scholarly journals Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

2022 ◽  
Author(s):  
Ja Hye Kim ◽  
Yunha Choi ◽  
Soojin Hwang ◽  
Gu-Hwan Kim ◽  
Han-Wook Yoo ◽  
...  
Keyword(s):  
Short Stature ◽  
Hypogonadotropic Hypogonadism ◽  
Charge Syndrome ◽  
Large Deletion ◽  
Hormone Deficiency ◽  
Delayed Puberty ◽  
Unilateral Deafness ◽  
Phenotypic Spectrum ◽  
Ear Anomalies ◽  
Spectrum Of Patients

Objective: Heterozygous CHD7 mutations cause a broad spectrum of clinical phenotypes ranging from typical CHARGE syndrome to self-limited delayed puberty. This study aimed to investigate the clinical characteristics of endocrine dysfunction in patients with CHD7 mutations. Methods: The clinical features and endocrine findings from 30 patients with CHD7 variants were retrospectively reviewed. A diagnosis of CHARGE syndrome was based on the Verloes diagnostic criteria. Results: Seventeen patients fulfilled the criteria for typical CHARGE syndrome, one patient for partial/incomplete CHARGE, and the remaining 11 patients had atypical CHARGE syndrome. One patient was diagnosed with Kallmann syndrome and unilateral deafness. The most frequently observed features were inner ear anomalies (80.0%), intellectual disability (76.7%), and external ear anomalies (73.3%). The mean height and weight SDSs at diagnosis were -2.6 ± 1.3 and -2.2 ± 1.8, respectively. Short stature was apparent in 18 patients (60%), and one patient was diagnosed with growth hormone deficiency. Seventeen males showed genital hypoplasia, including micropenis, cryptorchidism, or both. Seven patients after pubertal age had hypogonadotropic hypogonadism with hyposmia/anosmia and olfactory bulb hypoplasia. Truncating CHD7 mutations were the most common (n = 22), followed by missense variants (n = 3), splice-site variants (n = 2), and large deletion (n = 2). Conclusions: A diverse phenotypic spectrum was observed in patients with CHD7 variants, and endocrine defects such as short stature and delayed puberty occurred in most patients. Endocrine evaluation, especially for growth and pubertal impairment, should be performed during diagnosis and follow-up to improve the patient’s quality of life.

Phenotypic Spectrum of Idiopathic Hypogonadotropic Hypogonadism Patients With CHD7 Variants From a Large Chinese Cohort

2019 ◽  
Vol 105 (5) ◽  
pp. 1515-1526
Author(s):  
Jia-Da Li ◽  
Jiayu Wu ◽  
Yaguang Zhao ◽  
Xinying Wang ◽  
Fang Jiang ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Hypogonadotropic Hypogonadism ◽  
Choanal Atresia ◽  
Charge Syndrome ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Phenotypic Spectrum ◽  
Skeletal Defects ◽  
Chinese Cohort ◽  
Heart Abnormalities ◽  
Extended Charge

Abstract Purpose Idiopathic hypogonadotropic hypogonadism (IHH) and CHARGE (C, coloboma; H, heart abnormalities; A, choanal atresia, R, retardation of growth and/or development; G, gonadal defects; E, ear deformities and deafness) syndrome are 2 distinct developmental disorders sharing features of hypogonadism and/or impaired olfaction. CHD7 variants contribute to >60% CHARGE syndrome and ~10% IHH patients. A variety of extended CHARGE-like features are frequently reported in CHARGE patients harboring CHD7 variants. In this study, we aimed to systematically analyze the diagnostic CHARGE features and the extended CHARGE-like features in patients with IHH with CHD7 variants. Methods Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 177 IHH probands. Detailed phenotyping was performed in the IHH patients harboring CHD7 variants and their available family members. Results CHD7 RSVs were identified in 10.2% (18/177) of the IHH probands. Two diagnostic CHARGE features, hearing loss and ear deformities, were significantly enriched in patients with CHD7 variants. Furthermore, CHD7 variants were significantly associated with a panel of extended CHARGE-like phenotypes, including mild ocular defects, dyspepsia/gastroesophageal reflux disease and skeletal defects. We also developed a predictive model for prioritizing CHD7 genetic testing in IHH patients. Conclusion CHD7 variants rarely cause isolated IHH. Surveillance of symptoms in CHARGE syndrome-affected organs will facilitate the proper treatment for these patients. Certain clinical features can be useful for prioritizing CHD7 genetic screening.

