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Mosaic terminal del(19)(q13.33:) in a girl with seizures and mental retardation

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Editor—Constitutional deletions of chromosome 19 are very rare.1 At present, only one case of 19p deletion2 and six cases of a de novo proximal deletion of 19q have been reported. The 19q deletions include an interstitial deletion del(19)(q12q13.1) and a submicroscopic de novo deletion of 19q13 resulting from t(X;19)(p21;q13) in a patient with Diamond-Blackfan anaemia and congenital anomalies.3 ,4 The analysis of familial and sporadic cases of Diamond-Blackfan anaemia showed four additional patients with de novo microdeletions that overlap the 19q13.2 region.5-7 No cases with a deletion of the terminal segment of 19q have been described so far. We report the first case of a constitutional terminal mosaic deletion of 19q with a breakpoint at band 19q13.33.

The proband, a girl, was the result of the first pregnancy of healthy, unrelated, Estonian parents. At the child's birth, the mother was 20 and father 24 years old. The pregnancy was uneventful and the child was born at 42 weeks. Birth weight was 3920 g, length 51 cm, and head circumference (OFC) 35 cm. She was asphyxiated at birth (Apgar score was 2 at five minutes) and required artificial ventilation for two hours. On the third day she had severe muscle spasticity (diplegia spastica II) and opisthotonos. At 1 year, spasticity of the muscles became progressively severe and her psychomotor development was delayed; she was not able to sit or stand. At the age of 10 years, she had severe mental retardation, absence of speech, and extremely severe spasticity of the muscles (tetraparesis spastica, ankylosis). Seizures began at the age of 21 years (once a week). Physical examination at the age of 25 years (fig 1) showed a girl with short stature (130 cm, <3rd centile) and microcephaly (OFC 52.5 cm, <2nd centile), corresponding to the development of a 9 year old child. She was very thin with little subcutaneous fat. Minor anomalies included a low forehead, a beaked nose with hypoplastic nasal alae, a high palate, malocclusion of the teeth, and a transverse palmar crease on the left palm. The vertebral column was very deformed with lumbar lordosis and kyphoscoliosis. The lower extremities were deformed with flexion contractures of the knees. Secondary sex characteristics were undeveloped. The heart, urinary system, and other internal organs showed no congenital anomalies.

Figure 1

The proband aged 25 years.

Chromosome analysis was done on cultured lymphocytes using GTG and RHG banding according to standard procedures. Fluorescence in situ hybridisation was performed with whole chromosome 19 painting probe (WCP 19) directly labelled with Spectrum Orange fluorophore (Vysis Inc, Downers Grove, IL, USA). To detect the chromosome specific subtelomeric regions, TelVysion DNA probes specific for 19q directly labelled with Spectrum OrangeTM fluorophore (Vysis Inc) were used. The parents were unavailable for chromosome analysis. Urinary amino acids and serum levels of TSH, T3, T4, cortisol, testosterone, progesterone, and oestradiol were measured by an Arcus fluorometer with DELFIA kits (Wallac, Turku, Finland).

Cytogenetic studies on cultured lymphocytes showed a mosaic deletion in the distal part of 19q in 14% of the 300 metaphases studied. The breakpoint was at q13.33 (fig 2). FISH analysis with a WCP19 probe showed a signal only on the chromosome 19 and no other chromosomes (fig3). Hybridisation of a telomeric probe specific for 19q gave one signal in the metaphases with a deleted chromosome 19, while all other metaphases had two signals on the normal 19q. The proband's karyotype was interpreted as: mos 46,XX,del(19)(q13.33:)/46,XX.

Figure 2

Partial karyotype of the proband showing GTG and RHG banding of normal and deleted chromosome 19 (arrowed).

Figure 3

(A) FISH with WCP19 probe showed metaphase with one deleted and one normal chromosome 19. Hybridisation of the telomeric probe for 19q directly labelled with Spectrum Orange fluorophore showed metaphase with (B) normal 19q and (C) deleted 19q.

Serum levels of hormones were normal, except for the decreased oestradiol level (0.044 nmol/l, normal range 0.1-2.0 nmol/l). Urinary amino acids were normal. Haematological examination showed no anaemia.

We describe the first case of terminal deletion for the region of 19q13.33-qter, it being the seventh one with a constitutional deletion of 19q. The small number of cases of 19q deletion reported so far may either be because of their rarity or early lethality. In our patient the longer survival was probably the result of the mosaicism of the deletion. The clinical features of our patient and the previously reported six cases of deletion 19q are not similar (table 1). This is probably because of the differences in the size and position of the deleted segments. Although a complete genotype-phenotype correlation cannot be established in this patient, some genes mapped in 19q may help to explain the specific features. The comparison of phenotypes in patients showed some common features, such as growth retardation, mental retardation, and skeletal anomalies of the long bones and spine. These features were described in most patients including four patients with both Diamond-Blackfan anaemia and deletion of 19q13.2.5-7 Absence of anaemia in our patient may confirm that the deleted segment is more distal to the Diamond-Blackfan anaemia critical gene region on 19q13.2. Growth retardation has many causes including deletion of the gene encoding transforming growth factor β-1 (TGFB1, 19q13.1-13.3). This patient and some of the other patients also have a high palate, strabismus, and little subcutaneous fat.

Table 1

Clinical features in patients with 19q deletions3–7

Our patient has a pattern of features that seem to be more specific to the deleted 19q13.33-qter region, such as a beaked nose, malocclusion of the teeth, transverse palmar crease, seizures, and absence of both anaemia and major congenital anomalies of the internal organs. The impact of the known genes which are hemizygously deleted in this patient (for example, carcinoembryonic antigen gene family) on the phenotype is unclear. Prepubertal external genitalia in our patient could be related to the decreased level of oestradiol in serum. These clinical features might constitute a distinct 19q distal deletion syndrome.

Acknowledgments

We thank all the staff of Karula Homeschool for help in the management of patients. This study was supported by grant No 3025 from the Estonian Science Foundation.

References

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