Summary The congenital myasthenic syndromes (CMS) are a diverse group of genetic disorders caused by abnormal signal transmission at the motor endplate, a special synaptic contact between motor axons ...and each skeletal muscle fibre. Most CMS stem from molecular defects in the muscle nicotinic acetylcholine receptor, but they can also be caused by mutations in presynaptic proteins, mutations in proteins associated with the synaptic basal lamina, defects in endplate development and maintenance, or defects in protein glycosylation. The specific diagnosis of some CMS can sometimes be reached by phenotypic clues pointing to the mutated gene. In the absence of such clues, exome sequencing is a useful technique for finding the disease gene. Greater understanding of the mechanisms of CMS have been obtained from structural and electrophysiological studies of the endplate, and from biochemical studies. Present therapies for the CMS include cholinergic agonists, long-lived open-channel blockers of the acetylcholine receptor ion channel, and adrenergic agonists. Although most CMS are treatable, caution should be exercised as some drugs that are beneficial in one syndrome can be detrimental in another.
Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess.
We conducted a systematic review and critical ...assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed.
Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents.
The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-off values are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy.
Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.
Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, ...delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy.
KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, ...two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.
TBX5, a member of the T-box family of transcription factors, is a dosage sensitive regulator of heart development. Mutations in TBX5 are responsible for Holt-Oram Syndrome, an autosomal dominant ...disease with variable and partially penetrant cardiac defects suggestive of the existence of genetic and environmental modifiers. KLF13, a member of the Krüppel-like family of zinc finger proteins is co-expressed with TBX5 in several cardiac cells including atrial cardiomyocytes and cells of the interatrial septum. We report that KLF13 interacts physically and functionally with TBX5 to synergistically activate transcription of cardiac genes. We show that TBX5 contacts KLF13 via its T-domain and find that several disease-causing mutations therein have decreased KLF13 interaction. Whereas Klf13 heterozygote mice have no detectable cardiac defects, loss of a Klf13 allele in Tbx5 heterozygote mice significantly increases the penetrance of TBX5-dependent cardiac abnormalities including atrial, atrial-ventricular and ventricular septal defects. The results reveal for the first time combinatorial interaction between a T-box protein and a KLF family member and its importance for heart and possibly other organ development. The data also suggest that, in human, KLF13 may be a genetic modifier of the Holt-Oram Syndrome gene TBX5.
We aimed to examine trends in timing of diagnosis of critical congenital heart defects (CCHDs) and factors associated with delayed diagnosis (diagnosis after discharge home following delivery).
We ...examined a population-based retrospective cohort of CCHD cases among live births identified through the Massachusetts Birth Defects Monitoring Program. Congenital heart defects were considered critical if the infant received corrective surgery, interventional catheterization, palliative care, or died as a result of the defect within 12 months of birth. Timing of initial diagnosis was classified as prenatal, postnatal before discharge home, or delayed. Demographic, perinatal, and mortality information was obtained from the Registry of Vital Records and Statistics. Prevalence ratios (PRs) were used to examine associations with delayed diagnosis.
Among 460 467 live births to Massachusetts residents between 2004 and 2009, we identified 916 CCHD cases, of which 126 (13.8%) had delayed diagnosis. Rates of prenatal CCHD diagnosis increased from 44.9% in 2004 to 63.8% in 2009, whereas rates of delayed diagnosis decreased from 17.1% to 10.6% over the same time period. Among cases with delayed diagnosis, the most common defects were coarctation, pulmonary valve stenosis, and tetralogy of Fallot. Delayed diagnosis was associated with delivery outside a tertiary hospital (adjusted PR: 3.6 95% confidence interval: 2.5-5.2) and isolated CCHD (adjusted PR: 1.7 95% confidence interval: 1.1-2.7).
Despite increasing prenatal diagnosis of CCHDs, delayed diagnosis still occurs in over 10% of cases. Understanding factors associated with delayed diagnosis could help to improve prenatal and postnatal screening efforts, including pulse oximetry testing.
Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early ...infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.
Diagnosis and management of congenital lung malformations has evolved dramatically over the past several decades. Advancement in imaging technology has enabled earlier, more definitive diagnoses and, ...consequently, more timely intervention in utero or after birth, when indicated. These advancements have increased overall survival rates to around 95% from historical rates of 60%. However, further refinement of diagnostic technique and standardization of treatment is needed, particularly as the increased sensitivity of diagnostic imaging results in more frequent diagnoses. In this article, we provide an updated review of the diagnostic strategies, management, and prognosis of congenital lung malformations.
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