Etiology of combined pituitary hormone deficiency: GNAO1 as a novel candidate gene

in Endocrine Connections
Authors:
Lukas Plachy Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Lukas Plachy in
Current site
Google Scholar
PubMed Close
,
Petra Dusatkova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Petra Dusatkova in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-8647-9088
,
Klara Maratova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Klara Maratova in
Current site
Google Scholar
PubMed Close
,
Shenali Anne Amaratunga Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Shenali Anne Amaratunga in
Current site
Google Scholar
PubMed Close
,
Dana Zemkova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Dana Zemkova in
Current site
Google Scholar
PubMed Close
,
Vit Neuman Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Vit Neuman in
Current site
Google Scholar
PubMed Close
,
Stanislava Kolouskova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Stanislava Kolouskova in
Current site
Google Scholar
PubMed Close
,
Barbora Obermannova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Barbora Obermannova in
Current site
Google Scholar
PubMed Close
,
Marta Snajderova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Marta Snajderova in
Current site
Google Scholar
PubMed Close
,
Zdenek Sumnik Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Zdenek Sumnik in
Current site
Google Scholar
PubMed Close
,
Jan Lebl Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Jan Lebl in
Current site
Google Scholar
PubMed Close
, and
Stepanka Pruhova Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu, Prague, Czech Republic

Search for other papers by Stepanka Pruhova in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to P Dusatkova: petra.dusatkova@lfmotol.cuni.cz
DOI:
https://doi.org/10.1530/EC-24-0217
Volume/Issue:
Volume 13: Issue 10
Article ID:
e240217
Article Type:
Research Article
Online Publication Date:
29 Aug 2024
Copyright:
© the author(s) 2024
Collections:
Pituitary and Hypothalamus
Open access

Sign up for journal news

Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was −3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

Abstract

Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was −3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

Keywords: combined pituitary hormone deficiency; genetics of short stature; growth hormone deficiency; next-generation sequencing; short stature

Introduction

Combined pituitary hormone deficiency (CPHD) is characterized by growth hormone deficiency (GHD) associated with a shortage of at least one other pituitary hormone (1). The etiology of CPHD is complex, including acquired conditions such as brain tumors, trauma, infection or irradiation, and congenital forms of CPHD with a presumed genetic background (1).

Pathogenic variants in more than 70 genes expressed during the prenatal development of the head, hypothalamus, and pituitary have been associated with CPHD to date (2, 3). With the progress of next-generation sequencing (NGS) methods (3), the number of genes involved in pituitary development is increasing rapidly (4, 5). Moreover, bigger genomic rearrangements have been described with CPHD typically associated with severe syndromic features (6, 7, 8). However, despite these advancements, more than 80% of congenital CPHD still remain without genetic diagnosis (1, 5, 9, 10).

Molecular diagnosis of CPHD is valuable for understanding the etiology of the disease, predicting its progression, and genetic consulting in family planning (1). Moreover, imaging studies sometimes detect a pituitary mass in children with congenital CPHD mimicking a brain tumor. Genetic testing may be able to predict the spontaneous regression of this lesion and may therefore prevent unnecessary and burdensome surgery (1, 11, 12). Further progress in genetic diagnostics of CPHD is therefore essential. The aim of our study was to identify the genetic etiology of CPHD using NGS in a single-center cohort treated with growth hormone (GH).

Materials and methods

Study population

Inclusion criteria

Children with CPHD were selected from the database of children treated with GH in the Centre of Pediatric Endocrinology of Motol University Hospital, Prague, Czech Republic. Children with secondary CPHD due to brain tumor, injury, infection, or other causes were excluded. Children whose legal guardians signed a written informed consent for genetic testing were enrolled in the study. The study was approved by the Institutional Ethics Committee of the 2nd Faculty of Medicine, Charles University and University Hospital Motol, Czech Republic (no. EK-753.3.5.21).

Clinical evaluation and diagnostics of CPHD

CPHD was defined as GHD associated with a deficit of at least one other pituitary hormone.

  1. GHD was defined according to the current guidelines (13, 14). In children with auxological and/or other clinical features suggestive of GHD (14) and IGF-1 concentration <0 s.d. (reference ranges standardized for age and sex), GHD was confirmed by GH stimulation tests. Two different stimulation tests (clonidine and insulin hypoglycemia tests) were performed in most children. In children with other pituitary hormone deficiencies and/or clear midline brain pathology diagnosed before GHD examination, only one of the tests was performed (14). Maximal stimulated GH concentration <10 ug/L was used as a cutoff for GHD diagnosis.

  2. The diagnosis of central hypothyroidism was made by a combination of low circulating free thyroxine concentrations associated with inadequately increased serum thyroid-stimulating hormone (15).

  3. The diagnosis of central adrenal insufficiency was made by a combination of low cortisol concentration (morning cortisol concentration <100 nmol/L or maximal stimulated cortisol concentration in the insulin hypoglycemia test <500 nmol/L) associated with inadequately increased adrenocorticotropic hormone (16, 17).

  4. Hypogonadotropic hypogonadism (HH) was diagnosed as delayed puberty (no breast development (Tanner stage 1) in girls ≥13 years old or testes <4 mL in boys ≥14 years old) associated with low gonadotropin concentration (18). In younger children with high suspicion of HH based on the signs of HH during minipuberty, the presence of deficiency of multiple pituitary hormones and/or known genetic etiology were evaluated individually by a pediatric endocrinologist. The specific reason for diagnosing HH will be specified in all individuals.

  5. The diagnosis of central diabetes insipidus was made by a combination of polyuria, hypotonic urine, and increased serum sodium concentration and/or osmolality in a random sample or during a water deprivation test that adequately responded to desmopressin administration (19).

The heights of all study participants were measured to the nearest 1 mm. Data regarding birth parameters, previous height development, and other important information were obtained from medical records. All data were standardized according to recent normative values (20, 21).

