Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS; OMIM 617330) is an extremely rare human neurodevelopmental syndrome caused by a heterozygous loss-of-function mutation in the
Here, we describe a 3-year-old child who presented with dysmorphism, developmental delay, vesicoureteral reflux (VUR), strabismus, and vermian hypoplasia. WES identified a
A 2-month-old male was referred to Medical Genetics Center, Asan Medical Center, Seoul, Korea due to hypotonia. He was born after 39 weeks of gestation to a 24-year-old mother, who had previously experienced 2 spontaneous abortions. Family history for developmental delay was rejected. His birth weight was 2.95 kg (10-50th percentile), height was 47.6 cm (10th percentile), and head circumference was 34 cm (10-50th percentile). He was admitted to the neonatal intensive care unit at birth due to perinatal distress. Dysmorphic features were reported at admission, such as a long and triangular face, hypertelorism, low set ears, high nasal bridge, broad nasal tip, short anteverted nostrils, deep philtrum, and downturned corners of the mouth. In addition, short stature, hypotonia, constipation, micropenis, cryptorchidism, VUR, and clubfoot were noted.
At 3 months of age, a left VUR grade V with ureterovesical stenosis was observed following urinary tract infection (Fig. 1). At 6 months of age, he was unable to control his head. In addition, his muscle tone was decreased, with a normoactive deep tendon reflex. Brain magnetic resonance imaging (MRI) showed prominent retrocerebellar CSF spaces with suspected vermian hypoplasia (Fig. 2). His karyotype is 46, XY; chromosomal microarray did not find any significant copy number variant.
At 9 months of age, ureteroneocystostomy was performed for left obstructive refluxing megaureter and bilateral orchiopexy for cryptorchidism. Strabismus, ataxic hand movement, and insensitivity to pain were noted. At that time, the patient’s height was 65 cm (<3rd percentile), his head circumference was 44.5 cm (10-50th percentile), and body weight was 6.9 kg (3th percentile).
The Denver Development Scale Test (DDST) at 12 months revealed global developmental delay; his developmental stages were 6, 6-7, 2-3, and 5-6 months in each personal-social, fine motor-adaptive, language, and gross motor domain, respectively.
Based on the multi-systemic clinical features, including global developmental delay, short stature, brain anomaly, genitourinary abnormality, and normal chromosomal microarray results, WES was performed, as described previously. Informed consent was obtained from the parents. This study was approved by the Institutional Review Board for Human Research of Asan Medical Center (IRB number 2017-0988).
WES identified a novel mutation, c.589A>G (p.Asn197Asp), in the
Echocardiography revealed a retroaortic left innominate vein with hemiazygos inflow and no other structural cardiac anomaly. Anticholinergic and laxative drugs were prescribed for areflexic bladder and constipation, respectively.
At the latest evaluation at 2 years and 10 months of age, developmental status was severely delayed despite comprehensive rehabilitation treatment. DDST scores were 7, 6, 6, and 9 months in each personal-social, fine motor-adaptive, language, and gross motor domain, respectively.
In the current report, we described the first Korean case of HADDS caused by an
To date, 27 out of 33 patients who have been diagnosed with HADDS with a proven
In conclusion, this is the first report of a case with HADDS in the Korean population caused by a
This research was supported by Institute for Information and Communications Technology Promotion (IITP) grant funded by the Korean government (MSIT) (2018-0-00861, Intelligent SW Technology Development for Medical Data Analysis).
The authors declare that they do not have any conflicts of interest.
Clinical manifestations of Hypotonia, Ataxia, and Delayed Development Syndrome patients
|Clinical features||Harms (n=10)||Chao (n=3)||Sleven (n=8)||Tanaka (n=7)||Blackburn (n=5)||Total number||Our case|
|Ataxia issue||6/10||1/3||8/8||5/7||4/5||24/33 (72.7)||+|
|Intellectual disability||10/10||3/3||8/8||-||5/5||26/26 (100.0)||+|
|Speech delay||10/10||3/3||8/8||7/7||5/5||33/33 (100.0)||+|
|High pain tolerance||-||2/3||1||2||2||7||+|
|Facial dysmorphism||6/8||3/3||7/8||-||5/5||21/24 (87.5)||+|
|Brain MR abnormality||2/8||2/3||3/8||3/6||3/5||13/30 (43.3)||+|
|Vermis hypoplasia||2/8||2/3||1/8||1/6||3/5||9/30 (30.0)||+|
|Congenital heart defectc||1||-||-||-||-||1||+|
Values are presented as number only or number (%).
MR, magnetic resonance; VUR, vesicoureteral reflux.
aIncluding attention deficit, and limited facial expression. bIncluding cryptorchidism, hypospadias, dysplastic kidney, VUR. Reduction in volume of the labia majora, micropenis, and recurrent urinary tract infection. cAtrial septal defect.