- Email: [email protected]
A novel GLI2 mutation responsible for congenital hypopituitarism and polymalformation syndrome
Growth Hormone & IGF Research 44 (2019) 17–19
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
A novel GLI2 mutation responsible for congenital hypopituitarism and polymalformation syndrome
T
Álvaro Martín-Rivadaa, Francisco Javier Rodríguez-Contrerasb, Mª. Teresa Muñoz-Calvoa,c, María Güemesa, Isabel González-Casadod, Jaime Sánchez del Pozoe, Ángel Campos-Barrosb,f, ⁎ Jesús Argentea,c,g,h, Hospital Infantil Universitario Niño Jesús, Departments of Pediatrics & Pediatric Endocrinology, Research Institute “La Princesa”, Madrid, Spain Institute of Medical & Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, Madrid, Spain c Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain d Department of Pediatric Endocrinology, Hospital Universitario La Paz, Madrid, Spain e Pediatric Endocrinology and Dysmorphology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain f Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain g Universidad Autónoma de Madrid, Department of Pediatrics, Madrid, Spain h IMDEA, Food Institute, CEIUAM+CSI, Crta. de Cantoblanco, 8, 28049 Cantoblanco, Madrid, Spain a
b
A B S T R A C T
Objective: We report a novel GLI2 frameshift mutation and describe the phenotypic spectrum of mutations within this gene. Patients and methods: A male with congenital hypopituitarism and polymalformation syndrome was clinically, biochemically and neuroradiologically characterized. Genetic analysis for congenital hypopituitarism was performed using a targeted NGS custom gene panel. Results: A heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15), was identified in GLI2 exon 12. This mutation has not been previously reported and confirms the diagnosis of Culler-Jones syndrome (MIM #615849). Conclusion: GLI2 mutations should be suspected in the presence of congenital hypopitutarism, characteristic facial abnormalities and polydactyly.
1. Introduction Congenital hypopituitarism has a genetic, environmental or combined etiology and its incidence is estimated to be between 1 in 3000–4000 births [1]. The identification of various genes implicated in pituitary development and hormonal production has allowed certain cases to be attributed to specific genetic disorders. The GLI2 gene (GLI2), also known as GLI2 oncogene, belongs to the GLI-Kruppel family, named according to its initial amplification in brain gliomas [2]. GLI2 is a transcription factor that contains a zincfinger DNA-binding region, as well as an amino-terminal region with repressor activity and a carboxy-terminal domain responsible for transcriptional activation [3]. GLI2 is a large polymorphic gene located on chromosome 2q14.2 and genetic analysis may identify variants of uncertain significance (VUS) which are often difficult to interpretate. Variants in GLI2 with functional effects may also be found in unaffected individuals due to incomplete penetrance [2]. The Gli family of proteins (including Gli1, Gli2 and Gli3) is involved in the Sonic Hedgehog (SHH)
signaling pathway. SHH is a morphogen involved in the formation of the limbs, and structures in the central nervous system midline and has a key role in pituitary development [4]. In mice, inactivation of Gli2 causes variable absence of the pituitary gland and an abnormal midline diencephalon [5]. However, homozygous deletion of both Gli1 and Gli2 results in complete absence of the pituitary [5]. This present case report illustrates the clinical, laboratory, imaging and genotype analysis of a novel loss of function GLI2 mutation. 2. Case report and methods A male newborn with no family history of interest was delivered at term (41 weeks) following a controlled pregnancy. His birth weight was 3480 g (0 SD), length 49.5 cm (−0.75 SD) and head circumference 35 cm (−0.32 SD). His Apgar score was 5/7 and the initial examination revealed a polymalformation syndrome consisting of bilateral labial cleft, elevated maxilla with normally configured palate, polydactyly of the ulnar border of both hands with a rudimentary sixth finger, bilateral
⁎ Corresponding author at: Hospital Infantil Universitario Niño Jesús, Department of Pediatrics & Pediatric Endocrinology, Avenida Menéndez Pelayo, 65, 28009 Madrid, Spain. E-mail address: [email protected] (J. Argente).
https://doi.org/10.1016/j.ghir.2018.12.002 Received 30 November 2018; Received in revised form 16 December 2018; Accepted 17 December 2018 Available online 18 December 2018 1096-6374/ © 2018 Elsevier Ltd. All rights reserved.
