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All cases of ichthyosis prematurity syndrome (IPS), registered at the National Center for Fetal Medicine in Trondheim, Norway between 1987 and 2010 were identified and the findings analyzed. Five fetuses with IPS were identified between 1988 and 2000. All five developed polyhydramnios between 28 and 31 weeks. The fetal stomach appeared to be empty in four cases, and was not described in one case. The fetal skin was described as ‘uneven’ at ultrasound examination in two cases. Separation of chorionic and amniotic membranes with a peculiar appearance of echo-free fluid in the chorionic cavity and echogenic sediment in the amniotic cavity were observed between 28 + 5 and 32 + 3 weeks in all cases. All fetuses were delivered prematurely between 30 and 34 weeks. All neonates had difficulties in breathing, two developed aspiration pneumonia, and one had bilateral pneumothorax after intubation and died at 6 months because of pulmonary and cardiac sequelae. Prenatal sonographic signs of IPS are separation of the membranes, echogenic amniotic fluid and echo-free chorionic fluid occurring between 28 and 32 weeks' gestation. Delivery occurs at 30–34 weeks and, as there is a high risk of asphyxia, an experienced neonatal intensive care unit team should be present at delivery. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.
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Information about cases of ichthyosis prematurity syndrome (IPS) in the population of fetuses with anomalies registered between 1987 and 2010 at the National Center for Fetal Medicine in Trondheim, Norway was analyzed. Maternal, fetal and neonatal records were reviewed to determine the reasons for referral, and to assess pre- and postnatal findings and pregnancy outcome. The study was approved by the ethical committee for clinical research. The prenatal course, delivery and perinatal and postnatal outcome of five cases of fetal IPS, identified between 1988 and 2000, are shown in Table 1. Two cases (Cases 2 and 3) were siblings. The mean age of the mothers was 28.4 (range, 22–34) years.
Table 1. Clinical and sonographic characteristics and perinatal outcomes of five cases of ichthyosis prematurity syndrome (IPS)
|Characteristic/outcome||Case 1||Case 2||Case 3||Case 4||Case 5|
|Year of birth||1988||1991||1991||1996||2000|
|Clinical aspects|| || || || || |
| GA at contractions (weeks)||28||31||30||30||29|
|Ultrasound findings|| || || || || |
| GA at polyhydramnios (weeks)||32 + 0||30 + 5||30 + 2||30 + 0||29 + 5|
| Fetal stomach||Not visible||Not described||Filled with debris||Filled with debris||Filled with debris|
| Fetal skin||—||—||—||Uneven||Uneven|
| GA at which IPS signs detected† (weeks)||32 + 0||30 + 5||30 + 2||32 + 3||28 + 5|
|Intervention|| || || || || |
| GA at amniodrainage (weeks)||32 + 0||31 + 2||N/A*||32 + 3||N/A*|
|Pregnancy outcome|| || || || || |
| GA at delivery (weeks)||32 + 0||32 + 4||30 + 2||34 + 0||31 + 1|
| Mode of delivery||Cesarean||Vaginal||Vaginal||Vaginal||Vaginal|
| Skin at birth||Greasy, thick vernix caseosa-like ‘scaling’||Greasy, thick vernix caseosa-like ‘scaling’||Greasy, thick vernix caseosa-like ‘scaling’||Greasy, thick vernix caseosa-like ‘scaling’||Greasy, thick vernix caseosa-like ‘scaling’|
| Lungs and heart at birth||Intubation, bilateral pneumothorax||Aspiration pneumonia||Aspiration pneumonia||Tachycardia (> 100 bpm)||Breathing difficulties|
| Birth weight (g)||2390||2570||2220||2080||2290|
| Apgar score at 1 min||4||4||5||7||4|
| Apgar score at 5 min||8||6||8||9||6|
|Long-term outcome||Died at 6 months||Survived||Survived||Survived||Survived|
The reasons for referral were pain and contractions (Case 1) or increased abdominal circumference/polyhydramnios (Cases 2 and 4). Cases 3 and 5 had a previous child affected with IPS so these pregnancies were followed prospectively with repeat ultrasound examinations.
