1- New
Horizons Child Development Centre, Mumbai, Maharashtra, India.
2- Nanavati
Super Speciality Hospital, Mumbai, Maharashtra, India.
Background: Phelan McDermid syndrome (chromosome 22q13.3 deletion) is a neurodevelopmental disorder presenting with global developmental delay (GDD)/Intellectual Disability (ID) and autism spectrum disorder (ASD) with multisystemic involvement of varying severity.
Aims: By highlighting this case we would like to increase awareness among general pediatricians of this underreported condition from/within a specific/limited cohort of children with GDD/ID and ASD.
Clinical Description: Our case is a 7 year child who presented to our neurodevelopmental center with GDD, facial dysmorphism, unilateral multicystic dysplastic kidney, limb swelling, behavioral concerns and MRI Brain findings, He was diagnosed with chromosome 22q13.3 deletion on karyotyping and interphase FISH and given multidisciplinary care focusing on all comorbidities.
Conclusion: This case highlights the role of comprehensive
testing and evaluation in a child with neurodevelopmental concerns for
establishing a diagnosis for prognostication.
Keywords: Phelan McDermid syndrome, 22q13.3 deletion, SHANK3, GDD, ID, ASD, MCDK, dysmorphism, lymphedema
INTRODUCTION
Phelan McDermid
syndrome (PMS) is a neurodevelopmental disorder characterized by global
developmental delay (GDD), intellectual disability (ID) and autism spectrum
disorder (ASD) with mild nonspecific dysmorphic features and several
comorbidities. It is a result of terminal deletion of chromosome 22q13.3
leading to SHANK3 gene haploinsufficiency. It is estimated to be a frequently
recurring monogenic form of ASD and ID in 0.5% and 2% of cases respectively
(1,2). However, it has been under-reported perhaps due to lack of awareness. We
present a classic case of PMS, who reported at our multidisciplinary
neurodevelopmental clinic for developmental and behavioural concerns. We would
like to increase the awareness of this condition among general paediatricians
by highlighting its classic diagnostic features to allow for its timely
diagnosis and better follow-up.
CLINICAL
DESCRIPTION
Our patient, a
7year boy, presented to our center with complaints of GDD, delayed and deviant
social communication and behavioral concerns.
He was first born
to a non-consanguineous marriage. Antenatally, fetal antenatal ultrasound was
suggestive of right multi-cystic dysplastic kidney (MCDK). He was delivered at
term by emergency caesarian section in view of meconium stained liquor with birth
weight 3 kg, did not cry at birth, received resuscitation and was admitted in
NICU for 4 days. However, he did not require invasive ventilation, but received
phototherapy for neonatal hyperbilirubinemia.
Parents noticed
him to be floppy since early infancy with difficulty in swallowing and drooling
of saliva. He had developmental delay in all domains. He had neck holding by 10
months, rolling by 1 year, sitting without support by 18 months, crawling by 2
years, standing with support by 2.5 years, walking without support by 3.5
years. In fine motor skills, he started reaching out for objects by 1 year,
developed pincer grasp after 2 years, and at 7 years started scribbling and
undressing. In language development, he started cooing by 6 months, babbling by
a year and had no meaningful words by 7 years of age. He achieved social smile
at 4 months and started recognizing mother by 6 months. At 7 years, he still
needed assistance with activities of daily living, was not toilet trained, had
difficulty blowing. Parents reported deficits in social communication and
interaction like fleeting eye contact, delayed response to name call, absence
of pointing. He was hyperactive, restless and had sensory concerns.
Parents also
reported presence of a painless swelling over left foot since infancy,
progressively increasing to currently reaching the knees, causing him to drag
foot while walking.
He had no history
of seizures, dystonia, tremor or tics, abnormal body odor, skin or hair
changes, echolalia, repetitive behavior, aggression, self- harm. No family
history of similar illness, developmental delay, seizures, early death, genetic or metabolic disorders.
On examination, he
displayed facial dysmorphism in terms of a long face, dysplastic ears,
prominent forehead, bulbous nose, conical teeth, pointed chin with large hands,
broad fingers and flat feet. A soft, pitting nontender swelling over left feet
and leg with overlying skin normal. He had normal spine, genitalia and no
neurocutaneous markers. His head circumference (52 cm), height (124 cm), weight
(26.1 kg), BMI (16.7) were within normal limits.
