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

Abstract

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.

Keywords: delayed puberty; facial dysmorphism; growth hormone insensitivity; short stature; truncal obesity; widely-spaced breasts.

Figure 1

Pedigree of the family. Horizontal lines above individuals indicate that physical examination was performed. * indicates subjects participated in genetic study.

Figure 2

Phenotypes of patients. Short stature, truncal obesity, widely-spaced breasts, protruding forehead, depressed nose, large ears, and blue sclera. X-ray image of hands depicting the delayed bone age and late epiphyseal closure at the age of 19 of subject 401.

Figure 3

Graphical representation of homozygosity intervals obtained by HomozygosityMapper with default parameters. Red bars depict the longer stretches of homozygous genotypes on chromosomes and black bars revealed short intervals of homozygous genotypes. Note the largest interval at chromosome 5.

Figure 4

Summary of Exome filtration scheme.