The clinical presentation of patients suffering from Laron syndrome, occurring due to growth hormone (GH) insensitivity, is diverse, but the two most important features are dwarfism and obesity [1] [2]. The majority of patients exhibit short stature from birth, and a progressive deficit in growth and development throughout childhood leads to finite body heights between 4 and 10 height standard deviations (SDs) below the average for appropriate age [1]. In addition, very small hands and feet (known as acromicria) are observed, as well as short limbs compared to the size of the trunk [1]. Obesity is progressive, despite the fact that the caloric intake is normal or even reduced, and occurs on the grounds of reduced muscle and bone content [1]. It often predisposes patients to sleep apnea, skin wrinkling and joint pain as a result of poor muscle strength, which may be quite debilitating [1] [2] [3]. Genital and hormonal abnormalities, such as hypogonadism and underdevelopment of the genital organs (or hypogenitalism, manifesting as micropenis, small testes, and reduced ovarian size, respectively) are frequent findings in children suffering from this genetic disorder. Moreover, puberty is often delayed, and secondary sexual characteristics typically develop later in adolescence [1] [3] [4]. Facial changes, including protrusion of the forehead, a saddle nose, hypoplasia of the mandible and other facial bones, thin hair and delayed teething are common features as well [1] [5]. Delayed nail growth and blue sclerae may also be present [1].

• Short Stature

  stature due to growth hormone resistance Complete growth hormone insensitivity Primary GH resistance GH receptor deficiency Primary growth hormone insensitivity edit English Laron syndrome congenital disorder characterized by marked short stature associated [wikidata.org]

  We describe the case of a 3.8 years old girl with symmetrical short stature (-3.76 SDS), low IGF-1 and IGFBP-3, in presence of normal GH levels. Parents were not relatives and there was no family history of short stature. [ncbi.nlm.nih.gov]

  Approach to short stature. Indian J Pediatr 2015; 82: 462-470. Hasegawa K, Tanaka H. Children with short‐limbed short stature in pediatric endocrinological services in Japan. Pediatr Intern 2014; 56; 809-812. [alliedacademies.org]

• Short Stature in Children

  The studies enrolled a total of 71 children suffering from extreme short stature; all children exhibited symptoms of Primary IGFD, including slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. [centerwatch.com]

  English - treatment of short stature in children with turner syndrome, confirmed by chromosome Finnish - kromosomitutkimuksella varmistetun turnerin oireyhtymään liittyvän lyhytkasvuisuuden Last Update: 2012-04-10 Usage Frequency: 3 Quality: Reference [mymemory.translated.net]

• Fever

  It is excreted by the kidney. [3, 4, 5, 6] Persons may become deficient in thiamine by not ingesting enough vitamin B-1 through the diet or may become deficient through excess use; the latter may result from hyperthyroidism, pregnancy, lactation, or fever [emedicine.medscape.com]

  Conversely, the term pseudo-relapse refers to recrudescence of previously experienced MS symptoms concomitant to an elevation of body temperature, as during physical activity or infection-related fever. [frontiersin.org]

  Hydration deficiencies and abnormal losses (e.g., fever, vomiting, diarrhea) should be addressed at the start of a replenishment phase. The choice of replacement fluid is thereby especially relevant. [mdpi.com]

• Atrial Septal Defect

  Valvular pulmonary stenosis and a secundum atrial septal defect was detected by echocardiography. [content.sciendo.com]

• Weight Gain

  A prospective examination of weight gain in hospitalized adolescents with anorexia nervosa on a recommended refeeding protocol. J. Adolesc. Health 2012, 50, 24–29. [mdpi.com]

• High Pitched Voice

  Clinically, all three presented with the typical craniofacies of Laron syndrome, consisting of prominent forehead and hypoplastic nasal bridge, high-pitched voice, short stature, and central obesity. [ncbi.nlm.nih.gov]

