| Skraban–Deardorff syndrome | |
|---|---|
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| Facial features associated with Skraban–Deardorff syndrome include broad nasal tip, shortphiltrum, flatCupid's bow, wide mouth, widely spaced teeth, andgingival enlargement. | |
| Specialty | Medical genetics and genomics |
Skraban–Deardorff syndrome is anultra-raregenetic disorder caused bypathogenic variants of theWDR26 gene. It is characterized byglobal developmental delay,intellectual disability,friendly demeanor,unusual walking,seizures, feeding difficulties and distinctfacial features. The condition occurs due toinsufficient levels of functional WDR26 protein, which disrupt various cellular mechanisms involved in thedevelopment of the nervous system. While cases reported in medical literature have occurred spontaneously (de novo), it can be inherited in anautosomal dominant manner.
Skraban–Deardorff syndrome shares significant clinical overlap with chromosome 1q41q42microdeletion syndrome. Diagnosis is established throughgenetic testing in individuals with characteristic features. Management issupportive and individualized, includinginterventions for developmental and behavioral concerns,educational programs based on cognitive abilities, andtreatment of seizures. First described in 2017, approximately 150 individuals have been diagnosed with Skraban–Deardorff syndrome as of 2023.
Every individual with Skraban–Deardorff syndrome experiencesglobal developmental delay.Speech is typicallydelayed, and some individuals remainnonverbal throughout childhood.Gross motor delays are reflected inlate milestones—for example, sitting may be delayed by about 11 months, and walking typically begins between 17 and 36 months.Fine motor impairments lead to difficulties withactivities of daily living such as eating, putting on clothes and writing.[1] Individuals are generally described associable andhappy,[1] and have variable degree ofintellectual disability.Abnormal and repetitive behaviors like rocking, unusual hand movements and posture are also observed.[2]
Seizure disorders are common,[3] and may includegeneralized tonic–clonic,absence,rolandic andfebrile seizures.[4]Neuroimaging usually revealsbenign brain anomalies.[5] Otherneurodevelopmental findings include mildlydecreased muscle tone,poor motor coordination andunusual walking. Feeding difficulties—made worse by decreased tone of muscles—begin in infancy and may lead tofailure to thrive.[6] Children can also experiencereflux andconstipation.[7] Heart defects such asventricular septal defect and lung conditions liketracheomalacia occur rarely.[1]
Individuals with Skraban–Deardorff syndrome frequently present with distinct facialdysmorphisms. Common features include acoarse facial appearance, broad nasal tip, prominent maxilla, flatCupid's bow, wide mouth, widely spaced teeth andgingival enlargement. Findings seen less often includemicrocephaly,cleft palate, shortphiltrum, pointed chin,small jaw and tapering eyebrows on the sides. The eyes often appear large due to prominent eyebrows and large-appearingirides. Ocular abnormalities such aseye misalignment,lazy eye,near orfar-sightedness may also be present. Skeletal findings have been observed in only a few individuals, and have included mild lower limbcontractures,high arch of foot, forefootvarus,hip dysplasia andosteopathia striata.[1][2]
An adult with Skraban–Deardorff syndrome was reported to havesyndromic autism, and experienceanxiety,psychomotor agitation,sensory overload andavolition.[8]
TheWDR26 gene providesinstructions for making the WD repeat-containing protein 26 (WDR26), which is produced by most human cells.[2] One of WDR26's many roles is to help build alarger structure called the C-terminal to LisHE3 ubiquitin ligase complex (CTLH E3 complex), whichmarks several proteins for degradation. It also helps anchor anothercomponent,Yippee-Like 5, to support the stability and function of this complex. As apart of its role, WDR26 directs the degradation of specific proteins, such asHMG-box transcription factor 1, atranscriptionalrepressor involved ingene regulation.[9]
