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Vol. 89. Num. 1.01 July 2018
Pages 1-66
Vol. 89. Num. 1.01 July 2018
Pages 1-66
Scientific Letter
DOI: 10.1016/j.anpede.2017.08.007
Open Access
Phenotype variability in thirteen 16p11.2 deletion patients
Variabilidad fenotípica en 13 casos de deleción 16p11.2
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Diana Rodàa,
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droda@tauli.cat

Corresponding author.
, Elisabeth Gabaua, Neus Baenab, Miriam Guitartb
a Unidad de Genética Clínica, Servicio de Pediatría, Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain
b Laboratorio de Genética, UDIAT-Centre Diagnòstic Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, Spain
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Tables (1)
Table 1. Clinical characteristics of index cases.
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In the past 10 years, comparative genomic hybridization array (aCGH) methods have allowed the identification and characterization of numerous syndromes caused by copy-number variations. The deletion of approximately 600kb in chromosome 16p11.2 is one of the most frequent disorders of this type.1 It was initially associated with autism, but at present there is evidence of its association with a wide phenotypic spectrum with incomplete penetrance and variable expression, manifesting most frequently with language disorders, obesity and psychiatric disorders.2–4

Chromosome 16p11.2 deletion syndrome (OMIM 611913) has an autosomal dominant pattern of inheritance. Most cases correspond to de novo mutations, but the deletion can be inherited from a symptomatic or asymptomatic parent.

We present 6 index cases (Table 1) and the cases of 7 relatives with chromosome 16p11.2 deletion syndrome diagnosed by means of aCGH.

Table 1.

Clinical characteristics of index cases.

  Case 1  Case 2  Case 3  Case 4  Case 5  Case 6 
Sex, age  M, 7 y  M, 6 y  M, 8 y  F, 11 y  F, 15 y  F, 26 y 
Size of deletion (number of contained genes)  596kb (29)  598kb (29)  448kb (26)  516kb (28)  514kb (27)  552kb (29) 
Inheritance  Maternal  Maternal  de novo  de novo  Maternal  Undetermineda 
Perinatal history  Delivery at 36 weeks  IUGR  TTN  −  −  − 
Anthropometry
Wt (kg)
Ht and HC (cm)
BMI 
Wt: 33 (82th PCTL)
Ht: 124 (15th PCTL)
HC: 54 (83th PCTL)
BMI: 21.5 (96th PCTL) 
Wt: 32.5 (97th PCTL)
Ht: 120 (45th PCTL)
HC: 54 (92th PCTL)
BMI: 22.6 (>99th PCTL) 
Wt: 46.5 (98th PCTL)
Ht: 130 (31th PCTL)
HC: 55 (94th PCTL)
BMI: 27.5 (>99th PCTL) 
Wt: 41.5 (42th PCTL)
Ht: 149 (47th PCTL)
HC: 55 (70th PCTL)
BMI: 18.9 (43th PCTL) 
Wt: 63 (74th PCTL)
Ht: 158 (26th PCTL)
HC: 55 (88th PCTL)
BMI: 25.3 (88th PCTL) 
Wt: >100 (>99th PCTL)
Ht: 159 (20th PCTL)
HC: 58 (>98th PCTL)
BMI >39.6 (>99th PCTL) 
Dysmorphic features  Cupid's bow upper lip, macroglossia  −  Cupid's bow upper lip, single palmar crease  High-arched palate, clinodactyly in 5th finger  Cupid's bow upper lip, high-arched palate, short neck  High-arched palate, short neck 
Psychomotor retardation  + (mild)  −  + (mild)  + (mild)  −  − 
Cognitive impairment  + (mild)  + (borderline)  + (mild)  + (mild)  + (mild)  + (mild) 
Social impairment  −  −  −  − 
Language disorder  NR 
Behavioural/psychiatric disorder  −  ADHD
Self-harm 
−  −  NR  Depression
Bulimia 
Epilepsy  −  −  + (resolved) 
Macrocephaly  −  −  −  −  − 
Obesity (years of age at onset)  + (6)  + (5)  + (6)  −  Overweight  + (6) 
Other  Strabismus  SAHS
AT
Submucous cleft palate 
Hypotonia  Spina bifida occulta
Pes cavus 
VOUS at 14q11.2  HPS
Hydrocephalus
SAHS
AT 

+: present; −: absent; ADHD, attention-deficit hyperactivity disorder; AT, adenotonsillectomy; BMI, body mass index; F, female; HC, head circumference; HPS, hypertrophic pyloric stenosis; Ht, height; IUGR, intrauterine growth restriction; M, male; NR, not reported; PCTL, percentile; SAHS, sleep apnoea hypopnoea syndrome; TTN, transitory tachypnoea of the newborn; Wt, weight; VOUS, variant of unknown significance.

a

Father not available.

We obtained the informed consent of all the patients or their legal guardians.

Case 1. Boy aged 7 years presenting with psychomotor retardation (PMR), social impairment and nasal flaring. In the past few months, the patient had exhibited spells during which he was unaware of his surroundings during the evaluation. The mother was a carrier of the deletion and reported having had problems in school and dropping out of compulsory secondary education.

