Laron Syndrome

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Laron's syndrome, or Laron-type dwarfism, is an autosomal recessive disorder characterized by an insensitivity to growth hormone (GH), usually caused by a mutant growth hormone receptor. It causes short stature and an increased sensitivity to insulin which means that they are less likely to develop diabetes mellitus type 2[1] and possibly cancer as well. It can be treated with injections of recombinant IGF-1.

Contents

1 Clinical characteristics 2 Pathophysiology 3 Diagnosis 4 Treatment 5 Prognosis 6 Incidence 7 Eponym 8 Homo floresiensis 9 See also 10 References 11 External links

Clinical characteristics[edit] The principal feature of Laron syndrome
Laron syndrome is abnormally short stature (dwarfism). Physical symptoms include: prominent forehead, depressed nasal bridge, underdevelopment of mandible, truncal obesity,[2] and micropenis in males. The breasts of females reach normal size, and in some are large in relation to body size.[3] It has been suggested that hyperprolactinemia may contribute to the enlarged breast size.[4] Seizures
Seizures are frequently seen secondary to hypoglycemia. Some genetic variations decrease intellectual capacity.[5] Laron syndrome
Laron syndrome patients also do not develop acne, except temporarily during treatment with IGF-1
IGF-1 (if performed).[4] In 2011, it was reported that people with this syndrome in the Ecuadorian villages are resistant to cancer and diabetes and are somewhat protected against aging.[6][7][8] This is consistent with findings in mice with a defective growth hormone receptor gene.[9] Pathophysiology[edit]

Laron syndrome
Laron syndrome has an autosomal recessive pattern of inheritance.

Molecular genetic investigations have shown that this disorder is mainly associated with mutations in the gene for the GH receptor. These can result in defective hormone binding to the ectodomain or reduced efficiency of dimerization of the receptor after hormone occupancy. There are exceptionally low levels of insulin-like growth factor (IGF-1) and its principal carrier protein, insulin-like growth factor binding protein 3. A related condition involving postreceptor insensitivity to growth hormone has been associated with STAT5B.[10] Diagnosis[edit]

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Treatment[edit] Administration of GH has no effect on IGF-1
IGF-1 production, therefore treatment is mainly by biosynthetic IGF-1. IGF-1
IGF-1 must be taken before puberty to be effective.[9] The drug product Increlex
Increlex (mecasermin), developed by the company Tercica, purchased by Ipsen, was approved by the US Food and Drug Administration in August 2005 for replacing IGF-1
IGF-1 in patients who are deficient.[11] IPLEX (Mecasermin rinfabate) is composed of recombinant human IGF-1 (rhIGF-1) and its binding protein IGFBP-3. It was approved by the U.S. Food and Drug Administration
Food and Drug Administration (FDA) in 2005 for treatment of primary IGF-1
IGF-1 deficiency or GH gene deletion.[12][13] Side effects from IPLEX are hypoglycemia. IPLEX's manufacturing company, Insmed, after selling its protein production facility, can no longer develop proteins, thus can no longer manufacture IPLEX as of a statement released in July 2009.[14] Prognosis[edit] People with Laron syndrome
Laron syndrome have strikingly low rates of cancer and diabetes, although they appear to be at increased risk of accidental death due to their stature.[9][7] Incidence[edit] The majority of reported cases of Laron syndrome
Laron syndrome have been in people with Semitic origins, almost all of them being Jews
Jews or assimilated descendants of Jews. Numerous Laron syndrome
Laron syndrome patients are found in Israel
Israel among the country's diverse Jewish population composed of Jews
Jews from around the world, as well as patients outside Israel
Israel originally from communities of the Jewish diaspora, such as Egypt
Egypt and Iraq. There is also a disproportionate number of sufferers found in remote villages in Ecuador
Ecuador who are descended from colonial-era Jewish-origin New Christian conversos (Sephardi Jews
Jews who themselves, or whose forebears, had been compelled to convert to Catholicism back in Spain) who had covertly migrated to Ecuador
Ecuador during the Spanish Conquest despite the Spanish Crown's prohibition of their emigration to its colonies and territories as a result of the Inquisition.[6][9] Other patients include people of other Semitic non-Jewish origins, including from Saudi Arabia. Eponym[edit] It is named after Zvi Laron, the Israeli researcher who, with A. Pertzelan and S. Mannheimer, first reported the condition in 1966,[15][16] based upon observations which began in 1958.[17] Resistance to GH was first reported by Laron in 1966. Since then, severe resistance to GH, characterized by grossly impaired growth despite normal levels of GH in serum, has been termed Laron syndrome. Homo floresiensis[edit] Recent publications have proposed that Homo floresiensis
Homo floresiensis represented a population with widespread Laron syndrome.[18][19] This is only one of several competing hypotheses, and has received criticism as insufficient to explain the "range features observed in H. floresiensis".[20] See also[edit]