Genetic testing

Genomic DNA was extracted from peripheral blood (QIAamp Blood Mini Kit, Quiagen, Hilden, Germany) in all children included in the study. Children with a clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization (aCGH). Children without a detected causal variant after the first-tier testing or those whose phenotype did not lead to a suspicion of a specific genetic disorder were examined using the NGS custom-targeted panel containing 398 genes associated with growth (Supplementary Table 1, see section on supplementary materials given at the end of this article). All variants from NGS were confirmed by Sanger sequencing as described previously (22). The method of genetic examination is described in detail in previous studies (23, 24, 25, 26). Briefly, variant filtering was mainly based on their (low or absent) frequency in control databases like gnomAD, ExAc, and 1000 Genomes. Furthermore, in silico prediction software (Revel, CADD, DANN, SIFT, PolyPhen2, MutationTaster, SpliceAI, etc.) was used to predict the functional impact of the studied variant. We also assessed the localization of the variants in the functional domains of the respective proteins. Subsequently, copy number variants (CNVs) were studied using DECon software (27) using data generated by NGS.

All variants with potential clinical importance were evaluated by the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (28). For variant evaluation, we also used the ACMG criteria implemented into the Franklin software (https://franklin.genoox.com version date 3 May 2024) that scores each ACMG rule as very strong, strong, moderate, or supporting based on ACMG recommendations and its more up-to-date modifications. In some cases, the strength of the rules was modified according to an extended investigation of various databases and clinical evaluation of the patient. To evaluate the segregation of genetic variants with short stature in the families, DNA and height data of other relatives were obtained. The guidelines formulated by Jarvik et al. were followed (29) and applied to co-segregation in the pathogenicity classification. In the end, all genetic variants were classified as pathogenic (P), likely pathogenic (LP), benign (B), likely benign (LB), or as variants of uncertain significance (VUS).

Results

In total, 35 children with congenital CPHD are currently treated with GH in our center. In 34 of them (12 girls), their legal guardians consented to genetic testing and were enrolled in the study. Their age at study enrollment, first endocrinological examination, and GH treatment initiation was 11.2 years (median; IQR: 8.2–14.4 years), 2.5 years (1.3–4.9 years), and 2.7 years (1.6–5.7 years), respectively. Prior to GH treatment initiation, their height was −3.2 s.d. (−4.0 to −2.0 s.d.). Ten children had IGF-1 concentrations below the detection limit of our laboratory (15 μg/L), and the IGF-1 concentration of the remaining 24 children was −1.9 s.d. (−2.1 to −1.7 s.d.). The average maximum stimulated GH concentration of the study cohort was 1.4 μg/L (0.6–3.4 μg/L). Thirty children had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Magnetic resonance imaging (MRI) of the brain was performed in 32/34 children: 6/32 had a normal brain MRI, 5/32 had hypoplastic pituitary, 7/32 had pituitary stalk interruption syndrome (thin or interrupted pituitary stalk, ectopic or absent posterior pituitary, or hypoplastic or aplastic anterior pituitary), 13/32 had complex midline brain defect, and 1/32 had pituitary hyperplasia. Of the 34 children from the study cohort, 18 (53%) had complex syndromic phenotypes (presenting with significant associated clinical features – e.g. psychomotor retardation, epilepsy, and anophthalmia).

The genetic etiology of CPHD was elucidated in 7/34 (21%) of children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining six children had pathogenic or likely pathogenic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. The genetic etiology was discovered more frequently in children with a complex syndromic phenotype (28% (5/18) children – genes OTX2, GLI2, TBX3, PMM2, and GNAO1) than in children with isolated CPHD (13% (2/16) children – genes PROP1 and POU1F1). In 11 additional children, a genetic variant of uncertain significance was discovered. The phenotype characteristics are displayed in Table 1, and the genetic findings of children with a genetic diagnosis and those with VUS are summarized in detail in Table 2.

Table 1

Clinical characteristics.
Patient Sex Age at last follow-up (years) IGF-1 (s.d.) Stimulated GH maximum (μg/L) Additional pituitary hormone deficiency Brain MRI Additional phynotypic features Age at GH treatment initiation (years) Height s.d. at GH treatment initiation Height s.d. after 1 year of GH treatment Height s.d. after 3 years of GH treatment Height s.d. after 5 years of GH treatment
1 M 12.8 −1.9 1.8 CHT, CAI Optic nerves and chiasm agenesis, anophtalmia Bilateral anophtalmia, PMR, cryptorchidism 2.3 −4.4 −4.0 −3.1 −3.8
2 M 13.1 −1.7 1.1 CHT, CAI, HH Pituitary hyperplasia – 3.5 −3.4 −1.3 +0.3 +1.0
3 M 10.3 BDL 0.3 CHT NA Neonatal hypoglycaemia 1.1 −5.4 −3.7 −2.0 −0.9
4 F 15.6 −2.3 0.2 CHT, CAI, HH Pituitary hypoplasia PMR, hypoplastic kidney, atrial septal defect, metatarsal dephormity, delayed dental development, incomplete dentition 9.8 −4.5 −3.3 −2.2 −0.8
5 M 7.8 BDL 1.8 CHT, CAI Pituitary hypoplasia, ectopic posterior pituitary, CC hypoplasia Micropenis, cryptorchidism, scrotal hypoplasia, anal atresia 3.5 −3.9 −1.7 +0.1 NA
6 F 10.9 BDL 0.7 CHT, CAI, HH Corpus callosum hypoplasia Neonatal hypoglycemia, severe vision impairment, PMR, cerebellar syndrome, pulmonary stenosis, hepatopathy, myopathy, koagulopathy, craniofacial dysmorphia 2.7 −4.1 −3.7 −3.4 −2.4
7 F 14.7 −1.7 6.7 CHT, CAI, HH Partial empty sella PMR, epilepsy 6.7 −3.8 −2.9 −2.1 −2.0
8 M 17.6 −3.1 2.5 CHT Pituitary hypoplasia PMR, unilateral renal agenesis, scoliosis, myopia 14.8 −3.6 −3.3 −1.7 NA
9 M 17.1 −1.2 4.4 CHT, CAI, HH Pituitary hypoplasia Micropenis 1.4 −2.6 −1.6 −0.3 +0.1
10 M 16.3 −1.7 3.4 CHT, CAI Ectopic posterior pituitary PMR, epilepsy, mandibular hypoplasia 1.6 −0.7 −0.8 −0.7 −0.6
11 F 16.7 −1.9 0.8 CAI Normal – 9.5 −2.5 −1.9 −1.1 −0.8
12 M 6.8 −2.0 CAI Ectopic posterior pituitary, partial empty sella Hypermetropia, strabism 2.2 −3.3 −2.0 −0.6 +0.2
13 F 9.7 −2.2 6.7 CHT, CAI Ectopic posterior pituitary, Chiari malformation type I Gastroschisis, hand fingers deformities, ventricular septal defect 5.9 −4.1 −3.9 −3.4 NA
14 M 6.7 BDL 2.4 CHT, CAI Optic nerve hypoplasia Vision impairment, autism 2.3 −3.0 −3.0 −2.9 NA
15 M 9.4 −1.8 4.0 CAI Normal PMR, autism 5.7 −2.7 −2.0 −1.3 NA
16 M 10.7 BDL 0.7 CHT, CAI Pituitary hypoplasia, ectopic posterior pituitary, optic nerves hypoplasia PMR, autism 7.0 −4.0 −2.3 −1.0 NA
17 M 6.0 −0.5 3.1 CAI Pituitary hypoplasia – 3.3 −3.4 −2.4 −1.3 NA
18 M 13.6 −1.9 1.5 CHT, CAI, HH Brain hemispheres hemoragia Severe PMR, cryptorchidism, neonatal hypoglycaemia 1.5 −2.7 −2.8 −2.4 −2.9