  Genitalia : Small gonads and external genitalia Other features : include neonatal hypoglycaemia, high pitched voice, decreased sweating. Bloods : Growth hormone level is increased or normal. Low levels of Insulin growth factor 1(IGF1). [genetics4medics.com]

  Other features include hypoplasia of the base of the skull with small face and mandible, delayed closure of the fontanels, saddle nose, hypotrichosis, delayed dentition, tooth discoloration, crowding of defective teeth, high-pitched voice, acromicria, [whonamedit.com]

• Saddle Nose

  They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. [ncbi.nlm.nih.gov]

  Other features include hypoplasia of the base of the skull with small face and mandible, delayed closure of the fontanels, saddle nose, hypotrichosis, delayed dentition, tooth discoloration, crowding of defective teeth, high-pitched voice, acromicria, [whonamedit.com]

  Upon examination she was noted to have protruded forehead, thin hair, small hands and feet, and a saddle nose. No teething defects were found, and no blue sclera was observed (Figure 1). [alliedacademies.org]

  Facial changes, including protrusion of the forehead, a saddle nose, hypoplasia of the mandible and other facial bones, thin hair and delayed teething are common features as well. Delayed nail growth and blue sclerae may also be present. [symptoma.com]

• Failure to Thrive

  […] to Thrive Fairbank Disease - Multiple Epiphyseal Dysplasia Familial Dysautonomia Fanconi Anemia Fetal Alcohol Syndrome and Support Fetal Anti-Convulsant Syndrome Fetal Veapkote Syndrome / Fetal Balproate Acid Syndrome Froelich's Syndrome Gerneralized [magicfoundation.org]

  As a result, they often have fatty, foul-smelling stools (steatorrhea); are slow to grow and gain weight (failure to thrive); and experience malnutrition. Pancreatic insufficiency often improves with age in people with Shwachman-Diamond syndrome. [ghr.nlm.nih.gov]

  PATIENT REPORT A 19-month old girl was admitted to the fourth Pediatric Dept of Aristotle University because of failure to thrive. According to the parents, both weight and length had remained unchanged since the age of 6 months. [hormones.gr]

  Failure to thrive became evident after the first year of life, when both her height (61 cm, -7.06 standard deviations (SDs)) and weight (6610 g) were well below the third percentile. [jmedicalcasereports.biomedcentral.com]

• Blue Sclera

  It is characterized by short stature, blue sclerae, hip degeneration, and delayed bone age. Growth Hormone Insensitivity Syndrome; Laron Dwarfism (or Laron-type Dwarfism); Primary GH Insensitivity (Primary GH Resistance); Pituitary Dwarfism II. [accessanesthesiology.mhmedical.com]

  Patients occasionally have blue sclera and hip degeneration. Etiology The disease is due to mutations in the GHR gene (5p14-p12). [orpha.net]

  The siblings had typical dysmorphic facies: frontal bossing, shallow orbit with blue sclera, saddle nose, mid-face hypoplasia, thin and silky hair and pale texture of skin. [pubs.sciepub.com]

  No teething defects were found, and no blue sclera was observed (Figure 1). [alliedacademies.org]

• Severe Short Stature

  short stature and IGF-1 deficiency caused by GH insensitivity, of whom 54 were treated for at least 1 year (45 had Laron syndrome, 7 had GH antibodies, and 2 had unspecified defects). [medical-dictionary.thefreedictionary.com]

  The proband is a 3.5 year-old Druse girl with severe short stature (height SDS -5.1), high GH (250 micrograms/l), low IGF-I (2.7 nmol/l) and IGFBP-3 (410 micrograms/l), both unresponsive to exogenous GH. [ncbi.nlm.nih.gov]

• Short Arm

  Laron syndrome is characterized by short stature, obesity, low blood sugar in infancy, as well as short arms and legs. [patientworthy.com]

