Spondylocostal Dysplasia and Brachydactyly: a case report
Surasak Puvabanditsin, MD
surasak1@aol.com
Department of Pediatrics, Rutgers Robert Wood Johnson
Medical School, New Brunswick, New Jersey
Michelle Gorbonosov, MD mg1687@rwjms.rutgers.edu
Department of Family Medicine, Rutgers RWJ Medical School
Kristin Blackledge, MA ket79@rwjms.rutgers.edu
Rutgers Robert Wood Johnson Medical School
Jeffrey Manzano, MD jm2385@rwjms.rutgers.edu
Department of Pediatrics, Rutgers RWJ Medical School
Matthew Federici, MD mcf92@rwjms.rutgers.edu
Department of Pediatrics, Rutgers RWJ Medical School
Rajeev Mehta, MD mehtara@rwjms.rutgers.edu
Department of Pediatrics, Rutgers RWJ Medical School
Running Title: Puvabanditsin et al. Spondylocostal Dysplasia
Written informed consent was obtained from the patient/guardian to
publish this report in accordance with the journal’s patient consent
policy.
ABSTRACT
We report a preterm male neonate presenting with a skeletal dysplasia
associated with multiple congenital anomalies. Radiologic findings and
genetic studies are consistent with spondylocostal dysostosis (SCD) and
autosomal dominant brachydactyly. This is the first case report of
spondylocostal dysostosis and brachydactyly associated with TBX6and IHH variants.
Key words: spondylocostal dysplasia; costovertebral malformation;
Jarcho-Levin syndrome; congenital anomaly
Correspondence about the manuscript or reprint:
Surasak Puvabanditsin, MD
Department of Pediatrics, Rutgers Robert Wood Johnson Medical School
1 Robert Wood Johnson Place, New Brunswick, NJ 08903
Tel. (732) 235-5691, Fax (732) 235-5668,
e-mail: surasak1@aol.com
INTRODUCTION:
Costovertebral malformations are rare and result in significant
disabilities because they are associated with spinal deformities (e.g.
scoliosis, kyphosis) and rib abnormalities that could compromise
respiratory function. Spondylocostal dysostosis (dysplasia) [SCD] is
an autosomal recessive disorder that is characterized by multiple
segmental defects of the vertebrae and abnormalities of the ribs. The
phenotypes include a short trunk, short neck, and scoliosis (1,2). In
neonates, SCD can cause respiratory problems due to reduced size of the
thorax. With advancement in diagnosing genetic anomalies, the genetic
etiology of congenital vertebral malformation (CVM) is acceptably based
on the DNA analysis of single nucleotide polymorphism (SNP) arrays or
the next generation sequencing technology [whole exome sequence (WES)
and whole genome sequence (WGS)]. We report a new case of SCD with an
accompanying genetic analysis.
CASE PREPORT
A 2950-g Hispanic male neonate was born at 36 weeks gestation to a
16-year-old primigravida by vacuum-assisted vaginal delivery. Apgar
scores were 9 and 9 at one and five minutes respectively. Pregnancy was
uncomplicated. The family history was negative for congenital anomalies,
and there was no history of in-utero exposure to any known teratogens.
There was no history of consanguinity. Physical examination revealed a
weight of 2950 grams (50th centile), length of 45 cm
(5th centile), and head circumference of 34 cm
(25th centile). Anomalies noted at birth included:
cleft soft palate, coloboma of the iris, wide anterior fontanelle, wide
sagittal suture, low set ears, short neck, deformed ear, short fingers
and toes, transposition of the penis and prominent median raphe of the
scrotum and perineum (Figure 1). Neurosonogram and echocardiography were
normal. Chest and spinal radiographs showed segmentation anomalies of
the thoracic spines; [“butterfly”] hypoplastic and hemivertebrae
were present from the 1st to 12ththoracic vertebral bodies. The ribs were abnormal (fused and
dysplastic). L3 and L4 hemi-vertebra and lumbar scoliosis were also
noted (Figure 2). Renal sonography and MRI showed cross-fused and
dysplastic kidneys, and left hydronephrosis. Radiographs of the hands
and feet showed hypoplasia/absence of the middle phalanges (Figure 3).
Abdominal ultrasound and MRI studies revealed a small enteric
duplication cyst (1.6 x 1.5x 1.3 cm) anterior to the rectum. An upper
gastrointestinal contrast study performed at three weeks of age because
of feeding difficulties (initially thought to be due to the cleft soft
palate and disorganized sucking) showed malrotation of the small
intestine. The patient underwent an exploratory laparotomy, lysis of
Ladd’s band, and appendectomy on the 30th day of life.
Concurrently, gastrostomy tube placement and Nissen fundoplication were
done to help with the feeding. The infant remained in the hospital for
50 days because of the feeding difficulties.
CYTOGENETIC AND MOLECULAR STUDIES
The karyotype was 46 XY. The whole genome SNP (Single Nucleotide
Polymorphisms) microarray analysis was normal. No significant DNA copy
number changes in the 2.695 million region specific SNPs were detected.
The SNP microarray analysis was performed using CytoScan HD platform,
which uses over 730,000 SNP probes and 1,953,000 NPCN probes with median
spacing of 0.88 kilobase.
A high density of short runs [1.8 Megabase (Mb)] of allele
homozygosity (ROH) were observed throughout the genome, consistent with
a limited gene pool present in isolated populations. This finding
reflects an increased risk of recessive allele pairing. The study also
showed additional longer ROH on chromosomes 2, 5, and 16, consistent
with a distantly related parental relationship [ROH Bp linear
position: chr2:56149474-66950851; chr5:17410451-38717348;
chr16:25974475-35220544. Total 41 Mb (1.5% of autosomal genome)].