BDL, below detection limit; CAI, central adrenal insufficiency; CHT, central hypothyroidism; F, female; GH, growth hormone; HH, hypogonadotropic hypogonadism; M, male; MRI, magnetic resonance imaging; NA, not available; PMR, psychomotor retardation.

Table 2

Genetic examination.
Patient Genetic examination method Gene Zygozity Transcript variant* Protein variant* Classification ACMG criteria Previously published patient
1 aCGH OTX2 HET del14q22.3-14q23.1 NA P NA (8)
2 Sanger PROP1 COMB HET c.109+1G>T; c.150del NA; p.Arg53fs P PVS1vs, PM2m, PM3m; PVS1vs, PM2m, Pm3m, PS3sp –
3 tNGS POU1F1 HET c.437T>G p.Leu146Ter LP PVS1vs, PM2m (38)
4 tNGS GLI2 HET c.3390_3391insAA p.Phe1131fs LP PVS1vs, PM2m –
5 tNGS TBX3 HET c.910C>T p.Arg304Trp LP PM2m, PM1m, PP3sp, PP4sp –
6 Sanger PMM2 COMB HET c.338C>T; c.696del p.Pro113Leu; p.Ala233fs P PM1m, PM2m, PM3m, PM5m, PS3sp, PP2sp, PP3sp; PVS1st, PM2m, PM3sp –
7 Sanger GNAO1 HET c.614A>T p.Gln505Leu LP PM1m, PM2m, PM5m, PP2sp, PP3sp –
8 aCGH NA HEM dupXp22.3 NA VUS NA –
9 tNGS FBN1 HET c.8537A>G p.Glu2846Gly VUS PM2m, PP2sp, PP3sp –
10 tNGS FLNB HET c.6407C>T p.Pro2136Leu VUS PM2m, PP2sp –
11 tNGS EVC HET c.1186C>T p.Arg396Trp VUS PM2m –
12 tNGS FBN1 HET c.6025G>A p.Glu2009Lys VUS PM2m, PP2sp –
13 tNGS PTCH1 HET c.3292G>A p.Val1098Ile VUS PM2m, PP2sp –
14 tNGS USP9X HEM c.4120G>A p.Asp1374Asn VUS PM2m –
15 tNGS LZTR1 HET c.1781T>C p.Leu594Pro VUS PM2m, PP2sp, PP3sp –
16 tNGS GLI2 HET c.2717C>T p.Pro906Leu VUS PM2m, BP4sp –
17 tNGS GLI2 HET c.2126T>C p.Leu709Pro VUS PM2m, BP4sp –
18 tNGS FLNB HET c.7719C>G p.Tyr2573Ter VUS PVS1m, PM2m –

*Reference sequences: EVC: NM_153717.3, NP_714928.1; FBN1: NM_000138.5, NP_000129.3; FLNB: NM_001457.4, NP_001448.2; GLI2: NM_001374353.1, NP_001361282.1; GNAO1: NM_020988.3, NP_066268.1; LZTR1: NM_006767.4, NP_006758.2; PMM2: NM_000303.3, NP_000294.1; PROP1: NM_006261.5, NP_006252.4; POU1F1: NM_000306.4, NP_000297.1; PTCH1: NM_000264.5, NP_000255.2; TBX3: NM_005996.4, NP_005987.3; USP9X: NM_001039591.3, NP_001034680.2.

aCGH, microarray-based comparative genomic hybridization; ACMG, American College of Medical Genetics and Genomics; COMB HET, combined heterozygous; HEM, hemizygous; HET, heterozygous; LP, likely pathogenic; NA, not available; P, pathogenic; tNGS, target next-generation sequencing panel; VUS, variant of uncertain significance.

Discussion

In our study, we searched for the genetic etiology of congenital combined pituitary hormone deficiency in 34 children followed up in a single center. Using modern genetic methods, including NGS, we elucidated the genetic diagnosis in 21% of the children.

Previous studies mostly examined only a limited spectrum of genes known to cause CPHD. The detection rate of a genetic etiology varied substantially, ranging from 0 to 65% depending on the inclusion criteria and the population studied (10, 30, 31, 32, 33). Of note, in the studies reporting higher percentages of elucidated genetic etiology of CPHD, causative variants in the PROP1 gene clearly dominated. Importantly, children reported in these studies were known to be selected for genetic testing of the PROP1 gene (and in some studies also for other genes), which may have led to a selection bias. Interestingly, the children with syndromic CPHD were rarely reported in these studies (33, 34, 35). In our study, we managed to gather 34/35 children with CPHD treated in our center regardless of their associated phenotype, and only 1/34 (3%) of the study cohort carried causative variants in the PROP1 gene. We, therefore, propose that PROP1 pathogenic variants might be substantially less prevalent in the non-preselected CPHD population, even in the East-Central Europe region where a high prevalence of PROP1 gene variants is generally presumed (33).

