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Background: Antenatally detected occipital encephalocele and polycystic kidneys are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber syndrome which have considerable genetic and phenotypic overlap. Case reports: We describe 3 cases of antenatally diagnosed occipital encephalocele and enlarged kidneys with fetal autopsy, histopathology & exome sequencing results. A novel nonsense variant in the CEP290 gene was reported in first case (Meckel syndrome). The second case shows the importance of fetal exome where the parents were carriers for 2 ciliopathy genes (TMEM138 & SDCCAG8). Diagnosis in this case was confirmed by fetal exome sequencing (Joubert syndrome). Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance. Conclusion: We report 2 cases of Meckel syndrome with a novel variant and multiexon deletion, and 1 case of Joubert syndrome which depicts the limitations of preconceptional carrier screening in ciliopathies due to overlapping phenotypes.

Meckel syndrome is a lethal autosomal recessive disorder characterized by the triad of cystic renal dysplasia, occipital encephalocele, or other anomaly of the central nervous system and post-axial polydactyly. Malformation of the ductal plate is an integral component of Meckel syndrome. Ductal plate malformations include congenital hepatic fibrosis, biliary hamartoma, autosomal dominant polycystic liver disease, Caroli disease, and choledochal cyst. The occurrence of cystic hepatic disease, Caroli disease, and choledochal cyst have not been highlighted. This is a report of a 26-week fetus with features of Meckel syndrome, Caroli disease, and choledochal cyst.

A critical relationship exists between ordered ciliary ultrastructure and optimal mucociliary clearance in the respiratory airways. Structurally defective cilia derived from heritable syndromes or from epithelial cell injury may promote or exacerbate chronic disease processes. A lesion of airway epithelial cilia characterized by microtubular discontinuities and previously associated with primary ciliary dyskinesia (PCD) has been documented in other forms of chronic airways diseases, including cystic fibrosis (CF). Nasal cilia obtained by curettage of the inferior nasal turbinate from 89 patients without CF but exhibiting symptoms favoring PCD were evaluated by transmission electron microscopy. Of the 89 patients in the study group, 19 (21.4%) were diagnosed with PCD. Among the PCD patients, 16 (84.2%) exhibited microtubular discontinuities. Nine patients from this group without ultrastructural evidence of PCD also exhibited these defects, however. Furthermore, seven of eight nasal biopsy specimens from patients with CF in a separate disease control group exhibited microtubular discontinuities. Microtubular discontinuities were quantitatively negligible among control groups of healthy human subjects and individuals experimentally and naturally subjected to acute airway injury. These data provide evidence that ciliary microtubular discontinuities represent acquired ciliary defects reflective of chronic airway disease injury and are not components of a primary structural abnormality in PCD.

Twenty-eight subjects with chronic respiratory disease were investigated for clinical data, ciliary beat frequency of nasal mucosa (10 cases), and ciliary ultrastructure. The cases were divided into two groups: those considered compatible with primary ciliary dyskinesia (genetic), and those not fitting into this category (others). A case was defined as genetic if one or more of the following were present: dextrocardia, ciliary beat frequency less than 10 Hz, or an average dynein arm count (outer, inner, or both) of less than two per ciliary cross-section. In each of the genetic cases at least two of these parameters were present. The percentage of malformed microtubules was calculated from the total number of evaluated cross-sections for each case. Ciliary microtubular abnormalities of any kind were no more frequent in cases of primary ciliary dyskinesia than in other cases. The same was true for transposition and radial spoke defects.

his report describes the ultrastructural alterations observed in the tracheal epithelium of a 13-year-old male with a history of recurrent pneumonia, chronic bronchitis, chronic otitis media, and situs inversus. The epithelium consisted of globlet and basal cells with many columnar cells that lacked cilia and basal bodies. The surface of these cells had regular microvilli and cytoplasmic features typical of brush cells.

Twenty-two cases displaying potentially precancerous epithelial changes of the bronchial mucosa--including basal and goblet cell hyperplasia, epidermoid metaplasia, and dysplasia--showed a wide variety of cilial abnormalities on the ultrastructural level. The changes comprised abnormal configurations of the ciliary plasma membrane, variations in the amount of ciliary matrix, disorganization of basal bodies, and diverse alterations of the axonemal microtubular pattern. More than one such alteration was observed in one and the same case, and there was no correlation with the actual type of epithelial lesion nor the degree of dysplasia. These changes, interpreted as abnormal ciliary regeneration in severely damaged ciliated cells, are potentially reversible and seem to represent a nonspecific response of the affected cells to an ample spectrum of noxes. Their diagnostic significance is poor, especially with regard to the modification of the axonemal microtubular pattern, unless the entire clinical picture suggests an immotile cilia syndrome.

This article reports on the experience with 38 biopsies from nasal mucosa, submitted with the question of immotile cilia syndrome. Fixation in glutaraldehyde with MgSO4 is preferable. At least 50 cilia should be scrutinized in the electron microscope, and dynein arms, radial spokes, sheaths, nexin links and orientation should be tabulated. Six cases displayed virtual absence of inner and outer dynein arms. The orientation of these cilia was random. Two of the patients had situs inversus. In biopsies considered not to represent the immotile cilia syndrome, about four inner and seven outer dynein arms were found per cilium.