WD40-Repeat Proteins in Ciliopathies and Congenital Disorders of Endocrine System.

WD40-repeat (WDR)-containing proteins constitute an evolutionarily conserved large protein family with a broad range of biological functions. In human proteome, WDR makes up one of the most abundant protein-protein interaction domains. Members of the WDR protein family play important roles in nearly all major cellular signalling pathways. Mutations of WDR proteins have been associated with various human pathologies including neurological disorders, cancer, obesity, ciliopathies and endocrine disorders. This review provides an updated overview of the biological functions of WDR proteins and their mutations found in congenital disorders. We also highlight the significant role of WDR proteins in ciliopathies and endocrine disorders. The new insights may help develop therapeutic approaches targeting WDR motifs.

Activation of sonic hedgehog signaling by a Smoothened agonist restores congenital defects in mouse models of endocrine-cerebro-osteodysplasia syndrome.

BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome is a genetic disorder associated with congenital defects of the endocrine, cerebral, and skeletal systems in humans. ECO syndrome is caused by mutations of the intestinal cell kinase (ICK) gene, which encodes a mitogen-activated protein (MAP) kinase-related kinase that plays a critical role in controlling the length of primary cilia. Lack of ICK function disrupts transduction of sonic hedgehog (SHH) signaling, which is important for development and homeostasis in humans and mice. Craniofacial structure abnormalities, such as cleft palate, are one of the most common defects observed in ECO syndrome patients, but the role of ICK in palatal development has not been studied. METHODS: Using Ick-mutant mice, we investigated the mechanisms by which ICK function loss causes cleft palate and examined pharmacological rescue of the congenital defects. FINDINGS: SHH signaling was compromised with abnormally elongated primary cilia in the developing palate of Ick-mutant mice. Cell proliferation was significantly decreased, resulting in failure of palatal outgrowth, although palatal adhesion and fusion occurred normally. We thus attempted to rescue the congenital palatal defects of Ick mutants by pharmacological activation of SHH signaling. Treatment of Ick-mutant mice with an agonist for Smoothened (SAG) rescued several congenital defects, including cleft palate. INTERPRETATIONS: The recovery of congenital defects by pharmacological intervention in the mouse models for ECO syndrome highlights prenatal SHH signaling modulation as a potential therapeutic measure to overcome congenital defects of ciliopathies.

Rate of gestational weight gain and adverse pregnancy outcomes in rural nulliparous women: a prospective cohort analysis from China.

Both inadequate and excessive gestational weight gain (GWG) have been shown to increase the risk of adverse pregnancy outcomes, but the risk profiles of GWG rate are unclear. We aimed to examine the associations between GWG rate in the second/third trimester and a spectrum of pregnancy outcomes. This study consisted of 14 219 Chinese rural nulliparous women who participated in a randomised controlled trial of prenatal micronutrient supplementation during 2006-2009. The outcomes included stillbirth, neonatal and infant death, preterm birth, macrosomia, low birth weight (LBW) and large and small for gestational age (LGA and SGA, respectively). GWG rate was divided into quintiles within each BMI category. Compared with women in the middle quintile, those in the lowest quintile had higher risks of neonatal death (adjusted OR 2·27; 95 % CI 1·03, 5·02), infant death (adjusted OR 1·85; 95 % CI 1·02, 3·37) and early preterm birth (adjusted OR 2·33; 95 % CI 1·13, 4·77), while those in the highest quintile had higher risks of overall preterm birth (adjusted OR 1·28; 95 % CI 1·04, 1·59), late preterm birth (adjusted OR 1·25; 95 % CI 1·00, 1·56), LBW (adjusted OR 1·48; 95 % CI 1·02, 2·15), macrosomia (adjusted OR 1·89; 95 % CI 1·46, 2·45) and LGA (adjusted OR 1·56; 95 % CI 1·31, 1·85). In conclusion, very low and very high GWG rates in the second/third trimester appear to be associated with adverse pregnancy outcomes in Chinese nulliparous women, indicating that an appropriate GWG rate during pregnancy is necessary for neonatal health.

A rare cause of neonatal hypoglycemia in two siblings: TBX19 gene mutation.

