Extremely preterm infant with persistent peeling skin: X-linked ichthyosis imitates prematurity

Introduction

X-linked ichthyosis (XLI) is a disorder of keratinization characterized by generalized scaling of the skin with extracutaneous manifestations, inherited in an X-linked recessive manner [1]. The prevalence of XLI is about 1 in 4,000 male births, and almost exclusively affects males [2]. In 90% of cases, a deletion in the steroid sulfatase (STS) gene is implicated [2]. Adjacent genes may be affected depending on the size and location of the deletion, leading to associations with Kallmann Syndrome (hypogonadotropic hypogonadism, hearing loss, color blindness, and impaired sense of smell due to a gonadotropin releasing hormone deficiency), cryptorchidism, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder [3]. XLI is one of the most common forms of ichthyosis, along with ichthyosis vulgaris [1].

The typical clinical presentation is characterized by dry, scaly skin which becomes more pigmented over time [1]. Since dry and flaky skin in extremely preterm infants is common, identification of XLI creates a diagnostic challenge in this population [4]. The diagnosis can be made through a skin biopsy which tests STS activity levels, or through mutation analysis of the STS gene on the X chromosome [1]. Skin biopsies are often nonspecific and challenging in extremely preterm infants, and therefore genetic testing is increasingly relied on for diagnosis [4]. This case report describes a 24 week gestation male who presented with dry peeling skin and was subsequently diagnosed with XLI via genetic testing on day of life 105 (39 weeks postmenstrual age). To our knowledge, this case report documents both the most preterm infant and earliest postnatal age of XLI diagnosis, while highlighting a potential novel association with pulmonary findings.

Case presentation

A 25-year-old mother gravida 3 para 0020 presented at 24 weeks gestation with preterm premature rupture of membranes. The mother's past medical history was notable for obesity and pre-eclampsia. One course of antenatal steroids and magnesium sulfate were administered 22 h prior to delivery. On the day of delivery, labor was induced due to signs of chorioamnionitis. The labor period was prolonged for two days in this case, which is common during the delivery of infants with XLI [5]. Mothers of babies with XLI often have a delayed delivery or failed induction of labor leading to cesarean delivery due to low levels of estrogen secondary to low STS activity [5]. The infant was delivered vaginally at 24 and 2/7 weeks gestation and required chest compressions, intubation, and positive pressure ventilation prior to transfer to the neonatal intensive care unit. Apgar scores were 1, 1, 2, and 7 at 1, 5, 10, and 20 min, respectively.

The physical exam revealed cryptorchidism, which is common in preterm infants, but also attributable to XLI and adjacent gene deletion. The initial skin exam noted pink, thin, translucent and sticky skin, with scattered petechiae on extremities, consistent with extreme prematurity. Dry and flaky skin was visible on the chest as early as day of life 9, with hyperpigmentation on the lower extremities on day of life 81 (Figure 1). On day of life 105, chromosomal microarray revealed a 1.7 megabase deletion at Xp22.31, which included the STS gene and confirmed the diagnosis of XLI. The patient's mother was subsequently found to be a carrier of the deletion via fluorescence in situ hybridization, excluding a novel mutation in the infant. In addition, the family history was notable for dry and scaly skin in the patient's maternal uncle.

Figure 1:

X-Linked ichthyosis imitates prematurity: time lapse of physical exam during NICU hospitalization.Dry, peeling skin on day of life 9 (A), day of life 17 (B), day of life 29 (C). Hyperpigmentation and scales seen on lower extremities on day of life 81 (D).

Despite the high degree of prematurity, the patient's respiratory course was out of proportion for the infant's gestational age and receipt of antenatal steroids. After receiving two doses of surfactant therapy, the infant failed conventional mechanical ventilation, and was quickly escalated to high frequency ventilation and developed pulmonary interstitial emphysema. Postnatal steroids were started on day of life 14, which resulted in the infant transitioning to a conventional ventilator. A second course of postnatal betamethasone one month later resulted in successful extubation to noninvasive ventilation. At 36 weeks post menstrual age (PMA), the patient was diagnosed with bronchopulmonary dysplasia, requiring nasal intermittent positive pressure ventilation with an FiO₂ of 23%. He was discharged on day of life 135 (43 weeks PMA) on ¼ liter FiO₂ 100% as well as inhaled budesonide, with no evidence of pulmonary hypertension. To our knowledge, there are no other reported cases of a child with XLI and severe respiratory problems.

