A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder.

Proliferating cell nuclear antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a rare DNA repair disorder known as PCNA-associated DNA repair disorder (PARD). PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging.

Clinical and Genetic Characterization of Familial Central Precocious Puberty.

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.

Contribution of Clinical and Genetic Approaches for Diagnosing 209 Index Cases With 46,XY Differences of Sex Development.

Context: Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD).

Objective: To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients.

Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes.

Objectives: The aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes.

Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations.

Background: Mutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP).

Objective: To identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian).

Design And Methods: We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives.

Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2.

Background: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response.

Case Presentation: The proband was a healthy boy who presented at the age of 5.

SOCS2 polymorphisms are not associated with clinical and biochemical phenotypes in acromegalic patients.

Purpose: Suppressor of cytokine signaling 2 (SOCS2) is a STAT5b-regulated gene and one of its functions is to influence growth and development through negative regulatory effects on GH/IGF-1 pathway. So, we evaluate the potential influence of SOCS2 single nucleotide polymorphisms (SNPs) on clinical and laboratorial characteristics of a large cohort of Brazilian patients with acromegaly.

Methods: Four SOCS2 SNPs (rs3782415, rs3816997, rs3825199 and rs11107116) were selected and genotyped by real-time PCR using specific Taqman probe assays.

Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation.

Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies.

Patients And Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing.

Diagnosis and management of Silver-Russell syndrome: first international consensus statement.

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited.

A homozygous point mutation in the GH1 promoter (c.-223C>T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD).

Context: Mutations in the GH1 promoter are a rare cause of isolated growth hormone deficiency (IGHD).

Objective: To identify the molecular aetiology of a family with IGHD.

Design: DNA sequencing, electromobility shift (EMSA) and luciferase reporter assays.

Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia.

Background: Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene (FBN1).

Methods: Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx.

Nutritional aspects of Noonan syndrome and Noonan-related disorders.

Rasopathies are a group of rare disorders characterized by neurocardiofaciocutaneous involvement, and caused by mutations in several genes of the RAS/MAPK pathway. In the present study, we characterized growth parameters, body composition, and nutritional aspects of children and adults (n = 62) affected by these disorders, mainly Noonan syndrome, using an indirect method-anthropometry-and a 24-hr recall questionnaire. The growth parameters in our cohort showed short stature, especially in individuals with RAF1 and SHOC2 mutations, lower obesity rates compared to the control population, and BMI scores highest in individuals with BRAF mutations and lowest in individuals with SHOC2.

Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical.

Non-viral transfer of the growth hormone gene to different muscles of immunodeficient dwarf (lit/scid) mice is under study with the objective of improving phenotypic correction via this particular gene therapy approach. Plasmid DNA was administered into the exposed quadriceps or non-exposed tibialis cranialis muscle of lit/scid mice followed by electroporation, monitoring several growth parameters. In a 6-month bioassay, 50μg DNA were injected three times into the quadriceps muscle of 80-day old mice.

Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

Background: Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC.

Good response to long-term therapy with growth hormone in a patient with 9p trisomy syndrome: A case report and review of the literature.

The 9p trisomy syndrome is a rare condition, clinically characterized by a wide range of dysmorphic features, intellectual disability, and, in most patients, by short stature. Recombinant human growth hormone (rhGH) therapy is still controversial in syndromic disorders, the reason for which it is not currently indicated. Here we report a 7-year-old boy with 9p trisomy syndrome and marked short stature.

Association Study of GWAS-Derived Loci with Height in Brazilian Children: Importance of MAP3K3, MMP24 and IGF1R Polymorphisms for Height Variation.

Background/aim: The single nucleotide polymorphisms (SNPs) rs2282978 (CDK6), rs2425019 (MMP24), rs8081612 (MAP3K3), rs2871865 (IGF1R) and rs3782415 (SOCS2) were among the SNPs most strongly associated with height in a meta-analysis of 47 genome-wide association studies (GWAS) involving 114,223 adults from six ethnic groups. The present study aimed to examine associations between these SNPs and height in Brazilian children.

Methods: Cross-sectional heights of 1,008 healthy unrelated 4.

Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis.

Context: SHOX mutations have been detected in approximately 70% of Léri-Weill dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. The recent identification of NPR2 mutations in ISS suggested that NPR2 mutations may also be involved in disproportionate short stature.

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability.

Context And Objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations.

Role of GLI2 in hypopituitarism phenotype.

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2.

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

Background: Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases.

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2.

Influence of growth hormone receptor (GHR) exon 3 and -202A/C IGFBP-3 genetic polymorphisms on clinical and biochemical features and therapeutic outcome of patients with acromegaly.

Background: The association of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms with clinical presentation, biochemical measurements and response to therapies in acromegaly have been suggested.

Objective: To evaluate the presence of these polymorphisms in acromegaly and their influence on clinical and laboratorial characteristics of patients at diagnosis and after treatment in a large cohort of acromegalic patients.

Patients And Methods: This is a cross-sectional study developed in a single tertiary reference center.

Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center.

Background: Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up.

Objective: To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time.

Patients And Methods: We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.