Title

[原著］EXPRESSION OF 4P MONOSOMY PHENOTYPEIN HETEROZYGOUS PERICENTRIC INVERSION OFCHROMOSOME 4 ASSOCIATED WITH 18 TRISOMYMOSAICISM

Author(s) Nantomi, Kenji; Miyagi, Chuken; Izumikawa, Yosinori;Yosida, Kaoru; Hirayama, Kiyotake

Citation 琉球大学医学会雑誌 : 医学部紀要 = Ryukyu medicaljournal, 10(2): 87-93

Issue Date 1987

URL http://hdl.handle.net/20.500.12001/2312

Rights 琉球医学会

Ryukyu Med. J., 10(2) : 87-93, 1987.

EXPRESSION OF 4P MONOSOMY PHENOTYPE IN

HETEROZYGOUS PERICENTRIC INVERSION

OF CHROMOSOME 4 ASSOCIATED WITH

18 TRISOMY MOSAICISM

Kenji Nantomi, Chuken Miyagi, Yosinori IzumikawaKaoru Yosida, and Kiyotake Hirayama

Department of Pediatrics, School of Medicine

University of the Ryukyus

Abstract

A patient with pencentric inversion of chromosome 4 associated with 18 trisomy mosaicism is

reported. The phenotype of the patient was complicated with relatively mild phenotypes of 4p

monosomy and 18 trisomy. Chromosomal analysis by high-resolution banding technique revealed

inversion(4) associated with 18 trisomy mosaicism. The karyotype was designated as 46, XY, inv(4)

(pl6q21ユ)/47, XY, inv(4) (p16q21」L), +18. The pericentric inversion was transmitted by the healthy

father with normal phenotype and mentality. This is the first case that phenotype of 4p monosomy was

expressed in inversion(4) heterozygosity.

Introduction

Pencentric inversions of autosomes are relatively rare except for those of chromosomes 1,

9 and 16 (Nielsen and Sillesen, 1975). A problem originated from pericentric inversion is

aneusomie de recombinaison (Lejeune and Berger, 1965), which may produce a recombinant

chromosome resulting from crossing-over in gametogenesis. This recombination is known as

one of the major causes of duplication/deficiency (chromosomal aberration) syndromes.

Previous reports of pericentric inversion of chromosome 4 were found almost always associated

with 4p tnsomy due to aneusomie de recombinaison of pericentric inversion.

We present a patient with pencentric inversion of chromosome 4 associated with 18

trisomy mosaicism. The phenotype of the propositus was consisted of features characteristic

to 4p monosomy and 18 tnsomy, though both of them were relatively mild. This phenomenon

is not in conformity with a general agreement that inversion heterozygosity does not have

apparent ill effects to phonotype (Wahrman et al., 1972 and Carpenter et al., 1982).

Case Report

The propositus was a 57-day-old boy born to a 34-year-old primigravida healthy mother and

a 36-year-old healthy father. The parents are not related. The mother conceived him after

88 Kenii Naritomi et al.

inductions of ovulation because of infertility. She was treated for threatening abortion at the

second month of gestation. The infant was delivered at 39th week by Cesarean section because

of fetal distress. His birth weight was 2,064g. Mild asphyxia and cloudiness of amniotic fluid

were noted. Cyanosis due to respiratory distress developed so soon after birth and malforma-

tions of the left forearm were noted that he was transported to NICU of a regional hospital.

His physical condition progressed to apnea, bradycardia and convulsions of the upper extrem-

ities. He was intubated and managed with a ventilator. He was referred and admitted to our

hospital for further examinations of multiple congenital anomalies and convulsions when he

was 57 days of age.

At the time of admission his stature was dwarfed and malnourished. He weighed 3,010g (-

2.8SD) and was 49.5 cm in length仁2.8SD). Head circumference was 32.5 cm (-3.4SD) (Fig. 1).

Head was microcephalic and brachycephalic with a wide anterior fontanel. Small round

median scalp defect was noted on the occiput. Forehead was high and bossing. Glabella was

prominent with capillary hemangioma in the middle portion. Eyebrows were sparse toward the

interior. Palpebral fissures were slanted downward slightly. Nasal bridge was high with

normal nasal tip. Corners of mouth were downturned and its opening was small. Chin was

small and slightly receded. Ears were slightly low-set.

In the thorax and the abdomen, mild short sternum, hepatomegaly and bilateral inguinal

Fig. 1 Facies of the propositus at 57 days of age (a), and 6 months of age (b). Relatively mild

expression of 4p monosomy phenotype and 18 trisomy phenotype was noted.

INV 4) WITH 18 TRISOMY 89

hernia were noted (herniorraphy was carried out at ll months of age). Heart sound was

normal. External genitalia was also normal.

