Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome

McCormack, Shana E.; Liu, Dong; Kim, Yeon Joo; Lee, Ji Young; Rapaport, Robert; Levine, Michael A.

doi:10.1210/jc.2017-00332

Cited by 40 publications

(38 citation statements)

References 23 publications

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“…It seems that there is a variable intrafamilial expressivity of FOXL2 in the pituitary phenotype, as has been described for the ovarian phenotype [13]. This variable expressivity of FOXL2 could be the result of interactions with environmental factors and/or oligogenicity, as recently reported for other hypopituitarism features [31], even if no pathogenic variants were identified in the genes analyzed in our series.…”

Section: Discussionsupporting

confidence: 76%

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations

Castets¹,

Roucher‐Boulez²,

Saveanu³

et al. 2020

Horm Res Paediatr

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Background: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. Methods: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2 mutation. Results: Three patients had an FOXL2 mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. Conclusion: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

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Section: Discussionsupporting

confidence: 76%

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations

Castets¹,

Roucher‐Boulez²,

Saveanu³

et al. 2020

Horm Res Paediatr

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“…The existence of oligogenism in CHH patients has largely been suggested and demontrated over the past ten years by several independent teams (109,134,136,(148)(149)(150). Its prevalence, which will probably vary according to the more or less stringent criteria used either to select genes for sequencing or identified variants, appears to be significantly higher in more recent studies, in which the exons of the dozens of genes so far implicated in CHH/KS were analyzed simultaneously by means of massively parallel sequencing (157) (see below).…”

Section: The Emergence Of Oligogenism In Chh/ksmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

132

166

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Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

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“…Mutations have been found in early development genes (10,11) involved in pathways critical for hypothalamic-pituitary development such as Wnt, Notch and Sonic Hedgehog (SHH) signaling pathways. After candidate gene approach, whole-exome sequencing made it possible to identify new genetic disorders implicated in PSIS (12,13,14,15,16). Those are autosomal (dominant or recessive) or X-linked, with possible digenic (15) and polygenic inheritance (16).…”

Section: Genetic Diversitymentioning

confidence: 99%

“…After candidate gene approach, whole-exome sequencing made it possible to identify new genetic disorders implicated in PSIS (12,13,14,15,16). Those are autosomal (dominant or recessive) or X-linked, with possible digenic (15) and polygenic inheritance (16).…”

Section: Genetic Diversitymentioning

confidence: 99%

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DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations

Vergier

Castinetti

Saveanu

et al. 2019

European Journal of Endocrinology

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Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.

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Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome

Cited by 40 publications

References 23 publications

Hypopituitarism in Patients with Blepharophimosis and <b><i>FOXL2</i></b> Mutations

Hypopituitarism in Patients with Blepharophimosis and <b><i>FOXL2</i></b> Mutations

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations

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