scholarly journals Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1128
Author(s):  
Marilena Nakaguma ◽  
Nathalia Garcia Bianchi Pereira Ferreira ◽  
Anna Flavia Figueredo Benedetti ◽  
Mariana Cotarelli Madi ◽  
Juliana Moreira Silva ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Male Patient ◽  
Missense Variant ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Incomplete Penetrance ◽  
Growth Hormone Gene ◽  
Posterior Lobe ◽  
Allelic Variants ◽  
Phenotypic Spectrum

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

scholarly journals Allelic Variants in Established Hypopituitarism Genes Expands Our Knowledge of Phenotypic Spectrum

2021 ◽  
Author(s):  
Marilena Nakaguma ◽  
Nathalia Garcia Bianchi Pereira Ferreira ◽  
Anna Flavia Figueredo Benedetti ◽  
Mariana Cotarelli Madi ◽  
Juliana Moreira Silva ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Male Patient ◽  
Missense Variant ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Incomplete Penetrance ◽  
Growth Hormone Gene ◽  
Posterior Lobe ◽  
Allelic Variants ◽  
Phenotypic Spectrum

We report four allelic variants (3 novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p. Phe 57Leufs * 43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in 3 genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

scholarly journals CDON gene contributes to pituitary stalk interruption syndrome associated with unilateral facial and abducens nerve palsy

2021 ◽  
Author(s):  
Monika Obara-Moszyńska ◽  
Bartłomiej Budny ◽  
Małgorzata Kałużna ◽  
Katarzyna Zawadzka ◽  
Aleksander Jamsheer ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Nerve Palsy ◽  
Abducens Nerve ◽  
Abducens Nerve Palsy ◽  
Pituitary Stalk ◽  
Hormone Deficiency ◽  
Congenital Defects ◽  
Pituitary Hormone ◽  
Incomplete Penetrance ◽  
Posterior Lobe

AbstractThe relationship between congenital defects of the brain and facial anomalies was proven. The Hedgehog signaling pathway plays a fundamental role in normal craniofacial development in humans. Mutations in the sonic hedgehog (SHH) signaling gene CDON have been recently reported in patients with holoprosencephaly and with pituitary stalk interruption syndrome (PSIS). This study’s aim was an elucidation of an 18-year-old patient presenting PSIS, multiple pituitary hormone deficiency, and congenital unilateral facial and abducens nerve palsy. Additionally, bilateral sensorineural hearing loss, dominating at the right site, was diagnosed. From the second year of life, growth deceleration was observed, and from the age of eight, anterior pituitary hormone deficiencies were gradually confirmed and substituted. At the MRI, characteristic triad for PSIS (anterior pituitary hypoplasia, interrupted pituitary stalk and ectopic posterior lobe) was diagnosed. We performed a comprehensive genomic screening, including microarrays for structural rearrangements and whole-exome sequencing for a monogenic defect. A novel heterozygous missense variant in the CDON gene (c.1814G > T; p.Gly605Val) was identified. The variant was inherited from the mother, who, besides short stature, did not show any disease symptoms. The variant was absent in control databases and 100 healthy subjects originating from the same population. We report a novel variant in the CDON gene associated with PSIS and congenital cranial nerve palsy. The variant revealed autosomal dominant inheritance with incomplete penetrance in concordance with previous studies reporting CDON defects.

A novel diagnostic tool for the evaluation of hypothalamic-pituitary region and diagnosis of growth hormone deficiency: pons ratio

2020 ◽  
Vol 33 (6) ◽  
pp. 735-742
Author(s):  
Meliha Demiral ◽  
Mehmet Salih Karaca ◽  
Edip Unal ◽  
Birsen Baysal ◽  
Rıza Taner Baran ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Cost Benefit ◽  
Practical Method ◽  
Hormone Deficiency ◽  
Small Scale ◽  
Pituitary Hormone ◽  
Clinical Value ◽  
Pubertal Status ◽  
Sensitive Tool

