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Heterozygous mutation in the receptor gene of the growth hormone as cause of short stature
Med Clin (Barc). 2017;148(2):e9–e10
www.elsevier.es/medicinaclinica
Letter to the Editor Heterozygous mutation in the receptor gene of the growth hormone as cause of short stature夽 Mutación en heterocigosis en el gen del receptor de la hormona de crecimiento como causa de la talla baja Dear Editor, Short stature is one of the main reasons for consultation in Paediatric Endocrinology. Also, it tends to have a family origin, a constitutional growth delay or both. The presence of stunted growth or short stature is a sign indicative of alteration.1 An auxological definition of short stature would be any height that is below 2 standard deviations, without apparent disease findings after a complete evaluation including growth hormone (GH) stimulation test values. One of the criteria is: pathological short stature in cases where the etiopathogenesis that caused the stunted growth is known and the idiopathic short stature for cases in which the aetiology is unknown and where the so-called variants of normality would be included.1 GH resistance syndrome, severe, classically termed Laron syndrome, is very rare; it is usually inherited recessively, although some mutations are described with dominant effect.2 Numerous mutations have been described in the GH receptor gene, most of them with specific amino acid change, although they can affect the splicing areas. Deletions have also been described.3 An 8-year-old male patient was referred to Paediatric Endocrinology due to short stature (109.80 cm), weight of 17,900 g and growth rate 5.3 cm/year, with a birth weight of 3080 g, size 48 cm, head circumference of 32.5 cm and Apgar score of 7/10. The child’s mother had short stature (150 cm), studied during childhood, without GH deficiency. The hormonal profile was analyzed in the index case and a nocturnal GH secretion test was performed. Normal GH and low IGF-1 levels were detected. The GHR genetic study revealed the presence of Arg161Cys mutation in exon 6, heterozygous, whose phenotype is related to a partial GH insensitivity, as described in the HGMD mutation database (CM984041), first described by Amselem et al.4 The mother did not present the mutation and the father did not do the genetic study. GH insensitivity is a very heterogeneous group of diseases that are associated with short stature and a resistance to GH action.
夽 Please cite this article as: Barrio-Ollero E, Izquierdo-Álvarez S, de Arriba Munoz ˜ A. Mutación en heterocigosis en el gen del receptor de la hormona de crecimiento como causa de la talla baja. Med Clin (Barc). 2017;148:e9-e10. ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
The phenotype is quite variable, presenting very severe forms such as Laron syndrome,4 caused by homozygous or compound heterozygous mutations of the GHR gene or by autosomal dominant inheritance mutations that are associated with a much milder phenotype, known as partial GH insensitivity.5 Since its first description in 1966, more than 250 patients with GHR gene mutations have been identified and over 70 different mutations of the said gene are known, resulting in a stunted growth phenotype associated with IGF-1 deficiency in the presence of normal GH values. Moreover, children affected with idiopathic short stature have moderate stunted growth, without specific endocrine abnormalities, so that they exhibit a partial GH sensitivity, as it occurs in the case of the proband. Unlike children, GH deficiency is never idiopathic in adults. Children diagnosed with idiopathic GH deficiency can have a normal GH response when they undergo a re-evaluation in adult life. However, children with pituitary or hypothalamic tumours, who have received radiation or have other hormonal deficiencies, generally show deficiency in adult life. Adolescents with GH deficiency require a new study to confirm this in adulthood. Up to 20% of patients treated due to GH deficiency of childhood onset had enough hormone levels when the study was repeated in adult life. In conclusion, searching for and finding heterozygous mutations in the GHR5 gene is a breakthrough for clinicians, as it allows them to find and characterize the aetiology of idiopathic short stature in children with normal GH levels and low IGF-1 values, and provide appropriate genetic counselling to other family members. References 1. Cohen LE. Idiopathic short stature: a clinical review. JAMA. 2014;311:1787–96. 2. Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel WJ, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 1987;330:537–43. 3. Tauber MT, Porra V, Dastot F, Molinas C, Amselem S, Cholin S, et al. Heterozygous mutation in the WSXWS equivalent motif of the growth hormone receptor in a child with poor response to growth hormone therapy. Growth Horm IGF Res. 1998;8:211–6. 4. Amselem S, Duquesnoy P, Duriez B, Dastot F, Sobrier ML, Valleix S, et al. Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet. 1993;2:355–9. 5. Wit JM, de Luca F. Atypical defects resulting in growth hormone insensitivity. Growth Horm IGF Res. 2016;28:57–61.
e10
Letter to the Editor / Med Clin (Barc). 2017;148(2):e9–e10
Eva Barrio-Ollero a,∗ , Silvia Izquierdo-Álvarez b , ˜ c Antonio de Arriba Munoz
c
a
∗ Corresponding
Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain Sección de Genética Clínica y Reproducción Asistida, Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain
b
Sección de Endocrinología Pediátrica, Servicio de Pediatría, Hospital Infantil, Hospital Universitario Miguel Servet, Zaragoza, Spain
author. E-mail address: [email protected] (E. Barrio-Ollero).
