West syndrome associated with a novel chromosomal anomaly; partial trisomy 8P together with partial monosomy 9P, resulting from a familial unbalanced reciprocal translocation.

West syndrome is classified according to the underlying etiology into an acquired West syndrome, a congenital/developmental West syndrome, and West syndrome of unknown etiology. Causes of a congenital/developmental West syndrome are extensive and include chromosomal anomalies. We report on a patient carrying a derivative chromosome originating from the reciprocal unbalanced translocation t (8;9) (p11.2;p22) and presenting with macrocephaly, West syndrome, severe mental motor retardation and hypotonia. As far as we know, this is a new chromosomal anomaly associated with West syndrome.

Introduction

West syndrome is characterized by hypsarrhythmia on electroencephalography (EEG) examination, infantile spasms, and mental retardation. West syndrome is classified according to the underlying etiology into (1) an acquired West syndrome, (2) a congenital/developmental West syndrome, and (3) West syndrome of unknown etiology.[12] The reported percentage of total cases of congenital/developmental infantile spasms has increased in recent years as the causes of West syndrome have become more readily identified.

We report on a patient, carrying a derivative chromosome originating from the reciprocal unbalanced translocation t (8;9) (p11.2;p22), presenting with macrocephaly, West syndrome, severe mental motor retardation and hypotonia. As far as we know, this is a new chromosomal anomaly associated with West syndrome.

Case Report

The patient was a boy, now 3 years of age, born to healthy non-consanguineous parents after an unremarkable pregnancy. He presented at 5 months of age with hypotonia and craniofacial anomalies, including macrocephaly (head circumference; 48 cm), low-set ears, coarsened appearance and downslanting palpebral fissures, long eyelashes, long philtrum, hypertelorism and a short, broad nose [Figure 1]. We have obtained consent from both parents for publication of pictures of patients in this journal. Family medical history was remarkable for the presence of severe mental motor retardation, epilepsy and macrocephaly in one paternal aunt, one uncle, and one paternally related male cousin. Neurological examination revealed profound hypotonia with brisk deep-tendon reflexes. Fundoscopic examination was normal. Laboratory analyses revealed a normal complete blood count and normal blood chemistry values, including levels of lactate, pyruvate, and ammonia. Tandem mass spectrometry of serum and urine organic acid analysis was normal. Magnetic resonance imaging revealed a dysmorphic corpus callosum with an underdeveloped splenium and absent rostrum together with volume loss of white matter and dilated perivascular spaces [Figure 2]. Magnetic resonance spectroscopy was normal. Cardiac echocardiography and renal ultrasonography revealed no abnormalities. He began to display clusters of sudden flexions of the head, trunk, arms, and legs that occurred several times daily and particularly soon after arousal from sleep at 8.5 months of age. EEG indicated modified hypsarrhythmia, and the patient was diagnosed as having West syndrome. Vigabatrin was administered, and his spasms were resolved after 3 weeks. We examined the affected 5-year-old paternally related male cousin whose physical and neurologic examination was similar to that of our patient and whose medical history was consistent with West syndrome. We were not able to examine the other affected family members.

Figure 1

Dysmorphic features including macrocephaly low-set ears, coarsened appearance, downslanting palpebral fissures, long eyelashes, long philtrum, hypertelorism and a short, broad nose

Figure 2

Sagittal T1-weighted image shows dysmorphic corpus callosum with an underdeveloped splenium and absent rostrum

Cytogenetic analysis of both the patient and his cousin was performed on peripheral blood lymphocyte cultures. To obtain metaphase spreads, peripheral blood lymphocyte cultures were performed in RPMI 1640 culture medium containing 20% fetal calf serum, L-Glutamine, and penicillin-streptomycin. The cultures were incubated for 72 h at 37°C and colcemid were added after 70 h to arrest cell division. Chromosomes were harvested after incubation in a hypotonic solution and fixed with Carnoy's fixative containing acetic acid and methanol in a 1:3 ratio. The obtained chromosomes were observed under light microscope after trypsin-Giemsa staining. At least 30 metaphase spreads were analyzed numerically, and five were analyzed structurally. The results of chromosome analysis revealed a karyotype reported as 46, XY, der (9) t (8;9) (p11.2;p22) [Figure 3a]. Parental chromosome analyses were also performed in the parents of both cases. The origin of the derivative chromosome was a familial translocation detected in our patient's father and his cousin's mother [Figure 3b]. Genetic counseling was given to the family.

Figure 3

(a) Partial karyotype of the patient. The derivative chromosome 9 originating from t(8;9) (p11.2;p22) is seen in the middle (b) Partial karyotype of the patient's father with the translocation chromosomes der (8) and der (9) as well as normal 8 and normal 9

Discussion

Genetic causes should be considered as the standard program for evaluation of the etiology of infantile spasms. The best-documented chromosomal anomalies associated with West syndrome include 1p36 monosomy, chromosome 15 anomalies, trisomy 21, partial duplication of chromosome 2p, monosomy 4p, Williams syndrome, Smith–Magenis syndrome, Pallister-Killian syndrome and monosomy 18p.[345] Our patient and his cousin had a new chromosomal anomaly with West syndrome.

Both subjects had an unbalanced karyotype with a derivative chromosome 9 resulting from a familial translocation between chromosomes 8p and 9p. The karyotypes of the parents were 46, XX, t (8;9) (p11.2;p22) and 46, XY, t (8;9) (p11.2;p22), which means that the translocation is of maternal origin in one case and of paternal origin in the other. This is a reciprocal translocation, and both carrier parents were healthy otherwise.

Previous studies have aimed to characterize the critical deleted region in 9p deletion syndrome.[67] Swinkels et al. (2008) have distinguished two different groups of patients: The first group encompasses those patients that have the clinically recognizable phenotype of 9p deletion (consensus phenotype consisting of trigonocephaly, small palpebral fissures, flat nasal bridge with anteverted nostrils, long philtrum, and micro-/retrognathia); the second group encompasses those patients who, although they have 9p deletion, do not meet the criteria for the consensus phenotype (in particular, they lack the trigonocephaly).[7] A critical region for the consensus phenotype was mapped to the 9p 22.3 region. Our patient does not present with trigonocephaly but presents with other facial dysmorphisms considered characteristic for the 9p deletion phenotype, such as a flat nasal bridge and long philtrum.

In partial trisomy 8p, the clinical picture of the patients comprises hypotonia, structural brain abnormalities, facial anomalies that include a large mouth with a thin upper lip, a highly arched palate, a broad nasal bridge, an abnormal maxilla or mandible, malformed, low-set ears, and orthopedic anomalies.[8] The phenotypes of our patient and his cousin were not similar to both described phenotypes, with the exception of some similarities. We also know that the 8p deletion phenotype differs according to the partner translocation chromosome. Thus, we believe that these siblings are the first in the literature with West syndrome and derivative chromosome 9, which emphasizes the importance of chromosome analysis in cases with congenital abnormalities.

An etiologic diagnosis of West syndrome is very important because it may lead to initiation of a specific therapy that could markedly improve the long-term developmental outcome.[9] Another important reason, for establishing an etiologic diagnosis, is that some of the disorders are genetic in nature, which may carry a significant risk of recurrence in offspring like in our patient. In conclusion, although West syndrome is not a rare finding among chromosomal abnormalities, partial trisomy 8p together with partial monosomy 9p, resulting from a familial translocation, has not, to the best of our knowledge, previously been reported.