Importantly, NGS methods have facilitated substantial progress in understanding the pathogenesis of short stature (36, 37, 38, 39, 40). Massive parallel sequencing has enabled the discovery of more than 50 new genes associated with CPHD in the last 10 years (1, 3, 4). In our current study, 5 children with a genetic etiology discovered carried a causative variant in genes that have long been known to cause CPHD (OTX2, PROP1, POU1F1, GLI2, and TBX3). However, in an additional two children, we discovered causative variants in the GNAO1 and PMM2 genes that corresponded with the complex phenotype of their carriers and are known to cause syndromic short stature (41, 42, 43), but are not typically associated with CPHD. Notably, a variant in the PMM2 gene was previously described in one patient with CPHD and pituitary stalk interruption syndrome (44) and another patient with central adrenal insufficiency (45). Moreover, thin corpus callosum is a common feature in children with GNAO1 gene variants (46).

Despite the progress in genetic examination, the etiology of most children with congenital CPHD remains unsolved (5). This is in line with our study results despite complex genetic examination. Considering other possible causes of CPHD is therefore essential. First, in 11/34 patients, we discovered a genetic variant of uncertain significance that might be responsible for the disease, with the evidence clearly proving that the pathogenicity is lacking. Secondly, variants in genes not present in our panel or deep intronic variants that are not captured by our examination might have been missed. Thirdly, epigenetic and environmental factors might be another possible cause of CPHD (1, 47, 48).

We acknowledge that our study had several limitations. Apart from the limitations mentioned above, no functional studies have been performed. However, according to current guidelines, other methods can be used to assess the pathogenicity of genetic variants (28). Additionally, our study contained only children from one center of pediatric endocrinology. Further studies performed on different populations are needed to confirm our results. Lastly, NGS examination was not performed in patients 1 and 2 with genetic diagnosis of CPHD obtained using different methods (aCGH or Sanger sequencing); therefore, a possible multiple genetic etiology could have been missed.

Conclusion

Genetic etiology was discovered in 21% of children with CPHD. Our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0217.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This work was supported by the Ministry of Health of the Czech Republic: grant no. NU22J-07-00014 and conceptual development of research organization, Motol University Hospital, Prague, Czech Republic, 00064203.

Acknowledgements

We would like to thank Katerina Kolarova and Klara Vesela, laboratory workers at our center, for their devoted work and dedication to the study. We would like to acknowledge the cytogenetic investigation of selected patients performed by Zuzana Slamova, PhD from the Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital.

References

  • 1↑

    Fang Q, George AS, Brinkmeier ML, Mortensen AH, Gergics P, Cheung LYM, Daly AZ, Ajmal A, Pérez Millán MI, Ozel AB, et al.Genetics of combined pituitary hormone deficiency: roadmap into the genome era. Endocrine Reviews 2016 37 636–675 (https://doi.org/10.1210/er.2016-1101)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2↑

    Bando H, Urai S, Kanie K, Sasaki Y, Yamamoto M, Fukuoka H, Iguchi G, & Camper SA. Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing. Frontiers in Endocrinology 2022 13 1008306. (https://doi.org/10.3389/fendo.2022.1008306)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3↑

    Hietamaki J, Karkinen J, Iivonen AP, Vaaralahti K, Tarkkanen A, Almusa H, Huopio H, Hero M, Miettinen PJ, & Raivio T. Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: a single center experience from over 30 years. EClinicalMedicine 2022 51 101556 . (https://doi.org/10.1016/j.eclinm.2022.101556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4↑

    Budny B, Karmelita-Katulska K, Stajgis M, Żemojtel T, Ruchała M, & Ziemnicka K. Copy number variants contributing to combined pituitary hormone deficiency. International Journal of Molecular Sciences 2020 21 1–10. (https://doi.org/10.3390/ijms21165757)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5↑

    Hage C, Gan HW, Ibba A, Patti G, Dattani M, Loche S, Maghnie M, & Salvatori R. Advances in differential diagnosis and management of growth hormone deficiency in children. Nature Reviews. Endocrinology 2021 17 608–624. (https://doi.org/10.1038/s41574-021-00539-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6↑

    Chehadeh-Djebbar El S, Callier P, Masurel-Paulet A, Bensignor C, Méjean N, Payet M, Ragon C, Durand C, Marle N, Mosca-Boidron AL, et al.17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome. European Journal of Medical Genetics 2011 54 369–373. (https://doi.org/10.1016/j.ejmg.2011.03.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7↑

    Correa FA, Jorge AAL, Nakaguma M, Canton APM, Costa SS, Funari MF, Lerario AM, Franca MM, Carvalho LR, Krepischi ACV, et al.Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes. Clinical Endocrinology 2018 88 425–431. (https://doi.org/10.1111/cen.13535)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8↑

    Brisset S, Slamova Z, Dusatkova P, Briand-Suleau A, Milcent K, Metay C, Simandlova M, Sumnik Z, Tosca L, Goossens M, et al.Anophthalmia, hearing loss, abnormal pituitary development and response to growth hormone therapy in three children with microdeletions of 14q22q23. Molecular Cytogenetics 2014 7 17 . (https://doi.org/10.1186/1755-8166-7-17)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9↑

    Rienzo De F, Mellone S, Bellone S, Babu D, Fusco I, Prodam F, Petri A, Muniswamy R, Luca De F, Salerno M, et al.Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort. Clinical Endocrinology 2015 83 849–860. (https://doi.org/10.1111/cen.12849)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10↑

    Pérez Millán MI, Vishnopolska SA, Daly AZ, Bustamante JP, Seilicovich A, Bergadá I, Braslavsky D, Keselman AC, Lemons RM, Mortensen AH, et al.Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism. Molecular Genetics and Genomic Medicine 2018 6 514–525. (https://doi.org/10.1002/mgg3.395)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11↑