WDR26 also helps stabilize a protein calledRan-binding protein 9 (RANBP9; green components in the image). RANBP9 brings the CTLH complex to DNA regions (chromatin), where it helps controlgene expression by affecting how accessible certain genes are totranscription factors likeNuclear factor I andAP-1.[10] Skraban–Deardorff syndrome is caused bypathogenic variants of the WDR26 gene. These variants can occur due tomissense,nonsense orframeshift variations.[7] These variants reduce the amount of functional WDR26 protein, disrupting protein degradation, gene regulation and expression—processes important during thedevelopment of the nervous system.[9][10]
A single abnormal copy of the WDR26 gene is sufficient to cause Skraban–Deardorff syndrome, as the remaining normal copy does not produce enough protein for proper function—a mechanism known ashaploinsufficiency. Reported cases in the medical literature have beende novo, meaning the variants arose spontaneously and were not inherited from either parent. Because only one abnormal copy is needed to cause disease, the syndrome follows anautosomal dominant inheritance pattern, and an affected individual has a 50% chance of passing it on to each offspring.[7]
The WDR26 gene is located on the long arm ofchromosome 1 at 1q42.11–q42.12. Chromosome 1q41q42microdeletion syndrome results from the loss of several genes, including WDR26. This deletion leads to aphenotype that overlaps significantly with Skraban–Deardorff syndrome. Both conditions share core features such as developmental delays, intellectual disability, seizures and distinctive facial characteristics, resulting from WDR26 haploinsufficiency. However, individuals with 1q41q42 deletions often exhibit additional clinical manifestations not typically seen in Skraban–Deardorff syndrome, likely due to the effects of the loss of other genes in the region.[1]
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In addition to overlapping with chromosome 1q41q42 microdeletion syndrome, Skraban–Deardorff syndrome shares clinical features with several other genetic disorders. These includeAngelman syndrome,ATR-X syndrome,Kleefstra syndrome andPitt–Hopkins syndrome. There is no consensus on diagnostic criteria for Skraban–Deardorff syndrome. Diagnosis involves confirming the presence of apathogenic or likely pathogenic WDR26 gene variant in an individual with typical clinical characteristics.[1]
When Skraban–Deardorff syndrome is suspected,genetic testing typically includes chromosomal microarray analysis usingSNP array oroligonucleotide—able to detect 1q42 microdeletions containing the WDR26 gene. A multi-gene panel that includes the WDR26 gene, or comprehensivegenomic testing such asexome orwhole genome sequencing—which can discover a broader range of genetic variants—are also used. Exome sequencing is used most often, and if its results are inconclusive, anexome array can be used to identify exon-level deletions or duplications missed by sequencing; although such variants have not been reported to cause the syndrome.[1]
Management of Skraban–Deardorff syndrome focuses on addressing the individual's specific symptoms and developmental needs through a multidisciplinary approach. Specialists routinely involved in care includephysician geneticists,developmental pediatricians andneurologists.Genetic counseling is typically involved in helping families understand inheritance patterns, explore implications for family planning, and provide psychosocial support.[1]
Growth parameters and milestones are regularly evaluated to monitor progress.Early intervention is often necessary, and involvesphysical therapy to improve motor skills,occupational therapy to enhance daily functioning andspeech therapy to support language development. AnIndividualized Education Program can be used to tailor education to a child's cognitive profile and address specific learning needs. Individuals who have experienced seizures may undergo further evaluation withelectroencephalography andMR brain.[1]Anticonvulsant medications may be needed based on clinical history.[2] In some cases, temporaryfeeding tube placement has been required due to failure to thrive and persistent feeding difficulties.[11]
Skraban–Deardorff syndrome was first delineated by physician geneticistsCara Skraban andMatthew Deardorff in 2017 at theChildren's Hospital of Philadelphia.[12][13] The syndrome is estimated to be present in approximately 1 in 1,500 individuals with intellectual disability (without an identified cause for their disability).[2] However, only about 150 individuals have been formally diagnosed as of 2023.[14]
