Loss of function <i>BMP4</i> mutation supports the implication of the BMP/TGF‐β pathway in the etiology of combined pituitary hormone deficiency

Rodríguez-Contreras, Francisco Javier; Marbán-Calzón, Mercedes; Vallespín, Elena; Pozo, Ángela del; Solís-López, Mario; Lobato-Vidal, Nerea; Fernández-Elvira, María; Rex-Romero, María Del Valle; Heath, Karen E.; González‐Casado, Isabel; Campos-Barros, Ángel

doi:10.1002/ajmg.a.61201

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…In another study Simm et al (45) reported two new genes contributing to CPHD, SLC20A1, and SLC15A4 and evidenced that a significant portion of cases arise as a de novo event. Another study utilizing NGS sequencing also shed a new light on the combination of rare variants in different genes that might explain the incomplete penetrance in CPHD and the complexity of the disorder (46,47). In conclusion, we confirmed the major contribution of PROP1 gene mutations in CPHD.…”

Section: Discussionsupporting

confidence: 73%

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

et al. 2020

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Background: The mutation frequencies of pituitary transcription factors genes in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. However, apart from PROP1 the mutation rate of other genes is low and for almost half of the patients with CPHD the routine sequencing of known genes is unsuccessful in the identification of genetic causes.Methods: A cohort of 66 sporadic and nine familial CPHD cases (80 patients in total) were subjected to initial testing of the genes PROP1, POU1F1, LHX3, LHX4, and HESX1 using a targeted gene panel and MLPA. In patients who tested negative, a whole exome sequencing approach was employed.Results: In nine of the familial cases and 32 of the sporadic patients mutations in the PROP1 gene were found (the common pathogenic variants included c.301_302delAG and c.150delA). Mutations were also found in genes so far not related directly to CPHD. A unique homozygous and clinically relevant variant was identified in the SEMA3A gene, which may contribute to neural development and his phenotypic spectrum including short stature and isolated hypogonadotropic hypogonadism (IHH). Another pathogenic variant p.A1672T was found in the IGSF10 gene reported to be responsible for delayed puberty and neuronal migration during embryogenesis. Several suspected novel but predicted benign variants were also identified for the CHD7, WDR11 and FGF17 genes. Conclusion:Although PROP1 defects account for a majority of CPHD patients, identification of rare, less frequent variants constitutes a big challenge. Multiple genetic factors responsible for CPHD are still awaiting discovery and therefore the usage of efficient genomic tools (i.e., whole exome sequencing) will further broaden our knowledge regarding pituitary development and function.

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Section: Discussionsupporting

confidence: 73%

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

et al. 2020

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“…Genetic investigations embrace both pragmatic and research-based activities and new genetic associations are being identified as new technologies become more sensitive, cheaper, and widely applied. Novel genes and genetic pathways are being identified that affect pituitary function and are associated with post-natal growth failure, such as bone morphogenic protein ( BMP ) gene mutations ( 64 ), and the multiple genes involved in RASopathies, including some, such as LZTR1 mutations, that correlate with the Noonan syndrome phenotype ( 65 , 66 ). Many of these short stature genetic variants respond to GH therapy, although not all ( 17 , 64 , 67 ).…”

Section: Genomics In Precision Medicinementioning

confidence: 99%

“…Novel genes and genetic pathways are being identified that affect pituitary function and are associated with post-natal growth failure, such as bone morphogenic protein ( BMP ) gene mutations ( 64 ), and the multiple genes involved in RASopathies, including some, such as LZTR1 mutations, that correlate with the Noonan syndrome phenotype ( 65 , 66 ). Many of these short stature genetic variants respond to GH therapy, although not all ( 17 , 64 , 67 ). Hence, clinicians should be continuously up-dated of new developments and actively encouraged to build working relationships with genetic laboratories to discuss the indications and potential treatment options ( 17 ).…”

