Human MutationRAPID COMMUNICATION
Germline Gain-of-Function Mutations of ALK Disrupt
Central Nervous System Development
Loı¨c de Pontual,1,2 Dania Kettaneh,1 Christopher T. Gordon,1 Myriam Oufadem,1 Nathalie Boddaert,3 Melissa Lees,4
Laurent Balu,5 Eric Lachassinne,2 Andy Petros,6 Julie Mollet,9 Louise C. Wilson,4 Arnold Munnich,1,7 Laurence Brugie`re,8
Olivier Delattre,9 Michel Vekemans,1,7 Heather Etchevers,1 Stanislas Lyonnet,1,7 Isabelle Janoueix-Lerosey,9
and Jeanne Amiel1,7
1Universite´ Paris Descartes, INSERM U-781, Paris, France; 2Service de Pe´diatrie, Hoˆpital Jean Verdier, AP-HP, Bondy, France; 3Service de
Radiologie Pe´diatrique, INSERM U-1000, Hoˆpital Necker-Enfants Malades, AP-HP, Paris, France; 4Department of Clinical Genetics, Great-Ormond
Street Hospital for Children, London, United Kingdom; 5Service de Re´animation Pe´diatrique, Hoˆpital Biceˆtre, AP-HP, Kremlin-Biceˆtre, France;
6Paediatric and Neonatal Intensive Care Unit, Great Ormond Street Hospital for Children, London, United, Kingdom; 7De´partement de Ge´ne´tique,
Faculte´ de Me´decine; AP-HP, Hoˆpital Necker-Enfants Malades, Paris, France; 8Service d’Oncologie Pe´diatrique, Institut Gustave Roussy, Villejuif,
France; 9INSERM U-830, Institut Curie, Paris, France
Communicated by Andrew O.M. Wilkie
Received 6 November 2010; accepted revised manuscript 21 December 2010.
Published online 18 January 2011 in Wiley Online Library (www.wiley.com/humanmutation). DOI 10.1002/humu.21442
ABSTRACT: Neuroblastoma (NB) is a frequent embryonal
tumor of sympathetic ganglia and adrenals with extremely
variable outcome. Recently, somatic amplification and gain-
of-function mutations of the anaplastic lymphoma receptor
tyrosine kinase (ALK) gene, either somatic or germline,
were identified in a significant proportion of NB cases. Here
we report a novel syndromic presentation associating
congenital NB with severe encephalopathy and abnormal
shape of the brainstem on brain MRI in two unrelated
sporadic cases harboring de novo, germline, heterozygous
ALK gene mutations. Both mutations are gain-of-function
mutations that have been reported in NB and NB cell lines.
These observations further illustrate the role of oncogenes
in both tumour predisposition and normal development,
and shed light on the pleiotropic and activity-dependent
role of ALK in humans. More generally, missing germline
mutations relative to the spectrum of somatic mutations
reported for a given oncogene may be a reflection of severe
effects during embryonic development, and may prompt
mutation screening in patients with extreme phenotypes.
Hum Mutat 32:272–276, 2011. & 2011 Wiley-Liss, Inc.
KEY WORDS: ALK; neuroblastoma; NB; neurodevelop-
ment; syndrome with cancer
Introduction
Neuroblastoma (NB; MIM] 256700) is the most frequent
extracranial solid tumour in children. Both familial cases with
vertical transmission, and predisposition in chromosomal and
monogenic syndromes, have long supported the involvement of
genetic factors. Several NB predisposing genes were recently
identified, such as PHOX2B, CREBBP, NSD1, HRAS, NF1, and
ALK. The last three genes encode proteins involved in the RAS/
MAPK pathway [Chiarle et al., 2008; Palmer et al., 2009] and ALK
is a downstream target of PHOX2B [Bachetti et al., 2010].
