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When the face says it all: dysmorphology in identifying syndromic causes of epilepsy
  1. Abhijit Dixit,
  2. Mohnish Suri
  1. Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK
  1. Correspondence to Dr Mohnish Suri, Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK; mohnish.suri{at}nuh.nhs.uk

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.

  • EPILEPSY
  • Syndromes
  • Dysmorphic features
  • Diagnosis
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Introduction

Epilepsy is one of the commonest diagnoses that neurologists make. This is no surprise as the lifetime cumulative incidence of epilepsy is about 3%.1 Epilepsy can result from acquired environmental factors such as trauma, infection or stroke, but a genetic contribution has always been suspected. Helbig et al's2 review gives an insightful discussion of the role of genetic factors in various epilepsies. Advances in molecular genetic techniques have led to the identification of a number of genes where mutations cause various epilepsy syndromes.3 The role of large-scale variation in human genomic DNA sequence (deletion or duplication) in causing genetic generalised epilepsies (GGEs) is also increasingly being recognised.4

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.

Definitions of selected terms (italicised in the paper) are provided in Box 1. 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:

  1. Many adults with intellectual disability have not had aCGH analysis.

  2. 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.

Developments in genetic testing have revolutionised the process of clarifying the genetic basis of neurological disorders and we conclude with a brief discussion of the role of currently available genetic testing in patients with epilepsy.

Clinical approach

Table 1 summarises the main features (inheritance pattern, gene, locus, main clinical features and neuroimaging findings) of epilepsy syndromes that are associated with distinctive facial features. This section highlights aspects of history and physical examination that should help clinicians to find the specific clues that relate to several genetic conditions (box 1).

Table 1

Genetic basis, clinical features and neuroimaging findings of epilepsy syndromes associated with distinctive facial features in adult patients

Box 1

Definitions of selected terms

CGH: Comparative genomic hybridisation is a technique that allows the detection of losses (deletions) and gains (duplications/triplications, etc) in DNA copy number across the entire genome. This technique cannot detect point mutations within genes

Derivative chromosome: An abnormal chromosome comprising segments from two or more chromosomes joined together as a result of a translocation or other rearrangement

Heterozygous (mutation or deletion): Mutation or deletion involving only one of two copies of the gene

Interstitial deletion (or duplication): A deletion (or duplication) that does not involve the ends of the chromosome

Microdeletion syndrome: A syndrome caused by a chromosomal deletion encompassing several genes that is too small to be detected by conventional cytogenetic karyotyping

Next-generation sequencing: A laboratory technique that allows millions of small fragments of DNA to be sequenced simultaneously. This allows several genes (eg, a panel of genes linked to a specific phenotype) to be analysed as a single test

Subtelomeric region: The chromosomal region just proximal to the telomere (end of the chromosome) comprising highly polymorphic repetitive DNA sequences that are typically located adjacent to gene-rich areas

Trinucleotide repeat: Sequences of three nucleotides repeated in tandem on the same chromosome a number of times. A normal, polymorphic variation in repeat number with no clinical significance commonly occurs between individuals; however, repeat numbers over a certain threshold can, in some cases, adversely affect the gene function, resulting in genetic disease

Whole-exome sequencing: A laboratory technique that sequences all the protein-coding regions (exons) of all genes. The exome comprises only 1% (about 30 million base pairs) of the total genome but it contains the vast majority of pathogenic mutations

Whole-genome sequencing: A laboratory technique that determines the DNA sequence of the entire genome (about 3.3 billion base pairs) as a single test