www.elsevier.es/medicinaclinica
Letter to the Editor Heterozygous mutation in the receptor gene of the growth hormone as cause of short stature夽 Mutación en heterocigosis en el gen del receptor de la hormona de crecimiento como causa de la talla baja Dear Editor, Short stature is one of the main reasons for consultation in Paediatric Endocrinology. Also, it tends to have a family origin, a constitutional growth delay or both. The presence of stunted growth or short stature is a sign indicative of alteration.1 An auxological definition of short stature would be any height that is below 2 standard deviations, without apparent disease findings after a complete evaluation including growth hormone (GH) stimulation test values. One of the criteria is: pathological short stature in cases where the etiopathogenesis that caused the stunted growth is known and the idiopathic short stature for cases in which the aetiology is unknown and where the so-called variants of normality would be included.1 GH resistance syndrome, severe, classically termed Laron syndrome, is very rare; it is usually inherited recessively, although some mutations are described with dominant effect.2 Numerous mutations have been described in the GH receptor gene, most of them with specific amino acid change, although they can affect the splicing areas. Deletions have also been described.3 An 8-year-old male patient was referred to Paediatric Endocrinology due to short stature (109.80 cm), weight of 17,900 g and growth rate 5.3 cm/year, with a birth weight of 3080 g, size 48 cm, head circumference of 32.5 cm and Apgar score of 7/10. The child’s mother had short stature (150 cm), studied during childhood, without GH deficiency. The hormonal profile was analyzed in the index case and a nocturnal GH secretion test was performed. Normal GH and low IGF-1 levels were detected. The GHR genetic study revealed the presence of Arg161Cys mutation in exon 6, heterozygous, whose phenotype is related to a partial GH insensitivity, as described in the HGMD mutation database (CM984041), first described by Amselem et al.4 The mother did not present the mutation and the father did not do the genetic study. GH insensitivity is a very heterogeneous group of diseases that are associated with short stature and a resistance to GH action.
夽 Please cite this article as: Barrio-Ollero E, Izquierdo-Álvarez S, de Arriba Munoz ˜ A. Mutación en heterocigosis en el gen del receptor de la hormona de crecimiento como causa de la talla baja. Med Clin (Barc). 2017;148:e9-e10. ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
The phenotype is quite variable, presenting very severe forms such as Laron syndrome,4 caused by homozygous or compound heterozygous mutations of the GHR gene or by autosomal dominant inheritance mutations that are associated with a much milder phenotype, known as partial GH insensitivity.5 Since its first description in 1966, more than 250 patients with GHR gene mutations have been identified and over 70 different mutations of the said gene are known, resulting in a stunted growth phenotype associated with IGF-1 deficiency in the presence of normal GH values. Moreover, children affected with idiopathic short stature have moderate stunted growth, without specific endocrine abnormalities, so that they exhibit a partial GH sensitivity, as it occurs in the case of the proband. Unlike children, GH deficiency is never idiopathic in adults. Children diagnosed with idiopathic GH deficiency can have a normal GH response when they undergo a re-evaluation in adult life. However, children with pituitary or hypothalamic tumours, who have received radiation or have other hormonal deficiencies, generally show deficiency in adult life. Adolescents with GH deficiency require a new study to confirm this in adulthood. Up to 20% of patients treated due to GH deficiency of childhood onset had enough hormone levels when the study was repeated in adult life. In conclusion, searching for and finding heterozygous mutations in the GHR5 gene is a breakthrough for clinicians, as it allows them to find and characterize the aetiology of idiopathic short stature in children with normal GH levels and low IGF-1 values, and provide appropriate genetic counselling to other family members. References 1. Cohen LE. Idiopathic short stature: a clinical review. JAMA. 2014;311:1787–96. 2. Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel WJ, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 1987;330:537–43. 3. Tauber MT, Porra V, Dastot F, Molinas C, Amselem S, Cholin S, et al. Heterozygous mutation in the WSXWS equivalent motif of the growth hormone receptor in a child with poor response to growth hormone therapy. Growth Horm IGF Res. 1998;8:211–6. 4. Amselem S, Duquesnoy P, Duriez B, Dastot F, Sobrier ML, Valleix S, et al. Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet. 1993;2:355–9. 5. Wit JM, de Luca F. Atypical defects resulting in growth hormone insensitivity. Growth Horm IGF Res. 2016;28:57–61.
e10
Letter to the Editor / Med Clin (Barc). 2017;148(2):e9–e10
Eva Barrio-Ollero a,∗ , Silvia Izquierdo-Álvarez b , ˜ c Antonio de Arriba Munoz
c
a
∗ Corresponding
Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain Sección de Genética Clínica y Reproducción Asistida, Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain
b
Sección de Endocrinología Pediátrica, Servicio de Pediatría, Hospital Infantil, Hospital Universitario Miguel Servet, Zaragoza, Spain
author. E-mail address: [email protected] (E. Barrio-Ollero).