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]
This section is empty. You can help by adding to it. (July 2017)
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
.jpg/440px-A_map_of_Canaan_(8343807206).jpg)
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
.jpg/440px-A_map_of_Canaan_(8343807206).jpg)
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
.jpg/440px-A_map_of_Canaan_(8343807206).jpg)
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
anterior
Acromegaly
Hyperprolactinaemia
Pituitary

Pituitary ACTH hypersecretion
posterior (SIADH)
general (Nelson's syndrome)
Hypopituitarism
anterior
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
.png)
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)
GC
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)
See also
cell surfa