Growth Hormone & IGF Research 44 (2019) 17–19
Á. Martín-Rivada et al.
Fig. 1. A: Cranial MRI with hypoplastic/agenesis of the anterior pituitary and absence of the pituitary stalk and posterior pituitary. B: Phenotypic manifestations including bilateral labial cleft palate. C: Growth chart indicating when treatment with rhGH was stopped.
confirmed by Sanger sequencing and genotyped in the proband's parents to determine the inheritance and co-segregation pattern.
cryptorchidism and micropenis. Within the first 48 h of life, he developed low blood glucose concentrations (minimum: 46 mg/dl), which stabilized upon feeding, hyponatremia that required intravenous sodium supplements for 48 h, and non-isoimmune hyperbilirubinemia that resolved with phototherapy. The endocrine analyses performed during the neonatal period revealed: TSH: 0.085 mIU/ml (reference range 0.55–12.5), fT4: 0.25 ng/ml (reference range: 0.55–1.65), cortisol < 5 mg/ml (reference range: 78–272), IGFeI: < 10 ng/ml (reference range: 46–270), IGFBP-3: 0.3 μg/ml (reference range 0.88–4.29), LH: 0.01 mUI/ml (reference range 0.88–4.29), and FSH: 0.06 mUI/ml reference range (0.2–1.8). His blood karyotype was 46,XY. A cranial MRI showed anterior pituitary hypoplasia/agenesis and absence of the pituitary stalk and posterior pituitary (Fig. 1A). Upon diagnosis of ACTH, TSH, GH (and likely LH and FSH) deficiencies, hormone replacement therapy was started with hydrocortisone, recombinant biosynthetic growth hormone (rhGH) and levothyroxine. Neurodevelopment assessment revealed psychomotor retardation and secondary generalized epilepsy which was satisfactorily controlled with antiepileptic medication. Genomic DNA from the patient was extracted from peripheral blood leukocytes and genetic testing was carried out by targeted NGS using a custom designed gene panel (SeqCap® EZ Choice Probes, ROCHE), including 50 genes known to be implicated in the etiology of congenital hypopituitarism and 23 additional candidate genes implicated in pituitary gland embryonic development. All relevant variants were
3. Results The targeted NGS assay detected a heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15) in exon 12 of GLI2, which has not been previously described. This frameshift mutation introduces a premature stop codon that is predicted to generate a nonfunctional protein lacking the C-terminal domain, which is responsible for transcriptional activation. The mutation was not detected in the parents, and is absent from the population database gnomAD (http:// gnomad.broadinstitute.org/). This result confirms the diagnosis of Culler-Jones syndrome (CJS; MIM 615849). Currently, at the age of 12 years, the proband has a height of 127 cm (− 3.2 SD, according to the Spanish growth charts by Hernández et al., 1988) [6], body weight of 21 kg (−2.5 SD), head circumference of 51.5 cm (− 2.4 SD), Tanner stage I (1 ml testicles in scrotum, P1, A1), micropenis and facial features as described above (Fig. 1B). His bone age is delayed by 4 years and he remains on ongoing hormonal replacement therapy with levothyroxine and hydrocortisone. In contrast, treatment with rhGH was discontinued due to lack of response despite maintaining levels of IGF-I and IGFBP-3 within the normal range whilst on medication (Fig. 1C). He continues to take antiepileptic treatment and receives motor rehabilitation. 18
Growth Hormone & IGF Research 44 (2019) 17–19
Á. Martín-Rivada et al.
Disclosure summary
4. Discussion
The authors have nothing to disclose.
