Cenani–Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways

Cenani–Lenz (C–L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization, and other variable facial and systemic features. Most cases are caused by homozygous and compound heterozygous missense and splice mutations of the LRP4 gene. Currently, the syndrome carries one OMIM number (212780). However, C–L syndrome‐like phenotypes as well as other syndactyly disorders with or without metacarpal synostosis/phalangeal disorganization are also known to be associated with specific LRP4 mutations, adenomatous polyposis coli (APC) truncating mutations, genomic rearrangements of the GREM1‐FMN1 locus, as well as FMN1 mutations. Surprisingly, patients with C–L syndrome‐like phenotype caused by APC truncating mutations have no polyposis despite the increased levels of β catenin. The LRP4 and APC proteins act on the WNT (wingless‐type integration site family) canonical pathway, whereas the GREM‐1 and FMN1 proteins act on the bone morphogenetic protein (BMP) pathway. In this review, we discuss the different mutations associated with C–L syndrome, classify its clinical features, review familial adenomatous polyposis caused by truncating APC mutations and compare these mutations to the splicing APC mutation associated with syndactyly, and finally, explore the pathophysiology through a review of the cross talks between the WNT canonical and the BMP antagonistic pathways.     

Fryns syndrome with Hirschsprung disease: support for possible neural crest involvement

Fryns syndrome is an autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by coarse face, distal limb hypoplasia, and diaphragmatic anomalies. We describe a newborn girl with Fryns syndrome and Hirschsprung disease, an association that has been reported in five previous cases. These patients support the hypothesis that the neural crest plays a role in the pathogenesis of Fryns syndrome. Clinically asymptomatic or subtle anomalies that are in the spectrum of neural crest maldevelopment should be sought in all patients with Fryns syndrome including stillbirths, neonatal deaths, as well as long-term survivors. We suspect that the clinical observation about Hirschsprung disease and Fryns syndrome may provide insight into its molecular mechanisms and candidate genes.     

Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients

BackgroundWalker-Warburg syndrome (WWS), an autosomal recessive disease, is the most severe phenotype of congenital muscular dystrophies. Its diagnosis remains primarily clinical and radiological. Identification of its causative variants will assist genetic counseling. We aim to describe genetic and neuroimaging findings of WWS and investigate the correlation between them.MethodsWe retrospectively reviewed the clinical, genetic and neuroimaging findings of eleven Saudi neonates diagnosed with WWS between April 2012 and December 2018 in a single tertiary care center. Correlation between neuroimaging and genetic findings was investigated.ResultsAll patients had macrocephaly except one who had intrauterine growth restriction. Dysmorphic features were identified in nearly half of the patients. Creatine kinase levels were available in nine patients and were always elevated. Homozygous pathogenic variants were identified in all patients spanning POMT1 (n = 5), TMEM5 (n = 3), ISPD (n = 2) and POMT2 (n = 1) including one patient who had a dual molecular diagnosis of ISPD and PGAP2. On neuroimaging, all patients showed cobblestone cortex, classical infratentorial findings, and hydrocephalus. Other cerebral cortical malformations included subependymal heterotopia, polymicrogyria and open-lip schizencephaly in four, two and one patients, respectively. Buphthalmos and microphthalmia were the most prevalent orbital findings and found in all patients either unilaterally or bilaterally.ConclusionWWS is a genetically heterogeneous disorder among Saudis. The case with an additional PGAP2-related phenotype exemplifies the increased risk of dual autosomal recessive disorders in consanguineous populations. MRI is excellent in demonstrating spectrum of WWS brain and orbital malformations; however, no definite correlation could be found between the MRI findings and the genetic variant.     

NPHP4 mutation is linked to cerebello‐oculo‐renal syndrome and male infertility

Nephronophthisis is the most common genetic cause of renal failure in children and young adults. It is genetically heterogeneous and can be seen in isolation or in combination with other ciliopathy phenotypes. Here we report an index case where nephronophthisis is associated with oculomotor apraxia and cerebellar abnormalities, consistent with the clinical diagnosis of cerebello‐oculo‐renal syndrome. Prompted by a family history of an uncle with early onset end stage renal failure and infertility, we performed semen analysis on the index. This revealed marked reduction in the count of motile sperms as well as multiple abnormalities in the head and tail. Autozygome‐guided mutation analysis followed by exome sequencing and segregation analysis revealed a homozygous truncating mutation in NPHP4, indicating that mutations of this gene can on rare occasions cause cerebello‐oculo‐renal syndrome. Our finding of severe male infertility in a family with NPHP4 truncation is strongly supported by the mouse model and, to our knowledge, is the first reported male infertility phenotype in association with NPHP4 or any other nephrocystin in humans.     

A truncating mutation in B3GNT1 causes severe Walker–Warburg syndrome

Walker–Warburg syndrome (WWS) is a genetically heterogeneous form of congenital muscular dystrophy with significant brain and ocular involvement. In a multiplex consanguineous family with severe WWS phenotype, autozygome-guided sequencing of previously reported WWS genes was negative. Exome sequencing followed by autozygome filtration revealed a homozygous two-base pair insertion in B3GNT1 (NM_006876.2:c.821_822insTT), leading to premature truncation of the protein (p.Glu274Aspfs*94). Recently, two missense mutations in this gene have been reported as probably causal in a family with WWS. This report describes the first truncating mutation in B3GNT1 and confirms that this gene, which plays a role in αDG glycosylation, is a bona fide disease gene in WWS.     

Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome

Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications.