy VR (ed). Handbook of Growth and Growth Monitoring in Health and Disease Springer. New York: Verlag; p 2012:2743-2762.

  4. Woods KA, Camacho-Hübner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. Oct 31 1996;335(18):1363-7. [Medline].

  5. Walenkamp MJ, Karperien M, Pereira AM, et al. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab. May 2005;90(5):2855-64. [Medline].

  6. Bonapace G, Concolino D, Formicola S, Strisciuglio P. A novel mutation in a patient with insulin-like growth factor 1(IGF1) deficiency. J Med Genet. 2003;40:913–7.

  7. Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. Dec 4 2003;349(23):2211-22. [Medline].

  8. Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V. Defects in growth hormone receptor signaling. Trends Endocrinol Metab. May-Jun 2007;18(4):134-41. [Medline].

  9. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U. Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. Dec 1999;84(12):4436-43. [Medline].

  10. Laron Z, Kopchick JJ. History of Israeli cohort of Laron syndrome patients (1958-2009). In: Laron syndrome-from Man to Mouse. Springer-Verlag: Berlin-Heidelberg; 2011:3-7.

  11. Kranzler JH, Rosenbloom AL, Martinez V, Guevara-Aguirre J. Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. J Clin Endocrinol Metab. Jun 1998;83(6):1953-8. [Medline].

  12. Domene HM, Bengolea SV, Martinez AS, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med. Feb 5 2004;350(6):570-7. [Medline].

  13. Hwa V, Haeusler G, Pratt KL, et al. Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab. May 2006;91(5):1826-31. [Medline].

  14. Domene HM, Scaglia PA, Lteif A, et al. Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations. J Clin Endocrinol Metab. Nov 2007;92(11):4444-50. [Medline].

  15. Heath KE, Argente J, Barrios V, et al. Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. J Clin Endocrinol Metab. May 2008;93(5):1616-24. [Medline].

  16. van Duyvenvoorde HA, Kempers MJ, Twickler TB, et al. Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. Eur J Endocrinol. Aug 2008;159(2):113-20. [Medline].

  17. Fofanova-Gambetti OV, Hwa V, Kirsch S, et al. Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins. Horm Res. 2009;71(2):100-10. [Medline].

  18. Fofanova-Gambetti OV, Hwa V, Wit JM, Domene HM, Argente J, Bang P, et al. Impact of heterozygosity for acid-labile subunit (IGFALS) genemutations on stature: results from the international acid-labile subunit consortium. J Clin Endocrinol Metab. 2010/09;95(9):4184-91.

  19. Kawashima Y, Kanzaki S, Yang F, et al. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. Aug 2005;90(8):4679-87. [Medline].

  20. Walenkamp MJ, van der Kamp HJ, Pereira AM, et al. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab. Aug 2006;91(8):3062-70. [Medline].

  21. Inagaki K, Tiulpakov A, Rubtsov P, et al. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab. Apr 2007;92(4):1542-8. [Medline].

  22. Walenkamp MJ, de Muinck Keizer-Schrama SM, de Mos M, et al. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification. J Clin Endocrinol Metab. Jun 2008;93(6):2421-5. [Medline].

  23. Fang P, Schwartz ID, Johnson BD, et al. Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab. May 2009;94(5):1740-7. [Medline].

  24. Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone--a new inborn error of metabolism?. Isr J Med Sci. Mar-Apr 1966;2(2):152-5. [Medline].

  25. Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Diamond FB Jr, Rosenfeld RG. Growth hormone receptor deficiency in Ecuador: clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab. Feb 1993;76(2):417-23. [Medline].

  26. Rosenbloom AL, Guevara-Aguirre J. Lessons from the genetics of laron syndrome. Trends Endocrinol Metab. Sep 1998;9(7):276-83. [Medline].

  27. Ayling RM, Ross R, Towner P, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. May 1997;16(1):13-4. [Medline].

  28. Iida K, Takahashi Y, Kaji H, et al. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. Feb 1998;83(2):531-7. [Medline].

  29. Metherell LA, Akker SA, Munroe PB, et al. Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet. Sep 2001;69(3):641-6. [Medline]. [Full Text].

  30. Crosnier H, Gourmelen M, Prevot C, Rappaport R. Effects of nutrient intake on growth, insulin-like growth factors, and their binding proteins in a Laron-type dwarf. J Clin Endocrinol Metab. Jan 1993;76(1):248-50. [Medline].