Mutations in GLI2 have been reported to be responsible for both CJS [7] and holoprosencephaly 9 (HPE9; MIM 610829). CJS is characterized by the association of ectopic posterior pituitary, multiple pituitary hormone deficiencies, especially growth hormone deficiency, and/or postaxial polydactyly. Other midline defects and development delay have also been described [8]. CJS is inherited in an autosomal dominant mode with incomplete penetrance. There is a wide range of clinical expressivity both inter- and intrafamilial with no clear genotypephenotype correlation [9]. HPE9 is defined by a broad phenotypic spectrum of developmental brain abnormalities, with or without forebrain cleavage abnormalities, namely holoprosencephaly. HPE9 also shows incomplete penetrance and variable expressivity. Actually, these two conditions represent a continuous phenotypic spectrum, with the milder forms referred to as CJS and the more severe cases referred to as HPE9 [10]. As the inheritance pattern is usually autosomal dominant [2] with incomplete penetrance, the mutation is frequently inherited from an asymptomatic parent. However, in our patient the mutation has arisen due to a de novo event. It appears that only truncating GLI2 mutations result in polydactyly [2,7]. Therefore, the presence of polydactyly in a patient with hypopituitarism or in one of his relatives may be an additional indication for the implication of GLI2 [8]. In an extensive review of > 400 patients with HPE, Bear et al. concluded that the association of frank HPE with pathogenic GLI2 mutations is rare [7]. A wide phenotypic spectrum of pituitary hormone deficiency in subjects with GLI2 mutations has been reported. Growth hormone deficiency is the most prevalent pituitary hormone deficiency, and this may be due to a reduction in the number of somatotrophs, as found in Gli2 knockout mice [11]. However, the response to rhGH treatment is inconclusive in the literature. Our patient did not respond to rhGH, as it has been reported in other patients [12]. The reason for this lack of response remains uncertain, especially as both IGF-I and IGFBP-3 levels were increased during treatment. Insufficient levels of antidiuretic (ADH) hormone leading to diabetes insipidus has also been reported in patients with GLI2 mutations, as this gene is also expressed in the ventral diencephalon; hence, it seems relevant for hypothalamic, infundibular and posterior pituitary lobe formation [11]. Gonadotropin deficiencies [13], delayed puberty [8] and incomplete masculinization of the external genitalia have been also described in patients with GLI2 mutations. Our patient most likely has LH and FSH deficiencies, although he is yet prepubertal. Moreover, Shh is expressed in the urethral plate epithelium of mice during embryogenesis and this signal is mediated through Gli2 in the mesenchyme, confirming a role for Gli2 in the masculinization of external genitalia [14]. Two recent reviews on genetic of short stature can provide some extra background to the reader [15,16]. In conclusion, we report a novel GLI2 frameshift mutation in a child who manifests the most frequent anomalies described in the alteration of the SHH signaling pathway. Therefore, Culler-Jones syndrome due to GLI2 mutations should be suspected in the presence of congenital hypopituitarism, characteristic facial abnormalities and polydactyly.
Acknowledgement We would like to acknowledge and thank the patient, his parents and all of the researchers that are dedicated to performing complex studies to have a final diagnosis and the best therapeutical approach. JA was funded by the Spanish Ministry of Health (FIS-PI13/02195 & PI16/ 00485, co-funded by FEDER), Centro de Investigación Biomédica en Red for obesity and nutrition (CIBEROBN) from Instituto de Salud Carlos III, Spain and the Fundación de Endocrinología y Nutrición. ACB was funded by the Spanish Ministry of Health (FIS-PI12/00649, cofunded by FEDER) and Comunidad de Madrid (ENDOSCREEN S2010/ BMD-2396, co-funded by FEDER). References [1] K. Stochholm, T. Laursen, A. Green, et al., Morbidity and GH deficiency: a nationwide study, Eur. J. Endocrinol. 158 (2008) 447–457. [2] I.J. Arnhold, M.M. França, L.R. Carvalho, B.B. Mendonca, A.A. Jorge, Role of GLI2 in hypopituitarism phenotype, J. Mol. Endocrinol. 