Distal Limb Anomalies Research Articles

Epilepsy as a Novel Phenotype of BPTF-Related Disorders

BackgroundNeurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. MethodsWe enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. ResultsWe studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. ConclusionsOur study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.

A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase Bpathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.

Generation of a mouse model of the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome.

Heterozygous variants in bromodomain and plant homeodomain containing transcription factor (BPTF) cause the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) syndrome (MIM#617755) characterized by intellectual disability, speech delay and postnatal microcephaly. BPTF functions within nucleosome and remodeling factor (NURF), a complex comprising sucrose non-fermenting like (SNF2L), an Imitation SWItching (ISWI) chromatin remodeling protein encoded by the SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1 (SMARCA1) gene. Surprisingly, ablation of Smarca1 resulted in mice with enlarged brains, a direct contrast to the phenotype of NEDDFL patients. To model the NEDDFL syndrome, we generated forebrain-specific Bptf knockout (Bptf conditional Knockout (cKO)) mice. The Bptf cKO mice were born in normal Mendelian ratios, survived to adulthood but were smaller in size with severe cortical hypoplasia. Prolonged progenitor cell cycle length and a high incidence of cell death reduced the neuronal output. Cortical lamination was also disrupted with reduced proportions of deep layer neurons, and neuronal maturation defects that impaired the acquisition of distinct cell fates (e.g. COUP-TF-interacting protein 2 (Ctip2)+ neurons). RNAseq and pathway analysis identified altered expression of fate-determining transcription factors and the biological pathways involved in neural development, apoptotic signaling and amino acid biosynthesis. Dysregulated genes were enriched for MYC Proto-Oncogene, BHLH Transcription Factor (Myc)-binding sites, a known BPTF transcriptional cofactor. We propose the Bptf cKO mouse as a valuable model for further study of the NEDDFL syndrome.

Acro-callous syndrome: A case report.

A malformative syndrome of unknown prevalence, the diagnosis is based on morphological ultrasound and magnetic resonance imaging of the fetus. The transmission is genetic and autosomal recessive. Courtnes has established 4 diagnostic criteria to affirm the acrocal syndrome and to eliminate the amalgam with other polymalformative syndrome.

Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome (MCAP): A Rare Dynamic Genetic Disorder

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is an uncommon malformation syndrome, characterized by primary megalencephaly, capillary malformations of the midline face and body, or distal limb anomalies such as syndactyly and polymicrogyria. Herein, we report a young male child, who presented with complaints of increasing head size, delay in speech, and one episode of focal seizure with distinctive morphological and neuroradiological manifestations which led to the diagnosis of MCAP. We have also reviewed recently published literature and the various diagnostic criteria proposed by authors to achieve the early clinical diagnosis of these patients in the outpatient department.

Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is an autosomal recessive multisystem disorder caused by compound heterozygous or homozygous variants in the gene OTUD6B. Herein, we describe novel pathogenic compound heterozygous variants in OTUD6B identified via whole-exome sequencing in an index case exhibited the severe IDDFSDA phenotype. The potential pathogenicity of the novel frameshift and missense variants in the index case was investigated using in silico tools. The truncating frameshift variant in one allele was predicted to undergo degradation via nonsense-mediated decay of the mRNA molecule. To predict the severity of the damage to the protein caused by the missense variant in the other allele and its effects on phenotypic severity was further investigated together with a previously reported first homozygous missense variant in the same domain in another patient with a less severe IDDFSDA phenotype using structural modeling and molecular dynamics (MD) simulations for the first time. Based on these analyzes, it is anticipated that Tyr216Cys in the earlier reported case with less severe IDDFSDA will lead to localized destabilization, whereas Ile274Arg in the presented index case with the severe IDDFSDA phenotype will lead to significant distortion in the overall fold of OTUD6B. Our findings suggest that compound LOF and ultrarare missense variants may be contribute to the underlying variability expressivity associated with this disorder. In conclusion, our findings support that the clinical severity could be related with the predicted functional severity of the variations in OTUD6B. However, additional functional studies are required.

EP268: DVL2 – A newly identified genetic cause of Robinow syndrome?

Robinow syndrome is a clinically recognizable syndrome characterized by skeletal, genitourinary, and craniofacial findings and, less frequently, cardiac anomalies. The clinical picture is distinctive with short-limbed short stature, distal limb anomalies with broadening of the thumbs and great toes, and craniofacial features including frontal bossing, wide spaced and prominent eyes, and a depressed nasal root with short nose. It is a heterogeneous condition with six established Robinow-associated genes to date - ROR2, NXN, WNT5A, FZD2, DVL1, and DVL3 - all of which are involved in the well-described WNT/planar cell polarity signaling pathway.

Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability.

The OTUD6B and ZMIZ1 genes were recently identified as causes of syndromic intellectual disability (ID) with shared phenotypes of facial dysmorphism, distal limb anomalies, and seizure disorders. OTUD6B- and ZMIZ1-related ID are inherited in autosomal recessive and autosomal dominant patterns, respectively. We report a 5-year-old girl with developmental delay, facial phenotypes resembling Williams syndrome, and cardiac defects. The patient also had terminal broadening of the fingers and polydactyly. Cytogenomic microarray (CMA), whole exome sequencing (WES), and mRNA analysis were performed. The CMA showed a paternally inherited 0.118 Mb deletion of 8q21.3, chr8:92084087–92202189, with OTUD6B involved. The WES identified a hemizygous OTUD6B variant, c.873delA (p.Lys291AsnfsTer3). The mother was heterozygous for this allele. The WES also demonstrated a heterozygous ZMIZ1 variant, c.1491 + 2T > C, in the patient and her father. This ZMIZ1 variant yielded exon 14 skipping, as evidenced by mRNA study. We suggest that Williams syndrome-like phenotypes, namely, periorbital edema, hanging cheek, and long and smooth philtrum represent expanded phenotypes of OTUD6B-related ID. Our data expand the genotypic spectrum of OTUD6B- and ZMIZ1-related disorders. This is the first reported case of a compound heterozygote featuring point mutation, chromosomal microdeletion of OTUD6B, and the unique event of OTUD6B, coupled with ZMIZ1 variants.

Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF.

Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

PurposeGenitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. MethodsWe herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. ResultsWe demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. ConclusionOur work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

Microcephaly-Capillary Malformation Syndrome

AbstractMicrocephaly-capillary malformation is a relatively new syndrome, which has been reported since 2011 by three different research groups. It is an ultra-rare syndrome characterized by the co-occurrence of microcephaly and multiple capillary malformations in the skin, distal limb anomalies (ranging from nail dystrophy to total absence of one or more phalanxes and mostly localized in the foot), facial dysmorphisms, brain structural anomalies (reduced gyration, widened axial spaces, thin cortex, optic nerve atrophy), early-onset severe intractable epilepsy, and profound mental delay. Autosomal recessive mutations in STAMBP gene (2p13.1) have been reported as the only cause of the disorder, with a high penetrance. Currently, no definitive cure is available for the disorder, and treatment is mainly based on multiple antiepileptic drugs for the treatment of seizures, especially in the first years of life. Data on life-long concerns have not been reported, the older patient described so far being an 8-year-old boy.

Familial case of Fryns syndrome in two fetuses in second trimester

Fryns syndrome (FS) is a multiple congenital anomaly syndrome, inherited as an autosomal recessive defect with diagnostic triad including diaphragmatic hernia, abnormal face, and distal limb anomalies. Two cases of FS in the fetuses, whose mother had previous affected pregnancy with the infant having diaphragmatic hernia are presented. Both fetuses have atypical limb deformity, ectrodactyly. These cases illustrate the spectrum of FS and the importance of a family history in fetuses with congenital diaphragmatic hernia.

Megalencephaly-capillary malformation-polymicrogyria syndrome: the first case report in Korea.

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP), previously known as macrocephaly-cutis marmorata telangiectatica congenita and macrocephaly-capillary malformation syndrome, is a rare multiple-malformation syndrome that is characterized by progressive megalencephaly, capillary malformations of the midline face and body, or distal limb anomalies such as syndactyly. Herein, we report a female infant case that satisfies the recently proposed criteria of MCAP and describe the distinctive neuroradiological and morphological features. We have also reviewed recently published reports and the diagnostic criteria proposed by various authors in order to facilitate the clinical diagnosis of these children in pediatric neurology clinics.

Terminal osseous dysplasia with pigmentary defects (TODPD) due to a recurrent filamin A (FLNA) mutation.

Terminal osseous dysplasia with pigmentary defects (TODPD) is an X-linked dominant syndrome with distal limb anomalies, pigmentary skin defects, digital fibromas, and generalized bone involvement due to a recurrent mutation in the filamin A (FLNA) gene. We here report the mutation c.5217G>A in FLNA in three families with TODPD and we found possible germline and somatic mosaicism in two out of the three families. The occurrence of somatic and germline mosaicism for TODPD indicates that caution should be taken in counseling recurrence risks for these conditions upon presentation of an isolated case.