History

People with intellectual disability have a higher likelihood of a genetic cause for epilepsy. Many people affected with the conditions discussed below have moderate-to-severe intellectual disability, although there are some exceptions where the degree of learning disability can be mild, such as Kabuki, Koolen–deVries and Sotos syndromes, and some people with the 1p36 deletion. The onset of seizures in almost all the conditions described is in childhood but the seizure semiology does not usually help in making a specific diagnosis. Seizure control is not usually challenging although in those with 1p36 deletion, Mowat–Wilson and Nicolaides–Baraitser syndromes, the seizures can be difficult to control. A history of congenital anomalies or other medical problems can provide useful diagnostic clues. For example, pulmonary valve abnormalities and Hirschsprung's disease are very common in Mowat–Wilson syndrome. Structural cardiac defects are also common in patients with 1p36 deletion, Kleefstra and Kabuki syndromes. On the other hand, people with Angelman, Rett, Pitt–Hopkins and Nicolaides–Baraitser syndromes typically have no congenital anomalies.

Family history

The conditions described below are most likely occur sporadically as they usually result from a de novo heterozygous mutation. The only disorder in which there might be a family history is Coffin–Lowry syndrome, as it is X linked; women with the gene can be mildly affected or even completely normal. An affected individual will, in theory, have a 50% chance of passing the condition to their children, since there is a heterozygous mutation in an autosomal gene. Most conditions, however, result in a degree of intellectual disability that would make having children unlikely.

Physical examination

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.5–7 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).

Genetic syndromes

1p36 deletion syndrome

The clinical phenotype of 1p36 deletion syndrome was describe in detail in 1997.8 The widespread use of aCGH technology in the last decade has led to the identification of many more cases of this condition and the incidence is estimated at between 1:5000 and 1:10 000 births. The clinical presentation is distinctive, although the size and location of the deletion within the 1p36 region and mechanism of origin of the deletion are variable. Just over 50% of patients have an isolated subtelomeric deletion; other findings in decreasing order of frequency include interstitial deletions, complex rearrangements (multiple deletions or deletions with duplications, triplications, insertions and/or inversions) or a derivative chromosome 1 resulting from an unbalanced translocation.9

Affected individuals usually present with severe to profound intellectual disability, although 10% may have only mild-to-moderate cognitive impairment. Seizures occur in 50% of those with 1p36 deletion syndrome and usually start in early childhood. Loss of the KCNAB2 gene, encoding the potassium channel beta-subunit gene, is thought to correlate with severe epilepsy and infantile spasms in patients with this condition,10 although intractable epilepsy can occur in patients who are not deleted for this gene.11 Initial seizures can be of almost any type, although 20% have a history of infantile spasms associated with hypsarrhythmia on EEG during childhood. Many children respond well to antiepileptic treatment. Bahi-Buisson et al12 reported the long-term outcome in 53 people with 1p36 deletion and observed that 19/53 (36%) developed drug-resistant epilepsy, particularly if there was a history of infantile spasms and especially when these had not been treated with corticosteroids.

The facial features of 1p36 deletion patients are recognisable in childhood and remain so in adults as well (figure 1). These include microbrachycepahly, straight eyebrows, deep-set eyes, midface retrusion, long philtrum, pointed chin and posteriorly rotated, low-set ears.

Figure 1

A teenage girl with 1p36 deletion syndrome. Note straight eyebrows, deep-set eyes and midface retrusion. Reproduced from Gajecka et al9 Copyright 2007 with permission from John Wiley and Sons.

Apart from intellectual disability and epilepsy, the other major features of 1p36 deletion include hypotonia, ophthalmic abnormalities (strabismus, nystagmus and refractive errors), sensorineural hearing loss and structural heart malformations. Non-specific findings on neuroimaging include dilatation of lateral ventricles and subarachnoid spaces, cortical or diffuse brain atrophy and corpus callosum anomalies.

Coffin–Lowry syndrome

This is an X linked disorder in which affected men typically have severe or profound intellectual disability. Heterozygous women can range from normal to profoundly intellectually disabled. About 25–40% of people with a clinical diagnosis of Coffin–Lowry syndrome have pathogenic mutation in RPS6KA3 (present at Xp22.12).13 It is not known whether mutations in other genes also cause Coffin–Lowry syndrome or if the other patients actually have a different condition with an overlapping phenotype. There are no formal estimates of the prevalence of Coffin–Lowry syndrome, but experts believe it may be 1:40 000–1:50 000.