    Obermannova B, Pfaeffle R, Zygmunt-Gorska A, Starzyk J, Verkauskiene R, Smetanina N, Bezlepkina O, Peterkova V, Frisch H, Cinek O, et al.Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects. Hormone Research in Paediatrics 2011 76 348–354. (https://doi.org/10.1159/000332693)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12↑

    Zygmunt-Gorska A, Starzyk J, Adamek D, Radwanska E, Sucharski P, Herman-Sucharska I, & Pietrzyk JJ. Pituitary enlargement in patients with PROP1 gene inactivating mutation represents cystic hyperplasia of the intermediate pituitary lobe. Histopathology and over 10 years follow-up of two patients. Journal of Pediatric Endocrinology & Metabolism 2009 22 653–660. (https://doi.org/10.1515/jpem.2009.22.7.653)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13↑

    Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, Rossi WC, Feudtner C, & Murad MH. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Hormone Research in Paediatrics 2017 86 361–397. (https://doi.org/10.1159/000452150)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14↑

    Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society 1. Journal of Clinical Endocrinology and Metabolism 2000 85 3990–3993. (https://doi.org/10.1210/jcem.85.11.6984)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15↑

    Persani L, Brabant G, Dattani M, Bonomi M, Feldt-Rasmussen U, Fliers E, Gruters A, Maiter D, Schoenmakers N, & Paul Van Trotsenburg ASP. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. European Thyroid Journal 2018 7 225–237. (https://doi.org/10.1159/000491388)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16↑

    Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, et al.Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 364–389. (https://doi.org/10.1210/jc.2015-1710)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17↑

    Gruber LM, & Bancos I. Secondary adrenal insufficiency: recent updates and new directions for diagnosis and management. Endocrine Practice 2022 28 110–117. (https://doi.org/10.1016/j.eprac.2021.09.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18↑

    Nordenström A, Ahmed SF, Akker van den E, Blair J, Bonomi M, Brachet C, Broersen LHA, Claahsen-van der Grinten HL, Dessens AB, Gawlik A, et al.Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline. European Journal of Endocrinology 2022 186 G9–G49. (https://doi.org/10.1530/EJE-22-0073)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19↑

    Mishra G, & Chandrashekhar SR. Management of diabetes insipidus in children. Indian Journal of Endocrinology and Metabolism 2011 15(Supplement 3) S180–S187. (https://doi.org/10.4103/2230-8210.84858)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20↑

    Voigt M, Fusch C, Olbertz D, Hartmann K, Rochow N, Renken C, & Schneider K. Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland. Geburtshilfe und Frauenheilkunde 2006 66 956–970. (https://doi.org/10.1055/s-2006-924458)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21↑

    Kobzová J, Vignerová J, Bláha P, Krejćovsky L, & Riedlová J. The 6th nationwide anthropological survey of children and adolescents in the Czech Republic in 2001. Central European Journal of Public Health 2004 12 126–130.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22↑

    Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, Cinek O, & Lebl J. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatric Diabetes 2010 11 529–535. (https://doi.org/10.1111/j.1399-5448.2010.00646.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23↑

    Plachy L, Strakova V, Elblova L, Obermannova B, Kolouskova S, Snajderova M, Zemkova D, Dusatkova P, Sumnik Z, Lebl J, et al.High prevalence of growth plate gene variants in children with familial short stature treated with growth hormone. Journal of Clinical Endocrinology and Metabolism 2019 104 4273–4281. (https://doi.org/10.1210/jc.2018-02288)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24↑

    Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, Kucerova P, Toni L, Kolouskova S, Snajderova M, et al.NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. Journal of Clinical Endocrinology and Metabolism 2020 105 746–752. (https://doi.org/10.1210/clinem/dgaa037)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25↑

    Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Elblova L, Kolouskova S, Snajderova M, Obermannova B, Zemkova D, Sumnik Z, et al.Familial short stature - a novel phenotype of growth plate collagenopathies. Journal of Clinical Endocrinology and Metabolism 2021 106 1742–1749. (https://doi.org/10.1210/clinem/dgab084)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26↑

    Plachy L, Amaratunga SA, Dusatkova P, Maratova K, Neuman V, Petruzelkova L, Zemkova D, Obermannova B, Snajderova M, Kolouskova S, et al.Isolated growth hormone deficiency in children with vertically transmitted short stature: what do the genes tell us? Frontiers in Endocrinology 2022 13 1102968 . (https://doi.org/10.3389/fendo.2022.1102968)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27↑

    Fowler A. DECoN: a detection and visualization tool for exonic copy number variants. In: Variant Calling. Methods in Molecular Biology, vol 2493. New York, NY, USA: Humana, 2022. (https://doi.org/10.1007/978-1-0716-2293-3_6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28↑

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genetics in Medicine 2015 17 405–424. (https://doi.org/10.1038/gim.2015.30)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29↑

    Jarvik GP, & Browning BL. Consideration of cosegregation in the pathogenicity classification of genomic variants. American Journal of Human Genetics 2016 98 1077–1081. (https://doi.org/10.1016/j.ajhg.2016.04.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30↑

    Reynaud R, Gueydan M, Saveanu A, Vallette-Kasic S, Enjalbert A, Brue T, & Barlier A. Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. Journal of Clinical Endocrinology and Metabolism 2006 91 3329–3336. (https://doi.org/10.1210/jc.2005-2173)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31↑

    Coya R, Vela A, Perez de Nanclares G, Rica I, Castano L, Busturia MA, Martul P & GEDPIT group. Panhypopituitarism: genetic versus acquired etiological factors. Journal of Pediatric Endocrinology and Metabolism 2007 20 27–36 . (https://doi.org/10.1515/JPEM.2007.20.1.27)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32↑

    Vieira TC, Boldarine VT, & Abucham J. Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arquivos Brasileiros de Endocrinologia e Metabologia 2007 51 1097–1103. (https://doi.org/10.1590/S0004-27302007000700012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33↑

    Navardauskaite R, Dusatkova P, Obermannova B, Pfaeffle RW, Blum WF, Adukauskiene D, Smetanina N, Cinek O, Verkauskiene R, & Lebl J. High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency. Journal of Clinical Endocrinology and Metabolism 2014 99 299–306. (https://doi.org/10.1210/jc.2013-3090)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34↑

