A Recurrent Mutation in Growth Hormone Receptor (GHR) Gene Underlying Laron-type Dwarfism in a Pakistani Family. 2023

Rana Muhammad Kamran Shabbir, and Gökhan Nalbant, and Qamar Zaman, and Aslıhan Tolun, and Sajid Malik, and Sara Mumtaz
Department of Zoology, Division of Science and Technology, University of Education, Lahore, Pakistan.

Laron syndrome (LS) is a rare autosomal recessively segregating disorder of severe short stature. The condition is characterized by short limbs, delayed puberty, hypoglycemia in infancy, and obesity. Mutations in growth hormone receptor (GHR) have been implicated in LS; hence, it is also known as growth hormone insensitivity syndrome (MIM-262500). Here we represent a consanguineous Pakistani family in which three siblings were afflicted with LS. Patients had rather similar phenotypic presentations marked with short stature, delayed bone age, limited extension of elbows, truncal obesity, delayed puberty, childish appearance, and frontal bossing. They also had additional features such as hypo-muscularity, early fatigue, large ears, widely-spaced breasts, and attention deficit behavior, which are rarely reported in LS. The unusual combination of the features hindered a straightforward diagnosis and prompted us to first detect the regions of shared homozygosity and subsequently the disease-causing variant by next generation technologies, like SNP genotyping and exome sequencing. A homozygous pathogenic variant c.508G>C (p.(Asp170His)) in GHR was detected. The variant is known to be implicated in LS, supporting the molecular diagnosis of LS. Also, we present detailed clinical, hematological, and hormonal profiling of the siblings.

UI MeSH Term Description Entries
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009765 Obesity A status with BODY WEIGHT that is grossly above the recommended standards, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY).
D010154 Pakistan A country located in southern Asia, bordering the Arabian Sea, between India on the east and Iran and Afghanistan on the west and China in the north. The capital is Islamabad. Islamic Republic of Pakistan
D011628 Puberty, Delayed The lack of development of SEXUAL MATURATION in boys and girls at a chronological age that is 2.5 standard deviations above the mean age at onset of PUBERTY in a population. Delayed puberty can be classified by defects in the hypothalamic LHRH pulse generator, the PITUITARY GLAND, or the GONADS. These patients will undergo spontaneous but delayed puberty whereas patients with SEXUAL INFANTILISM will not. Delayed Puberty
D011986 Receptors, Somatotropin Cell surface proteins that bind GROWTH HORMONE with high affinity and trigger intracellular changes influencing the behavior of cells. Activation of growth hormone receptors regulates amino acid transport through cell membranes, RNA translation to protein, DNA transcription, and protein and amino acid catabolism in many cell types. Many of these effects are mediated indirectly through stimulation of the release of somatomedins. Growth Hormone Receptors,Receptors, Growth Hormone,Somatomammotropin Receptors,Somatotropin Receptors,Growth Hormone Receptor,Receptor, Growth Hormone,Receptors, Somatomammotropin,Somatomammotropin Receptor,Somatotropin Receptor,Hormone Receptor, Growth,Hormone Receptors, Growth
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D046150 Laron Syndrome An autosomal recessive disorder characterized by short stature, defective GROWTH HORMONE RECEPTOR, and failure to generate INSULIN-LIKE GROWTH FACTOR I by GROWTH HORMONE. Laron syndrome is not a form of primary pituitary dwarfism (GROWTH HORMONE DEFICIENCY DWARFISM) but the result of mutation of the human GHR gene on chromosome 5. Growth Hormone Insensitivity Syndrome,Growth Hormone Receptor Defect,Growth Hormone Receptor Deficiency,Laron Dwarfism,Laron Type Dwarfism I,Pituitary Dwarfism II,Primary GH Resistance,Primary Growth Hormone Resistance,Severe GH Insensitivity,Dwarfism II, Pituitary,Dwarfism IIs, Pituitary,Dwarfism, Laron,GH Resistance, Primary,Pituitary Dwarfism IIs,Syndrome, Laron

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