Seizures occur in only a small proportion (about 5%), but the occurrence of stimulus-induced drop episodes (SIDEs) may lead to referral to an epilepsy or movement disorder clinic. SIDEs occurred in 20% (34/170) on a survey of members of a Coffin–Lowry syndrome support group.14 The age of onset of SIDEs ranges from 4 to 17 years with a mean age at onset of 8.6 years.15 They are precipitated by an unexpected tactile or auditory stimulus or excitement and result from a 60 to 80 ms electromyographic silence in the lower limbs, causing a brief collapse without any loss of consciousness.16

The facial appearance is recognisable in the older boy or adult man. The forehead and supraorbital ridges are prominent and the eyebrows are thick. The eyes are widely spaced (hypertelorism) and palpebral fissures are downward slanting. The ears may be prominent. The nasal bridge is depressed, the nasal tip is blunt and the alae nasi and septum are thick, making the nares rather small. The lips appear full and the mouth is usually held open. The facial appearance in childhood is coarse and the features coarsen further with age. Examination of hands often provides further supportive findings. The hands appear short and feel soft and fleshy. The fingers are tapering and appear wide proximally and narrow distally and can be very hyperextensible. There may be a short horizontal palmar crease across the hypothenar area. Heterozygous women can have a similar facial and hand phenotype or a less obvious facial phenotype with the characteristic soft, tapering fingers. Figure 2 shows facial and hand photographs of a heterozygous female carrier.

Figure 2

A 29-year-old female carrier of Coffin–Lowry syndrome. The facial appearance is more subtle than an affected adult man. Note mild hypertelorism, blunt nasal tip with a thick nasal septum, full lips, open mouth and prominent ears (A). Hand photograph of the same patient showing short, tapering fingers (B).

Affected individuals are often short and develop progressive kyphoscoliosis. There may be cardiac valvular abnormalities and/or hearing loss in a few cases.

Kabuki syndrome

This condition's name derives from the facial resemblance to the make-up worn by performers in a traditional Japanese theatrical art form. About two-thirds of patients have a heterozygous mutation in KMT2D at 12q13.12 and fewer than 5% have the X linked form of Kabuki syndrome with a mutation in KDM6A at Xp11.3. The genetic basis of Kabuki syndrome in the remaining patients is not yet known. The prevalence of Kabuki syndrome in Japan is estimated at 1:32 000 and this figure probably applies to the rest of the world as well.

Kabuki syndrome is eminently recognisable in childhood and many affected children will already have received the diagnosis. Even in adulthood, the facial phenotype remains recognisable (figure 3). The palpebral fissures are long and the lower eyelids appear everted laterally. The eyebrows are often arched and laterally sparse with a notch in the middle. The ears are usually large, prominent or cupped, and often anteverted. The hands show persistence of fetal fingertip pads. Rarely, the lower lips have paramedian lip pits. Most affected people have only mild or moderate intellectual disability and are described as being pleasant and outgoing. Patients with Kabuki syndrome may have various congenital anomalies. About a third have left-sided obstructive cardiac anomalies, such as coarctation of aorta, bicuspid aortic valve, hypoplastic left heart, mitral or aortic stenosis and Shone complex.17 Other congenital anomalies include renal malformations and cleft lip and/or palate. Additional clues to the diagnosis in the past history include recurrent infections often with hypogammaglobulinaemia and/or autoimmune disorders.

Figure 3

A 22-year-old man with Kabuki syndrome. Note the interrupted eyebrows and long palpebral fissures (A). Hand photograph of the same patient showing persistent fetal pads at the fingertips (B).

Epilepsy occurs in about 25% of people with Kabuki syndrome. There are at least two series describing their seizure semiology and outcome.18 ,19 Most respond well to treatment.