Polyhydramnios (defined as a free amniotic fluid pouch ≥ 8 cm) occurred in all pregnancies between 29 + 5 weeks and 32 + 0 weeks (Table 1). In Case 4, polyhydramnios and an apparently empty stomach at 30 weeks first led to the suspicion of esophageal atresia. However, when separation of the membranes and increased echogenicity of the amniotic fluid were identified at 32 + 3 weeks, the presence of a skin disorder was suspected. In all five cases, increased echogenicity of the amniotic fluid and the presence of sediment, together with separation of the membranes, were described. The umbilical cord vessels appeared as dark areas in white amniotic fluid and the fluid in the chorionic cavity was echo-free (Figure 1). None of the pregnancies showed clinical or sonographic signs of IPS prior to 28 weeks.
Figure 1. Ultrasound images showing hyperechogenic amniotic fluid with sediment, separated membranes, polyhydramnios, ‘white’ amniotic fluid and increased echo-free fluid in the chorionic cavity in Case 1 (a); echogenic amniotic fluid (arrow points to the echo-free umbilical cord vessels) in Case 2 (b); echo-free chorionic fluid (arrow) and echogenic amniotic cavity in Case 3 (c); polyhydramnios in Case 4 (d); the split (arrows) between amniotic and chorionic membranes in Cases 4 (e) and 5 (f).
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In Case 1, fetal swallowing was observed but the stomach was not seen. Non-visibility of the stomach associated with polyhydramnios usually raises the suspicion of esophageal obstruction, as in Case 4 at 30 weeks. In Cases 3, 4 and 5 increased echogenic content of the stomach was identified (Figure 2) and examination of the fetal skin revealed an uneven surface (Figure 3). In Case 5 the amniotic fluid was normal at 25–26 weeks, but had sediment at 28 + 5 weeks.
Figure 3. Ultrasound images of uneven skin surface (arrows) of the lower arm in Case 4 (a) and Case 5 (b) and of the forehead (c) and back (d) and in Case 5.
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In Cases 1, 2 and 4 extensive polyhydramnios was present and therapeutic amniodrainage (1.2–3 liters) was performed. These infants were delivered after a mean of 4 (range, 0–10) days. In Case 4, preterm prelabor rupture of the membranes (PPROM) occurred 2 days after amniodrainage and 8 days before delivery. Mean gestational age at delivery in all cases was at 32 + 0 (range, 30 + 2 to 34 + 0) weeks. Mode of delivery was Cesarean section in Case 1 because of suspected placental abruption and was vaginal in the other four cases. Among the five cases, two infants were male and three were female. All infants had erythrodermic edematous skin covered by greasy, thick vernix caseosa-like scaling. Mean birth weight was 2310 (range, 2080–2570) g. Mean Apgar scores were 4.8 (range, 4–7) and 7.8 (range, 6–9) at 1 and 5 min, respectively.
In Case 1, the newborn was intubated and bilateral pneumothorax developed. Death at 6 months, after long-term hospitalization, was due to chronic respiratory disease, pulmonary heart disease, cardiac infarction and disseminated candidiasis. Autopsy showed widespread atelectasis in the lungs. In Cases 2 and 3, the infants developed aspiration pneumonia. The infant in Case 2 had a small atrial septum defect and also developed hydrocephaly which was treated by shunting. At the age of 18 years, the patient was well, with no neurological sequelae. The infant in Case 4 had tachypnea with a frequency of 100–120 bpm during the first few hours following delivery. The infant in Case 5 had breathing difficulties after birth and was intubated and treated with continuous positive airway pressure for 3 days. Further development of these children was normal.
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Inherited ichthyoses belong to a group of clinically heterogeneous, genetically determined disorders of keratinization. Individuals with ichthyosis usually have dry, thickened, scaly or flaky skin. The descriptive term ichthyosis is derived from the ancient Greek word for fish ( (ichthys)) and there are ichthyosis subtypes where the skin resembles the scales on a fish. Ichthyosis includes both congenital and non-congenital forms.
The prenatal diagnosis of severe congenital skin disease is usually based on fetoscopically or sonographically guided skin biopsies taken from fetuses at risk and is thus limited to previously affected families1, 2. Harlequin ichthyosis is a sonographically detectable subtype of congenital ichthyosis, which involves severe eyelid and lip anomalies and flattened ears in addition to large, thick plate-like scales over the entire body3–7. Intra-amniotic skin debris has been described as the sonographic ‘snowflake sign’ of Harlequin ichthyosis8. With its poor prognosis, the disease presents a major long-term therapeutic challenge9.
IPS, also called ichthyosis Type IV, is another rare autosomal recessive syndromic form of congenital ichthyosis with typical ultrastructural alterations of epidermal skin10 which is different from Harlequin ichthyosis. Although IPS is a relatively mild disease during adult life; all infants with this syndrome are born preterm, and many experience asphyxia at birth11. Prenatal diagnosis of IPS is therefore important to optimize perinatal care.
