Dysmorphology in identifying syndromic causes of epilepsy

Dixit A, Suri M. When the face says it all: dysmorphology in identifying syndromic causes of epilepsy. Pract Neurol. 2016 Apr;16(2):111-21.

Abstract

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient.

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From the paper:

In this paper, we outline the salient features of selected genetic conditions in which epilepsy is an important feature. Typically, an affected person will have other medical problems, including congenital malformations and a degree of intellectual disability. Almost all the conditions we describe are associated with a minimum 25% risk of developing epilepsy. The only exception is Coffin–Lowry syndrome with an incidence of epilepsy of only 5%, although 20% develop non-epileptic drop attacks that might lead to referral to an epilepsy clinic.

The seizure semiology or EEG features are not a strong clue to the diagnosis of these conditions. Rather, we focus on the genetic conditions that give distinctive findings on physical examination, particularly highlighting the facial 'gestalt' and other typical clinical features. Traditionally, genetic 'syndromes' are diagnosed in childhood. However, the clinical phenotype of many of the conditions we discuss has been clearly delineated only within the last two decades; it is therefore quite probable that affected individuals might present to an adult epilepsy clinic. We do not discuss conditions where facial features give no specific clues to the underlying diagnosis, for example, Rett syndrome, Dravet syndrome and CDKL5 mutations; nor genetic disorders in which neuronal migration defects are a major feature and neuroimaging strongly suggests the genetic aetiology, for example, lissencephaly or subcortical band heterotopia. We have also not included conditions that would have been diagnosed on a standard karyotype, for example, 4p deletion in Wolf–Hirschhorn syndrome, as most adults with intellectual disability, with or without epilepsy, will have been karyotyped in childhood…

Although array-comparative genomic hybridisation (aCGH) analysis is now widely available and has become a first-line investigation for a child presenting with developmental delay, we have included three chromosomal deletions or microdeletion syndromes that are detectable by aCGH (1p36 deletion, Koolen–deVries syndrome and Kleefstra syndrome) for two reasons:

Many adults with intellectual disability have not had aCGH analysis.

In Koolen–deVries and Kleefstra syndromes, some patients have a mutation within the causative gene that aCGH would not detect, who would require specific analysis of the relevant gene…

Traditionally, descriptions of dysmorphic features that may aid a clinician in the diagnosis of genetic conditions refer to the findings in children. Indeed, many genetic conditions have a 'diagnostic window' in which the facial gestalt is characteristic. For example, individuals with Sotos syndrome have a distinctive facial appearance that is most recognisable between the ages of 1 and 6 years. However, the adult phenotype and natural history of many genetic conditions are now much better described in the medical literature. Overall, the clinical picture in the conditions described below is characteristic, even in adults, and the facial features provide one of the strongest clues to the diagnosis. Coarsening of facial features may develop in many conditions with age. Other aspects of physical examination can be very important in certain conditions. For example, progressive loss of scalp hair is typical of Nicolaides–Baraitser syndrome, whereas silvery, hypopigmented hair occurs in Koolen–deVries syndrome. The hands provide specific clues in Coffin–Lowry syndrome (short, soft hands with hyperextensible joints and tapering fingers), Nicolaides–Baraitser syndrome (prominent interphalangeal joints) and Kabuki syndrome (persistent fetal fingertip pads). Growth features can provide supportive evidence. Microcephaly with or without short stature occurs in many disorders; Sotos syndrome is the only condition with overgrowth features (tall stature and macrocephaly).

A 19-year-old girl with Mowat–Wilson syndrome. Note the thick eyebrows, hypertelorism, deep-set eyes, prominent nasal bridge and particularly prominent nasal tip with overhanging columella, open mouth and prominent chin. There are also characteristic uplifted earlobes. 

Securing a specific diagnosis spares unnecessary further investigations and clarifies the prognosis and other implications for the health of the patient. We have illustrated nine conditions in which it is possible to make a clinical diagnosis in adults presenting to an epilepsy clinic, where characteristic facial features provide the strongest clue. In future, advances in genetic testing will allow a much better understanding of the genetic basis of syndromic and non-syndromic epilepsies. It is important for neurologists, as the main physicians caring for this group of patients, to keep up to date with developments in the field of epilepsy genetics.

Courtesy of: http://www.medscape.com/viewarticle/860709_5?nlid=107148_3001