Kleefstra syndrome

Kleefstra syndrome results from a microdeletion at 9q34.3 or a mutation in EHMT1 within this region. Three-quarters of patients have a microdeletion while the remainder have an EHMT1 mutation. Its incidence and prevalence are unknown, but subtelomeric 9q deletions were initially described only in the 1990s and EHMT1 was identified as the critical gene in 2006.20

The degree of intellectual disability ranges from moderate to severe. Willemsen et al21 noted that 26/80 (32.5%) of patients with Kleefstra syndrome had epilepsy. The seizure types include tonic–clonic, absence and complex partial epilepsy.

An emerging observation as diagnosed individuals have got older is the appearance of a progressive apathy syndrome in adults with Kleefstra syndrome.22 ,23 Younger patients with Kleefstra syndrome have severe expressive speech problems but understanding of language is at a higher level, making non-verbal communication possible. With the onset of this progressive apathy syndrome, there is a gradual loss of previously acquired skills, progressive immobility and severe deterioration of motivational abilities. This is accompanied by marked sleep disturbances and also abnormal posturing of the upper limbs when awake.

The facial gestalt of Kleefstra syndrome is characterised by microcephaly, synophrys, unusual (arched or straight) eyebrows, hypertelorism, mildly upslanted palpebral fissures, full and everted lower lip, protruding tongue, midface retrusion and prognathism of the lower jaw (figure 4). With advancing age, the facial features tend to appear coarser and the prognathism becomes more obvious.

Figure 4

An 18-year-old girl with Kleefstra syndrome. Note the hypertelorism, full and everted lower lip, protruding tongue, midface retrusion and prognathism of the lower jaw.

Other common clinical features include obesity, structural heart defects and genital anomalies in men.

Koolen–deVries syndrome

This condition usually results from a heterozygous microdeletion of 500–650 kb at 17q21.31. It is increasingly recognised that a proportion of cases have a point mutation in KANSL1, which is the critical gene within the region24 ,25 and, therefore, the suggested new nomenclature is KANSL1-related intellectual disability syndrome. An indirect estimate suggested a prevalence of 1:16 000,26 but this may be an overestimate; there are no reliable available figures.

Intellectual disability in Koolen–deVries syndrome is usually in the mild-to-moderate range and behaviour tends to be friendly and amiable. About 55% of affected people have epileptic seizures. Many patients have generalised seizures but information about their long-term outcome is not known.

Distinctive facial features are obvious from mid-childhood onwards (figure 5). These include broad forehead, small palpebral fissures that usually slant upwards, prominent ears, bulbous or tubular nose and everted lower lip. Many individuals have cutaneous abnormalities, including patches of hyperpigmentation and multiple naevi.27 There is often also an unusual texture or pigmentation of the hair (figure 5). Skin and hair findings in the context of suggestive facial features strongly suggest Koolen–deVries syndrome. Hypotonia occurs from early childhood and other common features include joint hypermobility, renal and urological anomalies and undescended testes in men.

Figure 5

An 11-year-old boy with Koolen–deVries syndrome (A). Note hypertelorism, upslanting palpebral fissures, tubular nose and everted lower lip. Supportive skin and hair findings in the photograph include an unusual number of cutaneous naevi, patchy pigmentation over skin on the right side of the neck and variable pigmentation of scalp hair. A 19-year-old boy with Koolen–deVries syndrome (B and C) with narrow, upslanting palpebral fissures, bulbous nasal tip, everted lower lip and cutaneous naevi.

Mowat–Wilson syndrome

This is caused by heterozygous mutations or deletions of ZEB2 located at 2q22.3. The first clear clinical description of this condition was published in 1998, with a report of six unrelated children with a distinctive facial phenotype, learning difficulties and Hirschsprung's disease in five out of six patients.28 ZEB2 was identified as the responsible gene within the next few years and almost all patients with a clear clinical diagnosis of Mowat–Wilson syndrome have a pathogenic ZEB2 mutation. It is a relatively rare condition with an estimated prevalence between 1:50 000 and 1:70 000 live births.