AbstractBackgroundsLimitations in the evaluation of the pituitary size and changes according to pubertal status make its validity questionable. Recently, in a small-scale study, pons ratio (PR) has been suggested as a more sensitive tool for diagnosis and etiological evaluation of growth hormone deficiency (GHD). The aim of the study is to evaluate the diagnostic value of PR in the diagnosis of GHD.MethodsWe retrospectively evaluated the pituitary magnetic resonance imaging (MRI) of 133 patients with a diagnosis of GHD. Primary axis (PA) was assigned as a line crossing the mid-sagittal dorsum sella and fourth ventricle. PR was defined as the pons height above the PA divided by total pons height. The PR of patients with GHD was compared to subjects without GHD.ResultsStudy included 133 patients with GHD and 47 controls. In total, 121 (91%) patients had isolated GHD and 12 (9%) patients had multiple pituitary hormone deficiency. The PR of the patient group (mean: 0.32 ± 0.89; range: 0.14–0.63) was significantly higher than controls (mean: 0.26 ± 0.067; range 0.19–0.44) (p: 0.000). The optimal cut-off value of PR for GHD diagnosis was 0.27 (sensitivity 71% specificity 56%). There was a negative correlation between anterior pituitary height (APH)-SDS and PR (p: 0.002; r: −0.27). APH was increased, but PR remained unchanged in pubertal patients (p: 0.089).ConclusionsPR measurement is a noninvasive, practical method with a cost-benefit clinical value. As it is not affected by pubertal status, PR is potentially a more sensitive tool for evaluation of pituitary gland in GHD patients compared to APH.

Growth hormone replacement for patients with adult onset growth hormone deficiency—what have we learned?

2004 ◽  
Vol 16 (4) ◽  
pp. 1-6
Author(s):  
Monique Piersanti
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Hormone Replacement ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Adult Onset ◽  
Gh Replacement ◽  
Term Benefit

Growth hormone (GH) deficiency is a condition recognized to occur in individuals who have had multiple pituitary hormone deficiencies as a result of pathological processes or neurosurgical interventions. The indications, benefits, and risks of GH replacement therapy will be reviewed with an emphasis on those patients who were adults with the deficiency first emerged. The results of this analysis indicate that, although a measurable improvement can be detected in the patient's quality of life, body composition, and some cardiovascular parameters, the larger questions of long-term benefit and patient selection currently remain unanswered.

scholarly journals Low FT4 Concentrations around the Start of Recombinant Human Growth Hormone Treatment: Predictor of Congenital Structural Hypothalamic-Pituitary Abnormalities?

2018 ◽  
Vol 89 (2) ◽  
pp. 98-107 ◽  
Author(s):  
Laura van Iersel ◽  
Hanneke M. van Santen ◽  
Gladys R.J. Zandwijken ◽  
Nitash Zwaveling-Soonawala ◽  
Anita C.S. Hokken-Koelega ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Treatment ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Hormone Treatment ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Gh Treatment ◽  
Central Hypothyroidism ◽  
Pituitary Disease

Background: Growth hormone (GH) treatment may unmask central hypothyroidism (CeH). This was first observed in children with GH deficiency (GHD), later also in adults with GHD due to acquired “organic” pituitary disease. We hypothesized that newly diagnosed CeH in children after starting GH treatment for nonacquired, apparent isolated GHD points to congenital “organic” pituitary disease. Methods: Nationwide, retrospective cohort study including all children with nonacquired GHD between 2001 and 2011 in The Netherlands. The prevalence of CeH, hypothalamic-pituitary (HP) abnormalities, and neonatal congenital hypothyroidism screening results were evaluated. Results: Twenty-three (6.3%) of 367 children with apparent isolated GHD were prescribed LT4 for presumed CeH within 2 years after starting GH treatment. Similarly to children already diagnosed with multiple pituitary hormone deficiency, 75% of these 23 had structural HP abnormalities. In children not prescribed LT4, low pre- or post-GH treatment FT4 concentrations were also associated with structural HP abnormalities. Neonatal screening results of only 4 of the 23 children could be retrieved. Conclusion: In children with nonacquired, apparent isolated GHD, a diagnosis of CeH after, or a low FT4 concentration around the start of GH treatment, is associated with congenital structural HP abnormalities, i.e., “organic” pituitary disease. Neonatal values could not be judged reliably.