He had mild
spasticity in lower limbs and ataxic gait. Except for left exotropia, rest of
cranial nerve examination was normal. Cardiovascular, respiratory and
gastrointestinal system examinations were within normal limits.
He was under
evaluation since 9 months of age for multisystemic involvement i.e. hypotonia,
GDD, dysmorphism and renal involvement with leg swelling. CT Scan Brain showed
left temporal arachnoid cyst and right parietal subgaleal hematoma. MRI brain
at 18 months revealed hyperintense signal on T2 in bilateral temporal white
matter region suggestive of delayed myelination for age, small area of gliosis
in right periventricular (peri-trigonal) region, with altered signal intensity
in cerebellum, brainstem and a 3.4*2.3*1.7 cm arachnoid cyst anterior to left
temporal pole. BERA was normal. Refractive errors were identified on
ophthalmology evaluation. Metabolic workup {blood Tandem mass spectroscopy
(TMS) and urine gas chromatography - mass spectroscopy (GCMS)} were normal,
muscular involvement ruled out by normal CPK and 2D ECHO ruled out cardiac
involvement. Repeated ultrasound KUB revealed a small right kidney with 4 cysts
with left kidney showing compensatory hypertrophy. Karyotype revealed a 46, XY chromosome complement with
derivative chromosome 22 {46, XY, der(22)t(?;22)}. Interphase fluorescence in
situ hybridization (FISH) showed heterozygous deletion of 22q13 (99% cells in
interphase) which clinched the diagnosis of Phelan McDermid Syndrome.
The child
presented to our centre for specialised holistic care for motor and speech
delay, hyperactivity and inattention, problems in visuo-motor coordination,
perceptual and sensory concerns. He was evaluated by the developmental
paediatrician and assessed on psychometric tests. He did not meet the DSM-5
criteria for ASD or ADHD.
Accordingly, he
was started on an individualised intervention program targeting development in
all domains inclusive of weekly sessions of occupational therapy, physiotherapy
and speech therapy and monthly parental counselling. He was prescribed oral
risperidone, fluoxetine and methylphenidate subsequently for his behavioural
and sensory concerns. He continued independent follow up with a paediatric
neurologist and nephrologist.
DISCUSSION
Phelan McDermid
syndrome, a 22q13 deletion syndrome presents with multiple comorbidities
affecting various systems with varying severity.
Kolevzon, et al,
highlighted presence of dolichocephaly or macrocephaly with normal growth in
majority with dysmorphic features including periorbital fullness, long eyelash,
wide nasal bridge, bulbous nose, malformed ears, pointed chin, large fleshy
hands and flat feet, all of which were manifest in our case(1,3). Other features
include, hypoplastic/ dysplastic nails, syndactyly of toes, ptosis, epicanthal
folds (1).
Our case did not
meet the DSM-5 criteria for ASD upon presentation to us, but had sensory and
behavioral concerns with motor and speech delays. However, a high prevalence of
ASD (up to 84%) is reported in these patients (4).
There is high
prevalence of hypotonia with feeding difficulties, delayed motor development,
and abnormal gait like high steppage gait, toe walking or broad-based ataxic
gait, as in our case (1,4). Further, there is also an increased risk of
scoliosis and macrocephaly with raised ICP with increasing age (1).
Hearing and vision
problems including strabismus, myopia and retinitis pigmentosa are common
(1,5,6).
Brain
abnormalities are evident in 73% of cases including corpus callosum thinning,
delayed myelination, generalized white matter atrophy, and nonspecific white
matter hyperintensities, ventricular dilatation and interventricular,
cerebellar, or temporal sylvian arachnoid cysts many of which were present in
our patient (1,4,7). Seizure disorders occur in up to 31% cases being highly
debilitating and associated with regression(1,7).
Our patient was
diagnosed with right MCDK antenatally. Renal abnormalities are relatively
common in PMS (38%) and include vesicoureteral reflux, hydronephrosis, renal
agenesis, horseshoe kidneys, pyelectasis, polycystic kidney, duplicate kidney,
MCDK and Wilms’ tumor (1).
Our patient had a
progressive swelling of left lower limb since early infancy. Lymphedema has
been reported in about 24% cases and represents an especially troubling symptom
with risk of cellulitis (1,6).