All affected people have moderate-to-severe intellectual disability and severely impaired language abilities. Mowat–Wilson syndrome was originally described as a syndromic form of Hirschsprung's disease, but only half of patients have this proven on biopsy. Many have chronic constipation. Other common medical problems include structural heart defects, particularly pulmonary valvular or pulmonary artery anomalies,29 and genitourinary malformations in both sexes. Nearly half have absence or hypoplasia of the corpus callosum.

Seizures occur in three-quarters of affected individuals.30 ,31 Cordelli et al31 published detailed electroclinical phenotype of epilepsy in Mowat–Wilson syndrome in 22 patients. Seizure onset occurred at a median age of 14.5 months (range 1–108 months); focal and atypical absence seizures were the most frequent seizure types. An interesting but mechanistically plausible observation was the reduced likelihood of atypical absences and bilateral synchronisation of EEG discharges in patients with complete agenesis of corpus callosum. Epilepsy proved difficult to treat, as reflected by use of a median of three antiepileptic drugs per patient and achievement of seizure freedom in only nine out of 20 treated patients.

The facial appearance is recognisable in young children, but the phenotype becomes even more pronounced with age (figure 6). Affected individuals often have hypertelorism, deep-set eyes, uplifted earlobes with a central depression (shape of the lobule likened to ‘orecchiette’ pasta or the erythrocyte) and prominent, triangular chin. The mouth is usually held open and the nasal tip is prominent. In the older child and adult, the nasal tip tends to lengthen and overhang, the face elongates further and the chin is even more prominent.

Figure 6

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. The photo showing frontal view of face has been reproduced from Zweier et al,43 Copyright 2005 with permission from Elsevier SAS.

Nicolaides–Baraitser syndrome

The genetic basis of this condition was established recently with identification of heterozygous mutations in SMARCA2 in clinically diagnosed patients.32 The prevalence is unknown, but a recent review paper described the clinical and genetic findings in 61 individuals.33

Sparse hair, characteristic facial features and typical hand findings in the context of intellectual disability, epilepsy and short stature make Nicolaides–Baraitser syndrome highly recognisable, particularly in the older child or adult. Figure 7 shows facial photographs of the original patient at different ages. The extent of intellectual disability can be variable. Epileptic seizures occur in two-thirds and are sometimes difficult to control.

Figure 7

The original woman with Nicolaides–Baraitser syndrome at 6, 11 and 32 years. In the adult photographs, note the aged appearance, sparse eyebrows and nearly absent scalp hair, prominent infraorbital grooves, broad nasal tip, thick and flared alae nasi, wide mouth, thick and everted lower lip and widening of the lower third of the face. Reproduced from Sousa et al,44 Copyright 2009 with permission from John Wiley and Sons.

The typical facial features include triangular shape head, upturned nose with thick nares, thin upper lip, thick lower lip and wide mouth. There is often loss of facial subcutaneous fat with age and an adult may have sunken infraorbital region with wrinkled skin. The lower jaw tends to get wider with age. The hair may start becoming sparse in childhood, but this is a nearly universal finding in adults. Microscopic examination of hair is usually normal. The hands are often normal in young children, but the small hand joints become stiffer with age, accompanied by characteristic prominence of interphalangeal joints.

Pitt–Hopkins syndrome

This results from heterozygous mutations in TCF4 at 18q21.2 or deletions involving this gene. The first description was in 1978, but the genetic cause was delineated only in 200734 and the exact prevalence is unknown. Empirical estimates indicate that Pitt–Hopkins syndrome may occur in 1:11 000 births.

Intellectual disability is universal in Pitt–Hopkins syndrome and is usually moderate to severe. Speech development is significantly impaired; only some patients have a few words but most remain non-verbal.

