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British Journal of Obstetrics and Gynaecology November 1992, Vol. 99, pp. 920-930 CASE REPORTS Recurrent miscarriage, cystic hygroma and incontinentia pigmenti P. D. TURNPENNY Medical Genetics, Medical School R. GUNASEGARAN N. C. SMITH Fetal Medicine Unit, Aberdeen Maternity Hospital J. C. S. DEAN Medical Genetics, Medical School, Foresterhill, Aberdeen AB9 2ZD, UK Case report In her first pregnancy in 1981, the propositus, 11.2 (see pedi- gree, Fig. l), then aged 22 years, presented at 26 weeks from her last menstrual period with no fetal movements. An ultra- sound scan showed a single fetus with no heart pulsation and a biparietal diameter equivalent to 16 weeks. The pregnancy was terminated and at post-mortem the fetus, although mac- erated, was seen to have a large nuchal cystic hygroma. The karyotype from the chorion was 46, XY. The following year she was delivered of an apparently healthy female infant at term, 111.2, who developed a right-sided hemiparesis fol- lowing an illness, described as ‘meningitis’, at 5 weeks of age. However, no pleiocytosis of the cerebrospinal fluid was detected and all cultures were sterile. In her third pregnancy in 1991 to a new partner, a booking scan at 16 weeks revealed cystic hygroma and generalized oedema in a single fetus with a biparietal diameter measurement equivalent to 14 weeks. A chorion biopsy undertaken to exclude chromosomal abnormality showed 46, XY. When she reattended the clinic a week later, the fetal heart pulsations were absent on ultra- sound and the pregnancy was terminated by suction evacu- ation. Following this the propositus was referred for genetic I counselling. Review of her general medical records disclosed a letter in 1972 in which a dermatologist, who had seen her because of atopic dermatitis, had noted classic pigmentary changes of incontinentia pigmenti. Examination of the propositus revealed the typical changes of incontinentia pigmenti with whorled pigmented lesions in the left axilla and on the chest wall (Fig. 2), as well as fine depigmented streaks on her arms and legs. She also had a central vitreous opacity of her right eye which was smaller than her left. Her daughter, 111.2, had typical pig- mented streaks of incontinentia pigmenti and a slightly short right leg with a mild right hemiplegia. The mother of the pro- positus, 1.2, and her two sisters, 11.6 and 11.7, were also found to have clear evidence of incontinentia pigmenti on examin- ation. 11.6 gave a history of two first trimester miscarriages, while 11.7 also had experienced two miscarriages, one at 12 weeks gestation, the other at 19 weeks by dates but of 12 weeks size. Karyotyping on these miscarried fetuses was not done and their sex is not known. Discussion Recurrent miscarriage and fetal cystic hygroma are both indications for determining the karyotype of both the parents and the fetus. Karyotype abnormalities are said to occur in 60-80% of fetuses with cystic hygroma (Edwards & Graham 1990), the most common being 45, X (Turner’s syndrome). followed by autosomal trisomies. Incontinentia pigmenti (Bloch-Sulzberger syndrome) is an X-linked dominant disorder characterized by the develop- ment of cutaneous linear vesiculation in early infancy and neurological involvement (mental retardation, spasticity, microcephaly, hydrocephalus, ocular abnormalities) in a quarter of cases (Baraitser 1990). The skin lesions become Ill 1 2 3 I 4 CH CH Fig. 1. The pedigree with the propositus, 11.2, arrowed. 0. female with incontinentia pigmenti; 0, normal male; 0, miscarriage; CH, cystic hygroma. 920

Recurrent miscarriage, cystic hygroma and incontinentia pigmenti

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Page 1: Recurrent miscarriage, cystic hygroma and incontinentia pigmenti

British Journal of Obstetrics and Gynaecology November 1992, Vol. 99, pp. 920-930

CASE REPORTS

Recurrent miscarriage, cystic hygroma and incontinentia pigmenti

P. D . T U R N P E N N Y

Medical Genetics, Medical School

R. G U N A S E G A R A N N. C. S M I T H

Fetal Medicine Unit, Aberdeen Maternity Hospital

J . C. S. D E A N

Medical Genetics, Medical School, Foresterhill, Aberdeen AB9 2ZD, UK

Case report In her first pregnancy in 1981, the propositus, 11.2 (see pedi- gree, Fig. l ) , then aged 22 years, presented at 26 weeks from her last menstrual period with no fetal movements. An ultra- sound scan showed a single fetus with no heart pulsation and a biparietal diameter equivalent to 16 weeks. The pregnancy was terminated and at post-mortem the fetus, although mac- erated, was seen to have a large nuchal cystic hygroma. The karyotype from the chorion was 46, XY. The following year she was delivered of an apparently healthy female infant at term, 111.2, who developed a right-sided hemiparesis fol- lowing an illness, described as ‘meningitis’, at 5 weeks of age. However, no pleiocytosis of the cerebrospinal fluid was detected and all cultures were sterile. In her third pregnancy in 1991 to a new partner, a booking scan at 16 weeks revealed cystic hygroma and generalized oedema in a single fetus with a biparietal diameter measurement equivalent to 14 weeks. A chorion biopsy undertaken to exclude chromosomal abnormality showed 46, XY. When she reattended the clinic a week later, the fetal heart pulsations were absent on ultra- sound and the pregnancy was terminated by suction evacu- ation. Following this the propositus was referred for genetic

I

counselling. Review of her general medical records disclosed a letter in 1972 in which a dermatologist, who had seen her because of atopic dermatitis, had noted classic pigmentary changes of incontinentia pigmenti.

