Growth Hormone insensitivity (Laron syndrome): Report of a new family and review of Brazilian patients.

Thais R Villela,Rodrigo R Arantes,Mariana F A Funari,Jorge A L Alexander,Nathalia T P Braga,Ivani N Silva,Bruna L Freire

doi:10.1590/1678-4685-gmb-2018-0197

Thais R Villela, Rodrigo R Arantes + Show 5 more

Open Access

https://doi.org/10.1590/1678-4685-gmb-2018-0197

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Abstract

Laron’s syndrome (LS) is a rare genetic disorder characterized by insensitivity to growth hormone (GH). Up to the present time, over 70 mutations of GH receptor (GHR) gene have been identified leading to GH/insulin-like growth factor type 1 (IGF1) signaling pathway defect. The number of LS patients worldwide is unknown, as many are probably undiagnosed. We report two sibs from a consanguineous family from Minas Gerais, southeastern Brazil. The parents have three children. The older, a 4-years-old girl was 80.2 cm tall (-5.7 SDS height/age), and the youngest sister, aged 3 years, was 73.2 cm tall (-5.82 SDS height/age). Their clinical and biochemical features are typical of LS patients, such as high serum level of GH and low IGF1 concentrations. A homozygous c.1A>T nucleotide substitution in GHR exon 2 in the probands’ samples was identified. Their parents and healthy sister are heterozygous for the same variant that abolishes the translation initiation codon of GHR. This mutation has not been reported in Brazilian patients and was previously associated with an LS phenotype in a single 29-year-old Spanish man. In addition to this case report, we summarize the main characteristics and molecular data of the 21 LS Brazilian patients who have been published to date.

Highlights

Laron’s syndrome (LS) is a rare genetic disorder characterized by inability to respond to endogenous or exogenous growth hormone (GH)
It is associated with mutations in the GH receptor (GHR; OMIM: *600946), leading to GH/insulin-like growth factor type 1 (IGF1) signaling pathway defect
Instead of being recognized as a single entity, it is accepted as a broad diagnostic category, comprising a range of molecular defects in the GH-IGF1 axis

Summary

Main reported Features

35-year-old male born from related parents of Jewish Iraqi origin. He reached a final height of 128.3 cm (-7.3 SDS for age). Parents are consanguineous (Jorge et al, 2004) Another patient carried a mutation in homozygous state, adenine duplication at nucleotide 338 (c.338dupA) of the exon 5. It determines a failure in receptor function caused by the lack of amino acids comprising the transmembrane and intracellular regions of GHR proteins (Diniz et al, 2008) Another 8 patients, from six families, carried a homozygous substitution of guanine by adenine in codon 198 of exon 6 The prevalence of their STAT5B mutation in the South of Brazil was higher than the frequency observed in public databases, supporting the existence of a founder effect (Scalco et al, 2017) Another three patients with dwarfism, high serum levels of GH and low IGF1 concentrations were reported in Brazil, but they hadnt undergone molecular tests (Jorge, 2008).

Type of mutation

No data

Deceased as a consequence of respiratory failure