ALK (MIM] 105590), a tyrosine kinase receptor gene of the
insulin receptor family, is activated by fusion with various partners
in anaplastic large cell lymphomas, inflammatory myofibroblastic
tumors, and in some lung cancers [Chiarle et al., 2008]. Recently,
somatic amplification and gain-of-function mutations of ALK
were identified in about 2–4 and 7–10% of NB cases, respectively
[Chen et al., 2008; De Brouwer et al., 2010; Janoueix-Lerosey et al.,
2008; Mosse et al., 2008]. Germline gain-of-function mutations
have also been reported in half of the familial cases of NB tested
thus far [Janoueix-Lerosey et al., 2008; Mosse et al., 2008]. ALK is
preferentially expressed in the central and peripheral nervous
systems during development, but its role in the normal
development of the nervous system remains speculative [Hurley
et al., 2006; Iwahara et al., 1997; Vernersson et al., 2006]. Indeed,
familial ALK gain-of-function mutations predispose to isolated
NB, but are not associated with developmental anomalies, and
Alk/ mice have no obvious embryonic phenotype. However,
behavioral impairment has been described in the Alk/ mice, a
phenotype attributed to neurochemical alterations in the
hippocampi and basal cortex [Bilsland et al., 2008].
Here we report two unrelated cases with an association of
congenital NB and severe encephalopathy characterized by a
specific abnormal shape of the brainstem on brain magnetic
resonance imaging (MRI). In both cases we identified a
heterozygous, germline de novo missense mutation located in
the tyrosine kinase domain (TKD) of ALK at positions previously
identified as somatic mutational hot spots in NB and NB cell lines.
Patients and Methods
Case 1, a female, was the second child born to unrelated healthy
parents, aged 29 and 31 years at the time of birth, with no relevant
family medical history. She was born at term by Caesarean section
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Correspondence to: Jeanne Amiel, De´partement de Ge´ne´tique, Hoˆpital Necker-Enfants
Malades, 149 rue de Se´vres, 75743 Paris Cedex 15, France. E-mail: jeanne.amiel@inserm.fr

with normal birth parameters following an uneventful pregnancy
(birth weight [BW]: 3100 g, body length [BL]: 46 cm, occipito
frontal circumference (OFC): 34 cm). She was hypotonic, hypo-
motile, and presented with major feeding difficulties, no sucking
and swallowing reflexes, episodes of abdominal distension and
apneas. Mechanical ventilation and tube feeding were required. An
adrenal NB with pelvic extension was diagnosed at 3 days of life.
Levels of urinary catecholamine and its metabolites were raised.
Rapid tumor progression led to chemotherapy by vincristine and
cyclophosphamide with no improvement of the tumor mass or
catecholamine excretion. Boli of corticosteroids were delivered and
plasmapheresis performed with the hypothesis of a paraneoplasic
syndrome, but no neurological improvement was seen.
There was no congenital malformation or morphologic
abnormality at clinical examination except for a high arched
palate. Neurologic development was poor. She could fix and
follow with normal eye movements and remained hypotonic with
little spontaneous movements, sucking and swallowing were
absent, she experienced severe episodes of desaturation and
sweating, and she displayed hyperextension of the limbs.
A tracheostomy tube was inserted at 6 weeks of age. Osteotendinous
reflexes were present. A deceleration of the head circumference’s
growth was noticeable with an OFC of 39 cm (fifth centile) at
4 months. She died at age 4.5 months from a severe apnea with no
attempt at resuscitation. Necropsy was not performed.
The tumor was classified as stage 3 by histology [Brodeur et al.,
1993]. Neither MYCN amplification nor 1p36 deletion were
detected by FISH. No antineuronal antibodies were secreted in the
cerebral spinal fluid (CSF). A computerized tomography (CT)
scan showed no spinal cord compression. Meta-iodo-benzyl-
guanidine (MIBG) scintiscan showed no bone fixation. Electro-
myography and muscle histology were within the normal limits.
Electroencephalography (EEG) showed slow activity without
epilepsy. Auditory evoked potential was normal. Histological
examination of a rectal biopsy showed normal enteric plexuses
eliminating Hirschsprung disease as the cause of abdominal
distension. Blood karyotype and a comparative genomic hybridi-
zation (CGH)-array with a 650-kb resolution showed normal
chromosomes 46, XX. Brain magnetic resonance imaging (MRI)
was performed at 3 days and again at 15 weeks of age. At the latter
time point, an abnormal shape of the brainstem was noted with an
enlarged medulla oblongata eclipsing the ovoid form of the pons.
In retrospect, the same image was present from birth (Fig. 1A).
