Characterized by a very short stature, facial changes, and obesity, Laron syndrome is an autosomal recessive genetic disorder in which insensitivity to growth hormone by tissues is the main pathological entity. Mutations in the growth hormone gene have shown to be responsible for the disorder, but the diagnosis can be made only after a thorough clinical and laboratory workup.
Presentation
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].
Entire Body System
- 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]
- 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]
Respiratoric
- 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]
Gastrointestinal
- Vomiting
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]
If a tumor is present, symptoms may include headaches, vomiting, double vision, sleep disturbances, and excessive thirst. [kidshealth.org]
Visual Loss, Retinal Hemorrhages, and Optic Disc Edema Resulting From Thiamine Deficiency Following Bariatric Surgey Complicated by Prolonged Vomiting. Ochsner J. 2017; 17: 112-4. [dergipark.org.tr]
Common adverse events included somnolence, decreased appetite, diarrhea, upper respiratory tract infection, pyrexia, and vomiting (Table 2). [nejm.org]
Moreover, chronic gastrointestinal symptoms (e.g., diarrhea, vomiting) and polypharmacy may increase the risk of RFS [19,20,40]. [mdpi.com]
Musculoskeletal
- 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]
- Normal Stature
In heterozygous patients, probably the normal stature may be achieved by a compensatory mechanism of GH secretion or signalling. [ncbi.nlm.nih.gov]
It is designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized statural growth. [centerwatch.com]
They had five older siblings of normal stature. According to their appearance, they resembled children with hypopituitarism, such as dwarfism, obesity, and severe hypoglycemia (Laron, 1995). [cags.org.ae]
Indeed, early cephalometry studies in patients with apnea who have normal stature showed that mandibular, maxillary, and anterior cranial base length are decreased (25), and the minimum airway area is significantly smaller than normal (7, 26). [ajnr.org]
Skin
- Acne Vulgaris
View Article Google Scholar Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J: Acne vulgaris. A disease of Western civilization. Arch Dermatol. 2002, 138: 1584-1590. 10.1001/archderm.138.12.1584. [nutritionandmetabolism.com]
Melnik. (2018) Acne vulgaris: The metabolic syndrome of the pilosebaceous follicle. Clinics in Dermatology 36 :1, 29-40. Online publication date: 1-Jan-2018. Crossref Inma Castilla-Cortazar, Giovana Femat-Roldán, Joel Rodríguez-Rivera, Gabriel A. [journals.aace.com]
- 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]
Neurologic
- Confusion
He developed confusion with disorientation and unsteady gait as well as profound strabismus due to bilateral paresis of the abductor muscle. [koreascience.kr]
Abstract Objective: Wernicke's encephalopathy (WE) is an acute disorder due to thiamine deficiency, characterized by ophthalmoplegia, ataxia, and mental confusion, similar to that classically observed in alcoholism. [pubmed.ncbi.nlm.nih.gov]
[…] involving myelin and worse distally than proximally, secondary to lesions in the peripheral nerves.1 WE is an acute syndrome that requires an emergent treatment due to its high morbi-mortality and that is characterized by the typical triad of mental confusion [scielo.isciii.es]
In the present paper, we will review the current evidence regarding the treatment of ACS in elderly patients and in those with diabetes mellitus (DM), chronic kidney dysfunction (CKD), and hematological abnormalities, which may confuse an early invasive [revespcardiol.org]
Severe hypokalemia (<2.5 mmol/L) and/or hypomagnesemia (<0.50 mmol/L) may trigger potentially lethal arrhythmia, neuromuscular dysfunctions such as paresis, rhabdomyolysis, confusion, and respiratory insufficiency [15]. – Thiamine is an essential coenzyme [mdpi.com]
Workup
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].
Treatment
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]
Prognosis
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
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]
Epidemiology
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]
Pathophysiology
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
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]
References
- Laron Z. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab. 2004;89(3):1031-1044.
- 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.
- 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.
- Goswami S, Ghosh S, Chowdhury S. Growth hormone insensitivity syndrome: A sensitive approach. Indian J Endocrinol Metab. 2012;16(5):817-818.
- 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.
- Guleria S, Sharma J, Kaushik SL. Laron syndrome. J Postgrad Med. 2014;60(3):322-323.