Examination of the propositus revealed the typical changes of incontinentia pigmenti with whorled pigmented lesions in the left axilla and on the chest wall (Fig. 2), as well as fine depigmented streaks on her arms and legs. She also had a central vitreous opacity of her right eye which was smaller than her left. Her daughter, 111.2, had typical pig- mented streaks of incontinentia pigmenti and a slightly short right leg with a mild right hemiplegia. The mother of the pro- positus, 1.2, and her two sisters, 11.6 and 11.7, were also found to have clear evidence of incontinentia pigmenti on examin- ation. 11.6 gave a history of two first trimester miscarriages, while 11.7 also had experienced two miscarriages, one at 12 weeks gestation, the other at 19 weeks by dates but of 12 weeks size. Karyotyping on these miscarried fetuses was not done and their sex is not known.

Discussion

Recurrent miscarriage and fetal cystic hygroma are both indications for determining the karyotype of both the parents and the fetus. Karyotype abnormalities are said to occur in 60-80% of fetuses with cystic hygroma (Edwards & Graham 1990), the most common being 45, X (Turner’s syndrome). followed by autosomal trisomies.

Incontinentia pigmenti (Bloch-Sulzberger syndrome) is an X-linked dominant disorder characterized by the develop- ment of cutaneous linear vesiculation in early infancy and neurological involvement (mental retardation, spasticity, microcephaly, hydrocephalus, ocular abnormalities) in a quarter of cases (Baraitser 1990). The skin lesions become

Ill 1 2 3

I 4

CH CH

Fig. 1. The pedigree with the propositus, 11.2, arrowed. 0. female with incontinentia pigmenti; 0, normal male; 0, miscarriage; CH, cystic hygroma.

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Page 2: Recurrent miscarriage, cystic hygroma and incontinentia pigmenti

CASE REPORTS 921

Fig. 2. The left axilla and chest wall of the propositus, showing the typical whorled, pigmented skin lesions of incontinentia pigmenti.

pigmentary by the age of two years but later resolve sponta- neously leaving atrophy or depigmentation. X-linked domi- nant inheritance is suggested by the finding that 97% of those affectCd are females. Males have only one X chromosome and it is assumed that early fetal loss almost invariably occurs in males who inherit the gene (Carney 1976). Consequently, miscarriage can be expected in one in four pregnancies in car- rier women and half of their daughters will be affected. Some isolated cases of incontinentia pigmenti have been associated with an X-autosome translocation involving a breakpoint a t Xp11.2 (Cannizaro & Hecht 1987) but molecular analysis in familial cases has shown linkage to Xq28 in one study (Sefiani et ul. 1989), and no linkage to either locus in another (HydCn- Granskog et ul. 1991).

Cystic hygroma is a rare developmental anomaly of the lymphatic system characterized by the formation of a multi- locular cystic mass of variable size, usually occurring in the region of the head and neck. This has given rise to the alter- native terminology: ‘jugular-lymphatic obstruction sequence’. A causal relation with aneuploidy is frequent but unexplained. Nonchromosomal causes include Noonan Syn- drome and a number of rare autosomal recessive syndromes (Edwards & Graham 1990). We believe this is the first report of cystic hygroma occurring in association with a nonchro- mosomal X-linked disease, namely incontinentia pigmenti. In this family cystic hygroma occurred in two male fetuses whose deaths can reasonably be attributed to the incon- tinentia pigmenti gene. Whether affected females develop transient cystic hygroma in utero is undetermined.

It is usually stated that incontinentia pigmenti is lethal in early pregnancy for affected males but this is not necessarily so. This family highlights the following important points: (a) the finding of cystic hygroma on prenatal ultrasound is an indication for thorough clinical examination of the mother, with review of her medical notes, prior to an invasive pro- cedure to determine fetal karyotype; (b) thorough clinical examination and review of medical records is indicated for couples presenting with recurrent miscarriage; and (c) a multi-disciplinary approach involving the clinical genetics service has the potential for avoiding unnecessary gynaeco- logical investigations.

References

Baraitser M. (1990) The Genetics of Neurological Disorders (2nd edn) Oxford University Press, Oxford, pp. 169-170.

Cannizaro L. A. & Hecht F. (1987) Gene for incontinentia pigmenti maps to band Xpl l with an (X; 10) (pll;q22) translocation. Clin Genet 32,66-69.

Carney R. G. (1976) Incontinentia pigmenti-a world statistical analysis. Arch Derm 112,535-542.

Edwards M. J. & Graham J. M. (1990) Posterior nuchal cystic hygroma. Clin Perinatoll7,611-640.

Hyden-Granskog C., Salonen R. & von Koskull H. (1991) Linkage studies in families with hereditary incontinentia pigmenti. A m J Hum Genet 49 (4), Suppl., p. 344.

Sefiani A., et al. (1989) The gene for incontinentia pigmenti is assigned to Xq28. Genomics 4,282-286.

Received 26 February 1992 Accepted 27 April 1992