scholarly journals A nonsense variant in FGFR1: a rare cause of combined pituitary hormone deficiency

2020 ◽  
Vol 33 (12) ◽  
pp. 1613-1615
Author(s):  
İbrahim Mert Erbaş ◽  
Ahu Paketçi ◽  
Sezer Acar ◽  
Leman Damla Kotan ◽  
Korcan Demir ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Growth Factor Receptor ◽  
Hormone Deficiency ◽  
Delayed Puberty ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Midline Defects ◽  
Relationship Of ◽  
The Relationship

AbstractObjectivesVariants in fibroblast growth factor receptor-1 (FGFR1) may either cause isolated hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS). Although the relationship of genes classically involved in IHH with combined pituitary hormone deficiency (CPHD) is well established, variants in FGFR1 have been presented as a rare cause of this phenotype recently.Case presentationHerein, we report an adopted 16-year-old male presented with delayed puberty and micropenis. He had undergone surgery for bilateral undescended testes in childhood. He was normosmic, and the pituitary imaging was normal. However, hypogonadotropic hypogonadism and growth hormone deficiency were detected, associated with a heterozygous nonsense variant (c.1864 C>T, p.R622X) in FGFR1.ConclusionsFGFR1 variants are among the causes of IHH and KS, which are inherited in an autosomal dominant manner and can be associated with midline defects. It should also be kept in mind that CPHD may be associated with FGFR1 variants in a subject with normal olfactory function.

scholarly journals Baseline Inhibin B and Anti-Mullerian Hormone Measurements for Diagnosis of Hypogonadotropic Hypogonadism (HH) in Boys with Delayed Puberty

2010 ◽  
Vol 95 (12) ◽  
pp. 5225-5232 ◽  
Author(s):  
Régis Coutant ◽  
Estelle Biette-Demeneix ◽  
Claire Bouvattier ◽  
Natacha Bouhours-Nouet ◽  
Frédérique Gatelais ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Early Stage ◽  
Hypogonadotropic Hypogonadism ◽  
Inhibin B ◽  
Hormone Deficiency ◽  
Delayed Puberty ◽  
Pituitary Hormone ◽  
Future Fertility ◽  
Testis Volume ◽  
Stage 1

Context: The diagnosis of isolated hypogonadotropic hypogonadism (IHH) in boys with delayed puberty is challenging, as may be the diagnosis of hypogonadotropic hypogonadism (HH) in boys with combined pituitary hormone deficiency (CPHD). Yet, the therapeutic choices for puberty induction depend on accurate diagnosis and may influence future fertility. Objective: The aim was to assess the utility of baseline inhibin B (INHB) and anti-Mullerian hormone (AMH) measurements to discriminate HH from constitutional delay of puberty (CDP). Both hormones are produced by Sertoli cells upon FSH stimulation. Moreover, prepubertal AMH levels are high as a reflection of Sertoli cell integrity. Patients: We studied 82 boys aged 14 to 18 yr with pubertal delay: 16 had IHH, 15 congenital HH within CPHD, and 51 CDP, as confirmed by follow-up. Subjects were genital stage 1 (testis volume <3 ml; 9 IHH, 7 CPHD, and 23 CDP) or early stage 2 (testis volume, 3–6 ml; 7 IHH, 8 CPHD, and 28 CDP). Results: Age and testis volume were similar in the three groups. Compared with CDP subjects, IHH and CPHD subjects had lower INHB, testosterone, FSH, and LH concentrations (P < 0.05), whereas AMH concentration was lower only in IHH and CPHD subjects with genital stage 1, likely reflecting a smaller pool of Sertoli cells in profound HH. In IHH and CPHD boys with genital stage 1, sensitivity and specificity were 100% for INHB concentration of 35 pg/ml or less. In IHH and CPHD boys with genital stage 2, sensitivities were 86 and 80%, whereas specificities were 92% and 88%, respectively, for an INHB concentration of 65 pg/ml or less. The performance of testosterone, AMH, FSH, and LH measurements was lower. No combination or ratio of hormones performed better than INHB alone. Conclusion: Discrimination of HH from CDP with baseline INHB measurement was excellent in subjects with genital stage 1 and fair in subjects with genital stage 2.