    Lebl J, Vosáhlo J, Pfaeffle RW, Stobbe H, Černá J, Novotná D, Zapletalová J, Kalvachová B, Hána V, Weiss V, et al.Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. European Journal of Endocrinology 2005 153 389–396. (https://doi.org/10.1530/eje.1.01989)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35↑

    Halász Z, Toke J, Patócs A, Bertalan R, Tömböl Z, Sallai A, Hosszú E, Muzsnai A, Kovács L, Sólyom J, et al.High prevalence of PROP1 gene mutations in Hungarian patients with childhood-onset combined anterior pituitary hormone deficiency. Endocrine 2006 30 255–260. (https://doi.org/10.1007/s12020-006-0002-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36↑

    Plachy L, Petruzelkova L, Dušátková P, Maratova K, Zemkova D, Elblova L, Neuman V, Kolouskova S, Obermannova B, Snajderova M, et al.Analysis of children with familial short stature: who should be indicated for genetic testing? Endocrine Connections 2023 12 . (https://doi.org/10.1530/EC-23-0238)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37↑

    Toni L, Plachy L, Dusatkova P, Amaratunga SA, Elblova L, Sumnik Z, Kolouskova S, Snajderova M, Obermannova B, Pruhova S, et al.The genetic landscape of children born small for gestational age with persistent short stature. Hormone Research in Paediatrics 2024 97 40–52 . (https://doi.org/10.1159/000530521)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38↑

    Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, Klinger P, Kraus C, Trautmann U, Zenker M, et al.Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genetics in Medicine 2018 20 630–638. (https://doi.org/10.1038/gim.2017.159)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39↑

    Homma TK, Freire BL, Honjo Kawahira RS, Dauber A, Funari MFA, Lerario AM, Nishi MY, Albuquerque EV, Vasques GA, Collett-Solberg PF, et al.Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing. Journal of Pediatrics 2019 215 192–198. (https://doi.org/10.1016/j.jpeds.2019.08.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40↑

    Freire BL, Homma TK, Funari MFA, Lerario AM, Vasques GA, Malaquias AC, Arnhold IJP, & Jorge AAL. Multigene sequencing analysis of children born small for gestational age with isolated short stature. Journal of Clinical Endocrinology and Metabolism 2019 104 2023–2030. (https://doi.org/10.1210/jc.2018-01971)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41↑

    Miller BS, Duffy MM, Addo OY, & Sarafoglou K. rhIGF-1 therapy for growth failure and IGF-1 deficiency in congenital disorder of glycosylation Ia (PMM2 deficiency). Journal of Investigative Medicine High Impact Case Reports 2013 1 2324709613503316. (https://doi.org/10.1177/2324709613503316)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42↑

    Apuzzo D, Cappuccio G, Vaisanen T, Alagia M, Pignataro P, Genesio R, & Brunetti-Pierri N. Two cases of 16q12.1q21 deletions and refinement of the critical region. European Journal of Medical Genetics 2020 63 103878. (https://doi.org/10.1016/j.ejmg.2020.103878)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43↑

    Girisha KM, Bidchol AM, Graul-Neumann L, Gupta A, Hehr U, Lessel D, Nader S, Shah H, Wickert J, & Kutsche K. Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients. BMC Medical Genetics 2016 17 27. (https://doi.org/10.1186/s12881-016-0290-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44↑

    Brauner R, Bignon-Topalovic J, Bashamboo A, & McElreavey K. Pituitary stalk interruption syndrome is characterized by genetic heterogeneity. PLoS One 2020 15 e0242358 . (https://doi.org/10.1371/journal.pone.0242358)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45↑

    Čechová A, Honzík T, Edmondson AC, Ficicioglu C, Serrano M, Barone R, Lonlay De P, Schiff M, Witters P, Lam C, et al.Should patients with phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency? Molecular Genetics and Metabolism 2021 133 397–399. (https://doi.org/10.1016/j.ymgme.2021.06.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46↑

    Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, et al.Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. European Journal of Human Genetics 2016 24 129–134. (https://doi.org/10.1038/ejhg.2015.92)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47↑

    Hong M, & Krauss RS. Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice. PLoS Genetics 2012 8 e1002999. (https://doi.org/10.1371/journal.pgen.1002999)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48↑

    Simeone P, & Alberti S. Epigenetic heredity of human height. Physiological Reports 2014 2 e12047. (https://doi.org/10.14814/phy2.12047)

Supplementary Materials

Endocrine Connections is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

As an open-access journal, Endocrine Connections articles are immediately available to read on publication, without restriction. The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 607 607 398
PDF Downloads 263 263 144

 

  • Collapse
  • Expand
Online ISSN:
2049-3614
Copyright:
© the author(s) 2024
Article ID:
e240217
Article Type:
Research Article
Received Date:
04 May 2024
Accepted Date:
30 Jul 2024
Online Publication Date:
29 Aug 2024
Keywords:
combined pituitary hormone deficiency; genetics of short stature; growth hormone deficiency; next-generation sequencing; short stature
  • 1