Hypothalamic–pituitary–somatic axis

References[edit]

^ Bartke A, Sun LY, Longo V. Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and Longevity. Physiological Reviews. 2013;93(2):571-598. doi:10.1152/physrev.00006.2012. ^ Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N (2006). "Body composition in untreated adult patients with Laron syndrome
Laron syndrome (primary GH insensitivity)". Clin. Endocrinol. 65 (1): 114–7. doi:10.1111/j.1365-2265.2006.02558.x. PMID 16817829. ^ Laron, Zvi (2004). "Laron Syndrome (Primary Growth Hormone Resistance or Insensitivity): The Personal Experience 1958–2003". The Journal of Clinical Endocrinology
Endocrinology & Metabolism. 89 (3): 1031–1044. doi:10.1210/jc.2003-031033. ISSN 0021-972X. PMID 15001582. ^ a b Zvi Laron; J. Kopchick (25 November 2010). Laron Syndrome - From Man to Mouse: Lessons from Clinical and Experimental Experience. Springer Science & Business Media. pp. 253, 255. ISBN 978-3-642-11183-9. ^ Shevah O, Kornreich L, Galatzer A, Laron Z (2005). "The intellectual capacity of patients with Laron syndrome
Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities". Horm. Metab. Res. 37 (12): 757–60. doi:10.1055/s-2005-921097. PMID 16372230. ^ a b Guevara-Aguirre, J; Balasubramanian, P; Guevara-Aguirre, M; Wei, M; Madia, F; Cheng, CW; Hwang, D; Martin-Montalvo, A; et al. (2011). "Growth Hormone
Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans". Science Translational Medicine. 3 (70): 70ra13. doi:10.1126/scitranslmed.3001845. PMC 3357623 . PMID 21325617. ^ a b Bai, Nina. "Defective Growth Gene
Gene in Rare Dwarfism
Dwarfism Disorder Stunts Cancer and Diabetes". Scientific American. Retrieved 17 February 2011. ^ Winerman, Lea. "Study: Dwarfism
Dwarfism Gene
Gene May Offer Protection From Cancer, Diabetes". PBS. Retrieved 17 February 2011. ^ a b c d Wade, Nicholas (17 February 2011). "Ecuadorean Villagers May Hold Secret to Longevity". The New York Times. ISSN 0362-4331. Retrieved 17 February 2011. ^ Hwa V, Camacho-Hübner C, Little BM, et al. (2007). "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene". Horm. Res. 68 (5): 218–24. doi:10.1159/000101334. PMID 17389811. ^ " Increlex
Increlex (mecasermin)". Centerwatch.com. Retrieved 21 Nov 2014. ^ Kemp, S.F. "Mecasermin rinfabate". Thomson Reuters. Retrieved 5 March 2011. ^ Meyer, Robert. "Approval letter (Mecasermin rinfabate)" (PDF). FDA. Retrieved 5 March 2011. ^ "Insmed Provides Update on Supply of IPLEX(TM)". Retrieved 25 Aug 2017. ^ synd/2825 at Who Named It? ^ Laron Z, Pertzelan A, Mannheimer S (1966). "Genetic pituitary dwarfism with high serum concentration of growth hormone—a new inborn error of metabolism?". Isr. J. Med. Sci. 2 (2): 152–5. PMID 5916640. ^ Laron Z (2004). " Laron syndrome
Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958–2003". J. Clin. Endocrinol. Metab. 89 (3): 1031–44. doi:10.1210/jc.2003-031033. PMID 15001582. ^ Hershkovitz I, Kornreich L, Laron Z (2007). "Comparative skeletal features between Homo floresiensis
Homo floresiensis and patients with primary growth hormone insensitivity (Laron syndrome)". Am. J. Phys. Anthropol. 134 (2): 198–208. doi:10.1002/ajpa.20655. PMID 17596857. ^ Culotta E (2007). "Paleoanthropology. The fellowship of the hobbit". Science. 317 (5839): 740–742. doi:10.1126/science.317.5839.740. PMID 17690271. ^ Aiello, Leslie C. (2010). "Five years ofHomo floresiensis". American Journal of Physical Anthropology. 142: NA–NA. doi:10.1002/ajpa.21255. ISSN 0002-9483. PMID 20229502.