Case 2. Boy aged 6 years with language delay, mainly in expressive language, and difficulty performing logical or sequential tasks. The mother, grandmother and 3 maternal uncles had the deletion.

The grandmother, aged 53 years, had epilepsy and overweight. The mother, aged 33 years, had anxiety and depression. A maternal aunt aged 27 years dropped out of compulsory education due to school failure. She had a history of morbid obesity but had lost weight as a result of anxiety and depression. A maternal uncle aged 16 years was obese and had no problems in school. The other uncle, aged 12 years, was receiving treatment for ADHD, had unilateral duplex kidney, 2 hemivertebrae, and academic difficulties on account of which he required adaptations to the regular curriculum. All family members had undergone adenotonsillectomy.

Case 3. Boy aged 8 years that presented with PMR and difficulties with expressive language and writing.

Case 4. Girl aged 11 years that presented with PMR, absence seizures with onset at age 18 months, expressive language disorder and polyphagia requiring monitoring to maintain an adequate weight.

Case 5. Girl aged 15 years with intellectual disability (ID), epilepsy and obesity. The aCGH evaluation also detected a 1 Mb deletion in chromosome 14q11.2 classified as a variant of unknown significance. Her mother carried the 16p11.2 deletion and was overweight.

Case 6. Woman aged 26 years. She had been evaluated as early as age 4 months for assessment of macrocephaly with a head circumference of 46cm (z-score, +4.4). She had moderate hydrocephalus that resolved spontaneously by age 4 years. From age 5 months to 3 years she had partial epilepsy of infancy, with no seizures after that age. She exhibited clear problems with language starting at age 3 years. The patient has had depression and bulimia as an adult. She was unable to graduate from high school. Her mother and siblings did not carry the deletion, and the father was not available for assessment.

The typical 16p11.2 deletion was first described in 2007 and encompasses 29 genes. The main reasons that lead to evaluation are ID, PMR and autism. In our series, the most frequent reason for evaluation was ID.

The clinical picture is variable. This deletion should be suspected in children with delayed language development with abnormal speech articulation, ID, social impairments, macrocephaly, seizures, vertebral malformations and/or Chiari malformation and obesity in the context of PMR.4

Intellectual disability is usually mild (IQ, 82.7), but with IQ scores nearly 2 SDs below those of non-carrier familial controls.2 Twenty-four percent have autism spectrum disorder (ASD), but up to 70% present with autism traits, such as repetitive behaviours. Cases 1, 2 and 5 in our series had autistic traits, but did not fulfil the criteria for diagnosis of ASD. Language disorders are present in 70% of affected individuals, and there seem to be anatomical abnormalities associated to problems in different areas of language development.5,6 In our case series, language disorders were the most frequent feature along with mild ID.

Ninety-three percent of adults with 16p11.2 deletion syndrome have at least one diagnosed psychiatric disorder; in our series, 3 out of 5 adults with the deletion had psychiatric disorders.

Seizures, described in 20% of patients in the literature, occurred in 4 of the index cases. Only one patient had macrocephaly, and only one relative of an index case had a vertebral malformation.

The management of chromosome 16p11.2 deletion syndrome should focus on the specific clinical manifestations presented by the patient. Early diagnosis helps identify the potential needs of patients, such as early stimulation, speech therapy and dietary management, thus leading to improved outcomes. It also makes genetic counselling possible.

In conclusion, chromosome 16p11.2 deletion syndrome is characterized by a wide phenotypic variability between individuals and within families, and the most frequent manifestations are language disorders, mild ID, mild dysmorphic features and obesity. Considering that this microdeletion can be inherited, we recommend genetic testing of individuals with compatible manifestations for the purpose of early intervention and genetic counselling.

References
[1]
E.B. Kaminsky,V. Kaul,J. Paschall,D.M. Church,B. Bunke,D. Kunig
An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities
[2]
E. Hanson,R. Bernier,K. Porche,F.I. Jackson,R.P. Goin-Kochel,L.G. Snyder
The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population
Biol Psychiatry, 77 (2015), pp. 785-793 http://dx.doi.org/10.1016/j.biopsych.2014.04.021
[3]
S. Jacquemont,A. Reymond,F. Zufferey,L. Harewood,R.G. Walters,Z. Kutalik
Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
Nature, 478 (2011), pp. 97-102 http://dx.doi.org/10.1038/nature10406
[4]
Miller DT, Chung W, Nasir R, Sobeih MM, Shen Y, Wu BL, et al. 16p11.2 recurrent Microdeletion; 2009 [updated 2015]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2009–2016.
[5]
J. Berman,D. Chudnovskaya,L. Blaskey,E. Kuschner,P. Mukherjee,R. Buckner
Abnormal auditory and language pathways in children with 16p11.2 deletion
Neuroimage Clin, 1 (2015), pp. 50-57
[6]
A.M. Maillard,A. Ruef,F. Pizzagalli,E. Migliavacca,L. Hippolyte,S. Adaszewski
The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity
Mol Psychiatry, 20 (2015), pp. 140-147 http://dx.doi.org/10.1038/mp.2014.145

Please cite this article as: Rodà D, Gabau E, Baena N, Guitart M. Variabilidad fenotípica en 13 casos de deleción 16p11.2. An Pediatr (Barc). 2018;89:62–63.

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