Extending Phenotypic Spectrum of 17q22 Microdeletion: Growth Hormone Deficiency

2020 ◽  
pp. 1-7
Author(s):  
Ceren Damla Durmaz ◽  
Şule Altıner ◽  
Elifcan Taşdelen ◽  
Halil Gürhan Karabulut ◽  
Hatice Ilgın Ruhi
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Hormone Deficiency ◽  
Phenotypic Spectrum

Growth hormone and insulin-like growth factor regulate insulin-like growth factor-binding protein-1 in Laron type dwarfism, growth hormone deficiency and constitutional short stature

1992 ◽  
Vol 127 (4) ◽  
pp. 351-358 ◽  
Author(s):  
Zvi Laron ◽  
Anne-Maria Suikkari ◽  
Beatrice Klinger ◽  
Aviva Silbergeld ◽  
Athalia Pertzelan ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Growth Hormone Deficiency ◽  
Short Stature ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Healthy Children ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Igf I

Insulin-like growth factors (IGFs) mediate the effects of growth hormone (GH), and the insulin-like growth factor-binding proteins (IGFBPs) modulate the actions of IGFs in tissues. We studied the circulating levels of IGFBP-1 in 6 children and 9 adults with Laron type dwarfism (LTD), in 11 children and 21 adults with growth hormone deficiency (GHD), and in 8 children with constitutional short stature. Compared with the situation in healthy children, the basal serum IGFBP-1 concentration was 5.4-fold higher in LTD children, 4.1-fold higher in GHD children, and 3.8-fold higher in children with short stature (p<0.02 vs controls in all groups). In adult patients with multiple pituitary hormone deficiency (MPHD), the IGFBP-1 concentration was 2-fold elevated, but it was normal in adult LTD patients. Intravenous (N= 10) or subcutaneous (N=9) administration ofIGF-I (75 μg·kg−1 and 150 μg·kg−1, respectively) in LTD children resulted in a rapid 50–60% fall in serum insulin (p<0.02), a decline in blood glucose and a concomitant 40–60% rise of IGFBP-1 levels (p<0.05). Treatment for seven days with IGF-I (150 μg·kg−1·d−1) resulted in a decrease by 34% and 44% of serum IGFBP-1 level in two out of three children with LTD. After prolonged GH therapy, the IGFBP-1 level fell in GHD children by 29% (p<0.05), in GHD adults by 52% (p<0.02) and in children with constitutional short stature by 17% (p<0.02). IGFBP-1 and insulin concentrations were inversely related in patients with GHD (r= −0.66, p<0.001) or with LTD (r= −0.57, p<0.05). Our data suggest that: (a) increased IGFBP-1 concentration in LTD, GHD and constitutional short children may, at least in part, be accounted for by an IGF-I deficiency; (b) both the rise in IGF-I and a fall in insulin contributed to the rise in IGFBP-1 after acute IGF-I administration; (c) prolonged IGF-I or GH treatment causes a persistent decline in IGFBP-1 concentration. In conclusion, IGF-I and GH may regulate IGFBP-1 secretion either directly or via insulin.