Congenital isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rarely seen disease characterized by low serum ACTH and cortisol levels accompanied by normal levels of the other anterior pituitary hormones. In these patients, severe hypoglycemia, convulsions, and prolonged cholestatic jaundice are expected findings in the neonatal period. In this paper, we present two siblings with TBX19 gene mutation. The first case was investigated at the age of 2 months for severe hypoglycemia, recurrent convulsions, and prolonged cholestatic jaundice persisting since the neonatal period. The second sibling presented with hypoglycemia in the neonatal period. In both cases, baseline cortisol and ACTH levels were low and cortisol response to the low-dose ACTH test was inadequate, while all other anterior pituitary hormones were normal. Thus, IAD was suspected. Genetic analysis of the TBX19 gene was performed. Both cases were homozygous for c.856 C>T (p.R286*), and hydrocortisone treatment was initiated. The first patient did not attend the clinic regularly. On attendance at another hospital, hydrocortisone treatment was discontinued and antiepileptic treatment was initiated because of suspected epilepsy. This led to developmental delay, measured with the Denver Developmental Screening Test II (DDST-II), because of cessation of the hydrocortisone therapy. The second sibling had normal development, as measured with the DDST. In conclusion, TBX19 gene analysis must be performed if adrenal insufficiency is associated with isolated ACTH deficiency. Delay in diagnosis may lead to inappropriate diagnoses, such as epilepsy, and thus inappropriate therapy, which may result in neonatal mortality.

Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly.

Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS-HPE. These manifestations have been described in case reports and in large cohorts of patients with "single-gene" mutations, suggesting that the NCNS-HPE phenotype can be more complex than traditionally thought. Likely, a complex network of interacting genetic variants and environmental factors is responsible for these systemic abnormalities that deviate from the usual brain and craniofacial findings in NCNS-HPE. In addition to the systemic consequences of pituitary dysfunction (as a direct result of brain midline defects), here we describe a number of extracephalic findings of NCNS-HPE affecting various organ systems. It is our goal to provide a guide of extracephalic features for clinicians given the important clinical implications of these manifestations for the management and care of patients with HPE and their mutation-positive relatives. The health risks associated with some manifestations (e.g., fatty liver disease) may have historically been neglected in affected families.

Gestational Weight Gain: Association with Adverse Pregnancy Outcomes.

Background It is unclear how adherence to the Institute of Medicine's (IOM) guidelines for weight gain affects pregnancy outcomes. Objective We investigated how weight gain outside the IOM's recommendations affects the risks of adverse pregnancy outcomes. Study Design We performed a secondary analysis of a prospective cohort study including singleton, nonanomalous fetuses. The risks of small for gestational age (SGA), macrosomia, preeclampsia, cesarean delivery, gestational diabetes, or preterm birth were calculated for patients who gained weight below or above the IOM's recommendations based on body mass index category. A time-to-event analysis was performed to account for gestational age at delivery. A Cox proportional model was fit to estimate hazard ratios accounting for possible confounders. Results Women who gained weight below recommendations were 2.5 times more likely to deliver SGA and twice as likely to deliver preterm. Normal-weight patients who gained below recommendations were 2.5 times more likely to deliver SGA and twice as likely to deliver preterm. Obese patients who gained inadequate weight were 2.5 times more likely to deliver SGA. Conclusion Among normal-weight patients, adhering to IOM recommendations may prevent growth abnormalities and preterm delivery. Among obese patients, a minimum weight gain requirement may prevent SGA infants.

Gestational diabetes mellitus in sub-Saharan Africa: systematic review and metaregression on prevalence and risk factors.

OBJECTIVE: We systematically reviewed publications on prevalence and risk factors for gestational diabetes mellitus (GDM) in the 47 countries of sub-Saharan Africa. METHODS: We conducted a systematic search in PUBMED and reviewed articles published until June 2014 and searched the references of retrieved articles. We explored sources of heterogeneity among prevalence proportions with metaregression analysis. RESULTS: Of 1069 articles retrieved 22 studies were included. Half were from West Africa, specifically Nigeria, five from South Africa and six from East and Central Africa. There were differences in screening methods and diagnosis criteria used, even between studies carried out in the same country and same time period. Metaregression analysis indicated high heterogeneity among the studies (I(2) = 100, P < 0.001), which could not be sufficiently explained by study setting, population, diagnostic criteria or time trend, although we observed a relatively higher prevalence in studies carried out after 2000 (5.1% vs. 3.2%), when women at risk were selected (6.5% vs. 3.8%) and when more current diagnostic criteria were used (5.1% vs. 4.2%). Associations with risk factors were reported in six studies. Significant risk factors reported in more than one study were overweight and/or obesity, family history for type 2 diabetes, previous stillbirth, previous macrosomic child and age >30 years. CONCLUSIONS: There are few studies on prevalence and risk factors for GDM in Sub-Saharan Africa and heterogeneity is high. Prevalence was up to about 14% when high-risk women were studied. Preventive actions should be taken to reduce the short- and long-term complications related to GDM in Sub-Saharan Africa.