External links[edit]

Classification

V · T · D

ICD-10: E34.3 ICD-9-CM: 259.4 OMIM: 262500 245590 MeSH: D046150 DiseasesDB: 7262

External resources

eMedicine: ped/1277 Orphanet: 633

Laron syndrome
Laron syndrome at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e

Diseases of the endocrine system (E00–E35, 240–259)

Pancreas/ glucose metabolism

Hypofunction

Diabetes mellitus

types:

type 1 type 2 gestational MODY 1
MODY 1 2 3 4 5 6

complications

coma angiopathy ketoacidosis nephropathy neuropathy retinopathy cardiomyopathy

insulin receptor (Rabson–Mendenhall syndrome) Insulin resistance

Hyperfunction

Hypoglycemia beta cell (Hyperinsulinism) G cell
G cell (Zollinger–Ellison syndrome)

Hypothalamic/ pituitary axes

Hypothalamus

gonadotropin

Kallmann syndrome Adiposogenital dystrophy

CRH (Tertiary adrenal insufficiency) vasopressin (Neurogenic diabetes insipidus) general ( Hypothalamic
Hypothalamic hamartoma)

Pituitary

Hyperpituitarism

Acromegaly Hyperprolactinaemia Pituitary
Pituitary ACTH hypersecretion

posterior (SIADH) general (Nelson's syndrome)

Hypopituitarism

Kallmann syndrome Growth hormone
Growth hormone deficiency Hypoprolactinemia ACTH deficiency/Secondary adrenal insufficiency GnRH insensitivity FSH insensitivity LH/hCG insensitivity

posterior (Neurogenic diabetes insipidus) general

Empty sella syndrome Pituitary
Pituitary apoplexy Sheehan's syndrome Lymphocytic hypophysitis

Thyroid

Hypothyroidism

Iodine deficiency Cretinism

Congenital hypothyroidism

Myxedema Euthyroid sick syndrome

Hyperthyroidism

Hyperthyroxinemia

Thyroid hormone resistance Familial dysalbuminemic hyperthyroxinemia

Hashitoxicosis Thyrotoxicosis factitia Graves' disease

Thyroiditis

Acute infectious Subacute

De Quervain's Subacute lymphocytic

Autoimmune/chronic

Hashimoto's Postpartum Riedel's

Goitre

Endemic goitre Toxic nodular goitre Toxic multinodular goiter

Thyroid nodule

Parathyroid

Hypoparathyroidism

Pseudohypoparathyroidism Pseudopseudohypoparathyroidism

Hyperparathyroidism

Primary Secondary Tertiary Osteitis fibrosa cystica

Adrenal

Hyperfunction

aldosterone: Hyperaldosteronism/Primary aldosteronism

Conn syndrome Bartter syndrome Glucocorticoid remediable aldosteronism

AME Liddle's syndrome 17α CAH

cortisol: Cushing's syndrome
Cushing's syndrome (Pseudo-Cushing's syndrome)

sex hormones: 21α CAH 11β CAH

Hypofunction/ Adrenal insufficiency (Addison's, WF)

aldosterone: Hypoaldosteronism

21α CAH 11β CAH

cortisol: CAH

Lipoid 3β 11β 17α 21α

sex hormones: 17α CAH

Gonads

ovarian: Polycystic ovary syndrome Premature ovarian failure

testicular: enzymatic

5α-reductase deficiency 17β-hydroxysteroid dehydrogenase deficiency aromatase excess syndrome