Marked phenotypic variable expression among brothers with duplication of Xq27.1 involving the SOX3 gene

2020 ◽  
Vol 33 (3) ◽  
pp. 443-447 ◽  
Author(s):  
Elizabeth T. Rosolowsky ◽  
Robert Stein ◽  
Seth D. Marks ◽  
Norma Leonard
Keyword(s):  
Growth Hormone ◽  
Mental Retardation ◽  
Growth Hormone Deficiency ◽  
Hormone Deficiency ◽  
Pharyngeal Arch ◽  
Pituitary Hormone ◽  
Facial Dysmorphisms ◽  
Pituitary Hormone Deficiency ◽  
Variable Expression ◽  
Sox3 Gene

AbstractWe describe four phenotypically different brothers who share the same microduplication of Xq27.1, which contains the SOX3 gene. SOX3 mutations have been associated with growth hormone deficiency, variable degrees of additional pituitary hormone deficiencies, and mental retardation. SOX3 also appears to play an important role in pharyngeal arch segmentation that gives rise to craniofacial structures. While these four brothers have inherited the same mutation, they manifest a spectrum of phenotypes, ranging from complete, multiple pituitary hormone deficiencies to no apparent pituitary hormone deficiency with or without craniopharyngeal/facial dysmorphisms. We look to the literature to provide putative explanations for the variable expression of the brothers’ shared SOX3 mutation.

Body composition and metabolic health of young male adults with childhood-onset multiple pituitary hormone deficiency after cessation of growth hormone treatment

2018 ◽  
Vol 31 (5) ◽  
pp. 533-537 ◽  
Author(s):  
Hongbo Yang ◽  
Linjie Wang ◽  
Xiaonan Qiu ◽  
Kemin Yan ◽  
Fengying Gong ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Composition ◽  
Growth Hormone Deficiency ◽  
Fat Mass ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Childhood Onset ◽  
Multiple Pituitary Hormone Deficiency ◽  
Pituitary Hormone Deficiency ◽  
Male Patients

Abstract Background: Recombinant human growth hormone (rhGH) replacement therapy is usually stopped after linear growth completion in patients with growth hormone deficiency. In patients with multiple pituitary hormone deficiency (MPHD), the long-term effects of discontinuation of rhGH replacement are unknown. Methods: In this study, the anthropometric and metabolic parameters of 24 male patients with adult growth hormone deficiency (AGHD) due to MPHD in childhood after cessation of rhGH therapy for a mean of 7.1 years were measured and compared with 35 age-matched controls. Body composition was evaluated by bioelectrical impedance analysis (BIA). Results: In the AGHD group, body mass index (BMI) was significantly increased and 29.2% had obesity. The AGHD group had a 17.7 cm increase in waist circumference (WC). The fat free mass (FFM) was significantly lower in the AGHD group. Both the fat mass (FM) and percentage of fat mass (FM%) were significantly increased in the AGHD group. Both the systolic blood pressure (BP) and diastolic pressure were significantly lower in AGHD group. The lipid profile was generally similar in both groups, except for a decrease of high density lipoprotein-cholesterol (HDL-C) in the AGHD group. There was significant hyperuricemia in the AGHD group. Conclusions: Cessation of rhGH leads to a significant increase of FM in early adulthood in male patients with childhood-onset MPHD (CO-MPHD).

scholarly journals Identification of a Novel PROP1 Mutation in a Patient with Combined Pituitary Hormone Deficiency and Enlarged Pituitary

2019 ◽  
Vol 20 (8) ◽  
pp. 1875 ◽  
Author(s):  
Laura Penta ◽  
Carla Bizzarri ◽  
Michela Panichi ◽  
Antonio Novelli ◽  
Francesca Romana Lepri ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Novel Mutation ◽  
Pituitary Hormones ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Familial Cases ◽  
Number Of Patients

Growth hormone deficiency (GHD) can be present from the neonatal period to adulthood and can be the result of congenital or acquired insults. In addition, GHD can be classified into two types: isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). CPHD is a disorder characterized by impaired production of two or more anterior and/or posterior pituitary hormones. Many genes implicated in CPHD remain to be identified. Better genetic characterization will provide more information about the disorder and result in important genetic counselling because a number of patients with hypopituitarism represent familial cases. To date, PROP1 mutations represent the most common known genetic cause of CPHD both in sporadic and familial cases. We report a novel mutation in the PROP1 gene in an infant with CPHD and an enlarged pituitary gland. Close long-term follow-up will reveal other possible hormonal defects and pituitary involution.

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