Case 2, a female, was the first child born to unrelated healthy
parents with no relevant family medical history. Intrauterine
growth retardation and sinusoidal cardiotocograph led to
emergency Cesarean section at 31 weeks gestation (BW 1300 g,
and a head circumference of 28.5 cm; both at approximately the
25th centile). Paternal and maternal ages at time of birth were 42
and 37 years, respectively. Hypotonia with little spontaneous
movements, poor sucking, gastrooesophageal reflux, and dis-
tended abdomen were noted at birth. She presented daily episodes
of desaturation and tracheobronchomalacia necessitating respira-
tory support and a tracheostomy tube was inserted at age 3
months. A thoracoabdominal CT scan at age 3 weeks showed
bilateral large heterogeneous and calcified adrenal masses. She
underwent four courses of chemotherapy leading to a reduction in
the size of the tumors, but a MIBG scintiscan showed uptake of
dye in the right hemithorax that was later confirmed by CT scan.
She had a patent foramen ovale with prolonged QT segments on
electrocardiography. Bilateral hernias were surgically repaired at
age 2 months. She was kept on nasogastric feeds for persistent
difficulties in swallowing. Intermittent abdominal distension
remained unexplained; a contrast enema showed no obstruction
and endoscopic intestinal biopsies were normal. Temperature
instability was also observed. At age 5 months, she developed
Figure 1. Brain MRI of the two patients and three controls. Note the abnormal shape of the brainstem with enlarged medulla oblongata
eclipsing the ovoid form of the pons (arrows) on brain MRI (T1-weighted sagittal images) in both cases (top) compared to controls (bottom,
arrowheads). A: Patient 1; B: patient 2; C: antenatal MRI of a control fetus at 34 weeks gestation; D–E: controls.
HUMAN MUTATION, Vol. 32, No. 3, 272–276, 2011 273

abnormal movements of the right arm and leg. Repeated EEGs
failed to show focal epileptiform activity and seizures arising from
the brainstem were hypothesized. Although initially normal,
cranial ultrasound showed an ischaemic cortical lesion on the
right inferior parietal lobe. Growth parameters had all fallen below
the 0.4th centile by age 5 months. At 9 months, she could fix, had
a left convergent squint with normal fundi, and responded to
sound. Sensory motor deficit was suspected. She died at age 9
months following a decision to withdraw intensive care. Necropsy
was not performed.
In retrospect, the brain MRIs performed at age 6 and 15 weeks
showed a brainstem shape very similar to that observed in case 1
(Fig. 1B). At histology, both adrenal biopsies showed infiltrating
islands of undifferentiated neuroblasts. FISH analysis identified
four copies of the MYCN gene, trisomy of chromosomes 1 and 9,
and tetrasomy of chromosome 17.
Blood samples for both cases were obtained with informed
consent and DNA was extracted according to standard
protocols. Direct sequencing of the ALK and PHOX2B genes was
performed on both strands as previously described using the Big
Dye Terminator Cycle Sequencing kit (Applied Biosystems,
Bedford, MA) and was analyzed on an ABI 3100 automated
sequencer.
Results
No nucleotidic variation of the PHOX2B gene was found.
A heterozygous variation of the ALK gene was identified in each case
(c.3733T4G, p.F1245V in case 1 and c.3520T4G, p.F1174V in case 2;
numbering is based on the cDNA sequence from NM_004304.3
(ALK_v001); Fig. 2). Each missense mutation altered a conserved
amino acid within the intracellular TKD of the protein at a position
already found mutated in several NB cell lines and tumours (reviewed
in [Palmer et al., 2009] and [Janoueix-Lerosey et al., 2010]). Both
mutations occurred de novo. A paternal contribution to the child
genotype was confirmed for nine unlinked and polymorphic CA repeat
microsatellite markers in case 1 and 2 (data available on request).
Discussion
In both cases described in this report, we identified a de novo
heterozygous germline ALK gene mutation. Importantly, mutations
Figure 2. ALK gene mutations. A: A constitutional heterozygous missense variation of the ALK gene having occurred de novo was identified
in each case (c.3733T4G, p.F1245V in case 1 and c.3520T4G, p.F1174V in case 2, with numbering based on the cDNA sequence from
NM_004304.3 (ALK_v001). There is no evidence that the ALK mutations are present in mosaic state. Indeed, mutant allele is not
underrepresented compared to wild-type allele. Residue F1245 is located in the catalytic loop and residue F1174 in the C helix of the TKD [Bossi
et al., 2010; Lee et al., 2010]. B: Published ALK mutations in NB (adapted from [Janoueix-Lerosey et al., 2010] with permission). Mutations are
indicated by arrows, with the number of mutations identified at each position to date indicated underneath. The mutations are mainly located
in the TK domain, with two hotspots at positions 1174 and 1275. [Color figure can be viewed in the online issue, which is available at
www.wiley.com/humanmutation.]
