Myopathy in a Patient with Chromosome 22q11 Deletion

Sir,

Deletions of chromosome 22 q11 have been associated with different phenotypes, including Di George syndrome, characterized by thymic hypoplasia, congenital heart disease and facial dysmorphism, velo-cardio-facial syndrome with added cleft palate and learning disabilities, conotruncal anomaly face syndrome and a number of other rare conditions (see [[8], [9]] for reviews). Limb anomalies belong to the clinical expression of the syndrome, but they have been rarely reported [[2], [6]]. Myopathies have never been documented. Recently, a 10-year-old girl with atrophy of the shoulder girdle muscles and cervicomedullary narrowing on MRI has been described, with normal serum CK and muscle biopsy [[1]].

We observed a boy with chromosome 22 q11 deletion, born with adducted thumbs, low-set ears, micrognathia, velopharyngeal insufficiency, fusion of the first cervical vertebrae and presenting mild mental retardation, impaired speech and hyperCKemia.

He was the second child of non-consanguineous healthy parents, his sister had scoliosis without neuromuscular problems. At birth the child had flexed and adducted thumbs, hyperflexion of the three central fingers of the hands for agenesis of the extensor muscles, clinodactyly of the fifth finger which was abnormally long, small low-set ears with shortened helix and antihelix, prominent nose and slight micrognathia. Analysis of the karyotype ruled out chromosomal abnormalities. He began to walk at 13 months, speech was grossly delayed. At 4 years he underwent surgical transposition of the tendons in the right hand and at 5 in the left hand. In spite of the surgical correction, difficulties of visuo-motor coordination and of fine movements of the hands were noted and treated by physiotherapy. In the first school years learning problems appeared; the boy did poorly and he also had communication problems with his peers. A phoniatric assessment detected velopharyngeal insufficiency with hypomotility of the uvula. The patient had to be assisted by remedial education and speech therapy through his childhood and adolescent years.

The patient was referred to us at age 17 (Fig. [1]). He was 165 cm tall. Neurological examination showed, besides micrognathia and malformed ears, a stiff face with slight ptosis of the lids, a pear-shaped nose, down-turned mouth, hypomotility of the palate with nasal speech. Hands were malformed with poor opposition of the thumbs and reduced extension of the fingers; there was slight wasting of the upper girdle, without winging scapulae. Muscle strength was normal, reflexes were present. Routine laboratory examinations and thyroid function tests were within normal limits. Serum creatine kinase (CK) was 1014 U/l (normal values up to 190). Electrocardiography was normal. X-ray of the skull and of the cervical spine demonstrated fusion of the first cervical vertebrae. Brain CT scan and MRI showed slight ventricle enlargement. Electromyography and motor and sensory conduction velocities were unremarkable.

Fig. 1 A, B The patient at 17 years. A Note the dysmorphic face and slight wasting of the shoulder girdle. B Abnormal hand with poorly functional thumb and atrophy of thenar and interossei muscles.

Muscle biopsy demonstrated very slight fibre size variability. There were no necroses, no basophilia, no increase of nuclei or of connective tissue. Fibre type distribution was normal. PAS reaction showed accumulation of positive material, especially in the subsarcolemmal location, which disappeared after amylase digestion. Acid phosphatase was negative. Phosphorylase was present. Dystrophin, sarcoglycans, emerin, caveolin, and merosin were normally distributed. The ultrastructural observation confirmed the increase of free glycogen, mostly subsarcolemmal, but also amidst the myofibrils (Fig. [2] A). Approximately 10 % of muscle fibres contained spiraling filaments with periodic twin subunit densities, intermingled with glycogen granules, corresponding to the so-called concentric laminated bodies (Fig. [2] B). Biochemical assay confirmed the increased amount of glycogen in the muscle tissue (2.12 g % with normal values 1 ± 0.05). Acid maltase, glycolytic and glycogenolytic enzymes were all within the normal range.

Fig. 2 A, B Quadriceps muscle biopsy: A Electron microscopy 6000 ×: increase of free glycogen within a muscle fibre; B Electron microscopy 24 000 ×: concentric laminated bodies in subsarcolemmal position.

Molecular analysis performed on lymphocytes by fluorescence in situ hybridization (FISH) performed according to the indications given by the provider (Appligene Oncor SA, France) detected a heterozygous chromosome 22 q11 deletion.

Five years' follow-up did not detect changes in the patient's neurological examination; serum CK is still high.

This patient has several typical features of the condition resulting from deletions within the chromosome band 22 q11 [[7], [8]]: craniofacial anomalies with narrow bitemporal diameter, ear anomalies, laterally built-up nose with prominent tip and small nasal alae, down-turned mouth and micrognathia; velopharyngeal insufficiency; small stature; developmental and language delay with learning difficulties. Cardiac malformations, which are common in cases with neonatal presentation, are usually absent in older patients [[7]], like in our case. Indeed 25 % of 545 patients recently reviewed [[8]] had normal hearts or clinically insignificant heart abnormalities.

Limb abnormalities are an uncommon feature of the syndrome and they are variable [[2], [3], [6], [8]]: most cases show syndactyly or polydactyly, but rare thumb anomalies have been reported [[2], [6]]. The presence of adducted thumbs in our case appears very unusual and resembles the so-called adducted thumbs syndrome [[4]], also characterized by velopharyngeal insufficiency, mental retardation, typical face, but still lacking a genetic characterization.

Neuromuscular involvement in velocardiofacial syndrome is not usually considered in the clinical spectrum of chromosome 22 q11 deletion, although hypotonia may be present [[3], [7]]. Muscle function has been only rarely evaluated by EMG, which failed to detect alterations [[3]]; neither CK determinations nor muscle biopsy are reported in the literature. No gene located in the area of the deletion has been related to any myopathy and no known myopathy has been linked to this area. Recently, a 10-year-old girl with velocardiofacial syndrome has been found to present wasting and weakness of the shoulder girdle muscles. Magnetic resonance revealed narrowing of the cervicomedullary junction; serum CK and muscle biopsy were normal [[1]].

Muscle biopsies were studied in occasional cases of adducted thumbs syndrome [[4]] and they showed non-specific myopathic findings.

In our patient, history did not suggest a congenital myopathy: no floppiness at birth was reported, motor milestones were regularly attained, the main disability regarded learning and speech, suggesting brain involvement rather than a neuromuscular disorder. Clinically there were no signs of neuromuscular impairment. EMG failed to demonstrate muscle or nerve abnormalities. The only clue to muscle pathology was the marked increase of serum CK at rest in several determinations. Muscle biopsy disclosed an unexpected accumulation of non-lysosomal glycogen without structural alterations of muscle fibres and in the absence of known enzyme deficiencies. A peculiar finding were the concentric laminated bodies, which may occur in a variety of neuromuscular disorders [[5], [10]]. They are usually associated with glycogen granules but their significance is unclear. Payne and Curless [[5]] described concentric laminated bodies in muscle biopsies of three small children without an overt muscular pathology, but presenting hypotonia presumably due to central nervous system involvement. In our case the marked increase of serum CK speaks against a pathology of the central nervous system alone and the presence of definite, though non-specific, ultrastructural alterations seems to hallmark a myopathy, the precise definition of which remains, however, unclear.

In conclusion, the presented case had a subclinical myopathy, fairly marginal in comparison with the clinical features typical of the chromosome 22 q11 phenotype and which would have been overlooked if serum CK had not been determined. We suggest that muscle involvement may be present in some cases of this syndrome and that it should be considered in the clinical spectrum of this condition.

References

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