A memorable patient
Clinical and Experimental Dermatology
Noonan syndrome with multiple lentigines and associated
B. S. McDonald,
D. P. Kelsell,
E. A. O’Toole,
Department of Dermatology, Watford General Hospital, Hertfordshire Hospitals NHS Trust, Watford, Hertfordshire, UK;
Centre for Cell Biology and Cuta-
neous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; and
ester Centre for Genomic Medicine, Genetic Medicine, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
A 7-year-old boy ﬁrst presented to us for management
of severe atopic eczema. He had previously been diag-
nosed with asthma and multiple food allergies. At
birth, he had a small patent ductus arteriosus, which
closed within the ﬁrst month of life. At the age of
6 years, he had been diagnosed with sagittal synosto-
sis, which required surgical correction due to develop-
ment of raised intracranial pressure. He also had mild
learning difﬁculties, but was otherwise well.
Physical examination revealed hypertelorism, frontal
prominence of the forehead, a wide nasal bridge, low-
set ears and presence of pectus excavatum (Fig. 1a)
He had relative macrocephaly with growth retarda-
tion. He was also noted to have multiple lentigines
scattered over his trunk and extremities with a few
e-au-lait macules, which had been present
since the age of 6 years.
The patient was kept under follow-up. At the age of
8 years, he developed multiple guttate hypopigmented
macules (Fig. 1b) There was no family history of simi-
lar pigmentary abnormalities.
Referral to the Clinical Genetics department at this
point did not identify a unifying diagnosis, as karyo-
typing and sequencing of the FGFR2 and FGFR3 genes
(associated with craniosynostosis) gave normal results.
A diagnosis of neuroﬁbromatosis type 1 (NF1) was
considered unlikely because of the small size of the
e-au-lait macules and lack of neuroﬁbromas.
When the patient was aged 14 years, exome
sequencing was performed, which revealed a hetero-
zygous mutation in PTPN11:exon13:c.C1492T:
p.R498W (GenBank: NM_002834.3), previously
reported in association with NSML.
ﬁlaggrin mutation (c.2282delCAGT; p.S761Cfs*36;
GenBank accession no. NM_002016.1) was also
found. The patient’s parents and siblings tested nega-
tive for this mutation, indicating it as a de novo muta-
tion. The family was referred for genetic counselling.
The patient’s subsequent cardiac and hearing assess-
ments were normal.
NSML is one of the RASopathies, which are caused
by gene mutations in the RAS–mitogen-activated pro-
tein kinase (MAPK) pathway, which control cell prolif-
eration, differentiation, survival and death.
mutations occur in approximately 1 : 1000 live births.
The syndromes have overlapping phenotypic features,
but each may have more speciﬁc ﬁndings, such as
neuroﬁbromas in NF1. The RASopathies cause a rela-
tively mild congenital dysregulation of the RAS–MAPK
pathway, whereas more strongly activating mutations
are mainly or exclusively found as somatic mutations,
associated with cancer.
NSML is an autosomal dominant condition charac-
terized by lentigines, electocardiographic abnormali-
ties, ocular hypertelorism, pulmonary stenosis,
retardation of growth and sensorineural deafness.
The characteristic facial features are hypertelorism, ﬂat
nasal bridge, low-set and posteriorly rotated ears,
palpebral ptosis, pterygium colli, and redundant skin
on the neck. Cardiac defects occur in 85% of cases;
hypertrophic cardiomyopathy is the most commonly
reported, with only rare reports of patent ductus arte-
Mild intellectual impairment (30%), hearing
Correspondence: Dr Bryan S. McDonald, Department of Dermatology,
Watford General Hospital, Hertfordshire Hospitals NHS Trust, Vicarage
Road, Watford, Hertfordshire, WD18 0HB, UK
Conﬂict of interest: the authors declare that they have no conﬂicts of
Accepted for publication 21 May 2017
ª 2018 British Association of Dermatologists Clinical and Experimental Dermatology (2018) 43, pp357–359