Aberrant upregulation of miR-21 in placental tissues of macrosomia.

OBJECTIVE: With China's rapid economic growth in the past 3 decades, an increase in rate of macrosomia has been reported in China. Fetal growth is a result of multiple factors including genetic potential for growth, maternal nutrition, maternal metabolism, endocrine factors and placental perfusion and function. However, the detailed mechanism of how macrosomia happened remains poorly known. Recent studies showed that the expression of a number of microRNAs (miRNAs) in placentas is involved in fetal growth. We hypothesized that aberrant expression of microRNA-21 (miR-21) and microRNA-16 (miR-16) in placenta is associated with macrosomia. STUDY DESIGN: Using quantitative real time PCR, we analyzed the expression level of miR-21 and miR-16 in terminal placentas of macrosomia pregnancies (n=35) and normal controls (n=35). Potential target genes of miRNA were predicted using TargetScan, miRanda and PicTar. Target genes were mapped to KEGG pathways using KEGG Mapper with an in-house Perl script with KEGG Gene IDs. RESULT: MiR-21 showed significant up-regulation in macrosomia (P=0.037). After controlling the potential confounders, multivariable logistic regression analysis suggested the risk of macrosomia increased, multivariable adjusted ORs of macrosomia for those in the highest tertile was 3.931 (95%CI: 1.049-14.736) compared with those in the lowest tertile in terms of miR-21 level. The target genes of miR-21 were involved in eight possible signaling pathways. They were pathways in P53 signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, TGF-beta signaling pathway and PI3K-Akt signaling pathway (P<0.001), Wnt signaling pathway, Jak-STAT signaling pathway and mTOR signaling pathway (P<0.05). CONCLUSION: Our study is the first to investigate the association between placental miRNA expression and macrosomia. Our results indicate that the expression level of miR-21 in placental tissue may be involved in the development of macrosomia.

Yunis-varon syndrome: further delineation of cardiovascular and endocrine outcome.

Yunis-Varon syndrome is a rare autosomal recessive condition initially characterized by specific skeletal and ectodermal abnormalities, and a poor prognosis, due to neurological and cardiovascular involvement. We describe the cardiovascular and endocrine complications in a 26-year-old man who had been reported previously, adding dilated cardiomyopathy to the clinical features consistent with Yunis-Varon syndrome. Short stature, successfully treated with growth hormone, and hypertension secondary to bilateral renal artery stenosis expand the phenotype.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.

BACKGROUND & AIMS: Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS: We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS: We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS: In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

[Diagnosis of congenital endocrinological disease in newborns with prolonged jaundice and hypoglycaemia]. / Diagnóstico de endocrinopatía congénita en neonatos con ictericia prolongada e hipoglucemia.

INTRODUCTION: The association of prolonged neonatal jaundice and hypoglycaemia may be secondary to an endocrinological disease. Pituitary insufficiency and primary adrenal insufficiency are the most likely endocrine diseases that need to be ruled out. MATERIAL AND METHODS: We retrospectively analysed the clinical and laboratory characteristics of thirteen patients referred to the Hospital de Niños Ricardo Gutiérrez between years 2003 and 2008 due to prolonged neonatal jaundice and hypoglycaemia secondary to pituitary insufficiency in twelve patients, and in one secondary to primary adrenal insufficiency. RESULTS: All patients had a history of neonatal hypoglycaemia. Ten patients had conjugated hyperbilirubinaemia and six also had elevated transaminases. Combined pituitary hormone deficiency was observed in the twelve hypopituitarism patients. Hormonal replacement normalised liver function and resolved the prolonged jaundice in all the patients. None of them underwent liver biopsy. Hypoglycaemia also remitted after hormonal therapy. CONCLUSIONS: Prolonged or cholestatic jaundice associated with neonatal hypoglycaemia is highly likely to be due to pituitary hormone deficiency or primary adrenal insufficiency. Early diagnosis and treatment of these children reverts the prolonged jaundice and prevents morbidity and mortality due to recurrent hypoglycaemia and hormone deficiencies.

Perinatal endocrinology: common endocrine disorders in the sick and premature newborn.