54 (2015) R141–R150. [3] E. Roessler, A.N. Ermilov, D.K. Grange, et al., A previously unidentified aminoterminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2, Hum. Mol. Genet. 14 (2005) 2181–2188. [4] C.C. Hui, S. Angers, Gli proteins in development and disease, Annu. Rev. Cell Dev. Biol. 27 (2011) 513–537. [5] H.L. Park, C. Bai, K.A. Platt, et al., Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation, Development 127 (2000) 1593–1605. [6] M. Hernández, J. Castellet, J.L. Narvaiza, et al., Curvas y tablas de crecimiento. Instituto de Investigación sobre Crecimiento y Desarrollo, Garsi, Madrid, 1988. [7] K.A. Bear, B.D. Solomon, S. Antonini, et al., Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly, J. Med. Genet. 51 (2014) 413–418. [8] M.M. França, A.A. Jorge, L.R. Carvalho, et al., Novel heterozygous nonsense GLI2 mutation in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly, J. Clin. Endocrinol. Metab. 95 (2010) E384–E391. [9] C.P.D. Bertolacini, L.A. Ribeiro-Bicudo, A. Petrin, A. Richieri-Costa, J.C. Murray, Clinical findings in patients with GLI2 mutations-phenotypic variability, Clin. Genet. 81 (2012) 70–75. [10] Y. Niida, M. Inoue, M. Ozaki, E. Takase, Human malformation syndromes of defective GLI: opposite phenotypes of 2q14.2 (GLI2) and 7p14.2 (GLI3) microdeletions and a GLIA/R balance model, Cytogenet. Genome Res. 153 (2017) 56–65. [11] Y. Wang, J.F. Martin, C.B. Bai, Direct and indirect requirements of Shh/Gli signaling in early pituitary development, Dev. Biol. 348 (2010) 199–209. [12] U. Kordab, C. Schörder, M. Elbracht, L. Soellner, T. Eggermann, A familial GLI2 Deletion (2q14.2) not associated with the holoprosencephaly syndrome phenotype, Am. J. Med. Genet. A. 167 (2015) 1121–1124. [13] K. Vaaralahti, T. Raivio, R. Koivu, L. Valanne, J. Tommiska Em Laitinen, Genetic overlap between holoprosencephaly and Kallmann syndrome, Mol. Syndromology 3 (2012) 1–5. [14] S. Miyagawa, D. Matsumaru, A. Murashima, et al., The role of sonic hedgehog-Gli2 pathway in the masculinization of external genitalia, Endocrinology 152 (2011) 2894–2903. [15] M. Grunauera, A.A.L. Jorge, Genetic of short stature, Growth Hormon. IGF Res. 38 (2018) 29–33. [16] J. Argente, L.A. Pérez-Jurado, Genetic causes of proportionate short stature, Best Pract. Res. Clin. Endocrinol. Metab. 32 (2018) 499–522.
19
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
A novel GLI2 mutation responsible for congenital hypopituitarism and polymalformation syndrome
T
Álvaro Martín-Rivadaa, Francisco Javier Rodríguez-Contrerasb, Mª. Teresa Muñoz-Calvoa,c, María Güemesa, Isabel González-Casadod, Jaime Sánchez del Pozoe, Ángel Campos-Barrosb,f, ⁎ Jesús Argentea,c,g,h, Hospital Infantil Universitario Niño Jesús, Departments of Pediatrics & Pediatric Endocrinology, Research Institute “La Princesa”, Madrid, Spain Institute of Medical & Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, Madrid, Spain c Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain d Department of Pediatric Endocrinology, Hospital Universitario La Paz, Madrid, Spain e Pediatric Endocrinology and Dysmorphology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain f Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain g Universidad Autónoma de Madrid, Department of Pediatrics, Madrid, Spain h IMDEA, Food Institute, CEIUAM+CSI, Crta. de Cantoblanco, 8, 28049 Cantoblanco, Madrid, Spain a
b
A B S T R A C T
Objective: We report a novel GLI2 frameshift mutation and describe the phenotypic spectrum of mutations within this gene. Patients and methods: A male with congenital hypopituitarism and polymalformation syndrome was clinically, biochemically and neuroradiologically characterized. Genetic analysis for congenital hypopituitarism was performed using a targeted NGS custom gene panel. Results: A heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15), was identified in GLI2 exon 12. This mutation has not been previously reported and confirms the diagnosis of Culler-Jones syndrome (MIM #615849). Conclusion: GLI2 mutations should be suspected in the presence of congenital hypopitutarism, characteristic facial abnormalities and polydactyly.