Section: Genomics In Precision Medicinementioning

confidence: 99%

Digital Health for Supporting Precision Medicine in Pediatric Endocrine Disorders: Opportunities for Improved Patient Care

et al. 2021

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Digitalization of healthcare delivery is rapidly fostering development of precision medicine. Multiple digital technologies, known as telehealth or eHealth tools, are guiding individualized diagnosis and treatment for patients, and can contribute significantly to the objectives of precision medicine. From a basis of “one-size-fits-all” healthcare, precision medicine provides a paradigm shift to deliver a more nuanced and personalized approach. Genomic medicine utilizing new technologies can provide precision analysis of causative mutations, with personalized understanding of mechanisms and effective therapy. Education is fundamental to the telehealth process, with artificial intelligence (AI) enhancing learning for healthcare professionals and empowering patients to contribute to their care. The Gulf Cooperation Council (GCC) region is rapidly implementing telehealth strategies at all levels and a workshop was convened to discuss aspirations of precision medicine in the context of pediatric endocrinology, including diabetes and growth disorders, with this paper based on those discussions. GCC regional investment in AI, bioinformatics and genomic medicine, is rapidly providing healthcare benefits. However, embracing precision medicine is presenting some major new design, installation and skills challenges. Genomic medicine is enabling precision and personalization of diagnosis and therapy of endocrine conditions. Digital education and communication tools in the field of endocrinology include chatbots, interactive robots and augmented reality. Obesity and diabetes are a major challenge in the GCC region and eHealth tools are increasingly being used for management of care. With regard to growth failure, digital technologies for growth hormone (GH) administration are being shown to enhance adherence and response outcomes. While technical innovations become more affordable with increasing adoption, we should be aware of sustainability, design and implementation costs, training of HCPs and prediction of overall healthcare benefits, which are essential for precision medicine to develop and for its objectives to be achieved.

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“…Genetic heterogeneity and variable penetrance of this mutation makes genetic diagnosis difficult considering that posterior pituitary ectopia may not present hormonal disturbance [ 25 ]. Additionally, as proposed by Rodriguez-Contreras [ 26 ], an oligogenic inheritance may contribute to modify phenotypic expressivity of BMP4 pathogenic variants.…”

Section: Discussionmentioning

confidence: 99%

Novel Variant in Exon 3 of the BMP4 Gene Resulted in Ectopic Posterior Pituitary, Craniocervical Junction Dysmorphism and Limb Anomaly

Calcaterra

Lamberti

Viggiano

et al. 2022

Case Reports in Pediatrics

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Introduction. Pituitary differentiation involves a large number of transcription factors. In particular, BMP4 expression is fundamental for pituitary gland commitment from the ventral diencephalon, suppressing Shh expression in Rathke’s pouch. Pathogenic variants in BMP4 are reported in the literature with a broad phenotypic spectrum, including pituitary and brain malformations. Case Presentation. A five-year-old girl came to medical attention following a mild cervical trauma with onset of cervical pain. On clinical examination at birth, postaxial polydactyly type B of the left hand was observed and removed at 10 months of age. A cervical radiography was performed, and a suspicion of craniocervical junction malformation was made. A magnetic resonance imaging of the cervical spine was made, showing an ectopic posterior pituitary, associated with dysmorphism of the craniocervical junction. The anthropometric parameters were pubertal Tanner stage 1, weight 16 kg (z-score: −1.09), height 107 cm (z-score: −0.76), and BMI 14 kg/m2 (z-score: −0.92). Normal hormonal assessment was detected. Genetic analysis via next generation sequencing showed a novel de novo heterozygous variant (c.277 G > T, p.Glu93 ∗ ) in exon 3 of BMP4. Discussion. We described a novel mutation in BMP4, resulting in ectopic posterior pituitary with normal hormonal assessment, associated to craniocervical junction dysmorphism and limb anomaly. It is important to monitor patient’s growth and puberty and to screen the onset of symptoms related to the deficiency of one or more anterior as well as posterior pituitary hormones.

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Loss of function BMP4 mutation supports the implication of the BMP/TGF‐β pathway in the etiology of combined pituitary hormone deficiency

Cited by 9 publications

References 23 publications

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

Digital Health for Supporting Precision Medicine in Pediatric Endocrine Disorders: Opportunities for Improved Patient Care

Novel Variant in Exon 3 of the BMP4 Gene Resulted in Ectopic Posterior Pituitary, Craniocervical Junction Dysmorphism and Limb Anomaly

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