THE VARIABLE PHENOTYPE IN TETRASOMY 18p SYNDROME. A PROPOS OF A SUBTLE DYSMORPHIC CASE

Summary: The variable phenotype in tetrasomy i8p syndrome. A propos ofa subtle dysmorphic case: Tetrasomy 18 is a rare chromosomal syndrome. Its frequency is 1/40,000 newborns and more than 40 cases have been reported. In this paper we report a 25-month-old female patient referred for chromosome examination essentially because of delayed psychomotor development. The physical examination showed: microcephaly, mild generalized spasticity, arched eyebrows, horizontal palpebrai fissures with unilateral convergent strabismus, bilateral epicanthic folds, small nose, well placed ears, oral cavity with high arched palate and upper vestibular frenula, tented mouth with slightly everted upper lip, hands with normal palmar creases and long fingers. All the blood tests were normal, while the magnetic resonance imaging reported mild demyelination and polymicrogyria. The karyotype was 47,XX,-H(18)(plO).ish i(18)(plO)(D18Zl+) de novo. Key-words: Tetrasomy 18p - Mental retardation - Karyotype indications - Phenotype ________________.






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Publication: Genetic Counseling
Author: Tapia, A J Brambila
Date published: July 1, 2010

INTRODUCTION

The isochromosomes are, in general, supernumerary chromosomes composed of two copies of the same arm ofa chromosome that may contain one or two centromeres, resulting in a tetrasomy of the involved arm. The range of prevalence of various isochromosomes, considering only the supernumerary, varies from 0.14 to 0.72 per 1000 live births (18).

The tetrasomy 1 8p was first reported by Froland et al. in 1 963 ( 1 9) and confirmed by several other authors. It is considered as a clinical and cytogenetic recognizable disorder (12, 17) resulting from the presence of an extra i(18p). It has a prevalence of 1/140,000 live births and affects both genders equally (16).

The tetrasomy 18p syndrome is characterized by low weight for gestational age, moderate to severe mental and language retardation, signs of pyramidal lesion (muscular hypertonia, abnormal deep tendon reflexes and Babinski sign), inability to feed without aid, asthénie habitus, microcephaly, dolicocephalic skull, strabismus, low-set ears, blepharophimosis, high arched palate, delicate facial features with small mouth and nose, scoliosis and long fingers. Cardiac and renal malformations are rare. Over time, these patients develop facial asymmetry, severe osteoarticular abnormalities, as well as an irritable and destructive behavior. (17, 21).

The diagnosis is usually done with conventional cytogenetics (G bands), although the multicolor fluorescent in situ hybridization (FISH) and multicolor BAND is more specific (3).

In this report, a new tetrasomy 18p case snowing slight signs is described and the "clinical picture" postulated by others is analyzed.

CASE REPORT

The female patient was seen at the age of 25 months. She was the product of the first and only pregnancy of a mother and father aged 28 and 30 years respectively, both healthy and unrelated. She was born by cesarean section at the 4 1 st week of an uneventful gestation. Her Apgar score was 9-9, birth weight 1900 g (< P 3 ) and height 45 cm (< P 3 ). She presented spontaneous breathing and crying and resuscitation was not required, despite having an apparent cyanosis and bradycardia. She remained hospitalized during 15 days because of low weight and sucking difficulties. A delay in her psychomotor development was noted: she controlled her head at 8 months, sat at 1 1 months, crawled at 1 year 1 month, started walking at 1 year 9 months and still does not speak.

Physical examination at 25 months showed weight of 11.1 kg (P 10), height of 88 cm ( P75-90), occipitofrontal circumference of 44.8 cm (< P 3), span/height ratio of 0.99, upper/lower segments ratio of 1 .2 (P 25), mild generalized spasticity (Fig. Ia) with normal osteotendinous reflexes and plantar response, slightly rounded face, arched eyebrows, horizontal palpebrai fissures with convergent strabismus of the left eye, bilateral epicanthic folds, small nose (Fig. Ib), ears with prominent antihelix and hypoplastic lobe (Fig. Ic), oral cavity with presence of three upper vestibular frenula (one in the center and in each canine side), tented mouth and slightly everted lower lip, thorax and abdomen without alterations, genital according to the age and gender, hands with normal creases, long fingers with fetal finger pads and feet with overlapping of the hallux over the second toe.

