KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kucinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.

Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families.

INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of abnormalities that affect structure of the kidneys or other structures of the urinary tract. The majority of CAKUT are asymptomatic and are diagnosed prenatally by ultrasound scanning or found incidentally in postnatal life. CAKUT varies in severity and may lead to life-threatening kidney failure and end-stage kidney disease. Renal agenesis, a severe form of CAKUT, is a congenital absence of one or both kidneys. Bilateral renal agenesis belongs to a group of prenatally lethal renal diseases and is often detected on fetal ultrasound scanning during the investigation of oligohydramnios. Approximately 40% of fetuses with bilateral renal agenesis are stillborn or die a few hours postnatally. Mutations in many renal development genes have been shown to be associated with renal agenesis. METHODS: Six consanguineous Saudi Arabian families were recruited to study the molecular genetic causes of recurrent miscarriages and lost fetuses due to oligohydramnios, renal agenesis and other congenital anomalies. Whole exome sequencing was employed to underlying detect genetic defects. RESULTS: Novel loss of function variants were detected in FRAS1 and FREM2. In FRAS1, a homozygous splice site variant c.9780+2T>C was found in an affected fetus, segregating form each parent. In addition, in three other families both parents were heterozygous for a frameshift variant (c.8981dupT; p.His2995Profs*3) and splice site variants (c.5217+1G>C and c.8098+2T>A), respectively. In FREM2, a homozygous nonsense variant (c.2303C>G; p.Ser768*) was found in an affected fetus, segregating from both parents. In another family, both parents carried a FREM2 heterozygous frameshift variant (c.3969delC; p.Asn1323Lysfs*5). CONCLUSION: We describe consanguineous families with clinical features of antenatal oligohydramnios and bilateral renal agenesis, in whom we have identified novel pathogenic variants in FRAS1 and FREM2. These finding highlights the association between mutations in FRAS1 and FREM2 and antenatal/perinatal death.

Effectiveness of Misoprostol for Induction of First-Trimester Miscarriages: Experience at a single tertiary care centre in Oman.

OBJECTIVES: Non-invasive methods of inducing a miscarriage are now considered an effective alternative to surgical evacuation (dilatation and curettage). This study aimed to evaluate the effectiveness of misoprostol in the termination of first-trimester miscarriages. METHODS: This prospective study was conducted between October 2009 and September 2010 and assessed all patients admitted to the Royal Hospital in Muscat, Oman, for the termination of first-trimester miscarriages during the study period. All patients received misoprostol and the rates of successful termination were measured. Patient satisfaction was assessed using a short questionnaire. RESULTS: A total of 290 women were included in the study. Termination with misoprostol was successful in 61.38% of the subjects. Of the remaining subjects requiring additional surgical evacuation (n = 112), 58.93% required evacuation due to failed termination with misoprostol and 65.18% underwent early evacuation (≤24 hours since their last misoprostol dose). The majority of patients experienced no side-effects due to misoprostol (89.66%). Pain was controlled with simple analgesics in 70.00% of the subjects. A high satisfaction rate (94.83%) with the misoprostol treatment was reported. CONCLUSION: Misoprostol was a well-tolerated drug which reduced the rate of surgical evacuation among the study subjects. This medication can therefore be used safely in the management of incomplete miscarriages.

Pregnancy in the Rudimentary Uterine Horn: Case report of an unusual presentation.

A unicornuate uterus with a rudimentary horn is a uterine anomaly resulting from the incomplete development of one of the Müllerian ducts and an incomplete fusion with the contralateral side. Pregnancy in a rudimentary horn of the uterus is a rare clinical condition with a reported incidence of 1 in 100,000 to 140,000 pregnancies. Usually the diagnosis is missed and may present as an emergency with haemoperitoneum. The standard treatment is the surgical excision of the horn. A gravida 2, para 1 patient presented at 23 weeks' gestation with fetal demise. Repeated failed attempts at induction of labour raised the suspicion of an abnormally located pregnancy which was confirmed by magnetic resonance imaging. She underwent a laparotomy with right rudimentary horn excision. The final diagnosis of a non-communicating rudimentary horn pregnancy was made intraoperatively and was confirmed by histopathology. This case highlights the importance of an early ultrasound in detecting uterine anomalies and the need for high clinical suspicion.