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

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

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

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Genetics and Molecular Biology

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Human and Medical Genetics • Genet. Mol. Biol. 42 (4) • 2019 • https://doi.org/10.1590/1678-4685-GMB-2018-0197 copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Keywords:
Laron Syndrome; growth hormone; growth hormone receptor; genetics

Patient	Age at the test	IGF 1 (μg/L)	IGFBP3 (mg/L)	Basal GH (ng/mL)	GH stimulation (ng/mL)
1	4 years old	12.3	0.70	21.5	GH peak>40
		(RV: 49-289)	(RV: 1.0-4.7)
2	1 year old	79	0.5	11.4
		(RV: 55-303)	(RV: 0.7– 3.9)

Patient	Consanguinity	Site of mutation	Type of mutation	c.DNA mutation	Amino Acid Change	Main reported Features	Ref.
1	+; Family I	GHR	Splice	Intron 6: c.619-1 G>C		At 13 years old: 87.5cm (-8.5 SDS) and 12.4kg. Several hypoglycemic episodes. Late closure of fontanelles. Trunkal obesity, high-pitched voice, doll-like face, irregular hypoplastic teeth and small external genitalia. Absence of pubertal development.	Saldanha and Toledo, 1981Saldanha PH and Toledo SP (1981) Familial dwarfism with high IR-GH: Report of two affected sibs with genetic and epidemiologic considerations. Hum Genet 59:367-372.
2	+; Family I	GHR	Splice	Intron 6: c.619-1 G>C		At 8 years old: 76cm (-9.4 SDS) and 10kg. Several hypoglycemic episodes. Late closure of fontanelles. Trunkal obesity, high-pitched voice, doll-like face, irregular hypoplastic teeth, small external genitalia and learning difficulties.	Saldanha and Toledo, 1981Saldanha PH and Toledo SP (1981) Familial dwarfism with high IR-GH: Report of two affected sibs with genetic and epidemiologic considerations. Hum Genet 59:367-372.
3	+; Family II	GHR	Missense	Exon 7: c.731 G>T	p.S244I	At 15.7 years old: 124cm (-6.1 SDS), 43.4 kg and BA=13.2 years. Weight at birth (full term) = 2 kg (< 3rd centile). GH=12mcg/L, IGF1 <18mcg/L, IGFBP3= 1.1mg/L.	*Jorge, et al., 2004*Jorge AA, Souza SC, Arnhold IJ and Mendonca BB (2004) The first homozygous mutation (S226I) in the highly-conserved WSXWS-like motif of the GH receptor causing Laron syndrome: Supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration. Clin Endocrinol 60:36-40.
4	?; Adopted; Family III	GHR	Nonsense	Exon 5: c.338 dupA	p.Y113X	At 12 years old: 87.8cm (SDS) and 11.1kg. Length at birth = 44cm, and Weight= 3kg. Facial asymmetry, prominent forehead, depressed nasal bridge, short face, blue sclerae and microstomia. Severe dental crowding and high-pitched voice. Small penis (10^th percentile). GH=26 mcg/L, IGF-1=22.5 ng/mL.	*Diniz et al., 2008*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
5	?; Family IV^* * Family IV-VII are proceeding from a small city of the state of Pernambuco, and consanguinity cannot be ruled out.	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	At 17.8 years old: 104.3cm (?7.8 SDS); GH =30mcg/L, GH peak =94mcg/L, IGF1 =23mcg/L, IGFBP3= 0.6mg/L.	*Jorge et al., 2005*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
6	+; Family V^* * Family IV-VII are proceeding from a small city of the state of Pernambuco, and consanguinity cannot be ruled out.	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	At 8.8 years old: 103.3cm (?5.0 SDS); GH 7.2mcg/L, GH peak 118mcg/L, IGF1 <18mcg/L.	*Jorge et al., 2005*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
7	?; Family VI^* * Family IV-VII are proceeding from a small city of the state of Pernambuco, and consanguinity cannot be ruled out.	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	At 11.3 years old: 113.8cm (-4.5 SDS); GH= 3.3mcg/L, GH peak= 36mcg/L, IGF1 <18mcg/L, IGFBP3= 0.6mg/L.	*Jorge et al., 2005*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
8	?; Family VI^* * Family IV-VII are proceeding from a small city of the state of Pernambuco, and consanguinity cannot be ruled out.	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	At 6.8 years old: 81cm (-7.6 SDS); IGF1 <18 mcg/L, IGFBP3= 0.4mg/L.	*Jorge et al., 2005*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
9	?; Family VII^* * Family IV-VII are proceeding from a small city of the state of Pernambuco, and consanguinity cannot be ruled out.	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	At 19.1 years old: 132cm (-6.4 SDS); GH 1.6mcg/L, GH peak= 38mcg/L, IGF1= 51mcg/L.	*Jorge et al., 2005*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