On day of life 56, the ophthalmic exam revealed stage one retinopathy of prematurity (ROP) in zone two. In a subsequent eye exam, there was stage two ROP in zone one bilaterally, for which the patient underwent corrective laser surgery. Interestingly, corneal opacity, a hallmark symptom, was not present in this patient.

Upon follow-up examination at adjusted age 8 months, the patient was weaned off oxygen and prescribed albuterol sulfate 2.5 mg/3 mL solution for three times daily usage. His ROP which was initially treated with laser surgery was found to have regressed. The patient's ichthyosis rash was controlled with petrolatum ointment daily as well as a steroid cream when necessary. He is receiving occupational therapy to ensure that he continues to meet his adjusted milestones, and his behavior was appropriate for his age.

Discussion

X-linked ichthyosis is a rare genetic condition caused by a deletion in the steroid sulfatase gene [2]. This STS deficiency manifests cutaneously as dry, scaly, pigmented skin in neonates [1]. Since it is common for desquamation and large scales to appear on the skin of very premature infants up to several weeks postnatally, XLI is challenging to diagnose in very preterm infants [4]. The differential diagnosis of preterm infants with dry, scaly skin includes cutaneous candidiasis, congenital ichthyosis including ichthyosis prematurity syndrome and congenital ichthyosiform erythroderma, or a bacterial infection such as Staphylococcal scalded skin syndrome [1, 4]. Management of cutaneous symptoms in neonates and infants is limited to maintaining skin hydration and use of emollients to decrease scale formation [2].

To date, the most premature infant reported in the literature with XLI was a 28 week gestation male diagnosed at 11 years of age [6]. His clinical findings included dry skin with peeling scales in addition to neurodevelopmental issues, including psychosis, intellectual disability, autism spectrum disorder, inattentive ADHD, and epilepsy [6]. The neurodevelopmental findings are consistent with other case reports, which note XLI associated with ADHD, autism, epilepsy, and other psychiatric disorders. For example, our patient had the same 1.7 megabase deletion at Xp22.31 as a patient in another case report, encompassing six genes; STS, PUDP, MIR4767, VCX, PNPLA4, and MIR651. This patient later presented with ADHD and mild autism in addition to the classic cutaneous features of XLI [7]. At an adjusted age 8 months, our patient has development appropriate for his age, yet this deletion necessitates the need for long term neurodevelopmental surveillance.

The severity of our patient's lung disease may also be attributable to the STS gene defect reported in XLI. While there are no reported studies specifically linking XLI to lung disease, STS is constitutively expressed in the lungs [8]. The role of STS is to hydrolyze estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, which is a crucial step in the synthesis of estrogen from its inactive precursor in human tissues [5]. Estrogen plays an important role in formation of lamellar bodies and release of surfactant [9]. In fetal rabbit lung tissue, estrogen stimulates the synthesis and release of surface active phospholipids and development of lamellar bodies [9]. In addition, glucocorticoids have been shown to decrease STS activity and expression in certain cells, which may partially explain our patient's poor response to both antenatal and postnatal steroid treatment [10]. Given that XLI has behavioral and developmental manifestations that have been attributed to decreased expression of STS in brain tissue, we cannot exclude the possibility that there may be a link to lung disease as well. Moving forward, this patient will continue to be monitored for neurodevelopmental delays as well as respiratory issues.

Conclusions

X-linked ichthyosis is a rare genetic condition that can have varying presentations at birth and can be exceptionally difficult to diagnose in a premature infant. In this case report, we outline the presentation and early diagnosis of a premature baby with XLI and bronchopulmonary disease. Clinicians should be aware of the expression of STS in other tissues, including the brain and lung, in order to understand that there can be an association between XLI and further clinical problems.