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Year : 2021  |  Volume : 2  |  Issue : 3  |  Page : 280-283

How to select a key finding for a syndrome searching: A systemic approach

Department of Pediatrics, Genetic Division, AIIMS, Rishikesh, Uttarakhand, India

Date of Submission25-Jul-2020
Date of Decision08-Jun-2021
Date of Acceptance09-Aug-2021
Date of Web Publication28-Dec-2021

Correspondence Address:
Dr. Prashant Kumar Verma
Department of Pediatrics, Genetic Division, AIIMS, Rishikesh, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JME.JME_135_20

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How to cite this article:
Verma PK. How to select a key finding for a syndrome searching: A systemic approach. J Med Evid 2021;2:280-3

How to cite this URL:
Verma PK. How to select a key finding for a syndrome searching: A systemic approach. J Med Evid [serial online] 2021 [cited 2022 Aug 10];2:280-3. Available from: http://www.journaljme.org/text.asp?2021/2/3/280/333952

Congenital anomalies are a growing health problem, and their prevalence is high in recent literature.[1] A birth defect is a general term that includes all structural and functional pathological changes. Dysmorphology (Dys – abnormal + morphology) is a branch of clinical medicine concerned with the study of structural deviations from the normal morphology in developing organisms. Dysmorphology studies are used to define the anomalies, understand the mechanism of congenital structural disabilities, make a syndromic diagnosis and utilise this knowledge for investigations, management and research purposes. Most congenital disabilities initiate with a single defect. Still, complex body system interaction and inter-tissue dependency at different developing stages leads to cascade of further consequences leading to a pattern of anomalies. If the underlying etiology for the congenital disability is known, then it is called a syndrome.[1],[2]

Out of 25,466 registries, 9176 entries in Online Mendelian Inheritance in Man (OMIM) have well-defined phenotypic details. Most of these syndromes have overlapping phenotypes, and it is challenging to reach the precise syndromic diagnosis without a characteristic anomaly or initiator for those anomalies. Searching a syndrome by a non-experienced clinician from the available online resource is challenging due to a lack of understanding of the basic strategies for syndromic searching and using the amiss anomalies or another MeSH term in the software, resulting in a heap of specific diagnoses.[3]

There is a lack of literature for a systemic approach to detect the characteristic anomaly or key finding for a particular syndrome. However, it can be of significant help in syndromic searching and help understand the mechanism of congenital disability. In addition, a key finding supports making a syndromic diagnosis if used as a MeSH term in online resources or software. The following are the characteristics of a clinical or lab key finding.

First, recognising the dysmorphology mechanism and pattern helps to understand the initiator for dysmorphism and labelling of key anomaly (primary anomaly). Moreover, secondary anomalies are less likely to allow for syndromic search because different mechanisms can develop them. For example, arthrogryposis will not help to reach the diagnosis or exact pathophysiology for joints immobility.[4] Understanding the embryonal developmental stages and finding out association with pathological events is extremely useful for interpreting the initiator. According to the severity of involvement, organising all clinical outcomes help to point out the initiator and participation by a particular germline or body system. For example, craniosynostosis or premature fusion of cranial sutures in Crouzon syndrome is the initiator for all the secondary facial dysmorphism, dental defects and ophthalmic findings. Similarly, developmental defect in the first and second pharyngeal arches is the underlying key finding in  Treacher Collins syndrome More Details.[5],[6] A congenital disability that can be explained by a different mechanism of dysmorphology and is multifactorial in origin is least likely to be helpful as a key anomaly.

Second, a key anomaly would not be a variation or the specific trend of minor deviation from normal morphology for that particular family, community or ethnicity.[1],[7] For example, midface hypoplasia and slight down slanting are common in few ethnic populations; the other widespread variations reported are cutaneous syndactyly and brachydactyly, synophrys, variations of ear shape and size and low-risk pilonidal sinus, etc.[8] These variations are ignored without detailed parents' examination and patient biodata. Hence, the parental examination should be an essential part of a dysmorphic case. These findings should be ruled out with caution because of the variable phenotype reported with autosomal dominant disorders.[3]

Third, lab-based finding is always helpful as a key finding because having less subjective error rates with precise data records such as radiological X-rays. Referral inputs from different speciality departments such as ophthalmologists and otolaryngologists also have a similar impact.

A skeletal survey is an essential part of syndromic evaluation with short stature or suspected skeletal dysplasia. A minimum of X-ray hands with both wrists is required in other cases.[9],[10] Various electrophysiological studies such as electrocardiogram (ECG), electroencephalogram (EEG), brainstem-evoked response audiometry, electroretinography and nerve conduction velocity (NCV) can provide valuable diagnostic findings, as ECG can help in making the diagnosis of Inherited arrhythmia syndromes (various Long QT, Brugada syndrome, etc.) and EEG for other selective channelopathies (e.g., hypsarrhythmia pattern in West syndrome). NCV helps to diagnose and classify hereditary motor sensory neuropathy.[11],[12] Other radiological investigations such as ultrasound and echocardiography, which are reasonably helpful in finding the internal malformations and providing invaluable information for making the antenatal diagnosis but imprecise isolated cardiac anomalies, are of minimal value.[13] Magnetic resonance imaging (MRI) of the brain is a practical tool for key characteristics identifications of syndromes with the central nervous system (CNS) malformations such as neural migration disorders, hindbrain malformations as Arnold Chiari and vermian agenesis, aplasia or hypoplasia and cystic posterior fossa anomalies. MRI also provides a unique pattern of CNS involvement in neurometabolic disorders as peculiar and unique demyelinating changes in the brain in various leucodystrophies.[14],[15]

