Atypical Smith-McCort dysplasia: A case report of skeletal dysplasia with cardiac anomaly

INTRODUCTION

Smith-McCort dysplasia (SMC) and Dyggve–Melchior–Clausen dysplasia (DMCD) are rare autosomal recessive disorders within the Spondyloepimetaphyseal dysplasia (SEMD) spectrum.^[1] SMC is considered a less severe variant of DMCD. The clinical features include short-trunk dwarfism, SEMD and platyspondyly with distinctive lacy iliac crests. However, SMC lacks the intellectual disability typically seen in DMCD.^[2,3] SMC is caused by a mutation in the Dymeclin (DYM) gene, located at chromosome 18q12-q21.1 and produces a Golgi protein expressed in bone, cartilage, and brain, whose function is unknown as of now.^[4,5] We report the case of an 8-year-old girl who presented with disproportionate short stature with clinical features consistent with SMC and a mutation in the DYM gene.

CASE REPORT

An 8-year-old girl, first in birth order, born of 3^rd-degree consanguinity (both Indian parents), was brought with concern of short stature. She was born full term by lower segment caesarean section for breech presentation with an approximate birth weight of 2.5 kg. The parents denied a history of neonatal hypoglycaemia, prolonged physiological jaundice, or respiratory distress. She had delayed motor milestones, while her school performance was good. She had no history of chronic diarrhoea, recurrent respiratory tract infections, breathlessness, or joint pains. Her parents also noticed progressive deformity in her legs. No other family members had similar complaints. On examination, her weight was 12.5 kg (−3.93 SDS), height was 96.6 cm (−5.2 SDS), BMI 13.56 kg/m², upper segment/lower segment ratio was 1.18, and head circumference was 48 cm. She had an arm span of 90 cm with rhizomelic shortening of the upper limbs, pectus carinatum, Harrison sulcus, and bowing of the legs [Figure 1]. Her higher mental functions were normal with no signs of neurological, hearing, or vision impairment. The spine was normal on examination. Her baseline investigations, including a haemogram, kidney function, and liver function tests, were routine. Her 25-hydroxy Vitamin D was low, and thyroid function tests were normal [Table 1]. A skeletal survey revealed lacy iliac crests, with wrist, knee, hip joints dysplasia and pubic symphysis defect [Figure 2]. Echocardiography showed a small secundum atrial septal defect with a left-to-right shunt, while abdominal ultrasound was unremarkable, showing no evidence of hepatosplenomegaly or renal abnormality.

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Figure 1:

Photograph of patients depicting rhizomelic shortening of upper limb, pectus carinatum, harrison sulcus.

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Figure 2:

Radiographic skeletal abnormalities. (a) Lucent metaphyseal band with metaphyseal widening, splaying, and cupping (arrowheads). (b) Decreased bone density with medullary widening (arrowhead). (c) Lacy outline of the iliac crests (arrows), dysplasia of the acetabulum and femoral heads (arrowheads), and pubic symphysis defect (arrowheads).

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Genetic analysis through whole-exome sequencing identified a homozygous 3’ splice site variant in intron 10 of the DYM gene (c.1126-2A>G), which is classified as likely pathogenic. This variant is associated with DMCD and SMC, both autosomal recessive conditions. Based on the clinical, radiological, and genetic findings, a diagnosis of SMC was made.

DISCUSSION

SMC was first described by Smith and McCort in 1958 as an allelic variant of DMCD. Both disorders are uncommon, autosomal recessive disorders caused by mutations in the DYM gene, localised to the 18q12-21.1 chromosomal region, resulting in shared skeletal dysmorphism.^[3] Some patients have also been identified to have mutations in the RAB33B gene. Despite identical skeletal abnormalities, patients with SMC have normal intellectual functions. The distinctive radiographic features include generalised platyspondyly with double-humped end-plates [Figure 3] and the lace-like appearance of iliac crests.^[2,6] Almost all patients have short stature, short trunks, and rhizomelia.

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Figure 3:

Lateral X-ray of spine showing characteristic generalised platyspondyly with double-humped end-plates (arrowhead).

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The mutations in DMCD result in premature truncations of the protein, while the mutations in the DYM gene in SMC are missense and heterogeneous, resulting in milder loss of protein functions.^[7-11] In this case, a homozygous 3’ splice site variant in intron 10 of the DYM gene (chr18: g.49272305T>C) that affects the invariant AG acceptor splice site upstream of exon 11 (c.1126-2A>G; ENST00000675505.1) was detected. The observed variant has been reported as likely pathogenic in the ClinVar database. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1) and top med databases. This variant was also found to be damaging by pathogenicity prediction tools, MutationTaster2.

The clinical features observed in this patient such as short trunk, barrel chest, rhizomelic upper limbs, pectus carinatum and genu varum or valgum, with normal intelligence, are typical clinical characteristics of SMC.^[6-8] The presence of a small secundum ASD (LDu shunt) on ECHO is not commonly associated with SMC. This finding may be an incidental anomaly or could represent a previously unreported association with DYM gene mutations.

CONCLUSION

SMD is closely related to DMCD with characteristic clinical and radiological findings, However, this is the first case reporting, the presence of ostium secundum atrial septal defect in SMD.