    Fang Q, George AS, Brinkmeier ML, Mortensen AH, Gergics P, Cheung LYM, Daly AZ, Ajmal A, Pérez Millán MI, Ozel AB, et al.Genetics of combined pituitary hormone deficiency: roadmap into the genome era. Endocrine Reviews 2016 37 636–675 (https://doi.org/10.1210/er.2016-1101)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Bando H, Urai S, Kanie K, Sasaki Y, Yamamoto M, Fukuoka H, Iguchi G, & Camper SA. Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing. Frontiers in Endocrinology 2022 13 1008306. (https://doi.org/10.3389/fendo.2022.1008306)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hietamaki J, Karkinen J, Iivonen AP, Vaaralahti K, Tarkkanen A, Almusa H, Huopio H, Hero M, Miettinen PJ, & Raivio T. Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: a single center experience from over 30 years. EClinicalMedicine 2022 51 101556 . (https://doi.org/10.1016/j.eclinm.2022.101556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Budny B, Karmelita-Katulska K, Stajgis M, Żemojtel T, Ruchała M, & Ziemnicka K. Copy number variants contributing to combined pituitary hormone deficiency. International Journal of Molecular Sciences 2020 21 1–10. (https://doi.org/10.3390/ijms21165757)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Hage C, Gan HW, Ibba A, Patti G, Dattani M, Loche S, Maghnie M, & Salvatori R. Advances in differential diagnosis and management of growth hormone deficiency in children. Nature Reviews. Endocrinology 2021 17 608–624. (https://doi.org/10.1038/s41574-021-00539-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Chehadeh-Djebbar El S, Callier P, Masurel-Paulet A, Bensignor C, Méjean N, Payet M, Ragon C, Durand C, Marle N, Mosca-Boidron AL, et al.17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome. European Journal of Medical Genetics 2011 54 369–373. (https://doi.org/10.1016/j.ejmg.2011.03.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Correa FA, Jorge AAL, Nakaguma M, Canton APM, Costa SS, Funari MF, Lerario AM, Franca MM, Carvalho LR, Krepischi ACV, et al.Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes. Clinical Endocrinology 2018 88 425–431. (https://doi.org/10.1111/cen.13535)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Brisset S, Slamova Z, Dusatkova P, Briand-Suleau A, Milcent K, Metay C, Simandlova M, Sumnik Z, Tosca L, Goossens M, et al.Anophthalmia, hearing loss, abnormal pituitary development and response to growth hormone therapy in three children with microdeletions of 14q22q23. Molecular Cytogenetics 2014 7 17 . (https://doi.org/10.1186/1755-8166-7-17)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Rienzo De F, Mellone S, Bellone S, Babu D, Fusco I, Prodam F, Petri A, Muniswamy R, Luca De F, Salerno M, et al.Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort. Clinical Endocrinology 2015 83 849–860. (https://doi.org/10.1111/cen.12849)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Pérez Millán MI, Vishnopolska SA, Daly AZ, Bustamante JP, Seilicovich A, Bergadá I, Braslavsky D, Keselman AC, Lemons RM, Mortensen AH, et al.Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism. Molecular Genetics and Genomic Medicine 2018 6 514–525. (https://doi.org/10.1002/mgg3.395)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Obermannova B, Pfaeffle R, Zygmunt-Gorska A, Starzyk J, Verkauskiene R, Smetanina N, Bezlepkina O, Peterkova V, Frisch H, Cinek O, et al.Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects. Hormone Research in Paediatrics 2011 76 348–354. (https://doi.org/10.1159/000332693)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Zygmunt-Gorska A, Starzyk J, Adamek D, Radwanska E, Sucharski P, Herman-Sucharska I, & Pietrzyk JJ. Pituitary enlargement in patients with PROP1 gene inactivating mutation represents cystic hyperplasia of the intermediate pituitary lobe. Histopathology and over 10 years follow-up of two patients. Journal of Pediatric Endocrinology & Metabolism 2009 22 653–660. (https://doi.org/10.1515/jpem.2009.22.7.653)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, Rossi WC, Feudtner C, & Murad MH. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Hormone Research in Paediatrics 2017 86 361–397. (https://doi.org/10.1159/000452150)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society 1. Journal of Clinical Endocrinology and Metabolism 2000 85 3990–3993. (https://doi.org/10.1210/jcem.85.11.6984)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Persani L, Brabant G, Dattani M, Bonomi M, Feldt-Rasmussen U, Fliers E, Gruters A, Maiter D, Schoenmakers N, & Paul Van Trotsenburg ASP. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. European Thyroid Journal 2018 7 225–237. (https://doi.org/10.1159/000491388)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, et al.Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 364–389. (https://doi.org/10.1210/jc.2015-1710)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Gruber LM, & Bancos I. Secondary adrenal insufficiency: recent updates and new directions for diagnosis and management. Endocrine Practice 2022 28 110–117. (https://doi.org/10.1016/j.eprac.2021.09.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Nordenström A, Ahmed SF, Akker van den E, Blair J, Bonomi M, Brachet C, Broersen LHA, Claahsen-van der Grinten HL, Dessens AB, Gawlik A, et al.Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline. European Journal of Endocrinology 2022 186 G9–G49. (https://doi.org/10.1530/EJE-22-0073)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Mishra G, & Chandrashekhar SR. Management of diabetes insipidus in children. Indian Journal of Endocrinology and Metabolism 2011 15(Supplement 3) S180–S187. (https://doi.org/10.4103/2230-8210.84858)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Voigt M, Fusch C, Olbertz D, Hartmann K, Rochow N, Renken C, & Schneider K. Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland. Geburtshilfe und Frauenheilkunde 2006 66 956–970. (https://doi.org/10.1055/s-2006-924458)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Kobzová J, Vignerová J, Bláha P, Krejćovsky L, & Riedlová J. The 6th nationwide anthropological survey of children and adolescents in the Czech Republic in 2001. Central European Journal of Public Health 2004 12 126–130.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, Cinek O, & Lebl J. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatric Diabetes 2010 11 529–535. (https://doi.org/10.1111/j.1399-5448.2010.00646.