The GeneReviews monograph provides a good summary of the clinical phenotype.35 Constipation is common, but the vast majority of those with Pitt–Hopkins syndrome have no congenital malformations. The neurobehavioural features and the presence of a characteristic facial phenotype, however, allow the clinical diagnosis to be suspected. Around 60% have distinctive episodes of hyperventilation, sometimes followed by breath holding, usually starting in the second half of the first decade but may be later. Anxiety and/or excitement are common triggers and the episodes do not occur in sleep. The clinician should actively elicit the history of breathing abnormalities if there is clinical suspicion of Pitt–Hopkins syndrome as parents or carers may not volunteer these. The episodes sometimes resolve after a few months, but in others may persist for several years. Many patients also show hand stereotypies and stereotypical head movements such as head rolling or rotation.

Seizures reportedly occur in 40–50% of patients. On average, the onset is in mid-childhood but ranges from early infancy to 18 years and there is good response to antiepileptic drugs. The seizures are not associated with the breathing abnormalities. Neuroimaging may be normal or show non-specific findings, including corpus callosum abnormalities and/or ventricular dilatation.

The characteristic facial features of Pitt–Hopkins syndrome typically become more obvious with age (figure 8). These include deep-set eyes, slightly upslanting palpebral fissures, wide nostrils, short philtrum, full and often everted lower lip, wide mouth with tented or cupid's bow upper lip in some individuals and prominence of the lower face, particularly the chin.

Figure 8

A 17-year-old girl with Pitt–Hopkins syndrome. Note the deep-set eyes, high nasal bridge, overhanging nasal tip, short philtrum, cupid's bow-shaped upper lip and prominent lower face. Reproduced from Zweier et al,45 Copyright 2008 with permission from BMJ Publishing Group Ltd.

Sotos syndrome

NSD1, located at 5q35, is the causative gene for Sotos syndrome; most affected patients have a heterozygous mutation or deletion involving this gene. It is estimated to occur in 1:14 000 live births.

The cardinal features, present in at least 90%, include intellectual disability, overgrowth and characteristic facial features. Tatton-Brown et al36 published the largest series of Sotos syndrome (over 250 patients) with NSD1 mutations or deletions. The spectrum of learning disability is broad, but most patients have a disability in the mild–moderate range. Overgrowth starts prenatally with above average length and head circumference at birth. The height and head circumference are over 2 SDs above mean by the age of 10 years. The height in affected adults falls over a broad range and all adults are not unusually tall. Epilepsy occurs in 25% of patients. In a report describing seizures in 19 patients with Sotos syndrome, the authors observed tonic–clonic, absence and temporal lobe seizures.37 Most people responded well to a single antiepileptic medication.

The typical facial appearance in childhood includes a dolichocephalic head with prominent forehead and sparseness of hair in the frontotemporal regions. The palpebral fissures are downslanting and the chin is long and pointed. The facial appearance remains recognisable in adults (figure 9); the chin tends to get square with age. In a review of the phenotype in 21 adults with Sotos syndrome, the head circumference was above the 97th centile in 18/21 (86%) patients.7 The mean height in men was 75th centile and that in women was 97th centile.

Figure 9

A 27-year-old woman with Sotos syndrome. Note the high forehead, slightly sparse hair in frontotemporal regions, hypertelorism, thick eyebrows and prominent, pointed chin. Photograph courtesy of Dr Trevor Cole, Birmingham, UK.

Investigations

Neurologists are likely to encounter one or more of these conditions in their practice. If a specific genetic condition is strongly suspected based on the clinical presentation and facial phenotype, targeted analysis of the relevant gene is the most efficient way to secure the diagnosis. Advice could be sought, if required, from clinical genetics colleagues to determine the best strategy to test for the specific condition. Some general principles are outlined below:

  1. aCGH:

    1. Detailed chromosome analysis by aCGH testing should be performed in all individuals with epilepsy and concomitant intellectual disability. Recurrent microdeletions at 15q13.3, 15q11.2 and 16p13.11 are enriched in individuals with GGEs, and the association is stronger in individuals with both epilepsy and intellectual disability.38 These microdeletions are much more common than the genetic syndromes described above, but epilepsy occurs in only a small proportion of patients. The overall presentation is non-specific and requesting aCGH is the only way to identify these patients. Other copy number variants associated with neurodevelopmental disorders may also be identified on aCGH.

