This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome.
While a syndrome due to a terminal deletion of 7q has been described [
We report on a patient with a 9.92 Mb interstitial chromosome deletion of 7q33-q35 and summarize the clinical features seen in this patient, other patients with 7q33-q35 deletions, and patients with other 7q interstitial and terminal deletions, to help understand the range of phenotypes seen in patients with interstitial 7q deletions. We also review the known genes in this region to assess relevant genotype-phenotype correlations.
The patient, now 16 years old, was born to a 23-year-old G4, P3→4 mother and 30-year-old father. During the pregnancy there was concern for decreased fetal movement. Labor was induced due to fetal distress at 36 weeks’ gestation. Birth weight was 2614 g (<3%) and birth length was 44.5 cm (<3%). She had a positive toxicology screen for barbiturates and was noted to have large open fontanels. The patient remained in the hospital for 5 days after birth due to feeding difficulties.
The patient came to attention again around 6 months of age due to developmental delay and was evaluated by neurology. At around one year of age, the patient also began having seizure activity. EEG results were normal; a brain MRI at 14 months of age showed prominent CSF space posterior to cerebellar vermis, most likely representing large cisterna magna. A karyotype revealed abnormal results, 46,XX,del (7)(q32-q34). The patient’s mother had a normal karyotype and her father remains unavailable for testing but is not known to have any features similar to the patient; her deletion is presumed to be de novo based on its large size. Her seizures resolved by 2.5 years of age.
The patient has had multiple recurrent infections throughout her life; by 28 months of age, she had been hospitalized for pneumonia 3 times. The patient has continued to experience multiple upper respiratory infections, recurrent otitis media, and urinary tract infections. Immunology work-up was normal; therefore the patient is not suspected of having a primary immunodeficiency. The patient has a history of chronic otitis media and abnormal tympanometry and audiology examinations; she had ear tubes placed at 30 months of age. An audiogram performed at age 8 showed right moderate conductive hearing loss and left borderline to mild hearing loss, and hearing aids were recommended. The patient was first evaluated by ophthalmology at 33 months and noted to have hyperopia and bilateral astigmatism but no evidence of optic atrophy, as reported in some patients with 7q interstitial deletions.
At age 7 the patient was diagnosed with likely obstructive sleep apnea syndrome. She has a history of snoring and insomnia. In the same year the patient was noted to have elevated ALT and AST levels, which have progressively increased; suspected etiology is nonalcoholic steatohepatitis. A liver biopsy revealed macrovesicular steatosis and a modest number of lymphocytes in a few portal triads. The patient has also been followed up by endocrinology since age 10 due to abnormal weight gain, acanthosis nigricans, and insulin resistance. She was diagnosed with type II diabetes at age 11 and started on metformin. Additionally, the patient is reported to have large, foul smelling stools since 12 years of age.
At age 14, the patient developed hemihypertrophy on her right side and swelling of the right side of her face in the morning that regresses during the day. The hypertrophy interferes with walking and causes pain in her right foot. Genetic testing for Beckwith-Wiedemann syndrome was negative. A CT scan of the lower extremities showed increased diameter of the right leg in relation to the left, with a relative increase in both subcutaneous fat and muscle size. The increased musculature may represent compensatory hypertrophy secondary to the increased overall mass of the right lower extremity, but idiopathic or genetic reasons for hemihypertrophy cannot be excluded. There is no visible mass to account for the apparent disparity in size. An abdominal ultrasound showed a diffusely echogenic liver, compatible with fatty infiltration. Previous echocardiograms and EKGs have been normal. At age 15, the patient’s lower left leg also appeared to be growing in size. The patient currently has menstrual cycles two times per month. She developed a hyperpigmented spot on her forehead at age 15.
The patient has a history of significant developmental delay and intellectual disability. She sat at one year and walked at two years. At 28 months she had one or two understandable words but was mostly nonverbal. At age 7 her vocabulary was 15 words, but she did not yet put words together in phrases or sentences. At age 13 she was in a special education class in the 7th grade, assessed to be at a 3-year-old level. Currently at age 16, she is not able to name colors or count, but she can write her name, speak in simple sentences, and name some body parts. She has not lost any skills over time. The patient has a history of violent behaviors towards others and self-injurious behavior, including skin picking which began around 3 years of age and continues to present. Methylation analysis for Prader-Willi syndrome (due to features of obesity, intellectual disability, and skin-picking behaviors) and testing for cystic fibrosis (due to bowel concerns) were both normal.
The patient has dysmorphic features including small ears, a right preauricular ear pit, a large mouth with downturned corners, a smooth philtrum, a thin upper lip, hypertelorism, bulbous nose, a low posterior hairline, and a short neck. Lumbar lordosis was first noted around 3 years of age and continues to present. The patient also has a small umbilical hernia.
The patient’s family history is not significant for chromosome abnormalities, developmental delay, or intellectual disability. She has six maternal half-siblings who all reportedly have ADD and several paternal half-siblings who have no known medical or developmental concerns and are not available for testing. She has no full siblings. She is of African American and Northern European descent.
SNP microarray was performed by Integrated Genetics using the Affymetrix Cytoscan HD platform, using 743,000 SNP probes and 1,953,000 NPCN probes. A 9.22 Mb interstitial deletion of 7q33-7q35 was identified, arr 7q33-q35 (133,297,307–143,218,955) × 1.
Table
Clinical features of individuals with interstitial 7q33-q35 deletions.