scholarly journals Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

2020 ◽  
Author(s):  
Félixe Pelletier ◽  
Stefanie Perrier ◽  
Ferdy K Cayami ◽  
Amytice Mirchi ◽  
Stephan Saikali ◽  
...  
Keyword(s):  
Short Stature ◽  
Hypogonadotropic Hypogonadism ◽  
Autosomal Recessive Disorder ◽  
Cross Sectional Study ◽  
Delayed Puberty ◽  
Cross Sectional ◽  
Pathogenic Variants ◽  
Neurological Features ◽  
A Prospective Study ◽  
Growth Abnormalities

Abstract Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency

2020 ◽  
Author(s):  
Jin-Ho Choi ◽  
Arum Oh ◽  
Yena Lee ◽  
Gu-Hwan Kim ◽  
Han-Wook Yoo
Keyword(s):  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Releasing Hormone ◽  
Delayed Puberty ◽  
Functional Assay ◽  
Functional Characteristics ◽  
Releasing Hormone ◽  
Phenotypic Spectrum ◽  
The Impact

Abstract Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). FGFR1 mutations have been identified in 3–10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of FGFR1 mutations in patients with IGD. Methods This study included 8 patients (from 7 families) with FGFR1 mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using in vitro studies. Results Seven heterozygous mutations in FGFR1 were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by in vitro functional assay, indicating loss-of-function mutations. Conclusions This study identified seven rare sequence variants in FGFR1 in patients with KS and nIHH. Probands with an FGFR1 mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of FGFR1 mutations and suggest a broader biologic role of FGFR1 in reproduction.

Negative correlation between peripheral plasma somatostatin levels and GH responses to GH-RH stimulation tests in children

1986 ◽  
Vol 113 (1) ◽  
pp. 1-4 ◽  
Author(s):  
C. Liapi ◽  
D. Evain Brion ◽  
J. Argente ◽  
H. Vaudry ◽  
M. Donnadieu
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Negative Correlation ◽  
Hormone Deficiency ◽  
Delayed Puberty ◽  
Peripheral Plasma ◽  
Basal Plasma ◽  
Stimulation Tests ◽  
Serum Gh

Abstract. On forty-six fasting and resting children, aged 5–17 years, with short stature (below −2 sd) a growth hormone releasing hormone (GH-RH) stimulation test (2 μg/kg iv bolus, Sanofi) was performed. Twenty-two children were prepubertal, of which, 13 had a constitutional short stature (CSS), nine an idiopathic growth hormone deficiency (IGHD). Twenty-four subjects were pubertal, at the stage II or III of Tanner. Among them, six had a constitutional short stature (CSS) and 18 an idiopathic delayed puberty (IDP). Blood samples were taken for determination of plasma somatostatin-like immunoreactivity (SLI) in chilled test tubes containing EDTA + aprotinin. Plasma SLI levels were measured after extraction and concentration on C 18 Sep Pack columns by radioimmunoassay using an antibody against 1–14 somatostatin. The sensitivity of this assay is around 3 pg/ml. After GH-RH stimulation the peak of GH (mean ± sem) was in prepubertal subjects: 25.3 ± 9.1 μg/l in CSS, and 18.6 ± 10.3 μg/l in IGHD. In pubertal subjects GH peaks were 17.6 ± 8.4 μg/l in CSS and 15.6 ± 3.8 μg/l in children with IDP. No significant differences was found between basal plasma SLI levels in the four groups of subjects, being respectively (mean ± sem) 11.9 ± 1.8 pg/ml in prepubertal subjects with CSS, 9.6 ± 2.6 pg/ml in IGHD, 7.6 ± 1.7 pg/ml in pubertal children with CSS and 6.6 ± 1.5 pg/ml in children with IDP. However, in the 46 children, a significant (r = −0.524, P < 0.001) negative correlation was found between the amplitude of the peak of serum GH after GH-RH injection, and the basal values of SLI. The results suggest a possible regulatory mechanism for circulating somatostatin on GH release after injection of GH-RH.