274 HUMAN MUTATION, Vol. 32, No. 3, 272–276, 2011

at position p.F1174 and p.F1245 have been reported already (with
substitution for I, C, V, and L amino acids in both cases), but were
invariably somatic [De Brouwer et al., 2010; Janoueix-Lerosey et al.,
2010; Palmer et al., 2009]. However, the missense mutations
p.G1128A, p.R1192P, and p.R1275Q, lying in the TKD of ALK, have
been reported in familial cases segregating NB predisposition with
incomplete penetrance and without presenting any neurological
symptoms, and have not been reported as somatic mutations
[Janoueix-Lerosey et al., 2008; Mosse et al., 2008]. Conversely, both
children reported here presented with multifocal NB of neonatal
onset and, severe, nonepileptic encephalopathy with a fatal out-
come. They were initially referred for possible central congenital
hypoventilation syndrome (CCHS, Ondine’s curse; MIM] 209880)
due to episodes of apnoeas and desaturation, abdominal distension,
and NB. However, these episodes were independent of the
sleep–wake state and direct sequencing of the PHOX2B gene failed
to identify a coding sequence mutation. Opsomyoclonic syndrome
had also been considered but electroencephalographic recordings
showed no epilepsy and eye movements were normal. Moreover,
plasmapheresis and corticosteroids did not lead to neurological
improvement. Compression by the abdominal mass and Hirsch-
sprung disease were also considered as explanations for the episodes
of abdominal distension. An alternative hypothesis is enteric
nervous system dysfunction given that Alk is expressed in the
developing gut in mice [Vernersson et al., 2006]. The brainstem
anomaly in the two patients reported here does not seem
progressive, although this could not be assessed fully, given that
both patients died at an early age. Nonetheless, the medulla
oblongata was enlarged from birth in both cases. The presence of
this feature upon brain MRI may be a good indication of an ALK
germline mutation in a newborn with severe encephalopathy and
brainstem dysfunction of unknown cause with or without NB.
Indeed, whether neonatal NB is a consistent feature of the
syndrome remains to be defined. The differential diagnosis would
be a tumor of the medulla (more often a pylocytic astrocytoma),
but enlargement would be asymmetric and presenting hypointen-
sity on T1-weighted images.
There is a sharp contrast between the brain phenotype of the
patients described in this report, and that of patients with Cardio-
Facio-Cutaneous syndromes, in which germline gain-of-function
mutations in several genes involved in the RAS signaling pathway
have been described, and for whom absolute or relative
macrocephaly is the rule (see [Tidyman and Rauen, 2009] for
review). This is particularly true for Costello syndrome, which is
ascribed to HRAS gain-of-function mutations, with amino acid
substitution hotspots at codons p.G12 and p.G13 [Aoki et al.,
2005]. Interestingly, a progressive enlargement of the cerebellum
leading to posterior fossa crowding and cerebellar tonsilar
herniation has been described in a majority of patients with
Costello syndrome, while the shape of the brainstem remains
normal [Gripp et al., 2010].
ALK is an extremely conserved tyrosine kinase receptor of the
insulin receptor family with Midkine and Pleiotrophin as putative
ligands in mammals. Ligand binding leads to ALK heterodimerisa-
tion, autophosphorylation, and activation of the RAS/MAPK,
phosphoinositide-3 kinase (PI3K)/AKT, JAK/STAT3, or PLCg
pathways, promoting proliferation, differentiation or survival
[Chiarle et al., 2008; Palmer et al., 2009; Wasik et al., 2009]. Fusion
proteins arising from somatic rearrangements have been reported in
anaplastic large cell lymphomas and other tumours (reviewed in
[Palmer et al., 2009]). In NB and NB cell lines, both ALK
amplification and gain-of-function missense mutations of con-
served codons of the TKD have been reported [Chen et al., 2008;
George et al., 2008; Janoueix-Lerosey et al., 2008; Passoni et al.,
2009]. Some experimental data indicate variable oncogenic
potential of ALK mutants with p.F1174L having an increased
transforming capacity compared to p.R1275Q and p.K1062M
[Chen et al., 2008; De Brouwer et al., 2010]. Altogether, these
observations suggest different effects on ALK signalling for different
mutations, with variable biological consequences. An interesting
possibility is that there is an ALK activity threshold, above which
CNS development would be impaired, but which is not reached by
all ALK gain-of-function mutations reported thus far. Animal
models are not yet available but knock-in mice bearing mutations at
codon p.F1174 and p.R1245 are being generated in several groups.