In the extremities, left forearm was short and left hand was clubbed. Ipsilateral thumb was

hypoplastic and distally implanted. Left second to fifth fingers were camptodactylic with no

second flexion creases. Left upper and lower extremities were shorter and hypoplastic

compared with the right. Muscular tonus was hypotonic. Dermal ridges were hypoplastic and

two arch patterns were noted.

Laboratory Findings

Except for moderate anemia, other routine biochemical and serological data were within

normal range. Congenital heart disease was denied by ECG and echocardiography. The

findings of EEG and brain CT-scanning were normal in spite of past history of convulsions. In

X-ray examination of left upper extremity, hypoplasia of radius and ulna was revealed. Radius

was more severely hypoplastic. Left first metacarpal bone was rudimentary and phalanges of

left thumb were also hypoplastic.

Cytogenetics

Chromosome preparations were obtained from conventional whole blood cultures for 72

hours. GTG banding technique was modified as 0.025% trypsin treatment for 30 seconds at 0 C,

and RHG banding technique was used to confirm the results (Dutrillaux and Lejeune, 1971).

High-resolution banding technique by ethidium bromide was carried out with a slight modifica-

tion to analyze the breakpoints more precisely (Ikeuchi and Sasaki, 1979).

Two kinds of cell populations were detected by an analyses of 62 cells. One was 46, XY

and the other was 47, XY,十18 with a ratio of 2/1 (40/22). Furthermore, abnormal arm ratio

(shorter p and longer q) was observed in one of chromosome 4 in all cells. Inversion of

chromosome 4 (4p-4q+) was suspected. The analyses of the parents revealed the same

inversion(4) in the father. The mother had a normal female karyotype. Paternal transmission

of inversion(4) to the propositus was confirmed.

As a result of analyses by high-resolution GTG and RHG bandings, the breakpoints of the

propositus and the father were same, namely pl6 and q21.1 (Fig. 2). The karyotype of the

propositus was designated as; 46, XY, inv(4) (pl6q21.1)/47, XY, inv(4) (pl6q21.1),+18. Those of

the father was 46, XY, inv(4) (pl6q21.1).

Discussion

The phenotype of the propositus is characterized by a mixture with those of 4p monosomy

and 18 trisomy, and its expression was relatively mild (Table. 1). The reason why mild

phenotype of 18 tnsomy was expressed is easily explained by the mosaicism. But the reason

why mild phenotype of 4p monosomy was expressed is not explained by inversion(4) by itself,

even though the critical deleted segment of 4p monosomy is from pl6 to terminal (Wilson et al.,

90 Kenji Naritomi et al.

Fig. 2　Partial karyotype of chromosome 4 0f the propositus. High-resolution GTG banding

(550 band stage) and RHG banding (400 band stage) revealed a pericentric inversion. The

karyotype was designated as 46, XY, inv(4) (pl6q21.1)/47, XY, inv(4) (pl6q21.1), + 18.

1981) and band pl6 involved in the breakpoints of the propositus. Generally inversion heter-

ozygosity does not cause an abnormal phenotype (Wahrman et al., 1972 and Carpenter et al.,

1982). Actually the father of the propositus, who had a same heterozygous inversion(4), is

phenotypically and mentally normal. One different situation in our case is that inversion(4) was

associated with 18 trisomy mosaicism. Several speculations are considered;

(1) Mild expression of 4p monosomy phenotype may be a phenocopy which has no concern

with the inversion(4) and 18 tnsomy mosaicism.

(2) Altered DNA sequence at the site of the breakpoint (pl6) might have expressed in combina-

tion with conjoined trisomic aneuploid mosaicism, though it might not have expressed inver-

sion(4) alone.

(3) A submicroscopic deletion at the bearkpoint (pl6) might have been induced newly in the

paternal gametogenesis or in mitotic nondisjunction which might have ocurred after fertiliza-

tion.

INV(4) WITH 18 TRISOMY

Table. 1 Comparison of clinical findings among the propositus, 18 tnsomy

and 4p monosomy.