1. Introduction Congenital hypopituitarism has a genetic, environmental or combined etiology and its incidence is estimated to be between 1 in 3000–4000 births [1]. The identification of various genes implicated in pituitary development and hormonal production has allowed certain cases to be attributed to specific genetic disorders. The GLI2 gene (GLI2), also known as GLI2 oncogene, belongs to the GLI-Kruppel family, named according to its initial amplification in brain gliomas [2]. GLI2 is a transcription factor that contains a zincfinger DNA-binding region, as well as an amino-terminal region with repressor activity and a carboxy-terminal domain responsible for transcriptional activation [3]. GLI2 is a large polymorphic gene located on chromosome 2q14.2 and genetic analysis may identify variants of uncertain significance (VUS) which are often difficult to interpretate. Variants in GLI2 with functional effects may also be found in unaffected individuals due to incomplete penetrance [2]. The Gli family of proteins (including Gli1, Gli2 and Gli3) is involved in the Sonic Hedgehog (SHH)
signaling pathway. SHH is a morphogen involved in the formation of the limbs, and structures in the central nervous system midline and has a key role in pituitary development [4]. In mice, inactivation of Gli2 causes variable absence of the pituitary gland and an abnormal midline diencephalon [5]. However, homozygous deletion of both Gli1 and Gli2 results in complete absence of the pituitary [5]. This present case report illustrates the clinical, laboratory, imaging and genotype analysis of a novel loss of function GLI2 mutation. 2. Case report and methods A male newborn with no family history of interest was delivered at term (41 weeks) following a controlled pregnancy. His birth weight was 3480 g (0 SD), length 49.5 cm (−0.75 SD) and head circumference 35 cm (−0.32 SD). His Apgar score was 5/7 and the initial examination revealed a polymalformation syndrome consisting of bilateral labial cleft, elevated maxilla with normally configured palate, polydactyly of the ulnar border of both hands with a rudimentary sixth finger, bilateral
⁎ Corresponding author at: Hospital Infantil Universitario Niño Jesús, Department of Pediatrics & Pediatric Endocrinology, Avenida Menéndez Pelayo, 65, 28009 Madrid, Spain. E-mail address: [email protected] (J. Argente).
https://doi.org/10.1016/j.ghir.2018.12.002 Received 30 November 2018; Received in revised form 16 December 2018; Accepted 17 December 2018 Available online 18 December 2018 1096-6374/ © 2018 Elsevier Ltd. All rights reserved.
Growth Hormone & IGF Research 44 (2019) 17–19
Á. Martín-Rivada et al.
Fig. 1. A: Cranial MRI with hypoplastic/agenesis of the anterior pituitary and absence of the pituitary stalk and posterior pituitary. B: Phenotypic manifestations including bilateral labial cleft palate. C: Growth chart indicating when treatment with rhGH was stopped.
confirmed by Sanger sequencing and genotyped in the proband's parents to determine the inheritance and co-segregation pattern.
cryptorchidism and micropenis. Within the first 48 h of life, he developed low blood glucose concentrations (minimum: 46 mg/dl), which stabilized upon feeding, hyponatremia that required intravenous sodium supplements for 48 h, and non-isoimmune hyperbilirubinemia that resolved with phototherapy. The endocrine analyses performed during the neonatal period revealed: TSH: 0.085 mIU/ml (reference range 0.55–12.5), fT4: 0.25 ng/ml (reference range: 0.55–1.65), cortisol < 5 mg/ml (reference range: 78–272), IGFeI: < 10 ng/ml (reference range: 46–270), IGFBP-3: 0.3 μg/ml (reference range 0.88–4.29), LH: 0.01 mUI/ml (reference range 0.88–4.29), and FSH: 0.06 mUI/ml reference range (0.2–1.8). His blood karyotype was 46,XY. A cranial MRI showed anterior pituitary hypoplasia/agenesis and absence of the pituitary stalk and posterior pituitary (Fig. 1A). Upon diagnosis of ACTH, TSH, GH (and likely LH and FSH) deficiencies, hormone replacement therapy was started with hydrocortisone, recombinant biosynthetic growth hormone (rhGH) and levothyroxine. Neurodevelopment assessment revealed psychomotor retardation and secondary generalized epilepsy which was satisfactorily controlled with antiepileptic medication. Genomic DNA from the patient was extracted from peripheral blood leukocytes and genetic testing was carried out by targeted NGS using a custom designed gene panel (SeqCap® EZ Choice Probes, ROCHE), including 50 genes known to be implicated in the etiology of congenital hypopituitarism and 23 additional candidate genes implicated in pituitary gland embryonic development. All relevant variants were
