Vasikarla Madhavi Fernandez Hospital, Hyderabad, Telangana, India Correspondence to: Dr V Madhavi, Email:drmadhavi@fernandezhospital.com
1 Abstract
We report a case of short stature with delayed mile stones. The child was evaluated and the diagnosis of
Dyggve-Melchoir-Clausen Syndrome was considered . Confirmation of the diagnosis was done by next generation
sequencing-based molecular genetic testing, as the mother had an ongoing pregnancy and prenatal diagnosis requires
confirmation in the index case. This case report highlights the utility of next generation sequencing in definitive diagnosis
of the proband and for offering prenatal diagnosis in the next pregnancy.
2 Background
Dyggve-Melchior-Clausen syndrome (DMC) is a rare type of autosomal recessive skeletal dysplasia. It is
characterized by microcephaly, coarse facies and progressive spondyloepimetaphyseal dysplasia leading to
disproportionate short stature. Dyggve-Melchior-Clausen disease (DMC) (OMIM # 223800) is caused by
homozygous or compound heterozygous mutation in the DYM gene. The diagnosis of Dyggve-Melchior-Clausen
syndrome is based on clinical and radiological findings. Prenatal diagnosis can be offered for the parents
who had a previous child with Dyggve-Melchior-Clausen syndrome which has been confirmed by molecular
diagnosis. We report a case wherein prenatal diagnosis of Dyggve-Melchior-Clausen syndrome was done after
confirming the molecular diagnosis in the previous sibling. This case report highlights the utility of next
generation sequencing in definitive diagnosis of the proband and for offering prenatal diagnosis in the next
pregnancy.
3 Case report
A consanguineous couple was referred to the genetic clinic during their second pregnancy as they had a 10-year-old child
with history of delayed milestones. The child was born at full term by Caesarean section with a birth weight of 3 kgs. His
development was normal till six months of age. From then on, he started having coarse facial features and failed to attain
new motor and mental milestones.
On examination, at ten years of age, he had coarse facies, a big mouth, prominent mandible (prognathism), short neck,
short trunk, protruding sternum, scoliosis with flaring of lower ribs, small hands and feet with clawing of fingers, and
enlarged elbow and knee joints causing knock knees. (Figure 1). There was no cataract or corneal clouding and no
hepatosplenomegaly. His head circumference was 50cms (< -3SD), height was 92 cm (< -3SD), weight 12 kg
(< -3SD), and his upper to lower segment ratio was 0.80. He was walking independently but had a clumsy gait.
There was no history of seizures, falls or abnormal behaviour. His developmental age was equivalent to
an infant of age 1 year or less. He was screened for mucopolysaccharidosis with urine glycosaminoglycan
assay which was normal. X rays of the spine revealed a double hump appearance, central beaking and
scoliosis with convexity towards the right (Figure 2a). X-ray of the hand showed short tubular and proximal
pointing metacarpals with mild radioulnar subluxation at wrist joint (Figure 2b). The pelvic Xray was
suggestive of a lacy pattern in the iliac crest (Figure 2c). Based on the clinical and radiological findings, a
provisional diagnosis of Dyggve-Melchior-Clausen syndrome was considered. Confirmation of the clinical
features by molecular diagnosis was offered as the couple had ongoing pregnancy and prenatal diagnosis
in the present pregnancy would be possible only after identifying the pathogenic mutations in the index
child.
Figure 1: Child with Dyggve-Melchior-Clausen syndrome.
a)
b)
c)
Figure 2: 2a) Xrays (anteroposterior and lateral views) of the thoracolumbar spine. 2b) Xray of the right hand
(anteroposterior and lateral). 2c) Xray of the pelvis and bilateral hip joints.
Clinical exome sequencing of the index child showed homozygous pathogenic variant p.Arg204Ter, caused by a
substitution in exon 7 of the DYM gene, which confirmed the diagnosis of Dyggve-Melchior-Clausen syndrome in the
proband. By then, the mother had ongoing 16 weeks of pregnancy and amniocentesis was done. Fetal genomic DNA was
isolated from the amniotic fluid. PCR amplification and Sanger sequencing of the fetal DNA was done for exon 7 of the
DYM gene. The sequence electropherogram was analysed and the presence of c.610C>T (p.Arg204Ter) variant in exon
7 was evaluated by comparing the sample sequence with the reference sequence. The variant c.610C>T
(p.Arg204Ter) was not observed in the DYM gene in the fetus, which suggested that the fetus was not
affected (Figure 3). The couple continued the pregnancy and delivered a healthy baby boy at full term.
Figure 3: Sanger sequencing of fetal DNA showing absence of the DYM gene mutation found in the proband.
4 Discussion
DMC is a rare, progressive genetic condition characterized by abnormal skeletal development, microcephaly, and
intellectual disability. It was initially described in 1962 by Dyggve and colleagues. The clinical and radiographic features
were described completely in 1975 by Spranger and colleagues (Schorr et al., 1977) Only about 100 cases have been
reported till date.
It is characterized by a short trunk and extremities and a barrel shaped chest, mental retardation and
microcephaly (Beighton, 1990). The radiographic appearance of generalized platyspondyly with double-humped end
plates and the lace-like appearance of iliac crests are pathognomonic and distinctive of DMC syndrome. The
lace-like appearance of the iliac crests, which is a characteristic radiologic sign, is found to be caused by bone
tissue deposited in a wavy pattern at the osteochondral junction. It is caused by biallelic mutations in the
DYM gene on chromosome 18q21. Mutations in the same gene cause Smith-McCort dysplasia (OMIM #
223800). Management requires both a multidisciplinary approach and a long-term follow-up as the disease is
progressive.
DMC needs to be differentiated from Smith-McCort dysplasia and Morquio syndrome. The differentiating findings are
detailed in Table 1.
Table 1: Features differentiating Dyggve-Melchior-Clausen syndrome from similar phenotypic conditions.
Differential Diagnosis
Clinical features
Dyggve-Melchoir-Clausen syndrome
Smith-McCortdysplasia
Morquio Syndrome
Coarse
features
Present
Present
Present
X
ray
findings
(pathognomonic)
Double
hump
vertebral
bodies
and
lacy
pattern
in
pelvic
crest
Lacy
pattern
in
pelvic
crest
Central
beaking,
goblet
shaped
vertebrae,
flared
iliac
wings,
increased
acetabular
angles
and
constricted
iliac
bone
Intelligence
Severe
mental
retardation
Normal
intelligence
Normal
intelligence
Associated
gene
DYM
gene
DYM
gene
GALNS
(Morquio
A)
or
GLB1
(Morquio
B)
Though DMC and Smith-McCort dysplasia are allelic disorders, in view of intellectual disability and the typical
clinical and radiographic findings, a clinical diagnosis of DCM was considered in our child. DYM is a relatively large gene
with 17 exons, but with next generation sequencing-based testing, the exact mutations could be identified, which helped
in confirmation of the diagnosis of the proband, in providing accurate genetic counselling to the family and in offering
prenatal diagnosis for their next pregnancy.
References
1. Beighton P. Dyggve–Melchior–Clausen syndrome. J Med Genet 1990; 27: 512-515.
2. Schorr S, et al. The Dyggve–Melchior–Clausen syndrome. Am J Roentgenol 1977; 128:107-113.
3. Spranger J, et al. Heterogeneity of Dyggve-Melchior-Clausen dwarfism. Hum Genet 1976; 33: 279-287.