A sequence analysis and deletion/duplication testing of 109 genes
(Invitae Skeletal Dysplasia Panel) were performed by Invitae Laboratory
Corporation, San Francisco, California 94103, USA. The result identified
four significant variants that possibly related to the clinical findings
in our patient (Table 1).
DISCUSSION
Jarcho–Levin syndrome (JLS) is a congenital vertebral malformation
(CVM) characterized by vertebral body and rib malformations. JLS was
first described by Saul Jacho [a pathologist] and Paul Levin [a
neurologist] from Baltimore, USA in 1938 (1,3). The syndrome
represents a hereditary malformation spectrum of short trunk and
moderate rib cage restrictions with variable involvement of vertebrae
[fused, hemi, and block vertebrae] and ribs [absent to overgrown
ribs]. Subsequently, these findings have been termed and known as
spondylocostal dysostosis/dysplasia (SCD). The affected individual
ethnicity was colored [Anglo-Saxon]. The DLL3 gene has been linked
to SCD (1).
Lavy-Moseley syndrome was first reported by Norman Lavy from Indiana
university, Indianapolis and John Moseley from Mt Sinai, New York City
(1,4,5). In 1966, Lavy reported infants of the same family from Puerto
Rico (PR) who died from severe respiratory insufficiency during infancy.
All had small chests, short trunks, symmetric posterior fusion of the
ribs with a
fan-like [crab-like] appearance, and fusion of the occiput of the
skull to the first cervical vertebra. Three years later, Moseley
reported two more cases of patients with similar findings and used the
term spondylothoracic dysplasia/dysostosis (STD) to describe these
congenital anomalies (4). MESP2 has been implicated in STD individuals.
STD is now described as a rare, pleiotropic genetic disorder with an
autosomal recessive inheritance. It is most reported in patients from PR
or of documented PR ancestry (5 Moseley and Bonforte, 1969). The MESP2
gene has been implicated in individuals with STD.
Notably, MESP2 has been implicated in STD individuals. Although the
trunk is short in both STD and SCD, the severity of vertebral
malformation and clinical course is much worse in STD.
For more than 50 years after the first JLS was reported there was still
confusion with regards to patients with vertebral anomalies and thoracic
cage deformities. The term JLS was inaccurately coined to mean SCD or
STD. However, SCD and STD are two distinct entities with distinct
skeletal anomalies, ethnic connections, modes of inheritance, and
survival. Other associated anomalies with SCD include: neural tube
defects, Arnold-Chiari malformation, hydrocephalus, diastematomyelia,
renal/urinary tract abnormalities, and hydrourteronephrosis (6). The
clinical course and vertebral malformations are, also, more severe in
patients with STD compared to SCD. Our patient is a Caucasian male with
Hispanic ethnicity who presented with malrotation of the small bowel,
which is a new reported malformation associated with SCD.
Autosomal recessive variation of TBX6 has been reported to be
associated with segmental defects of the vertebra (SDV), ranging from
congenital scoliosis (CS) to SCD (7,8,9,10). The TBX6 gene is located on
chromosome 16 [16p12.2], is 6,095bp in size, and contains 8 exons
(8). Our case supports that the autosomal recessive TBX6 variant
is associated with SCD. TBX6, a T-box gene, encodes a transcription
factor which plays an important role in embryonic development of somite
(somitogenesis). It plays a key role in human spine development.
In our patient, the genomic microarray findings are consistent with
autosomal recessive allele pairing as products of distantly related
parents. The DNA sequence analysis [Invitae Skeletal Dysplasia
Panel] identified variants in TBX6 and IHH, which
probably correlate with our patient’s distinct phenotypes. Our case
revealed that SCD could be associated with brachydactyly of both hands
and feet, deformed ears, cleft soft palate, and bilateral colobomas of
the irises. These associated abnormalities have not previously been
reported with SCD. The malformations of the hands and feet
(brachydactyly) due to lack of ossification of the middle and distal
phalanges, as seen in our patient, have been described with theIHH variant (autosomal dominant brachydactyly type
A1(BDA1)(MedGen UID 354673).
Based on DNA analysis of SNP arrays and advanced genomic sequencing
technology, we are able to identify the genetic etiology of SCD.
In summary, we report a case of a neonate with TBX6, DVA1, andIHH variants associated with SCD and new associated phenotypes.
We illustrate the use of the whole genome microarray and genomic
sequencing analysis to identify the genetic etiology of congenital
vertebral malformations.
The manuscript and its content have been approved by all co-authors.
The authors declare no conflict of interest.
The authors have no financial disclosure to declare.
Author Contributions
Surasak Puvabanditsin involved in manuscript design and written.
Michelle Gorbonosov and Rajeev Mehta involved in data analysis
and manuscript revision.
Kristin Blackledge and involved in manuscript written and
revision.
Jeffrey Manzano and Matthew Federici involved in manuscript
revision
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Figure 1a. Note a short neck and a deformed ear (notched helix
and prominent antihelix)
Figure 1b, 1c. Note a palmar crease and short fingers/nails
Figure 1d. Note a short and broad toes, small nails and
metatarsus abductus
Figure 1e, 1f. Note transposition of the penis and prominent
median raphe
Figure 2a & 2b Spinal radiographs shows segmentation anomalies
of thoracic spines and rib abnormalities, L3&L4
hemivertebra with lumbar scoliosis
Figure 3a Radiograph of the hand shows absence/short middle
phalanges of fingers
Figure 3b Radiograph of the foot shows absence/short middle
phalanges of toes