10	?; Family VII^* * Family IV-VII are proceeding from a small city of the state of Pernambuco, and consanguinity cannot be ruled out.	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	At 3.2 years old: 69cm (-7.4 SDS); GH peak =39mcg/L, IGF1 <18mcg/L.	*Jorge, et al., 2005*Diniz ET, Jorge AA, Arnhold IJ, Rosenbloom AL and Bandeira F (2008) Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome. Arq Bras Endocrinol Metabol 52:1264-1271.
11	?; Family VIII	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	No data	*Gonçalves et al., 2014*Goncalves FT, Fridman C, Pinto EM, Guevara-Aguirre J, Shevah O, Rosembloom AL, Hwa V, Cassorla F, Rosenfeld RG, Lins TS et al. (2014) The E180splice mutation in the GHR gene causing Laron syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World? Am J Medic Genet Part A 164a:1204-1208.
12	?; Family VIII	GHR	Splice	Exon 6: c.594 A>G	p.V199_M206del	No data	*Gonçalves et al., 2014*Goncalves FT, Fridman C, Pinto EM, Guevara-Aguirre J, Shevah O, Rosembloom AL, Hwa V, Cassorla F, Rosenfeld RG, Lins TS et al. (2014) The E180splice mutation in the GHR gene causing Laron syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World? Am J Medic Genet Part A 164a:1204-1208.
13	+; Family IX	GHR	Missense	Exon 5 (GHR): c.409 G>A	p.317N	At 6 years old: 86cm (SDS), 10kg and BA= 3 years. Length at preterm birth (28 weeks) =39cm and Weight= 1.7kg. Mild dysmorphic features, atopic eczema, interstitial lung disease, hyperprolactinemia. GH peak =20.6mcg/L, IGF1=34ng/mL. Treatment with GH whithout clear improvement.	*Pugliese-Pires et al., 2010*Pugliese-Pires PN, Tonelli CA, Dora JM, Silva PC, Czepielewski M, Simoni G, Arnhold IJ and Jorge AA (2010) A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. Eur J Endocrinol 163:349-355.
		STAT5B	Frameshift	Exon 5 (STAT5B): c.424_427 del	p.L142fs X161
14	+; Family IX	STAT5B	Frameshift	Exon 5: c.424_427 del	p.L142fs X161	At 2 years old: 76cm (SDS), 7,5kg and BA=6.0 months. Length at preterm birth (33 weeks) = 49cm and Weight= 2.4kg. Prominent forehead, depressed nasal bridge and obesity with centripetal fat distribution. Atopic eczema, thrombocytopenic purpura, interstitial lung disease, hyperprolactinemia.	*Pugliese-Pires et al., 2010*Pugliese-Pires PN, Tonelli CA, Dora JM, Silva PC, Czepielewski M, Simoni G, Arnhold IJ and Jorge AA (2010) A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. Eur J Endocrinol 163:349-355.
						GH peak =14.2mcg/L, IGF1 < 25ng/mL. Treatment with GH and IGF-1 whithout clear improvement
15	+; Family X	STAT5B	Frameshift	Exon 5: c.424_427 del	p.L142fs X161	Deceased as a consequence of respiratory failure	*Scalco et al.,* 2017**Scalco RC, Goncalves FT, Santos HC, Cardena M, Tonelli CA, Funari MFA, Aracava RM, Pereira AC, Fridman C and Jorge AAL (2017) Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: Evidence for a founder effect. Genet Mol Biol 40:436-441.
16	+; Family X	STAT5B	Frameshift	Exon 5: c.424_427 del	p.L142fs X161	Deceased as a consequence of respiratory failure	*Scalco et al.,* 2017**Scalco RC, Goncalves FT, Santos HC, Cardena M, Tonelli CA, Funari MFA, Aracava RM, Pereira AC, Fridman C and Jorge AAL (2017) Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: Evidence for a founder effect. Genet Mol Biol 40:436-441.
17	+; Family XI	GHR	Misstart	Exon 2: c.1A>T	p.M1?	At 4 years old: 80.2cm (??? SDS) and BA=2.0 years. Length at birth = 46cm and Weight= 3.450kg. Prominent forehead, depressed nasal bridge, high-pitched voice and delayed dentition.	Present study
GH peak>40.0mcg/L, IGF1=12.3ng/mL.
18	+; Family XI	GHR	Misstart	Exon 2: c.1A>T	p.M1?	At 2 years old: 73.2cm (SDS). Length at birth = 46cm and Weight= 3.400kg. Prominent forehead, depressed nasal bridge, high-pitched voice, sparse hair and late closure of fontanelles. GH =11.4mcg/L, IGF1=79ng/mL.	Present study

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[1] Send correspondence to Thais Ramos Villela. Universidade Federal de Minas Gerais, Faculdade de Medicina, Hospital das Clínicas, Divisão de Endocrinologia Infantil e do Adolescente, Belo Horizonte, MG, Brasil, Av. Alfredo Balena, 190, 30130-100 - Belo Horizonte, MG, Brazil. E-mail: thaisramosvillela@gmail.com.