Ambiguous genitalia, microcephaly, seizures, bone malformations, and early death: a distinct MCA/MR syndrome

We report on two siblings with hypotonia, ambiguous genitalia, microcephaly, ptosis, microretrognathia, thin lips, seizures, absent ossification of pubic rami, and brain abnormalities at the MRI. The two siblings died at 5 and 8 months, respectively. Molecular analysis indicated that SOX9, ARX, and DHCR7 genes were normal. Comparative genomic hybridization (CGH)-array analysis performed on the younger boy indicated two notable deletions, one on paternally inherited chromosome 4, and one on maternally inherited chromosome 5. The same deletions were found in a normal sister. Differential diagnoses and the possibility of a hitherto unreported syndrome are discussed.     

Three sibs with microcephaly,clubfeet and agenesis of corpus callosum: A new genetic syndrome?

Clubfoot is a common birth deformity, and agenesis of the corpus callosum is one of the most prevalent brain malformations. We describe three sibs of Arab origin, who were born with clubfeet, agenesis of corpus callosum, and minor anomalies. Two of them were born with microcephaly. This phenotype may represent a novel autosomal recessive genetic condition.     

New recessive syndrome of microcephaly, cerebellar hypoplasia, and congenital heart conduction defect

We identified a two-branch consanguineous family in which four affected members (three females and one male) presented with constitutive growth delay, severe psychomotor retardation, microcephaly, cerebellar hypoplasia, and second-degree heart block. They also shared distinct facial features and similar appearance of their hands and feet. Childhood-onset insulin-dependent diabetes mellitus developed in one affected child around the age of 9 years. Molecular analysis excluded mutations in potentially related genes such as PTF1A, EIF2AK3, EOMES, and WDR62. This condition appears to be unique of other known conditions, suggesting a unique clinical entity of autosomal recessive mode of inheritance.     

Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension

Microdeletions of the long arm of chromosome 17 are being reported with increasing frequency. Deletions of 17q22q23.2 may represent a genetically recognizable phenotype although its spectrum of genomic abnormalities, clinical manifestations, and critical regions are not fully delineated. Isolated reports and small case series suggest that deletions of 17q22q23.2 result in haploinsufficiency of dosage sensitive genes NOG, TBX2, and TBX4, which may be responsible for many aspects of the phenotype. Shared clinical features in this group of patients include microcephaly, prenatal onset growth restriction, heart defects, tracheoesophageal fistula, and esophageal atresia (TEF/EA), skeletal anomalies, and moderate to severe global developmental delay. We describe a female patient who presented with severe congenital microcephaly, thyroglossal duct cyst, sensorineural hearing loss, mild tracheomalacia, abnormal auricles, pulmonary hypertension, developmental delay, and postnatal onset growth delay. She had no TEF/EA or heart defects. Using a high density oligonucleotide microarray, we identified a microdeletion at 17q22q23.2, resulting in the heterozygous loss of several genes, including TBX2 and TBX4 but not NOG. The breakpoints did not lie within known segmental duplications. This case helps to further delineate the critical region for TEF/EA, which is likely confined to the chromosomal region proximal to 17q23.1, and suggests that genes in 17q23.1q23.2 may be associated with thyroglossal duct cysts. The role of TBX2 and TBX4 in pulmonary hypertension warrants investigation.     

Diagnostic approach to fetal microcephaly

Microcephaly in utero is conventionally defined as a fetal head circumference (HC) 3SD below the mean for gestational age according to Jeanty et al.’s reference range. Prediction of microcephaly at birth (micB) based on conventional prenatal biometry is associated with a high percentage of false positive diagnoses and as a result, in countries in which it is an option, termination of pregnancy may be offered in cases that would have culminated in birth of a normocephalic child. A false negative diagnosis is rarer, but may lead to the birth of a symptomatic microcephalic child.In this review we present the results of our recent studies aimed at improvement of accurate prenatal detection of microcephaly including: (1), application of two new reference ranges for fetal HC in cases with a prenatal diagnosis of microcephaly based on the conventional reference; (2) assessment whether integration of additional parameters (stricter fetal HC cut-offs, small-for-gestational age (SGA), decreased HC/abdominal circumference and HC/femur length ratios, presence of associated malformations and family history) can improve prediction; (3), estimation of the difference between Z-scores of prenatal HC and the corresponding occipitofrontal circumference (OFC) at birth in order to propose an adjustment for better prediction of the actual OFC deviation at birth; (4), assessment whether micB diagnosis can be improved by accurate detection of false positive Fmic cases whose small HC is due to an acrocephalic-like head deformation by applying a new reference range of a vertical measurement of the fetal head: foramen magnum-to-cranium distance (FCD).The conventional and new reference ranges for fetal HC, all result in considerable over-diagnosis of fetal microcephaly (ranging from 43% to 33%). The use of the new references does not significantly improve micB prediction compared with the conventional one, whilst integrating additional parameters results in a better positive predictive value (PPV), but an increase in false negatives. The degree of Fmic severity is significantly over-estimated compared to the corresponding micB. The difference between the postnatal OFC deviation from the mean and the prenatal HC ranges from ?0.74 SD to ?1.95 SD for various fetal HC references. Application of the reference range for vertical cranial dimensions enables exclusion of fetuses with a small HC associated with a vertical cranial deformity without missing those with actual micB. Combining the fetal HC with the developed FCD criteria raised the PPV of micB to 78%.

寨卡病毒病研究进展

寨卡病毒病是由寨卡病毒引起的一种自限性急性传染病。寨卡病毒主要通过埃及伊蚊和白纹伊蚊叮咬传播,有证据表明也可通过性传播和母婴传播。临床表现主要为皮疹、发热、关节痛或结膜炎等非特异性症状,但寨卡病毒感染与新生儿小头畸形、格林-巴利综合征等存在密切关系。实验室检测方法包括实时荧光定量PCR检测病毒核酸和ELISA检测Ig M抗体。该疾病目前无有效的抗病毒药物和疫苗。预防措施主要为预防蚊虫叮咬和采取虫媒控制措施。     

Zika病毒:虫媒病毒传染病的新挑战

Zika病毒(Zika virus,ZIKV)是一种新发的虫媒病毒,伊蚊是其主要的传播媒介。Zika病毒感染后主要引起发热,皮疹,关节痛等轻症症状。2015年起,Zika病毒在拉丁美洲及南美洲多个国家流行,并且Zika病毒感染患者不仅出现发热,皮疹和关节痛等症状,还发现Zika病毒病的流行与婴儿小头畸形,格林巴利综合征,病毒性脑膜炎病例的发生相关。不仅如此,Zika病毒感染还可以通过性途径传播。因此,从病毒感染症状的复杂性来看,目前流行的Zika病毒已经与1947年刚发现时的Zika病毒完全不同,而是成为了一种“新病毒”。 本文系统地梳理总结了Zika病毒感染相关的最新研究进展,并提出Zika病毒及其感染是对虫媒病毒传染病的新挑战的概念。