In the CNS of mice, Alk is expressed in several thalamic and
hypothalamic nuclei, the pons, the medulla oblongata, and the
ventral horn of the spinal cord [Vernersson et al., 2006]. It will be of
high interest to explore the consequences of endogenous expression
of mutant ALK on both neurological function and anatomic
development of the pons, medulla, and motor neurons.
There is a growing list of genes for which somatic and germline
gain-of-function mutations have been reported in tumours (of
various types) and syndromes, respectively (Table 1). Interestingly,
tumor predisposition burdens a minority of these syndromes. The
repertoire of mutations and the relative proportion of each
nucleotidic variation (and amino acid substitution) are different
between somatic and germline cases. As a general rule, mutations
exhibiting the highest activating effect in vitro are prevalent in the
somatic repertoire and absent from its germline counterpart. The
HRAS gene stands as a paradigm. Somatic gain-of-function
mutations at codons p.G12, p.G13, and p.Q61 are found in
various tumors, whereas germline mutations at codon p.Q61 have
not been reported in patients with Costello syndrome. Moreover,
when considering amino acid changes at codon 12, p.G12V is far
more frequent somatically than p.G12S (and leading to a greater
Table 1. List of Genes for Which Somatic and Germline Gain-of-Function Mutations Have Been Reported in Tumors and Syndromes,
Respectively
Gene OMIM Somatic mutation/tumour predisposition Germline mutation/Syndromes Reference
RET 164761 Thyroid MEN2A/MEN2B [Hofstra et al., 1994; Mulligan et al., 1993]
FGFR3 134934 Bladder/Skin/Haematopoietic Achondroplasia/TD [Rousseau et al., 1994]
FGFR2 176943 Uterus/Skin/Testicle Crouzon/Apert/Pfeiffer [Reardon et al., 1994; Wilkie et al., 1995]
HRAS 190020 Bladder/Thyroid/Skin Costello [Aoki et al., 2005]
KRAS 190070 Colon/Pancreas/Lung Noonan/CFC [Niihori et al., 2006]
BRAF 164757 Colon/Thyroid/Skin CFC [Niihori et al., 2006]
PTPN11 176876 Haematopoietic Noonan [Tartaglia et al., 2001]
IDH2 147650 CNS/Haematopoietic D2 Hydroxyglutaric Aciduria [Kranendijk et al., 2010]
ALK 105590 PNS Congenital encephalopathy This report
Syndromes predisposing to tumors are indicated with an asterisk. Several cases of leukemia have been reported in CFC. A paternal age effect is observed for germline mutations
of RET, FGFR2, FGFR3, HRAS, and PTPN11.
HUMAN MUTATION, Vol. 32, No. 3, 272–276, 2011 275

activation [Fasano et al., 1984]), while in Costello syndrome p.G12S
is the most common substitution, with p.G12V having been
reported only twice; both of these patients had a severe phenotype
[van der Burgt et al., 2007]. Most interestingly, two ‘‘missing
germline mutations’’ at codon 61 (Q61R and Q61K) of HRAS have
been identified in 5/30 spermatocytic seminomas (a rare testicular
germ cell tumor of late-age onset) [Goriely et al., 2009]. We thus
speculate that such mutations are to be found in patients with a
de novo germline mutation but probably lead to an extreme,
possibly foetal lethal phenotype, distinct from Costello syndrome.
Here we report a novel syndrome with predisposition to NB
due to constitutive ALK gain-of-function mutations. In doing so,
we provide evidence that normal CNS development requires
regulation of ALK activity, with a threshold being exceeded for
some mutations only, and therefore we add ALK to the list of
oncogenes with important roles in normal development.
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