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Plachy L, Strakova V, Elblova L, Obermannova B, Kolouskova S, Snajderova M, Zemkova D, Dusatkova P, Sumnik Z, Lebl J, et al.High prevalence of growth plate gene variants in children with familial short stature treated with growth hormone. Journal of Clinical Endocrinology and Metabolism 2019 104 4273–4281. (https://doi.org/10.1210/jc.2018-02288)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, Kucerova P, Toni L, Kolouskova S, Snajderova M, et al.NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. Journal of Clinical Endocrinology and Metabolism 2020 105 746–752. (https://doi.org/10.1210/clinem/dgaa037)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Elblova L, Kolouskova S, Snajderova M, Obermannova B, Zemkova D, Sumnik Z, et al.Familial short stature - a novel phenotype of growth plate collagenopathies. Journal of Clinical Endocrinology and Metabolism 2021 106 1742–1749. (https://doi.org/10.1210/clinem/dgab084)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Plachy L, Amaratunga SA, Dusatkova P, Maratova K, Neuman V, Petruzelkova L, Zemkova D, Obermannova B, Snajderova M, Kolouskova S, et al.Isolated growth hormone deficiency in children with vertically transmitted short stature: what do the genes tell us? Frontiers in Endocrinology 2022 13 1102968 . (https://doi.org/10.3389/fendo.2022.1102968)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Fowler A. DECoN: a detection and visualization tool for exonic copy number variants. In: Variant Calling. Methods in Molecular Biology, vol 2493. New York, NY, USA: Humana, 2022. (https://doi.org/10.1007/978-1-0716-2293-3_6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genetics in Medicine 2015 17 405–424. (https://doi.org/10.1038/gim.2015.30)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Jarvik GP, & Browning BL. Consideration of cosegregation in the pathogenicity classification of genomic variants. American Journal of Human Genetics 2016 98 1077–1081. (https://doi.org/10.1016/j.ajhg.2016.04.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Reynaud R, Gueydan M, Saveanu A, Vallette-Kasic S, Enjalbert A, Brue T, & Barlier A. Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. Journal of Clinical Endocrinology and Metabolism 2006 91 3329–3336. (https://doi.org/10.1210/jc.2005-2173)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Coya R, Vela A, Perez de Nanclares G, Rica I, Castano L, Busturia MA, Martul P & GEDPIT group. Panhypopituitarism: genetic versus acquired etiological factors. Journal of Pediatric Endocrinology and Metabolism 2007 20 27–36 . (https://doi.org/10.1515/JPEM.2007.20.1.27)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Vieira TC, Boldarine VT, & Abucham J. Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arquivos Brasileiros de Endocrinologia e Metabologia 2007 51 1097–1103. (https://doi.org/10.1590/S0004-27302007000700012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Navardauskaite R, Dusatkova P, Obermannova B, Pfaeffle RW, Blum WF, Adukauskiene D, Smetanina N, Cinek O, Verkauskiene R, & Lebl J. High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency. Journal of Clinical Endocrinology and Metabolism 2014 99 299–306. (https://doi.org/10.1210/jc.2013-3090)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Lebl J, Vosáhlo J, Pfaeffle RW, Stobbe H, Černá J, Novotná D, Zapletalová J, Kalvachová B, Hána V, Weiss V, et al.Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. European Journal of Endocrinology 2005 153 389–396. (https://doi.org/10.1530/eje.1.01989)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Halász Z, Toke J, Patócs A, Bertalan R, Tömböl Z, Sallai A, Hosszú E, Muzsnai A, Kovács L, Sólyom J, et al.High prevalence of PROP1 gene mutations in Hungarian patients with childhood-onset combined anterior pituitary hormone deficiency. Endocrine 2006 30 255–260. (https://doi.org/10.1007/s12020-006-0002-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Plachy L, Petruzelkova L, Dušátková P, Maratova K, Zemkova D, Elblova L, Neuman V, Kolouskova S, Obermannova B, Snajderova M, et al.Analysis of children with familial short stature: who should be indicated for genetic testing? Endocrine Connections 2023 12 . (https://doi.org/10.1530/EC-23-0238)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Toni L, Plachy L, Dusatkova P, Amaratunga SA, Elblova L, Sumnik Z, Kolouskova S, Snajderova M, Obermannova B, Pruhova S, et al.The genetic landscape of children born small for gestational age with persistent short stature. Hormone Research in Paediatrics 2024 97 40–52 . (https://doi.org/10.1159/000530521)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, Klinger P, Kraus C, Trautmann U, Zenker M, et al.Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genetics in Medicine 2018 20 630–638. (https://doi.org/10.1038/gim.2017.159)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Homma TK, Freire BL, Honjo Kawahira RS, Dauber A, Funari MFA, Lerario AM, Nishi MY, Albuquerque EV, Vasques GA, Collett-Solberg PF, et al.Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing. Journal of Pediatrics 2019 215 192–198. (https://doi.org/10.1016/j.jpeds.2019.08.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Freire BL, Homma TK, Funari MFA, Lerario AM, Vasques GA, Malaquias AC, Arnhold IJP, & Jorge AAL. Multigene sequencing analysis of children born small for gestational age with isolated short stature. Journal of Clinical Endocrinology and Metabolism 2019 104 2023–2030. (https://doi.org/10.1210/jc.2018-01971)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Miller BS, Duffy MM, Addo OY, & Sarafoglou K. rhIGF-1 therapy for growth failure and IGF-1 deficiency in congenital disorder of glycosylation Ia (PMM2 deficiency). Journal of Investigative Medicine High Impact Case Reports 2013 1 2324709613503316. (https://doi.org/10.1177/2324709613503316)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Apuzzo D, Cappuccio G, Vaisanen T, Alagia M, Pignataro P, Genesio R, & Brunetti-Pierri N. Two cases of 16q12.1q21 deletions and refinement of the critical region. European Journal of Medical Genetics 2020 63 103878. (https://doi.org/10.1016/j.ejmg.2020.103878)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Girisha KM, Bidchol AM, Graul-Neumann L, Gupta A, Hehr U, Lessel D, Nader S, Shah H, Wickert J, & Kutsche K. Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients. BMC Medical Genetics 2016 17 27. (https://doi.org/10.1186/s12881-016-0290-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Brauner R, Bignon-Topalovic J, Bashamboo A, & McElreavey K. Pituitary stalk interruption syndrome is characterized by genetic heterogeneity. PLoS One 2020 15 e0242358 . (https://doi.org/10.1371/journal.pone.0242358)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Čechová A, Honzík T, Edmondson AC, Ficicioglu C, Serrano M, Barone R, Lonlay De P, Schiff M, Witters P, Lam C, et al.Should patients with phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency? Molecular Genetics and Metabolism 2021 133 397–399. (https://doi.org/10.1016/j.ymgme.2021.06.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, et al.Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. European Journal of Human Genetics 2016 24 129–134. (https://doi.org/10.1038/ejhg.2015.92)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Hong M, & Krauss RS. Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice. PLoS Genetics 2012 8 e1002999. (https://doi.org/10.1371/journal.pgen.1002999)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Simeone P, & Alberti S. Epigenetic heredity of human height. Physiological Reports 2014 2 e12047. (https://doi.org/10.14814/phy2.12047)