Article Text

Smith-Magenis syndrome and tetralogy of Fallot
  1. ELIZABETH SWEENEY
  1. Mersey Regional Clinical Genetics Service, Royal Liverpool Children’s Hospital, Alder Hey, Eaton Road, Liverpool L12 2AP, UK
  2. Department of Paediatric Cardiology, Royal Liverpool Children’s Hospital, Alder Hey, Eaton Road, Liverpool 12 2AP, UK
  3. Department of Genetics, Royal Manchester Children’s Hospital, Pendelbury, Manchester M27 1HA, UK
    1. IAN PEART,
    2. MAGDI TOFEIG
    1. Mersey Regional Clinical Genetics Service, Royal Liverpool Children’s Hospital, Alder Hey, Eaton Road, Liverpool L12 2AP, UK
    2. Department of Paediatric Cardiology, Royal Liverpool Children’s Hospital, Alder Hey, Eaton Road, Liverpool 12 2AP, UK
    3. Department of Genetics, Royal Manchester Children’s Hospital, Pendelbury, Manchester M27 1HA, UK
      1. BRONWYN KERR
      1. Mersey Regional Clinical Genetics Service, Royal Liverpool Children’s Hospital, Alder Hey, Eaton Road, Liverpool L12 2AP, UK
      2. Department of Paediatric Cardiology, Royal Liverpool Children’s Hospital, Alder Hey, Eaton Road, Liverpool 12 2AP, UK
      3. Department of Genetics, Royal Manchester Children’s Hospital, Pendelbury, Manchester M27 1HA, UK

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        Editor—The interstitial deletion of the short arm of chromosome 17 was first reported in 1982 by Smithet al 1 in two unrelated patients presenting with congenital heart defects and facial clefts. Since then a clinically recognisable phenotype has been described,2-8 including brachycephaly, midfacial hypoplasia, a broad, flat nasal bridge, prominent lower jaw, inverted V shaped upper lip with a prominent cupid’s bow, hoarse voice, speech delay, psychomotor and growth retardation, and behavioural problems which are often characteristic. Behavioural problems are present in most patients and include self-injurious behaviour such as hand biting, head banging, onychotillomania (pulling out finger and toenails), and polyembolokiolamania (the insertion of foreign bodies into body orifices).9 A characteristic self hugging behaviour has also been described.10 Hearing loss, ocular problems,11 12 scoliosis, and sleep disturbance13 also occur.

        The estimated frequency of cardiac lesions is 37%4 and those which have previously been described include atrial septal defects, ventricular septal defects, tricuspid and mitral valve stenoses or regurgitation, mitral valve prolapse, subvalvular aortic stenosis, and supravalvular pulmonary stenosis.2 4

        The estimated frequency of SMS is 1 in 25 000 but this may be an underestimate, as if the deletion is small it may be missed on routine cytogenetic analysis and may only be detectable by fluorescence in situ hybridisation (FISH).

        Diagnosis of SMS is often delayed until the characteristic physical and behavioural phenotypes become evident and diagnosis in an infant can be difficult, particularly for a non-geneticist. We report two cases who presented with similar cardiac defects and in whom the diagnosis was made on the basis of routine cytogenetic investigation before the phenotype had fully evolved.

        Patient 1 was born at 38 weeks’ gestation after an uneventful pregnancy weighing 2100 g (<3rd centile). His head circumference was 31.5 cm (<3rd centile). He was admitted to the neonatal unit as he was small for gestational age and hypothermic. He became cyanotic at 12 hours of age and an echocardiogram showed features of TOF with a patent ductus arteriosus.

        Subtle dysmorphic features were noted in the patient. He had a round face, brachycephaly, hypertelorism, low set ears, a flat nasal bridge, a prominent cupid’s bow, and a short philtrum (fig 1). He had deep creases on the palms of his hands and soles of his feet, and his finger tips were square. He had bilateral inguinal herniae.

