Myotonic Dystrophy Associated with VACTERL? - A Case Report

Sir,

Myotonic dystrophy (DM; MIM 160900) is a well described multisystemic disorder with an incidence of 1 : 8000 newborn, which is associated with an expanded cytosine-thymine-guanine (CTG) trinucleotide repeat in the 3′-untranslated region of the DM protein kinase (DMPK) gene localized on 19 q13.2-q13.3 [[1]]. VACTERL (MIM 192350) is an acronym for a combination of associated defects of unknown etiology (i.e., vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, renal and limb anomalies) and has an incidence of approximately 1 : 6000 newborn [[7]]. Although DM and VACTERL are relatively frequent inherited diseases, a combination of DM and VACTERL has not been described before.

A 12¿-year old girl, born at term to non-consanguineous parents after uneventful pregnancy and delivery, presented with difficulties in handwriting lasting for four weeks due to painless muscle spasms in both hands. Physical examination, which revealed a myopathic facies with bilateral ptosis, weak eyelid closure, a high palate and an atrophic tongue, distal muscular atrophy and weakness as well as myotonia, led to the suggestion of DM. The diagnosis was confirmed by electromyography and molecular genetic analysis (500 - 1000 CTG repeats in the DMPK gene). Other characteristic manifestations of DM, such as beginning bilateral posterior cataracts, incomplete right bundle branch block, and mild hypertrophic cardiomyopathy, were also detected, whereas no evidence for endocrinopathies or immunological deficiencies was found.

Apart from DM, she presented with a variety of other defects and showed a medical history of surgical interventions. Anal atresia was corrected at age 1 month. At age 3 months an antireflux surgery and at age 8 years an ureterovesical neostomy were performed because of complex renal malformation (left-sided renal agenesis, right-sided fusion kidney with double ureter). At age 4 years a lumbar fusion was performed to correct hemivertebrae in T7 and L3 and progressing congenital scoliosis (Fig. [1]). At presentation she showed severe scoliosis, scapular winging, bilateral pes cavus and difficulties in walking on heels and toes. Tendon stretch reflexes were normal. Inspection of the integument revealed a sacral lipoma and hemangioma, highly suspicious of diastematomyelia. Spinal MRI demonstrated a tethering of the spinal cord, an intraspinal lipoma as well as a lumbo-sacral fusion defect. In the following 6 months she developed a progressive painful gait, which was treated by neurosurgical detethering. The described collection of defects in our patient are consistent with VACTERL association, whereas other inherited diseases like Schwartz-Jampel chondrodystrophic myotonia, MURCS association (acronym for Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia), and sacral agenesis syndrome have also been considered but fit less appropiately to the presented symptomatology. However, VACTERL association is the most favorable tentative diagnosis but cannot be confirmed by molecular genetic analysis.

Fig. 1 Back view of a female patient at age 12¿ years revealing severe scoliosis, scapular winging as well as lumbar and sacral cutaneous scars secondary to lumbar fusion at age 4 years and surgical correction of anal atresia at age 1 month. Note sacral lipoma and hemangioma which are both highly suspicious of diastematomyelia.

Our case demonstrated a combination of DM with VACTERL association which has not been described before. A coincidental manifestation of DM and VACTERL association, which are relatively frequent inherited disorders, seems to be the most likely interpretation. However, the exact pathomechanisms of both diseases are unknown. Thus, our case raises the question whether CTG repeat expansion could induce VACTERL phenotype by affecting developmental genes in the close vicinity of the DM locus, e.g., SIX5 gene which is a member of the SIX (sine oculis homeobox [Drosophila] homologue) family and is located less than 1 kilobase from the 3′-end of the DMPK gene. Recent studies revealed a reduced transcription of the SIX5 gene as a consequence of CTG expansions at the DM locus [[4]], and linked SIX5 deficiency to the development of cataracts in DM [[5]]. Mutations in other SIX genes and their signalling partners, EYA (eyes absent [Drosophila] homologue), resulted in severe developmental phenotypes, such as holoprosencephaly (SIX3; [[8]]), anophthalmia (SIX6; [[2]]), and branchio-oto-renal syndrome (EYA1; [[3]]). VACTERL association is proposed to present primary, polytopic developmental field defects of heterogenous origin [[6]]. However, a causal link between DM and VACTERL association seems unlikely as no other reported DM cases have presented with VACTERL phenotype although many of them had even larger CTG repeat expansions than our patient.

References

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