scholarly journals Growth hormone deficiency as a cause for short stature in Wiedemann–Steiner Syndrome

2018 ◽  
Vol 2018 ◽  
Author(s):  
George Stoyle ◽  
Siddharth Banka ◽  
Claire Langley ◽  
Elizabeth A Jones ◽  
Indraneel Banerjee
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Short Stature ◽  
Recombinant Human Growth Hormone ◽  
Growth Trajectory ◽  
Hormone Deficiency ◽  
Facial Dysmorphism ◽  
List Type ◽  
Height Range ◽  
Phenotypic Spectrum

Summary Wiedemann–Steiner Syndrome (WSS) is a rare condition characterised by short stature, hypertrichosis of the elbow, intellectual disability and characteristic facial dysmorphism due to heterozygous loss of function mutations in KMT2A, a gene encoding a histone 3 lysine 4 methyltransferase. Children with WSS are often short and until recently, it had been assumed that short stature is an intrinsic part of the syndrome. GHD has recently been reported as part of the phenotypic spectrum of WSS. We describe the case of an 8-year-old boy with a novel heterozygous variant in KMT2A and features consistent with a diagnosis of WSS who also had growth hormone deficiency (GHD). GHD was diagnosed on dynamic function testing for growth hormone (GH) secretion, low insulin-like growth factor I (IGF-I) levels and pituitary-specific MRI demonstrating anterior pituitary hypoplasia and an ectopic posterior pituitary. Treatment with GH improved height performance with growth trajectory being normalised to the parental height range. Our case highlights the need for GH testing in children with WSS and short stature as treatment with GH improves growth trajectory. Learning points: Growth hormone deficiency might be part of the phenotypic spectrum of Wiedemann–Steiner Syndrome (WSS). Investigation of pituitary function should be undertaken in children with WSS and short stature. A pituitary MR scan should be considered if there is biochemical evidence of growth hormone deficiency (GHD). Recombinant human growth hormone treatment should be considered for treatment of GHD.

scholarly journals P.004 Endocrine and growth abnormalities in 4H leukodystrophy patients with a molecular diagnosis

2016 ◽  
Vol 43 (S2) ◽  
pp. S22-S22
Author(s):  
F Pelletier ◽  
A Mirchi ◽  
FK Cayami ◽  
LT Tran ◽  
N Ulrick ◽  
...  
Keyword(s):  
Short Stature ◽  
Hypogonadotropic Hypogonadism ◽  
Autosomal Recessive Disorder ◽  
Delayed Puberty ◽  
Specific Gene ◽  
Cross Sectional ◽  
Neurological Features ◽  
International Multicenter Study ◽  
A Prospective Study ◽  
Specific Symptoms

