CLINICAL REPORT

Goldberg–Shprintzen Megacolon Syndrome with Associated Sensory Motor Axonal Neuropathy Hormos Salimi Dafsari,1 Susan Byrne,1 Jean-Pierre Lin,1 Matthew Pitt,2 Jan D. H. Jongbloed,3 Frances Flinter,4 and Heinz Jungbluth1,5,6* 1

Department of Paediatric Neurology, Evelina’s Children Hospital, Guy’s & St. Thomas’ Hospital NHS Foundation Trust, London, UK

2

Department of Neurophysiology, Great Ormond Street Hospital for Children, London, UK Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands

3 4

Department of Clinical Genetics, Guy’s Hospital, London, UK

5

Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King’s College, London, UK Department of Basic and Clinical Neuroscience, IoPPN, King’s College, London, UK

6

Manuscript Received: 13 June 2014; Manuscript Accepted: 20 October 2014

Goldberg–Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprung’s disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7-year-old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279-related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function. Ó 2015 Wiley Periodicals, Inc.

Key words: Goldberg–Shprintzen megacolon syndrome

(GOSHS); KIAA1279 gene; sensory motor axonal neuropathy; neurocristopathies

INTRODUCTION In 1981, Goldberg and Shprintzen reported two children with features of Hirschsprung’s disease, learning difficulties, short stature, microcephaly and characteristic facial dysmorphism [Goldberg and Shprintzen, 1981]. Additional cases with a similar combination of suggestive clinical features were subsequently identified, resulting in the designation of the disorder as Goldberg–Shprintzen syndrome or Goldberg–Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) [Yomo et al., 1991], in order

Ó 2015 Wiley Periodicals, Inc.

How to Cite this Article: Dafsari HS, Byrne S, Lin J-P, Pitt M, Jongbloed JDH, Flinter F, Jungbluth H. 2015. Goldberg–Shprintzen megacolon syndrome with associated sensory motor axonal neuropathy. Am J Med Genet Part A 167A:1300–1304.

to avoid confusion with the distinct but similarly named Shprintzen omphalocele (OMIM #182210) and Shprintzen–Goldberg craniosynostosis syndromes (OMIM 182212). In 2005, GOSHS was attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP). To date, only six families affected by GOSHS have been genetically resolved. In addition to the core clinical features already included in the original description, the phenotypical spectrum of KIAA1279-related GOSHS has further expanded and now includes ocular features, such as ptosis, iris coloboma [Brooks et al., 1999; Brooks et al., 2005] and megalocornea [Dre´villon et al., 2013], as well as cardiac, urogenital and skeletal abnormalities [Dre´villon et al., 2013]. GOSHS shares many features with Mowat–Wilson syndrome (MWS) (OMIM 235730) [Mowat et al., 1998], but the facial appearance in GOSHS is distinct from MWS; seizures, which Hormos Salimi Dafsari and Susan Byrne contributed equally. Conflict of interest: none.
Correspondence to: Dr Heinz Jungbluth, Children’s Neurosciences Centre, F01–Staircase D South Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 April 2015 DOI 10.1002/ajmg.a.36873

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DAFSARI ET AL. are common in MWS, are not a feature. Baraitser–Winter syndrome (BWS) (OMIM 243310) [Baraitser and Winter, 1988] is another condition that shares many manifestations with GOSHS except one of the defining features, Hirschsprung disease. Neurological features of GOSHS continue to emerge and are characterized by structural central nervous system abnormalities, in particular polymicrogyria and, less frequently, callosal agenesis [Dre´villon et al., 2013]. Peripheral nervous system abnormalities in GOSHS have not been reported to date. Here we report on clinical, neurophysiological and genetic features from a 7-year-old girl with typical features of GOSHS, referred with the suspicion of an underlying neuromuscular disorder because of features of developmental delay, hypotonia, fatigable ptosis and blepharospasm.

CLINICAL REPORT This girl was the third child of consanguineous Asian parents who were first degree cousins. Her parents and two older siblings were healthy and there was no family history of neurological or neuromuscular disorders. She was delivered by normal vaginal delivery at term following an uneventful pregnancy. At birth, she was found to have microcephaly (head circumference 12 >48 >30 >52

nt nt 7.2 29 nt absent

>30 >55

2.0 3.0 35 3.0 2.71 55

>1.5 >3.0 >40 >3.0 >2.5 >45

1.66 3.25 29 nt nt nt

>1.5 >3.0 >43

10.2 25 Nt Nt