        Cytogenetic analysis was requested by the cardiologists to exclude DiGeorge syndrome, but identified a microscopically visible deletion of the proximal short arm of chromosome 17. In situ hybridisation studies were consistent with a deletion within 17p11.2, confirming a diagnosis of SMS. Parental chromosomes were normal.

        His rate of growth is normal although he remains below the 3rd centile for weight. He has shown some signs of developmental delay. At 14 months he is sitting unsupported but not pulling to stand. He is alert, sociable, and vocalising but has no recognisable words. He has not yet encountered any problems with behaviour and has had no disruption of sleep pattern.

        The patient had a surgical correction of his congenital heart defect at the age of 9 months and is at present awaiting stenting of his left lower lobe pulmonary artery. Pulmonary valve replacement is planned to follow this.

        Patient 2 was born by elective caesarian section for breech presentation at 39 weeks’ gestation weighing 2730 g (25th centile). Her head circumference was 32 cm (9th centile) and length was 47.5 cm (9th centile). She was in good condition at birth and required no resuscitation. A systolic murmur was noted on her first day check and subsequently an echocardiogram confirmed TOF.

        Chromosome analysis was requested by the cardiologists, again to exclude DiGeorge syndrome. This patient also had a microscopically visible interstitial deletion of chromosome 17p11.2. FISH studies using the probe D17S258 confirmed a deletion in the region 17p11.2 known to be responsible for Smith-Magenis syndrome. Parental chromosomes were normal.

        This patient had dysmorphic features such as brachycephaly, a flat, wide nasal bridge, epicanthic folds, and a low set, prominent left ear. Her weight and head circumference have continued to follow the 10th centile. At the age of 1 year she began to manifest signs of developmental delay. She was still quite floppy, being unable to sit without support. Her hearing was normal on testing and she had two syllable babble. She smiled, was sociable and cooperative, and has not as yet had any problems with behaviour or sleep disturbance. An ophthalmology assessment has been normal apart from finding slight myopia. At the age of 18 months she was crawling but not yet walking. From the cardiac point of view, she has had her TOF repaired with an excellent result.

        There is a well known association between congenital heart disease and some interstitial chromosomal deletions, and chromosomal analysis is often requested by cardiologists to rule out deletions particularly of chromosome 22q11, characteristic of DiGeorge syndrome. This is the case with both of the patients we report. SMS is a syndrome which may not be well known to cardiologists and dysmorphic features may be subtle, making a clinical diagnosis difficult in an infant. It is fortuitous that the deletions in our patients were visible microscopically, as in some patients with SMS the deletion is not easily visible and the diagnosis would first have to be suspected and FISH for 17p11.2 be specifically requested. We suggest that SMS is a diagnosis worth considering in the differential diagnosis of children with congenital heart disease and appropriate dysmorphic features, even if initial routine cytogenetic analysis has been unfruitful. This may be particularly relevant to cardiologists who may not be familiar with the syndrome.

        It is also of interest that the heart lesion in our patients is not one that has previously been reported in association with SMS and we suggest that TOF should be considered as part of the spectrum of features which can be found in patients with SMS.

        It is not yet known whether children with deletions detectable only by FISH can be expected to have fewer problems than those with a cytogenetically visible deletion. It could be argued that a larger, visible deletion may involve more than just the genes in the critical region involved in the development of the classical SMS phenotype. If it was found that children with deletions visible only by FISH did have a milder phenotype, this would be useful in counselling parents.

        Our patients were diagnosed early, before the phenotype had fully evolved. If diagnosis is delayed parents may feel that they are in some way to blame for the behavioural problems encountered by their child. Early diagnosis would enable explanation of the condition so that parents could be aware of potential problems before they occur, although behavioural problems may be difficult to discuss with parents of a young baby. Early diagnosis would also enable discussion of recurrence risks and prenatal diagnosis as, even if the deletion appears de novo, the small risk of germline mosaicism remains.

        Acknowledgments

        The authors would like to thank Drs Alan Fryer and Ian Ellis for their help and advice.

        References

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