Background: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder characterized by hypomyelination, hypodontia and hypogonadotropic hypogonadism caused by mutations in POLR3A, POLR3B and POLR1C. The endocrine abnormalities have never been systematically studied. Methods: A cross sectional international multicenter study was performed and the following variables were assessed: weight, height, head circumference, pubertal history, hormone levels and neurological and non-neurological features. Data was analyzed to determine whether there was a correlation between the presence of endocrine abnormalities and mutations in a specific gene and/or the presence of specific symptoms such as other non-neurological symptoms. Results: Data was collected on 156 patients. Endocrine data were available for 144 patients. The most common endocrine abnormalities seen in this cohort were short stature (54/90 patients (60%)) and delayed puberty (53/70 patients (76%)). 13 of the 58 patients tested (22%) had abnormal thyroid function. Patients with POLR3A mutations were more likely to have endocrine abnormalities. Conclusions: Our results confirm that the most common endocrine features in 4H leukodystrophy are short stature and pubertal abnormalities. However, the other potential endocrine abnormalities are typically under-investigated in this patient population. A prospective study is required to investigate the extent and severity of the endocrine abnormalities in 4H leukodystrophy.

scholarly journals MON-355 Charge Syndrome: Unusual Cause of Hypogonadism Leading to Osteoporosis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ankur Modi ◽  
Veronica Piziak
Keyword(s):  
Bone Mineralization ◽  
Mass Density ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Charge Syndrome ◽  
Delayed Puberty ◽  
Bone Mass Density ◽  
Z Score ◽  
Total Hip

Abstract CHARGE syndrome is an unusual cause of hypogonadism; it is characterized by coloboma, heart defect, ateresia choanae, retarded growth and development, genital hypoplasia and ear anomalies. Two-thirds of affected patients have a mutation within the chromodomain helicase DNA-binding protein-7 gene, which is involved in embryonic development. The involvement of this gene in the pathogenesis of isolated idiopathic hypogonadotropic hypogonadism (HH) has been postulated. The reported incidence of this syndrome ranges from 0.1–0.2/10000 (1). A 24 year old female presented to our facility for further management of her HH and osteoporosis in the setting of her CHARGE syndrome. She was born full-term and diagnosed with this condition at the age of 6. Formal genetic testing as an adult demonstrated mutation within the CHD7 gene (chr 8:61,757,970). She had delayed puberty secondary to her hypogonadism; she was not treated with HRT as benefits were not considered significantly sufficient. She subsequently developed osteoporosis at the age of 20 which was treated at an outside facility with pamidronate IV Q4 months along with calcium and Vitamin D supplementation. Her initial Dual-energy X-ray absorptiometry (DXA) showed scoliosis in the lumbar spine [bone mass density (BMD): 0.514,osteoporosis by Z-score] with total hip showing BMD: 0.738,osteopenia by Z-score. Follow-up DXA after 3 years showed statistically significant improvement in bone mineralization of her L-spine [BMD: 0.595, +16%] and total hip [BMD: 0.777, +13.5%]. She presented to our facility in 2018 with labs showing normal calcium and 25-OH D; treatment with pamidronate was continued. She had a repeat DXA in 2019 which showed Z-scores of 0 in the left and right femoral necks. She was given the option of continued treatment for her osteoporosis versus monitoring and chose the latter with follow-up DXA. Hypogonadotropic hypogonadism is associated with delays in puberty or pubertal arrest. Luteinizing Hormone Releasing Hormone and HCG tests should be performed within the four months of life or at puberty in cases of hypogenitalism. GH deficiency should be investigated as a cause for growth retardation with GH stimulation levels. Hormone replacement is often required at puberty for females and is indicated for prevention of osteoporosis. Radiological testing with DXA scan should be included. Early proper endocrinological assessment and management is essential for adequate sexual development in these patients; this leads to improved overall quality of life along with prevention of serious morbidities, including bone demineralization (2). 1. Blake K D, Prasad C. CHARGE syndrome. Orphanet Journal of Rare Diseases 2006, 1:34. 2. Foppiani L, Maffe A. CHARGE syndrome as unusual cause of hypogonadism: endocrine and molecular evaluation. Andrologia (2010). 42: 326–330.

Mutations in HS6ST1 are causal in self-limited delayed puberty as well as idiopathic hypogonadotropic hypogonadism

2015 ◽  
Author(s):  
Sasha Howard ◽  
Ariel Poliandri ◽  
Helen Storr ◽  
Louise Metherell ◽  
Claudia Cabrera ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism
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