Fourth, it should be part of the clinical diagnostic criteria of a syndrome (if available) or a highly penetrating dysmorphic finding or with a significant P value as delineated by software. Like as per the NIH diagnostic criteria for NF1, the diagnosis of Townes–Brocks Syndrome is established in a proband with three notable features.[16] The diagnosis of Duane syndrome is established in a proband typically by an ophthalmic finding.[17] Having the idea of diagnostic criteria will orient the clinician to find out the characteristic anomalies. However, syndromes with age-dependent penetration led to delay in making the diagnosis.

Fifth, a unique anomaly that is rare in the community always needs attention and is usually a key finding for syndromic search. Few examples of genetic syndromes with characteristic diagnostic features with respected OMIM number are pursed up lips/whistling face in Freeman–Sheldon syndrome (193700), broad thumbs/great toes in Rubinstein–Taybi syndrome I and II (180849 and 613684), Mitten hands in Apert syndrome (101200), absent clavicles in cleidocranial dysostosis (119600), heterochromia iridis, dystopia canthorum with a white forelock of hair in Waardenburg syndrome type 1 (193500), inverted nipples in congenital disorder of glycosylation, Type 1A (212065), webbing of the neck in Turner and Noonan syndrome, eversion of the lateral third of the lower eyelid in Kabuki syndrome (147920), aplasia cutis congenita and absent nipple in Finlay–Marks syndrome (181270), skeletal dysplasia with hitchhiker's thumb in diastrophic dysplasia (222600), lip pits in Van der Woude syndrome type 1 and 2 (119300 and 606713) and so on.

Even a few unique and rare findings narrow your search and lead to focus on a particular pathway defect, for example, solitary median maxillary central incisor in SHH pathway, changes in growth parameters in overgrowth syndromes, and primordial short stature because of genetic variation of growth-regulating genes; syndromes with premature aging reported with mutations in genes responsible for DNA repair and maintenance and mutations in genes responsible for left-right determination or cilia movements turn to Heterotaxy.[18] A case with recurrent infections or unusual infections could be due to genes responsible for T, B cell maturation, and differentiation (key findings would be in immunophenotyping, immunoglobulin levels, and NBT tests, etc.).[19] The mitochondrial disease frequently involves two or more independent systems with increased lactic acid and the pyruvic acid molar ratio of more than 25.[20] Physicians need to be aware of rare morphology and take good clinical photographs for further search.

Sixth, the anomaly deviates most severely from the mean; it is always better to include these anomalies in search items rather than a borderline deviation from the norm. It is so because of the lack of anthropometric data of these anomalies for all races and ethnicities, resulting in misinterpretations. Dysmorphic facial findings with anthropometric measurements ≥ ±3 standard deviation from mean will always be the key feature for syndromic identification such as evident significant hypertelorism craniofrontonasal syndrome (304110), Opitz GBBB (300000) and autosomal dominant craniometaphyseal dysplasia (123000).

Seventh, using the complex neurological finding as behavioural, psychiatric manifestations, as illustrated in [Table 1], is primarily a high-yielding key finding. Other complex and unique neurological findings as the characteristic distribution of muscular weakness or hypertrophy and the onset of symptoms in diverse types of muscular dystrophy are of immense help for diagnosing hereditary muscular dystrophy. Mild-to-moderate learning disabilities, autistic spectrum disorders and central hypotonia are frequent concomitant findings in children with congenital disabilities and thus are less effective for syndromic searching. The patient's short video recording is an essential part of reviewing the case and naming complex neurogenic findings, as the clinical photograph can miss these.
Table 1: Behavioural and psychiatric visible signs with examples of few neurogenetic disorders

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Eighth, find out the exact MeSH terms to define the key anomaly. The best online resource for figuring out and understanding the anomaly with photos is elementsofmorphology.nih.gov. Using improper medical words or layman language will not be helpful for syndromic searching.

Identifying the key finding or an anomaly from all clinical and lab data for syndromic search would be helped by using these eight points as a checklist [Table 2].
Table 2: Specification for the properties of key finding or anomaly

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  Conclusion Top

Lack of proficiency and non-adherence to the systemic approach of syndromic searching can make it hard to recognise the syndrome. Hence, the author tried to make a structured checklist that would help to select the most characteristic clinical finding (key anomaly) from all patient data for syndromic searching. Thus, it will help to confine the different diagnoses and will also save time.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Lu X, Forte AJ, Sawh-Martinez R, Madari S, Wu R, Cabrejo R, et al. Facial malformation in Crouzon's syndrome is consistent with cranial base development in time and space. Plast Reconstr Surg Glob Open 2018;6:e1963.  Back to cited text no. 5
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  [Table 1], [Table 2]


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