Laboratory tests including thyroid profile, metabolic screening, blood cell count, blood chemistry and liver function were normal. A cranial magnetic resonance imaging reported mild demyelination and polymicrogyria mainly in frontal and parietal lobes. The electroencephalography showed acute waves and generalized diffuse peaks in all scalp derivations. X-rays of skull, spine and extremities were normal.

CHROMOSOME EXAMINATION

The analysis of 30 G-banded lymphocyte metaphases (Fig. 2a) revealed an extra i(18p) whose identity was confirmed by FISH (Fig. 2b) with the alphoid probe D18Z1 (Vysis 32-130018) in 10 DAPI counterstained metaphases. So, her karyotype was 47,XX,+i(18)(p10).ish i(18p)(D18Zl+). Parental chromosomes were normal.

DISCUSSION

So far, there are more than 40 reported cases of tetrasomy 18p, most of which are de novo, with some rare familial cases (Table I) (1, 22, 23). The molecular study of 19 patients with i(l 8p) revealed that 1 8 of them were due to a maternal non-disjunction error (mostly in meiosis II), while only one was of paternal origin (in meiosis I) (6, 9). These findings imply that the majority of de novo isochromosomes 18p arise from a non-disjunction error during maternal meiosis II as a first step, leading to a trisomie zygote and followed by a second error in the centromere division, resulting in the formation of the isochromosome (10, 19).

Although molecular studies assume that most isochromosomes arise during the maternal meiosis II, Boyle and colleagues showed that a germ mosaicism in parents and recombination with the normal homologous during meiosis, can be indistinguishable from an error in meiosis II. They suggested therefore that the recurrence risk should include this possibility of parental mosaicism (5).

In tetrasomy 18p syndrome, many of the clinical features in infancy evolve to a different phenotype (observe in table I the differences in the percentages before and after the age of twelve years). Thus, seizures, strabismus and scoliosis/xyphosis, which are age-dependent, are more frequent in older patients whereas the delicate face of infancy can change to a coarser one.

As shown in table I, tetrasomy 18 has a wide range of clinical manifestations and it is difficult to make a precise clinical diagnosis, because the more common features described such as mental retardation, spasticity, strabismus, low-set malformed ears, microcephlay or a delicate facies, are not specific. Besides the evolving phenotype, this lack of clinical specificity makes mandatory a careful physical examination with special consideration for the age-dependent features, before evoking tetrasomy 18p as a possible diagnosis.

Until now, all the reported patients with tetrasomy 18p are distributed along a broad age range (1 month-42 years) and in most of them the life expectancy does not seem to be reduced, largely owing to the low frequency of cardiac and other major malformations (Table I). However, the quality of life is poor, mainly due to mental retardation and the derived complications.

In the present case, no "recognizable tetrasomy 18p syndrome" was clinically detected and only a very subtle dysmorphism was observed. As the psychomotor delay was the most important criterion for karyotype request and subsequent diagnosis, the present report emphasizes the importance of this test in such cases with only affected psychomotor development and no or very little dysmorphism.

AKNOWLEDGEMENT

We are indebted to Dr. Horacio Rivera, and the Genetic Counseling referees because their help on manuscript revision.

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Author affiliation:

CYAJ. BMMBILA TAPIA1,2 L. FIGUERA2, N.A. VÁZQUEZ CÁRDENAS1,2 V. RAMÍREZ TORRES2, A.I. VÁZQUEZ VELAZQUEZ2, C. GARCÍA CONTRERAS1,2 AND M.L. RAMÍREZ DUEÑAS1,2

Author affiliation:

(1) División de Genética, Centro de Investigación Biomédica de Occidente, IMSS

(2) Doctorado en Genética Humana, Universidad de Guadalajara, México.

Author affiliation:

ADDRESS FOR CORRESPONDENCE:

María de Lourdes Ramírez Dueñas

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