Growth charts for individuals with Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder characterized by variable degrees of intellectual disability, an unusual face, distal limb anomalies including broad thumbs and broad halluces, a large group of variable other major and minor anomalies, and decreased somatic growth. The aim of the present study was to construct up-to-date growth charts specific for infants and children with RSTS. We collected retrospective growth data of 92 RSTS individuals of different ancestries. Data were corrected for secular trends and population of origin to the Dutch growth charts of 2009. On average, 17.9 measurements were available per individual. Height, weight and body mass index (BMI) references for males and females were constructed using the lambda, mu, sigma method. RSTS individuals had normal birth weight and length. Mean final heights were 162.6 cm [-2.99 standard deviation score (SDS)] for males and 151.0 cm [-3.01 SDS] for females. BMI SDS compared to the general Dutch population were -0.06 and 1.40 SDS for males and females, respectively. Head circumference SDS compared to the general Dutch population was -1.89 SDS for males and -2.71 SDS for females. This is the first study to publish growth charts using only molecularly proven RSTS individuals. These syndrome-specific growth charts can be used in managing problems related to growth in RSTS individuals.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.

Megalencephaly‐capillary malformation (MCAP) and megalencephaly‐polydactyly‐polymicrogyria‐hydrocephalus (MPPH) syndromes: Two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia.

Terminal osseous dysplasia with pigmentary defects (TODPD): Follow‐up of the first reported family, characterization of the radiological phenotype, and refinement of the linkage region

Terminal osseous dysplasia with pigmentary defects (TODPD) is an X-linked dominant syndrome with distal limb anomalies and pigmentary skin defects. We have previously described this syndrome in several females from a large, four-generation pedigree. The presentation in the affected patients included multiple anomalies, hypertelorism, iris colobomas, punched-out pigmentary abnormalities over the face and scalp, brachydactyly, and digital fibromatosis. The phenotype was highly variable thus suggesting that X-inactivation plays an important role in the expression of the disease. Following our initial description of this condition there have been reports of more cases supporting the initial phenotypic description of this disease. We report on the follow-up of this family at about 10 years from the first evaluation. A detailed clinical follow-up and a review of the skeletal surveys suggests that although the most striking features involves the hands and feet, the skeletal involvement is more generalized and affects many other areas. Our previous linkage analysis has demonstrated mapping to Xq27.3-Xq28. Using a 6,056 SNP array, we have further refined the critical region within the Xq28 region. We have also excluded two candidate genes (FLNA and FAM58A) mapping in the critical region. The identification of the gene responsible for this rare condition will shed light on the molecular pathways leading to the various congenital anomalies of TODPD and will allow a more accurate genetic counseling to the affected individuals.

Phenotype and 244k array‐CGH characterization of chromosome 13q deletions: An update of the phenotypic map of 13q21.1‐qter

Partial deletions of the long arm of chromosome 13 lead to variable phenotypes dependant on the size and position of the deleted region. In order to update the phenotypic map of chromosome 13q21.1-qter deletions, we applied 244k Agilent oligonucleotide-based array-CGH to determine the exact breakpoints in 14 patients with partial deletions of this region. Subsequently, we linked the genotype to the patient's phenotype. Using this approach, we were able to refine the smallest deletion region linked to short stature (13q31.3: 89.5-91.6 Mb), microcephaly (13q33.3-q34), cortical development malformations (13q33.1-qter), Dandy-Walker malformation (DWM) (13q32.2-q33.1), corpus callosum agenesis (CCA) (13q32.3-q33.1), meningocele/encephalocele (13q31.3-qter), DWM, CCA, and neural tube defects (NTDs) taken together (13q32.3-q33.1), ano-/microphthalmia (13q31.3-13qter), cleft lip/palate (13q31.3-13q33.1), lung hypoplasia (13q31.3-13q33.1), and thumb a-/hypoplasia (13q31.3-q33.1 and 13q33.3-q34). Based on observations of this study and previous reports we suggest a new entity, "distal limb anomalies association," linked to 13q31.3q33.1 segment. Most of the individuals with deletion of any part of 13q21qter showed surprisingly similar facial dysmorphic features, and thus, a "13q deletion facial appearance" was suggested. Prominent nasal columella was mapped between 13q31.3 and 13q33.3, and micrognathia between 13q21.33 and 13q31.1. The degree of mental delay did not display a particular phenotype-genotype correlation on chromosome 13. In contrast to previous reports of carriers of 13q32 band deletions as the most seriously affected patients, we present two such individuals with long-term survival, 28 and 2.5 years.