  The chromosome analysis with the high accuracy technique demonstrated a large deletion of the short arm in one allele of chromosome 5 from p11 to p13.1 [46, XX, del (5) (p11-p13.1)]. [ncbi.nlm.nih.gov]

  This process is due to mutations in the GHR ( growth hormone receptor ) gene, located on the short arm of chromosome 5 (5p13.1-p12). [ivami.com]

  The GHR gene is located on the short arm of chromosome 5 and includes 9 coding exons (Fang et al., 2007Fang P, Riedl S, Amselem S, Pratt KL, Little BM, Haeusler G, Hwa V, Frisch H and Rosenfeld RG (2007) Primary growth hormone (GH) insensitivity and insulin-like [scielo.br]

• Alopecia

  Young adults have various degrees of alopecia, more pronounced in males. OBJECTIVE: The aim of the present study was to investigate the effect of primary IGF-1 deficiency on hair structure. [ncbi.nlm.nih.gov]

  […] stature due to endocrine disorder Approximate Synonyms Ateliotic dwarf Ateliotic dwarfism without insulinopenia Congenital malformation syndromes associated with short stature Constitutional short stature Dolichocephalic dwarfism Dwarfism Dwarfism, alopecia [icd9data.com]

  Young adults have various degrees of alopecia, more pronounced in males. Objective: The aim of the present study was to investigate the effect of primary IGF-1 deficiency on hair structure. [karger.com]

• Suggestibility

  In cells expressing the I153T and V155G mutants, binding of [125I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. [ncbi.nlm.nih.gov]

  Studies suggest that people with Laron syndrome have a significantly reduced risk of cancer and type 2 diabetes. [ghr.nlm.nih.gov]

• Frontal Bossing

  She presented frontal bossing and depressed nasal bridge. IGF-1 generation test showed no response, suggesting a GH resistance evidence. [ncbi.nlm.nih.gov]

  Laron syndrome is characterized by severe short stature, severe growth retardation, delayed bone age, truncal obesity, severe hypoglycemia, blue sclerae, hip degeneration and characteristic facies with frontal bossing. [preventiongenetics.com]

  The siblings had typical dysmorphic facies: frontal bossing, shallow orbit with blue sclera, saddle nose, mid-face hypoplasia, thin and silky hair and pale texture of skin. [pubs.sciepub.com]

  In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability [flipper.diff.org]

  She had mild frontal bossing, midfacial hypoplasia, a high-pitched voice, and blue sclerae. [content.sciendo.com]

• Cesarean Section

  The younger sister, aged 3 years, was born at term by cesarean section because of breech presentation with a birth weight of 2,700 g (–1.0 SDS). Birth length was not recorded. [content.sciendo.com]

• Seizure

  He became seizure-free on antiseizure medications (ASMs). He did not suffer from hypoglycemic episodes throughout his childhood or adulthood and had normal glucose levels during his seizures. [karger.com]

  A focal (previously called partial) seizure is another common seizure type. Most focal seizures start in the temporal lobes and can show themselves in many different ways. [epilepsy.org.uk]

  This syndrome, also called LGS, has multiple types of seizures, including tonic (stiffening) and atonic (drop) seizures. Other types of generalized seizures are usually seen such as absence, myoclonic, and tonic clonic seizures. [epilepsy.com]

  These include myoclonic seizures, which are characterized by abnormal, jerky movements and may occur alone or in conjunction with atypical absence seizures; tonic-clonic seizures (once known as grand mal seizures), which last a couple of minutes and are [rarediseases.org]

• Convulsions

  It describes Laron Syndrome, a disease that results in dwarfism, obesity and an increased risk of convulsive disorders, but also results in a dramatically reduced risk for diabetes and cancer. [islaslab.blogspot.com]

  This includes convulsive and non-convulsive status epilepticus. Your child’s doctor will discuss a ‘rescue’ or emergency care plan with you to treat any prolonged or repeated seizures. [epilepsy.org.uk]

  Side Effects Adverse events associated with the use of Symlin may include, but are not limited to, the following: Bruising Lipohypertrophy Otitis Media Snoring Headache Dizziness Convulsions Vomiting Ear pain Hypoacusis Cardiac Murmur Arthralgia Hypoglycemia [centerwatch.com]

  Other types: Atypical absence seizures: staring spells with blinking, smacking or chewing, rubbing hands together (called automatisms) Myoclonic seizures: brief muscle twitches or jerks in the neck, shoulders, upper arms, and face Tonic-clonic seizures: convulsions [kidshealth.org]

  […] with Laron syndrome almost completely avoided cancer and diabetes (although, unlike yeast and mice, they didn't live longer -- the people with Laron syndrome were more likely than their relatives to die in accidents, of alchohol-related causes, or of convulsive [web.archive.org]

• Febrile Seizures

  Occasionally there is a history of previous febrile seizures, focal seizures or generalized seizures. [epilepsydiagnosis.org]

  In a series of 23 patients with cryptogenic LGS, 2.5-47.8% had a family history of epilepsy and febrile seizures. [emedicine.medscape.com]

The diagnosis of Laron syndrome can be difficult to attain without a thorough patient history and a meticulous physical examination. The autosomal recessive nature of the disorder may be the reason why it is identified almost exclusively in families with consanguineous marriages, and the majority of patients are of Middle-Eastern or Mediterranean origin [1] [2]. For this reason, the presence of similar symptoms and signs in among close relatives or siblings may be a valuable clue toward the diagnosis, whereas a complete physical examination provides sufficient clinical criteria to assume impaired growth hormone activity. Basic laboratory workup should include estimation of glucose levels, as many patients suffer from hypoglycemia, the later development of diabetes mellitus and insulin intolerance, together with serum alkaline phosphatase (ALP), creatinine, a full lipid profile, and hormonal assessment [1]. Paradoxically, growth hormone (GH) levels are normal or markedly elevated when exogenous stimulation is performed, but the values of insulin-like growth factor 1 (IGF-1) are quite low, which serves as one of the key regulators of GH activity [1]. Low IGF-1 levels are thought to explain the mild pancytopenia that is observed in patients, due to its potential role in erythropoiesis [1]. Imaging studies, such as plain radiography and computed tomography (CT), could be used to assess skeletal and soft-tissue changes, respectively. Even though the diagnosis is often made based on clinical and laboratory criteria [3] [6], genetic studies should be carried out, if possible, in order to confirm GH insensitivity [1].

• Hypercholesterolemia

  […] hormone) causes dwarfism, acromicria, organomicria, marked obesity, insulin resistance, retardation of skeletal maturation and osteoporosis, as well as muscular and central nervous tissue underdevelopment, and a series of biochemical changes including hypercholesterolemia [ncbi.nlm.nih.gov]

  […] the minimum volume for the test, please contact CGC Genetics 2 Maximum shipping time to ensure sample quality Turnaround Time (Days) - 60 CPT Codes - 81405 Specialties - Rare diseases, Endocrinology, Pediatrics CGC Reference - 1387 Associated Tests Hypercholesterolemia [cgcgenetics.com]

  Prognosis Prognosis seems good but with age, patients may develop obesity, hypercholesterolemia and have increased risk of fractures due to osteopenia. The documents contained in this web site are presented for information purposes only. [orpha.net]

• Dyslipidemia

  Codes - 81405 Specialties - Rare diseases, Endocrinology, Pediatrics CGC Reference - 1387 Associated Tests Hypercholesterolemia, familial (NGS panel of 15 genes) Syndromes with short stature (WES based NGS panel of 100 genes, including CNV analysis) Dyslipidemia [cgcgenetics.com]

  […] particularly education and marital status, leisure time activity such as physical activity, social engagement and mental activities, psychological factors such as depression, cardiovascular and metabolic risk factors: obesity, diabetes, hypertension and dyslipidemia [ukm.my]

  Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet. Endocrinology 146 : 920–930, 2005. Crossref PubMed ISI Google Scholar 229. [doi.org]

There is currently no approved treatment available for growth deficiency due to Laron syndrome. [medical-dictionary.thefreedictionary.com]

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]. [jmedicalcasereports.biomedcentral.com]

Growth velocity decreased in the 6-12th month of combined treatment (0.9 cm/6 months), and treatment was suspended. [ncbi.nlm.nih.gov]

What Is The Treatment For Laron Syndrome? To date, there is no cure for Laron syndrome. The primary treatment for Laron Syndrome is on improving growth. [hypogal.com]

Prevention - Laron syndrome Diagnosis - Laron syndrome Prognosis - Laron syndrome The long-term outlook (prognosis) for people with Laron syndrome is generally good. [checkorphan.org]

Prognosis Prognosis seems good but with age, patients may develop obesity, hypercholesterolemia and have increased risk of fractures due to osteopenia. The documents contained in this web site are presented for information purposes only. [orpha.net]

Etiology The disease is due to mutations in the GHR gene (5p14-p12). [orpha.net]

Deletions and mutations in the growth hormone receptor (GHR) gene are the underlying etiology of Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS), an autosomal recessive disease. [ncbi.nlm.nih.gov]

Epidemiological studies have shown that LS occurs more often in consanguineous families and isolates, and it has been described in several countries in South East Asia. [ncbi.nlm.nih.gov]

Summary Epidemiology The disease has been described in more than 250 cases and is more frequent in Semitic or Mediterranean populations. Males and females are equally affected. [orpha.net]

The genetic basis of the syndrome is fully considered, and all aspects of the pathophysiology of IGF-I deficiency are described. Data derived from the recently generated mouse model of LS are reviewed and compared with the human LS experience. [saxo.com]

Additional chapters examine the pathophysiology of insulin-dependent diabetes mellitus, the molecular genetics of thyroid cancer, the molecular basis of hypophosphatemic rickets, and inherited diabetes insipidus. [books.google.com]

Prevention - Laron syndrome Diagnosis - Laron syndrome Prognosis - Laron syndrome The long-term outlook (prognosis) for people with Laron syndrome is generally good. [checkorphan.org]

The community includes many members with Laron syndrome, a deficiency in a gene that prevents the body from using growth hormone. [medical-dictionary.thefreedictionary.com]

I love the woman's reaction when you said do you know you could be the key to preventing cancer in the world. It was a lovely expression. Thank you so much, john, for the journey. [abcnews.go.com]

Currently, cancer prevention mainly revolves around changing lifestyle factors. According to the World Health Organisation, "at least one-third of all cancer cases are preventable". [huffingtonpost.co.uk]

This mutation is expected to prevent the translation of the protein. We present clinical, biochemical and molecular evidence of Laron syndrome as the result of a mutation (ATG-->TTG) in the codon for the initial methionine of the GHR gene. [ncbi.nlm.nih.gov]

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2. Kanety H, Hemi R, Ginsberg S, et al. Total and high molecular weight adiponectin are elevated in patients with Laron syndrome despite marked obesity. Eur J Endocrinol. 2009;161(6):837-844.
3. Phanse-Gupte SR, Khadilkar VV, Khadilkar AV. Clinical features and endocrine profile of Laron syndrome in Indian children. Indian J Endocrinol Metab. 2014;18(6):863-867.
4. Goswami S, Ghosh S, Chowdhury S. Growth hormone insensitivity syndrome: A sensitive approach. Indian J Endocrinol Metab. 2012;16(5):817-818.
5. Cotta OR, Santarpia L, Curtò L, et al. Primary growth hormone insensitivity (Laron syndrome) and acquired hypothyroidism: a case report. J Med Case Reports. 2011;5:301.
6. Guleria S, Sharma J, Kaushik SL. Laron syndrome. J Postgrad Med. 2014;60(3):322-323.