  31. Guevara-Aguirre J, Vasconez O, Martinez V, et al. A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. Apr 1995;80(4):1393-8. [Medline].

  32. Rosenbloom AL. Mecasermin (recombinant human insulin like growth factor-I). Adv Therapy. 2009;26:40-54.

  33. Ekstrom K, Carlsson-Skwirut C, Ritzen EM, Bang P. Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growth. Horm Res Paediatr. 2011;76(5):355-66. [Medline].

  34. Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: comparison of two dosage levels and to GH-treated GH deficiency. J Clin Endocrinol Metab. Feb 1997;82(2):629-33. [Medline].

  35. Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. Feb 1989;10(1):68-91. [Medline].

  36. Ranke MB, Savage MO, Chatelain PG, Preece MA, Rosenfeld RG, Wilton P. Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes. Horm Res. 1999;51(3):128-34. [Medline].

  37. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE. 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. Mar 2007;92(3):902-10. [Medline].

  38. Klinger B, Laron Z. Three year IGF-I treatment of children with Laron syndrome. J Pediatr Endocrinol Metab. Jul-Sep 1995;8(3):149-58. [Medline].

  39. Rosenbloom AL, Rivkees SA. Is off label use of recombinant human insulin like growth factor (IGF)-I for growth promotion appropriate. J Clin Endocrinol Metab. 2010;95:505-508.

  40. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. Feb 2007;28(1):20-47. [Medline].

  41. Perry JK, Emerald BS, Mertani HC, Lobie PE. The oncogenic potential of growth hormone. Growth Horm IGF Res. Oct-Dec 2006;16(5-6):277-89. [Medline].

  42. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. Feb 16 2011;3(70):70ra13. [Medline].

 
Previous
Next
 
Diagram of the hypothalamic-pituitary-GH/IGF-I axis, showing mutational targets beginning with the GH-releasing hormone receptor (GHRHR), indicated in bold and italicized.
Reported patients with homozygous signal transduction and activator of translation (STAT5b) mutations.
Acid labile subunit (ALS) deficiency from mutations of the ALS gene in 15 patients. IGF-I, IGFBP3, target height, and near adult or adult height are expressed as standard deviation score (SDS). Target height is calculated as the mean parental height SDS.
Reported cases of mutations of the IGF-I receptor in 17 individuals from 7 families.
50-year-old woman with GHRD (right) and her 75-year-old mother, indicating premature aging appearance. Photos were taken at the same distance, emphasizing the small size of the subject and relative foreshortening of the facies.
10-year-old Ecuadorian girl with GHRD/Laron syndrome, who was performing at the top of the class, with her classmates.
15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for 11-year-old boy, 4th from the left and his 8-year-old brother holding the ball who is almost the same height.
21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, and his IGF-I level is 4 times hers and his IGFBP3 level twice hers.
Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Doctor Frank Diamond) and the seated chief.
Six-month, placebo-controlled, double-blind study of rhIGF-I in 16 Ecuadorian children with GHRD, followed by 6 months open label rhIGF-I therapy of the entire group.
Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
Table. Features of GH Resistance Causes
ConditionGrowth failureGHGH binding proteinIGF-IIGFBP3
Genetic
GHRD - Recessive formsSevereElevatedAbsent-low*Very lowVery low
GHRD - Dominant negative formsMild-moderateElevatedIncreasedVery lowLow-normal
STAT5b mutationSevereElevatedNormalVery lowVery low
ALS mutationNone-moderateNormalNormalVery lowVery low
IGF-I gene mutationSevereElevatedNormalAbsent-high**Low-normal
IGF-I receptor mutationMild-moderateNormal-elevatedNormalNormal-elevatedNormal-elevated
Acquired
GH inhibiting antibodiesSevereAbsentNormalVery lowLow
MalnutritionNone-mildElevatedDecreasedVariableVariable
Diabetes mellitusNone-mildElevatedDecreasedDecreasedIncreased
Renal diseaseMild-severeNormalDecreasedNormalIncreased
Hepatic diseaseMild-severeElevatedNormal-increasedDecreasedNormal
*Increased in mutations of or near the transmembrane domain of the GH receptor



**Absent with partial IGF-I gene deletion; very high with abnormal IGF-I



Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.