Other organ
involvements include congenital heart defects (25%) like tricuspid valve
regurgitation, atrial septal defect, patent ductus arteriosus, and total
anomalous pulmonary return (1,3). Gastrointestinal symptoms include
gastroesophageal reflux disease, constipation, cyclic vomiting, dental
malocclusions (1,6). Pica associated in 50% cases requires behavioral therapy.
Children are also prone to immune system dysfunction, including recurring ear
and upper respiratory tract infections, seasonal and food allergies and asthma
(1,6).
Our patient was
diagnosed with karyotype (G banding) showing a derivative chromosome 22 and
interphase FISH (using Vysis LSI DiGeorge/VCFS Spectrum Orange/ LSI ARSA
Spectrum Green probe) revealing terminal deletion on chromosome 22q13.
Deletions 22q13 occurs de novo in majority but in 20% cases, a parent carries a
balanced rearrangement leading to significant risk of recurrence in families
(1,8). Hence, karyotyping should be performed even with a positive CMA to rule
out ring chromosome and translocations along with FISH for biological parents
(8,9). Finally, Sanger or next generation sequencing can test for SHANK3 mutations
if CMA and karyotyping are unrevealing in a suspected case. SHANK3 gene, a
scaffolding brain protein which regulates postsynaptic density of glutamatergic
synapses and is identified as the critical gene for its neurological features
(10).
The natural
history is complicated by comorbidities and associated ASD, ID and behavioral
problems, it is imperative to have the child evaluated early by a developmental
pediatrician with early and intensive delivery of individualized intervention.
Appropriate referrals to orthopedics and physical therapist for neuromotor
deficits and regular monitoring for progressive scoliosis or raised ICP with
increasing age is warranted. There should be a low threshold for EEG with signs
of behavioral changes or regression. Other aspects include early referrals to
pediatric audiology, ophthalmology, nephrology and cardiology. Routine
management for lymphedema with preventive measures for infections is necessary
(6).
CONCLUSION
PMS, a 22q13
deletion syndrome, is not as rare as assumed. Early diagnosis and intervention
has prognostic implications. Further, we would like to reinforce the benefits
of extensive testing for establishing a diagnosis in view of the holistic care
that could be provided to the individual based on the spectrum of comorbidities
involved.
REFERENCES
1.
Kolevzon
A, Angarita B, Bush L, et al. Phelan-McDermid syndrome: a review of the
literature and practice parameters for medical assessment and monitoring. J
Neurodev Disord. 2014;6(1):39.
2.
Leblond
CS, Nava C, Polge A, et al. Meta-analysis of SHANK mutations in autism spectrum
disorders: A gradient of severity in cognitive impairments. PLoS Genet. 2014
Sep 4;10(9):e1004580. doi: 10.1371/journal.pgen.1004580. PMID: 25188300; PMCID:
PMC4154644.
3.
Phelan
MC. Deletion 22q13.3 syndrome. Orphanet J Rare Dis.2008 May 27;3:14.
4.
Soorya
L, Kolevzon A, Zweifach J, et al. Prospective investigation of autism and
genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3
deficiency. Mol Autism. 2013 Jun 11;4(1):18.
5.
Phelan
MC, Rogers RC, Saul RA, et al. 22q13 deletion syndrome. Am J Med Genet.
2001;101:91–99.
6.
Sarasua
SM, Boccuto L, Sharp JL, et al. Clinical and genomic evaluation of 201 patients
with Phelan-McDermid syndrome. Hum Genet. 2014;133:847–859.
7.
Philippe
A, Boddaert N, Vaivre-Douret L, et al. Neurobehavioral profile and brain
imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008
Aug;122(2):e376–e382. doi: 10.1542/peds.2007-2584. Epub 2008 Jul 14. PMID:
18625665
8.
Zwanenburg
R J, Dijkhuizen T, Groot M.J, et al. Increased Recurrence Risk in
Phelan-McDermid (22q13.3 Deletion) Syndrome: The Importance of FISH
Demonstrated by a Case Series of Five Families. OBM Genetics. 2018;2(4).
9.
Dhar
SU, Del Gaudio D, German JR, et al.
22q13.3 deletion syndrome: Clinical and molecular analysis using array CGH. Am
J Med Genet A. 2010 Mar;152A(3):573–581.
10.
Monteiro
P, Feng G. SHANK proteins: Roles at the synapse and in autism spectrum
disorder. Nat Rev Neurosci. 2017 Mar;18(3):147–57.