    2. Three of the above described conditions (1p36 deletion, Koolen–deVries and Kleefstra syndromes) will be identified by aCGH but specific molecular genetics analysis of KANSL1 (for strong clinical suspicion of Koolen–deVries syndrome) or EHMT1 (for suspected Kleefstra syndrome) will have to be requested separately if aCGH is negative. A small proportion of patients with Pitt–Hopkins syndrome have a deletion involving the TCF4 and some with Mowat–Wilson have a ZEB2 deletion; this group of patients may be identified by aCGH.

  2. Multigene panel analysis:

    This approach allows identification of the underlying cause for broad phenotypic categories such as epilepsy or peripheral neuropathy when there is no clear clinical diagnosis. Multiple genes can be analysed simultaneously by next-generation sequencing methods and clinically relevant findings are reported back to the referring clinician. At present, two molecular genetics labs in the UK offer multigene panels for severe epilepsy ( http://ukgtn.nhs.uk/). There are around 50 genes on each of these panels and most are associated with a severe epilepsy phenotype with onset in early childhood. EHMT1, TCF4 and ZEB2 are included in one of the panels, but the other panel has none of the single genes related to the conditions discussed above.

Angelman syndrome is worth mentioning, since it is a well-recognised cause of recurrent seizures in the context of severe intellectual disability. It will often have been diagnosed in childhood on the basis of characteristic developmental history and behavioural features. The facial features are sometimes suggestive in Angelman syndrome, but are not characteristic enough to make the diagnosis without supportive neurobehavioural features. Its genetic basis is complex and specific molecular genetic testing needs to be requested to confirm the diagnosis.

Fragile X syndrome is a common cause of intellectual disability in men, but epilepsy is not a major feature. Partial-onset seizures occur in 10–20% of affected people. It is worth pointing out that the genetic mechanism of fragile X syndrome is abnormal expansion of a CGG trinucleotide repeat and aberrant methylation of FMR1, resulting in loss-of-function of this gene. This requires a specific test and will not be picked up on aCGH or analysis of panel of epilepsy genes. However, most children with developmental delay and/or intellectual disability would almost certainly have had the molecular test for fragile X syndrome as part of their diagnostic work-up in childhood.

In a research setting, powerful technologies for interrogating the genome such as whole-exome sequencing and whole-genome sequencing (WGS) have been used to identify novel genetic causes of neurodevelopmental disorders.39 ,40 Whole-exome sequencing is also now becoming affordable and feasible in the clinical diagnostic setting for various clinical scenarios.41 It is also increasingly apparent that genes and copy number variants initially identified in the context of one syndrome may subsequently be found to have broader applicability within other epilepsy syndromes or neurodevelopmental disorders.42 The 100,000 Genomes Project, funded by the UK Department of Health, launched in England in 2015 ( http://www.genomicsengland.co.uk/the-100000-genomes-project/) and will offer WGS to over 15 000 National Health Service patients with rare diseases, including neurological disorders.

Conclusions

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.

Key points

  • Some genetic conditions associated with epilepsy with intellectual disability have a recognisable gestalt.

  • Typical facial features with other supportive findings on physical examination and growth features are often enough to make a clinical diagnosis.

  • All patients with epilepsy and intellectual disability should have array-comparative genomic hybridisation analysis.

  • Clinicians should consider multigene panel testing in the diagnostic evaluation of severe epilepsy.

Acknowledgments

We thank Dr Trevor Cole for providing figure 9 and also all the patients and/or their guardians for their consent to publish the photographs.

References

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Footnotes

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Helen Cross, London, UK.

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