3. Results The targeted NGS assay detected a heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15) in exon 12 of GLI2, which has not been previously described. This frameshift mutation introduces a premature stop codon that is predicted to generate a nonfunctional protein lacking the C-terminal domain, which is responsible for transcriptional activation. The mutation was not detected in the parents, and is absent from the population database gnomAD (http:// gnomad.broadinstitute.org/). This result confirms the diagnosis of Culler-Jones syndrome (CJS; MIM 615849). Currently, at the age of 12 years, the proband has a height of 127 cm (− 3.2 SD, according to the Spanish growth charts by Hernández et al., 1988) [6], body weight of 21 kg (−2.5 SD), head circumference of 51.5 cm (− 2.4 SD), Tanner stage I (1 ml testicles in scrotum, P1, A1), micropenis and facial features as described above (Fig. 1B). His bone age is delayed by 4 years and he remains on ongoing hormonal replacement therapy with levothyroxine and hydrocortisone. In contrast, treatment with rhGH was discontinued due to lack of response despite maintaining levels of IGF-I and IGFBP-3 within the normal range whilst on medication (Fig. 1C). He continues to take antiepileptic treatment and receives motor rehabilitation. 18
Growth Hormone & IGF Research 44 (2019) 17–19
Á. Martín-Rivada et al.
Disclosure summary
4. Discussion
The authors have nothing to disclose.
Mutations in GLI2 have been reported to be responsible for both CJS [7] and holoprosencephaly 9 (HPE9; MIM 610829). CJS is characterized by the association of ectopic posterior pituitary, multiple pituitary hormone deficiencies, especially growth hormone deficiency, and/or postaxial polydactyly. Other midline defects and development delay have also been described [8]. CJS is inherited in an autosomal dominant mode with incomplete penetrance. There is a wide range of clinical expressivity both inter- and intrafamilial with no clear genotypephenotype correlation [9]. HPE9 is defined by a broad phenotypic spectrum of developmental brain abnormalities, with or without forebrain cleavage abnormalities, namely holoprosencephaly. HPE9 also shows incomplete penetrance and variable expressivity. Actually, these two conditions represent a continuous phenotypic spectrum, with the milder forms referred to as CJS and the more severe cases referred to as HPE9 [10]. As the inheritance pattern is usually autosomal dominant [2] with incomplete penetrance, the mutation is frequently inherited from an asymptomatic parent. However, in our patient the mutation has arisen due to a de novo event. It appears that only truncating GLI2 mutations result in polydactyly [2,7]. Therefore, the presence of polydactyly in a patient with hypopituitarism or in one of his relatives may be an additional indication for the implication of GLI2 [8]. In an extensive review of > 400 patients with HPE, Bear et al. concluded that the association of frank HPE with pathogenic GLI2 mutations is rare [7]. A wide phenotypic spectrum of pituitary hormone deficiency in subjects with GLI2 mutations has been reported. Growth hormone deficiency is the most prevalent pituitary hormone deficiency, and this may be due to a reduction in the number of somatotrophs, as found in Gli2 knockout mice [11]. However, the response to rhGH treatment is inconclusive in the literature. Our patient did not respond to rhGH, as it has been reported in other patients [12]. The reason for this lack of response remains uncertain, especially as both IGF-I and IGFBP-3 levels were increased during treatment. Insufficient levels of antidiuretic (ADH) hormone leading to diabetes insipidus has also been reported in patients with GLI2 mutations, as this gene is also expressed in the ventral diencephalon; hence, it seems relevant for hypothalamic, infundibular and posterior pituitary lobe formation [11]. Gonadotropin deficiencies [13], delayed puberty [8] and incomplete masculinization of the external genitalia have been also described in patients with GLI2 mutations. Our patient most likely has LH and FSH deficiencies, although he is yet prepubertal. Moreover, Shh is expressed in the urethral plate epithelium of mice during embryogenesis and this signal is mediated through Gli2 in the mesenchyme, confirming a role for Gli2 in the masculinization of external genitalia [14]. Two recent reviews on genetic of short stature can provide some extra background to the reader [15,16]. In conclusion, we report a novel GLI2 frameshift mutation in a child who manifests the most frequent anomalies described in the alteration of the SHH signaling pathway. Therefore, Culler-Jones syndrome due to GLI2 mutations should be suspected in the presence of congenital hypopituitarism, characteristic facial abnormalities and polydactyly.
