Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS; Online Mendelian Inheritance in Man [OMIM] #603736), which overlaps with the originally described Ohdo syndrome, is an autosomal dominant disorder clinically recognizable at birth. Clinical features are blepharophimosis with ptosis, mask-like facial appearance, long thumbs/great toes, cryptorchidism, congenital heart defect, and thyroid dysfunction . The etiology of SBBYSS has been recognized as a heterozygous
A male newborn was the first baby of healthy nonconsanguineous parents. Family history was unremarkable and there were no antenatal problems. Amniocentesis with fetal chromosomal analysis was normal. He was born via vaginal delivery at 40+4 weeks’ gestation at the local obstetric clinic. He was transferred to our institute for multiple anomalies at birth. His weight, height, and head circumference were 2,720 g (3rd-10th percentile), 47.5 cm (3rd-10th percentile) and 34 cm (10th-50th percentile), respectively. He showed weak-cry and had generalized low muscle tone. Apgar scores at 1- and 5-minute were 7 and 9, respectively. Physical examination revealed hypertelorism, low set ear with underdeveloped antihelix, low nasal bridge, upward nostril, micrognathia, small scrotum with micropenis, overriding fingers, and long thumbs and toes (Fig. 1A, C, and D). The testes were not palpable in bilateral scrotums. Pelvic sonography performed at admission showed intra-abdominal testes. Simple cysts in both kidneys were seen in ultrasonography. Echocardiography showed a large atrial septal defect (ASD). There were unremarkable findings in brain sonography. Sensorineural hearing loss in the left ear was suspicious by automated auditory brainstem response test.
On the 7th and 14th day after birth, he experienced two events of atrial flutter, and flecainide was administered. No additional attacks were developed until 4 month and medication was stopped. Free thyroxine and thyroid-stimulating hormone levels measured at the 14 days old were 0.58 ng/dL and 445.18 μIU/mL, respectively. Thyroid scans showed diffuse goiter with significantly increased uptake in both lobes. Levothyroxine was administrated after the diagnosis of congenital hypothyroidism. His karyotyping was 46, XY and chromosomal microarray revealed no deletions or duplications. For underlying causes of the multiple abnormalities, we performed targeted exome sequencing by hereditary endocrine disorder panel (111 genes) and hereditary skeletal disorder panel (362 genes). A heterozygous nonsense mutation, c.5206C>T (p.Gln1736Ter), in exon 18 of
He was discharged at the age of one month. Then, at the age of 4 months, he was confirmed unilateral sensorineural hearing loss in the auditory brain threshold test. Clinical findings revealed an immobile mask-like face, a bulbous nasal tip, and severe blepharophimosis (Fig. 1B). He underwent patch closure for ASD at the age of 9 months. At the same time, the Denver developmental screening test was 5.9 months, 5.6 months, 4.3 months, and 5.4 months for personal-social, fine motor-adaptive, language, and gross motor, respectively. In the follow-up 12 months later, his weight, height, and head circumference were all less than 3rd percentile. He was undergoing rehabilitation treatment because of developmental delay. He is scheduled for surgery of cryptorchidism.
Vlckova et al.  summarized genotype-phenotype correlations and classified 62 reported
In summary, SBBYSS is a rare disease characterized by multiple congenital anomalies and developmental delay and a few cases have been reported in worldwide. In patients with these phenotypes, sequencing can be performed to confirm the diagnosis. We identified a novel mutation in
The authors declare that they do not have any conflicts of interest.
This work was supported by research fund of Chungnam National University.
Conception and design: HHL, JHS, MHG, MC. Acquisition of data: JHS, SYK. Analysis and interpretation of data: JHS, HHL, SY. Drafting the article: JHS, HHL, MC, SYK, MHG. Critical revision of the article: JHS, HHL, MC, MHG. Final approval of the version to be published: all authors.
Summary of clinical manifestations in patients with GPS or SBBYSS
|Genital anomalies||Long thumbs/great toes
|Patellar hypoplasia/agenesis||Immobile mask-like face
|Contractures at the hips, knees and/or club foot||Blepharophimosis and/or ptosis
|Agenesis of the corpus callosum||Lacrimal duct anomalies|
|Renal anomalies (hydronephrosis or multiple renal cysts)||Patellar hypoplasia/agenesis|
|Anal anomalies||Genital anomalies (cryptorchidism in male)
|Congenital heart defect
|Dental anomalies (delayed eruption of teeth)|
|Global developmental delay/intellectual disability
Diagnostic criteria: 2 majors or 1 major plus 2 minors .
aPresented in our patient.
GPS, genitopatellar syndrome; SBBYSS, Say–Barber–Biesecker–Young–Simpson syndrome.