Patient demographics | Present case | Malmgren et al. [ |
Nielsen et al. [ |
Stallard and Juberg [ |
Verma et al. [ |
Petrin et al. [ |
Rossi et al. [ |
Fagan et al. [ | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Patient | IV: 6 | III: 1 | III: 3 | III: 11 | III: 10 | III: 8 | ||||||
Deletion region | q33-q34 | q33-q34 | q33-q34 | q33-q34 | q32-q34 | q32-q34 | q32-q34 | q31-q34 | q33-q35 | q33-q35 | q33-q35 | q35 |
Gender/age | F/15 | M/15 | M/40 | F/25 | F/6 | M/6 | F/13.5 | F/1 | F/4 | M/22 | F/adult | F/11 |
Neurological/development | ||||||||||||
Intellectual disability | + | + | + | + | + | + | + | NA | + | − | + | + |
Developmental delay | + | + | + | + | + | + | + | + | + | + | + | |
Speech delay/disorder | + | + | NA | + | + | + | + | |||||
Abnormal brain MRI | + | + | + | |||||||||
Mood shifts | + | + | ||||||||||
Self-mutilating behaviors | + | |||||||||||
Seizures | + | + | + | + | ||||||||
Sleep difficulty | + | + | ||||||||||
Diparesis/truncal ataxia | + | |||||||||||
Craniofacial | ||||||||||||
Microcephaly | + | + | ||||||||||
Hypertelorism | + | + | + | + | + | + | + | + | ||||
Epicanthal folds | + | + | + | |||||||||
Broad/depressed nasal bridge | + | + | + | + | + | + | ||||||
Bulbous nose | + | + | + | + | + | + | + | + | + | + | ||
Large mouth | + | + | + | + | + | + | + | + | ||||
Long philtrum | + | + | + | + | + | + | + | |||||
Thin upper lip | + | + | + | + | + | + | + | |||||
Micrognathia | + | + | ||||||||||
Low set ears/ear | + | + | + | + | + | + | ||||||
Preauricular ear pits | + | + | ||||||||||
Growth | ||||||||||||
Slow growth/short stature | − | + | + | − | + | + | + | − | ||||
Truncal obesity | + | + | ||||||||||
Hemihypertrophy | + | |||||||||||
Hand and feet differences | + | + | + | |||||||||
Other | ||||||||||||
Ophthalmologic abnormality | + | + | − | + | ||||||||
Hearing deficit | + | + | + | − | ||||||||
Repeated infections | + | + | + | + | + | + | ||||||
Primary amenorrhea | − | N/A | N/A | N/A | N/A | + | ||||||
Frequent menses | + | N/A | N/A | N/A | N/A | − | ||||||
Umbilical hernia | + | + |
In addition to the features described in previous patients, our patient presents with additional findings of sleep apnea and insomnia, type 2 diabetes, obesity, echogenic liver, frequent menstruation, aggressive and self-mutilating behaviors, and her most recent concern of hemihypertrophy. Currently it is unclear which of these features can be explained by the patient’s deletion. However, Rossi et al. describe a patient with a 7q33-q35 deletion who also presents with obesity and sleep disturbances, as well as mood shifts [
The patients currently reported with interstitial 7q deletions show some phenotypic differences from patients with 7q34-ter or 7q35-ter deletions. Holoprosencephaly and Currarino triad have been reported in terminal deletions [
Rush et al. recently reported on a patient with a 7q34-q36.1 interstitial deletion and reviewed patients with similar deletions in overlapping q34-q36 regions [
There are 64 OMIM-described genes known to be located in the particular area of 7q deleted in our patient (Table
Known deleted genes in 7q33-q35 region in OMIM.
Known deleted genes in OMIM | ||
---|---|---|
AGK | HIPK2 | TAS2R3 |
AKR1B1 | KEL | TAS2R4 |
AKR1B10 | KIAA1549 | TAS2R5 |
AKR1D1 | LUC7L2 | TAS2R38 |
ATP6V0A4 | LUZP6 | TAS2R40 |
BPGM | MGAM | TAS2R41 |
BRAF | MTPN | TAS2R60 |
CALD1 | MRPS33 | TBXAS1 |
CASP2 | NUP205 | TRIM24 |
CHRM2 | OTSC2 | TRBC1 |
CLCN1 | PARP12 | TRBC2 |
CLEC5A | PIP | TRBD1 |
CNOT4 | PTN | TRBD2 |
CREB3L2 | PRSS1 | TRBJ@ |
D7S437 | PRSS2 | TRBV@ |
DFNB13 | SLC13A4 | TRPV5 |
DGKI | SLC35B4 | TRPV6 |
DHMN1 | SLI4 | UBN2 |
EPHA1 | SSBP1 | WEE2 |
EPHB6 | STRA8 | ZC3HAV1 |
GPDS1 | SVOPL | ZYX |
GSTK1 |
The gene
Mutations in
The patient presented exhibits similar features to other individuals with similar deletions, particularly intellectual disability and similar dysmorphic facial features, further helping to characterize a 7q interstitial deletion syndrome encompassing the q33-q35 region. This patient also exhibits unique features including recent onset of hemihypertrophy, frequent menses, and self-mutilation behaviors. There are many known genes in this region that play important roles in brain development and organ function whose haploinsufficiency could contribute to the features seen in our patient and others with similar deletions.
This report was approved by the Santa Clara Valley Medical Center Institutional Review Board.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to thank the patient and her family for their contribution to this report.