Acknowledgement We would like to acknowledge and thank the patient, his parents and all of the researchers that are dedicated to performing complex studies to have a final diagnosis and the best therapeutical approach. JA was funded by the Spanish Ministry of Health (FIS-PI13/02195 & PI16/ 00485, co-funded by FEDER), Centro de Investigación Biomédica en Red for obesity and nutrition (CIBEROBN) from Instituto de Salud Carlos III, Spain and the Fundación de Endocrinología y Nutrición. ACB was funded by the Spanish Ministry of Health (FIS-PI12/00649, cofunded by FEDER) and Comunidad de Madrid (ENDOSCREEN S2010/ BMD-2396, co-funded by FEDER). References [1] K. Stochholm, T. Laursen, A. Green, et al., Morbidity and GH deficiency: a nationwide study, Eur. J. Endocrinol. 158 (2008) 447–457. [2] I.J. Arnhold, M.M. França, L.R. Carvalho, B.B. Mendonca, A.A. Jorge, Role of GLI2 in hypopituitarism phenotype, J. Mol. Endocrinol. 54 (2015) R141–R150. [3] E. Roessler, A.N. Ermilov, D.K. Grange, et al., A previously unidentified aminoterminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2, Hum. Mol. Genet. 14 (2005) 2181–2188. [4] C.C. Hui, S. Angers, Gli proteins in development and disease, Annu. Rev. Cell Dev. Biol. 27 (2011) 513–537. [5] H.L. Park, C. Bai, K.A. Platt, et al., Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation, Development 127 (2000) 1593–1605. [6] M. Hernández, J. Castellet, J.L. Narvaiza, et al., Curvas y tablas de crecimiento. Instituto de Investigación sobre Crecimiento y Desarrollo, Garsi, Madrid, 1988. [7] K.A. Bear, B.D. Solomon, S. Antonini, et al., Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly, J. Med. Genet. 51 (2014) 413–418. [8] M.M. França, A.A. Jorge, L.R. Carvalho, et al., Novel heterozygous nonsense GLI2 mutation in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly, J. Clin. Endocrinol. Metab. 95 (2010) E384–E391. [9] C.P.D. Bertolacini, L.A. Ribeiro-Bicudo, A. Petrin, A. Richieri-Costa, J.C. Murray, Clinical findings in patients with GLI2 mutations-phenotypic variability, Clin. Genet. 81 (2012) 70–75. [10] Y. Niida, M. Inoue, M. Ozaki, E. Takase, Human malformation syndromes of defective GLI: opposite phenotypes of 2q14.2 (GLI2) and 7p14.2 (GLI3) microdeletions and a GLIA/R balance model, Cytogenet. Genome Res. 153 (2017) 56–65. [11] Y. Wang, J.F. Martin, C.B. Bai, Direct and indirect requirements of Shh/Gli signaling in early pituitary development, Dev. Biol. 348 (2010) 199–209. [12] U. Kordab, C. Schörder, M. Elbracht, L. Soellner, T. Eggermann, A familial GLI2 Deletion (2q14.2) not associated with the holoprosencephaly syndrome phenotype, Am. J. Med. Genet. A. 167 (2015) 1121–1124. [13] K. Vaaralahti, T. Raivio, R. Koivu, L. Valanne, J. Tommiska Em Laitinen, Genetic overlap between holoprosencephaly and Kallmann syndrome, Mol. Syndromology 3 (2012) 1–5. [14] S. Miyagawa, D. Matsumaru, A. Murashima, et al., The role of sonic hedgehog-Gli2 pathway in the masculinization of external genitalia, Endocrinology 152 (2011) 2894–2903. [15] M. Grunauera, A.A.L. Jorge, Genetic of short stature, Growth Hormon. IGF Res. 38 (2018) 29–33. [16] J. Argente, L.A. Pérez-Jurado, Genetic causes of proportionate short stature, Best Pract. Res. Clin. Endocrinol. Metab. 32 (2018) 499–522.
19