Clinical findings　　　　　　　　　　　18 trisomy　　4p mososomy propositus

General

Feeble fetal activity

Growth deficiency

Hypoplasia of skele亡al muscle

Mental deficiency

Hypotonia

Seizure

Cranio faCial

Low-set malformed auricles

Small oral opening

Micrognathia

Wide fontanels

Microcephaly

Epicanthal folds

Cleft lip +/- palate

Slanted palpebral fissures

Hypertelorxsm

Colobomata of iris

S亡rabismuS

Prominent glabella

Down亡urned fish-like mouth

Short upper lip and philtrum

more than　50%　　　　usual

more than　50完　　　　usual

more than　50完　　　　usual

more than　50完　　　　usual

more than　50完　　　　usual

usual

more than　50^

more than　50完

more than　50完　　　　usual

10-502

10-50%　　　　　　usual

10-50%　　　　　　usual

10-50%　　　　　　usual

less than 10%

less than lO%　　　usual

less than lO完　　　usual

usual

usual

usual

usual

posterior midline scalp defects　　　　　　-　　　　　　usual

Cranial asymmetry

Preauricular tag or pit

Frontal bossing

Exophthalmo s

Defec亡　of medial half of the

eyebrows

CNS

Hands and feets

Absence of distal crease

Arch dermal ridge pattern

Hypoplastic to absent thumbs

Simian crease

Rocker-bottom feet

Hypoplastic dermal ridges

Low dermal ridge count

Tellpes equmovarus

Other skeletals

Radial aplasia

Trunk

Short sternum

Inguinal or umbilical hernia

Sacral dimple

Cardiac

VSl)

ASD

PIA

Genitalia

Cryptorchidism

Hypospadias

Skin

Mild hirsutism of forehead and

back

Others

Hemangiomata

usual

usual

usual

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INV(4) WITH 18 TRISOMY 93

The first case of pericentric inversion of chromosome 4 was reported by Morishima et al.

(1964), which had an abnormal large submetacentric chromosome 4 and multiple anomalies.

This abnormal chromosome seemed to be rec(4), dup q. More detailed cases were reported by

Wilson et al. (1970), Rethore et al. (1974) and Dallapiccola et al. (1974). These three cases were

all rec(4), dup p, which contributed to delineate 4p trisomy syndrome (due to parental per-

icentric inversion). Five other reports were found in the literatures (Soukup et al., 1974, Serville

et al., 1977, Andersen et al., 1981, Baccichetti et al., 1982 and Carpenter et al., 1982) (Table 2).

In these previous reports neither the case with aneuploidy nor the case with the phenotype

similar to 4p.monosomy was found.

References

Andersen, 0., Lundsteen, C. and Niebuhr, E∴ A complex four break rearrangement betweeil chromo-

some 4 and 13 resulting in a recombinant chromosome 4. Cytogenet Cell Genet 30: 3-10, 1981.

Baccichetti, C, Tenconi, R., Caufin, D. and Bortotto, L∴ Study on segregation of the inversion of

chromosome 4 (pl5.2qll) in two unrelated families. Hum Genet 62: 117-120, 1982.

Carpenter, N.J., Say, B. and Barber, N.D.: A homozygote for pericentric inversion of chromosome 4. J

Med Genet 19: 469-471, 1982.

Dallapiccola, B., Capra, L., Preto, G., Covic, M. and Dutrillaux, B∴ Pencentnc inversion of chromosome

4: inv(4) (pl3q35) and trisomy 4p by aneusomie de recombinaison. Ann Gさn芭t 17: 115-118, 1974.

Dutrillaux, B. and Leieune, J.: Sur une nouvelle technique d'analyse du caryotype humain. C R Acad

Sc Paris 272: 2638-2640, 1971.

Ikeuchi, T. and Sasaki, M∴ Accumulation of early mitotic cells in ethidium bromide-treated human

lymphocyte cultures. Proc Jpn Acad 55B: 15-18, 1979.

Leieune, J. and Berger, R∴ Sur deux observations familiales de translocations complexed. Ann Genet

Paris　8: 21-30, 1965.

Morishima, A., Liu, N. and Grumbach, M.M∴ Multiple congenital anomalies associated with probable

pericentric inversion of chromosome No- 4 and mosaicism in an asymptomatic mother. J Pediatr 65:

1096-1097, 1964.

Nielsen, J. and Sillesen, I.: Incidence of chromosomal aberrations among ll,148 newborn children. Hum

Genet 30: 1-12, 1975.

Rethore, M.0., Dutrillaux, B., Job, J.C. and Lejeune, J∴ Trisomy 4p by aneusomie de recombinaison of

an inv(4) (pl4q35). Ann Genet 17: 109-113, 1974.

Soukup, S.W., Yarema, W. and Robinow, M∴ A pericentric inversion of chromosome 4 with a t (4q+

lOp-) and a familial t (DqDq) in a mentally retarded girl. Humangenetik 25: 69-78, 1974.

Wilson, M.G., Tower, J.W., Coffin, G.S. and Forsman, I.: Inherited pericentric inversion of chromosome

4. Amer J Hum Genet 22: 679-690, 1970.

Wilson, M.G., Tower, J.W., Coffin, G.S., Ebbin, A., Siris, E. and Brager, P∴ Genetic and clinical studies

in 13 patients with the Wolf-Hirschhorn syndrome. Hum Genet 59: 297-307, 1981.