Since the early 1980s, 17 Norwegian and three Swedish families with IPS have been identified. Single case reports from Denmark12, Finland13 and Italy14 have also been described. In 2004, Klar et al. mapped the gene locus for IPS to chromosome 9q3410, and recently it was demonstrated that the gene encoding for the fatty acid transporter protein 4 (FATP4 (encoded by the SLC27A4 gene)) was mutated in all Scandinavian families examined15. It was recently shown that ichthyosis patients from the Middle East and North Africa15 and patients in two German families (D.K., unpubl. data) were homozygous for four novel mutations in FATP4. The fact that IPS has been identified in different countries and with several distinct mutations indicates that it is probably more prevalent than previously described. The relatively mild clinical phenotype during childhood and adult life makes it likely that the disease may be underdiagnosed.
Most IPS patients suffer from perinatal asphyxia due to aspiration of skin debris in the amniotic fluid, and infant death due to respiratory complications has been reported11. Thus, it is important to recognize the disease prior to delivery to optimize perinatal care.
Clinical symptoms, such as abdominal pain and contractions, may occur as early as 28 weeks (Case 1), probably because of polyhydramnios. In our study, polyhydramnios was consistently present between 29 and 32 weeks. Polyhydramnios was also found in some cases of fetal Harlequin ichthyosis4, 16, while other Harlequin cases have been described with normal amounts of amniotic fluid, or even oligohydramnios due to PPROM5, 17. PPROM seems to be common in fetal ichthyosis, which may be due to polyhydramnios, although pathology of the fetal membranes may also be an etiological factor17.
Separation of chorionic and amniotic membranes with a peculiar appearance of echo-free fluid in the chorionic cavity was observed in all cases in our series, as well as echogenic sediment in the amniotic cavity. These phenomena were seen at a mean of 30 + 6 (range, 28 + 5 to 32 + 3) weeks and prior to invasive procedures. We suggest that these typical findings indicate the presence of this syndrome.
In Case 5, we prospectively monitored development from the mid-trimester. Separation of the membranes occurred during week 28. Separation of the fetal membranes is usually not seen in the second half of pregnancy and is often associated with adverse outcome including intrauterine growth restriction, intrauterine fetal death or aneuploidy (trisomy 21)18, 19. Some reports have suggested that, since the amniotic membrane and the surface ectoderm are both of ectodermal origin, there is a possible association between fetal skin disorders and chorioamniotic membrane separation as a result of disturbed membrane attachment17, 20. During embryonic development, amnion is continuous with surface ectoderm and outlines the amniotic cavity.
Echogenic sediment in the amniotic fluid is due to skin debris from the hyperkeratotic disorder and seems to be a common finding in fetal ichthyoses8, 16, 17, 21. It is more dense at the lower part of the amniotic sac, and moves because of gravity when the pregnant woman changes position. It is not seen during early pregnancy but becomes apparent at approximately 28 weeks. The phenomenon of echo-free fluid in the chorionic cavity may be a consequence of high colloid osmotic pressure in the amniotic fluid. In only one previous case report of siblings with a rare lethal restrictive dermopathy syndrome have similar findings been reported17.
The fetal stomach is usually filled with amniotic fluid. An empty stomach and polyhydramnios is a typical sign of esophageal atresia. However, a stomach filled with echogenic debris may appear empty at ultrasound examination, and only a closer look can determine whether the stomach is actually empty or filled with echogenic content (Figure 2). Stomach visibility has not been discussed in previous case reports of fetal ichthyosis. If a fetal skin disorder is suspected, a close look with ultrasound at the fetal skin may reveal abnormalities such as rugged skin surface.
Preterm delivery is an inevitable component of IPS and usually occurs between 30 and 34 weeks despite therapeutic amniodrainage and/or tocolytic treatment. The presence of thick skin debris in the stomach suggests that there is colloidal debris in the fetal airways also, which explains the high risk of aspiration of skin debris and the pulmonary sequelae commonly seen. All five infants in our series experienced reduced pulmonary function postnatally, despite the presence of a prepared neonatal intensive care unit (NICU) team in the delivery room.
We have found only two case reports describing similar clinical development and outcomes in ichthyotic newborns16, 21. Not all of the above sonographic features were discussed in these reports and diagnosis of the disease was not definitive.