Publications by authors named "Raja Brauner"

Aim: Height velocity is considered a key auxological tool to monitor growth, but updated height velocity growth charts are lacking. We aimed to derive new French height velocity growth charts by using a big-data approach based on routine measurements.

Methods: We extracted all growth data of children aged 1 month-18 years from the electronic medical records of 42 primary care physicians, between 1 January 1990 and 8 February 2018, throughout the French metropolitan territory.

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Context: Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found.

Objective: To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH.

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Background: Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP).

Objective: We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice.

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Background: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder.

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Article Synopsis
  • The melanocortin 3 receptor (MC3R) is important for regulating puberty, growth, and lean mass, and its variants may affect pubertal timing in humans.
  • The study aimed to find how often harmful MC3R variants occur in patients with constitutional delay of growth and puberty (CDGP) compared to those with normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
  • Results showed that MC3R loss-of-function variants were more common in CDGP patients, but not in those with nIHH, and such variants were also linked to delayed menarche in a broader UK Biobank cohort.
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Context: Central precocious puberty (CPP) can have a familial form in approximately one-quarter of the children. The recognition of this inherited condition increased after the identification of autosomal dominant CPP with paternal transmission caused by mutations in the MKRN3 and DLK1 genes.

Objective: We aimed to characterize the inheritance and estimate the prevalence of familial CPP in a large multiethnic cohort; to compare clinical and hormonal features, as well as treatment response to GnRH analogs (GnRHa), in children with distinct modes of transmission; and to investigate the genetic basis of familial CPP.

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Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants.

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Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown.

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Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist.

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Context: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism.

Aims: To describe main phenotype patterns and their evolution through life.

Design: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.

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Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis.

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In patients with pituitary stalk interruption syndrome (PSIS), long-term follow-up is necessary to address their gonadotrophic status. The objectives of this study were (1) to describe pubertal features of and (2) to assess the ability of serum inhibin B concentration to predict hypogonadotropic hypogonadism (HH) in patients with PSIS. This retrospective single-center study included 35 patients with PSIS and known gonadotrophic status for whom a serum sample preserved at -22°C (collected at initial evaluation or later) was available for measuring inhibin B by the same hormonal immunoassay method.

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Article Synopsis
  • The study investigates genetic causes of 46,XY disorders/differences of sex development (DSD), particularly gonadal dysgenesis and testis regression syndrome (TRS), which often have unknown origins.
  • Researchers used exome and Sanger sequencing on 145 individuals, discovering pathogenic variants in the DHX37 gene that are linked to these conditions.
  • The findings suggest that DHX37 variants contribute to an autosomal dominant form of 46,XY DSD, indicating a potential connection between these conditions and ribosomopathies.
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Human sex-determination is a poorly understood genetic process, where gonad development depends on a cell fate decision that occurs in a somatic cell to commit to Sertoli (male) or granulosa (female) cells. A lack of testis-determination in the human results in 46,XY gonadal dysgenesis. A minority of these cases is explained by mutations in genes known to be involved in sex-determination.

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Precocious and early puberty are reported findings in children with pre-existing medical conditions including certain syndromes. Series pertaining to such situations are limited. A retrospective, single-center study was conducted on children with central precocious puberty (onset before the age of 8 years in girls and 9 years in boys) or early puberty (onset between 8 and 9 years in girls and between 9 and 10.

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Objective: To compare the serum inhibin B, anti-Müllerian hormone (AMH) and leptin concentrations in girls with idiopathic central precocious puberty (CPP) to their concomitant characteristics and evaluate the capacity of each of these hormones to predict the age at first menstruation in those who were untreated and who completed their puberty.

Methods: This single-center study included 94 girls selected from a cohort of 493 girls seen between 1981 and 2012 and diagnosed with idiopathic CPP for whom a remaining serum sample collected at the initial evaluation was available. Of these 25 were untreated and completed their puberty.

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Background: A previous single-center study established a mathematical model for predicting the adult height (AH) in girls with idiopathic central precocious puberty (CPP).

Objective: To perform internal and external validations by comparing the actual AH to the calculated AH established by this model and to update it.

Methods: The original formula, calculated AH (cm) = 2.

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Background: Growth monitoring of apparently healthy children aims at early detection of serious conditions by use of both clinical expertise and algorithms that define abnormal growth. The seven existing algorithms provide contradictory definitions of growth abnormality and have a low level of validation.

Objective: An external validation study with head-to-head comparison of the seven algorithms combined with study of the impact of use of the World Health Organization (WHO) vs national growth charts on algorithm performance.

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Background: The bone markers bone alkaline phosphatase (BAP) and C-terminal telopeptide of type I collagen crosslinks (CTX) are correlated with growth rate during normal puberty. The objective of this study was to evaluate the relationship between the serum concentrations of BAP and CTX and growth evolution in girls with idiopathic central precocious puberty (CPP) to help predict adult height.

Methods: A retrospective single-center study was conducted in 74 girls with CPP for whom a serum sample at initial evaluation was available to retrospectively measure BAP and CTX concentrations; 66.

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Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice.

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Article Synopsis
  • SOX8 is a transcription factor involved in sex determination, and while its role in humans isn't fully understood, it is expressed in early gonadal development.
  • Research identified SOX8 mutations and chromosomal rearrangements in individuals with 46, XY disorders of sex development (DSD) and male infertility, suggesting a link to reproductive issues.
  • SOX8 mutations were found more frequently in infertile men and women with primary ovarian insufficiency, indicating that alterations in SOX8's function could contribute to various reproductive conditions.
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Background: Recent studies have shown a relationship between vitamin D status and growth hormone (GH) and insulin-like growth factor 1 (IGF1). The objective of this study was to assess vitamin D status in children with GH deficiency due to pituitary stalk interruption syndrome (PSIS) and to investigate the relationship between 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25 (OH) D) serum levels and patient characteristics.

Methods: A retrospective single-center study of 25OHD and 1,25(OH)D serum concentrations in 50 children with PSIS at the initial evaluation before treatment.

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Unlabelled: Vitamin D deficiency has been associated with several pathologies in humans and has recently been linked to idiopathic central precocious puberty in girls. We evaluated this potential link in a retrospective study. Among 493 girls with idiopathic central precocious puberty previously described, we selected 145 girls for whom a plasma sample at the initial evaluation was available to determine the concentration of 25OHD and 1,25(OH)2D.

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Background: Information sharing in chronic conditions such as disorders of/differences in sex development (DSD) is essential for a comprehensive understanding by parents and patients. We report on a qualitative analysis of communication skills of fellows undergoing training in paediatric endocrinology. Guidelines are created for the assessment of communication between health professionals and individuals with DSD and their parents.

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