Endocrine disorders are common in infants in the neonatal ICU. They often are associated with prematurity, low birth weight or very low birth weight, and small size for gestational age. They also frequently occur in infants who are critically ill or stressed. This article describes the most common conditions and current knowledge regarding management.

Preimplantation genetic diagnosis (PGD)--prevention of the birth of children affected with endocrine diseases.

OBJECTIVE: To develop a reliable and accurate preimplantation genetic diagnosis (PGD) method in six families with endocrine diseases: persistent hyperinsulinemic hypoglycemia of infancy (PHHI), congenital adrenal hyperplasia (CAH) salt-wasting form, Sanjat-Sakati syndrome and multiple endocrine neoplasia 2A (MEN 2A). METHODS: For each disease a battery of at least four informative markers surrounding the tested gene were identified and for each family a protocol of multiplex fluorescent markers was developed and performed on single cells. RESULTS: PGD for PHHI was performed in three families. In family 1 two healthy children were born from different cycles, in family 2 three healthy children were born from two cycles, and in family 3 a healthy boy was born. For CAH in one family a healthy girl was born. One PGD cycle for Sanjat-Sakati resulted in a clinical pregnancy that was terminated due to high nuccal translucency (46X0). For one family with MEN 2A disease, the eighth PGD cycle resulted in birth of healthy twins. In all children genetic confirmation of the healthy status was performed. CONCLUSIONS: PGD is an effective method for preventing birth of affected children with endocrine disorders. Increasing the awareness of clinicians to the availability of these methods is most important.

Familial glucocorticoid deficiency in five Arab kindreds with homozygous point mutations of the ACTH receptor (MC2R): genotype and phenotype correlations.

BACKGROUND/AIMS: Familial glucocorticoid deficiency type 1 (FGD1) is a rare autosomal-recessive disorder resulting from defective ACTH receptor (melanocortin receptor type 2, MC2R). Individuals with this condition usually present in infancy or early childhood with the signs and symptoms of isolated glucocorticoid deficiency. To date, hypothyroidism has been reported as an associated feature in a few cases. The clinical findings along with MC2R genetic analysis of five Arab kindreds are described. SUBJECTS/METHODS: The subjects were children with the clinical and biochemical features of FGD1. Three patients had associated thyroid dysfunction and two patients had associated growth hormone deficiency (GHD). Mutation analysis of MC2R was performed by direct gene sequencing. RESULTS: Analysis of the MC2R gene revealed a homozygous insertion of a cytosine nucleotide between codons 153 and 154 (c.459_460insC) in all of the patients. This mutation would be expected to cause a translation frame shift after codon 154 and a premature termination codon at 248 of the MC2R mRNA (p.I154fsX248). CONCLUSIONS: Associated thyroid dysfunction and GHD were clinical features in the Bedouin patients with FGD1 caused by identical homozygous frameshift mutation in the MC2R gene.

Late effects of disturbed IGF signaling in congenital diseases.

The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular alpha-subunits activates the tyrosine kinase intrinsic to the cytoplasmic portion of the IGF-1 receptor, leading to autophosphorylation of specific tyrosine residues in the receptor beta-subunit. One early molecular event that links the receptor kinase to the biologic actions of IGF-1 is tyrosine phosphorylation of the insulin receptor substrate family (IRS-1 to -4). IRS acts as a multisite 'docking' protein by binding to downstream signal-transducing molecules. Phosphorylation of multiple tyrosine residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other cytoplasmic signaling proteins, including phosphatidylinositol 3' kinase, Syp, Grb2 and Nck. By binding to Grb2, IRS proteins couple the IGF-1 receptor to the Ras/mitogenactivated protein kinase pathway. This pathway regulates cell growth, differentiation and proliferation. Severe pre- and postnatal growth retardation may arise from abnormalities of IGF-1 signaling such as IGF-1-binding alterations and IGF-1 receptor mutations. Knockout studies have shown severe growth impairment in mice lacking IRS family components or Akt. Finally, in human placentas from pregnancies complicated by intrauterine growth retardation, multiple alterations of IGF-1-signaling molecules have recently been described.

Management of neonatal endocrinopathies--best practice guidelines.

Neonatal emergencies are uncommon, but may lead to significant morbidity and mortality if not recognised and managed promptly. Disorders of sex development, hypoglycaemia, thyrotoxicosis and calcium balance are discussed, with emphasis on the clinical assessment, investigations and management of these disorders in the acute setting.