Androgen receptor
Androgen receptor (Androgen insensitivity syndrome)

general: Hypogonadism (Delayed puberty) Hypergonadism

Precocious puberty

Hypoandrogenism Hypoestrogenism Hyperandrogenism Hyperestrogenism Postorgasmic illness syndrome

Height

Dwarfism/Short stature

Midget Laron syndrome Psychosocial Ateliosis

Gigantism

Multiple

Autoimmune polyendocrine syndrome multiple

APS1 APS2

Carcinoid syndrome Multiple endocrine neoplasia

1 2A 2B

Progeria

Werner syndrome Acrogeria Metageria

Woodhouse–Sakati syndrome

v t e

Cell surface receptor
Cell surface receptor deficiencies

G protein-coupled receptor (including hormone)

Class A

TSHR ( Congenital hypothyroidism
Congenital hypothyroidism 1) LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty) FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis) GnRHR (Gonadotropin-releasing hormone insensitivity) EDNRB (ABCD syndrome, Waardenburg syndrome
Waardenburg syndrome 4a, Hirschsprung's disease 2) AVPR2
AVPR2 ( Nephrogenic diabetes insipidus 1) PTGER2 (Aspirin-induced asthma)

Class B

PTH1R
PTH1R (Jansen's metaphyseal chondrodysplasia)

Class C

CASR (Familial hypocalciuric hypercalcemia)

Class F

FZD4
FZD4 ( Familial exudative vitreoretinopathy
Familial exudative vitreoretinopathy 1)

Enzyme-linked receptor (including growth factor)

RTK

ROR2
ROR2 (Robinow syndrome) FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) FGFR2 (Apert syndrome, Antley–Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome) FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) INSR (Donohue syndrome Rabson–Mendenhall syndrome) NTRK1 (Congenital insensitivity to pain with anhidrosis) KIT (KIT Piebaldism, Gastrointestinal stromal tumor)

STPK

AMHR2 ( Persistent Müllerian duct syndrome
Persistent Müllerian duct syndrome II)

TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia) TGFBR1/TGFBR2 (Loeys–Dietz syndrome)

GUCY2D
GUCY2D ( Leber's congenital amaurosis 1)

JAK-STAT

Type I cytokine receptor: GH (Laron syndrome) CSF2RA ( Surfactant metabolism dysfunction 4)

MPL (Congenital amegakaryocytic thrombocytopenia)

TNF receptor

TNFRSF1A
TNFRSF1A (TNF receptor associated periodic syndrome) TNFRSF13B
TNFRSF13B ( Selective immunoglobulin A deficiency
Selective immunoglobulin A deficiency 2) TNFRSF5 (Hyper-IgM syndrome type 3) TNFRSF13C
TNFRSF13C (CVID4) TNFRSF13B
TNFRSF13B (CVID2) TNFRSF6 ( Autoimmune lymphoproliferative syndrome 1A)

Lipid receptor

LRP: LRP2
LRP2 (Donnai–Barrow syndrome) LRP4 (Cenani–Lenz syndactylism) LRP5
LRP5 (Worth syndrome, Familial exudative vitreoretinopathy
Familial exudative vitreoretinopathy 4, Osteopetrosis
Osteopetrosis 1)

LDLR (LDLR Familial hypercholesterolemia)

Other/ungrouped

Immunoglobulin superfamily: AGM3, 6

Integrin: LAD1 Glanzmann's thrombasthenia Junctional epidermolysis bullosa with pyloric atresia

EDAR
EDAR ( EDAR
EDAR hypohidrotic ectodermal dysplasia)

PTCH1
PTCH1 (Nevoid basal-cell carcinoma syndrome) BMPR1A
BMPR1A ( BMPR1A
BMPR1A juvenile polyposis syndrome) IL2RG
IL2RG (X-linked severe combined immunodeficiency)