Netherton Syndrome, a Rare Genetic Disorder—Case Report

Netherton syndrome is a rare genetic disorder inherited in an autosomal recessive pattern. Mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene are responsible for this disorder. Netherton syndrome can have multisystemic effects primarily involving the hair, skin and immune system. Currently, no definitive treatment has been reported beyond supportive care. Herein, we report the case of a newborn delivered in our facility with erythematous skin with peeling rash, respiratory distress and suspected early onset sepsis. In the neonatal intensive care unit, the newborn was managed with continuous positive airway pressure support, initial antibiotics and supportive treatment. Diagnosis was established after a skin biopsy, hair sample showing a characteristic bamboo stick appearance and elevated immunoglobulin E levels.


Introduction
Netherton syndrome (NS) is a rare disorder inherited in autosomal recessive pattern [1]. It was discovered by E. W. Netherton in 1958, who reported a unique case of "bamboo stick hair"; this syndrome was later named after him [2]. SPINK5 gene mutation has been found to be responsible for this disorder [3]. The estimated prevalence of NS is 1 in 50,000 to 200,000 live births. It affects the hair, skin and immune system and involves a triad of erythroderma, bamboo stick hair and atopy (elevated immunoglobulin E, IgE) [4]. No specific treatment is available beyond symptomatic management with emollients and the treatment of concurrent complications. Here, we present a case report of a newborn who was delivered in our facility and diagnosed with NS, who had dry scaly skin, high IgE levels and bamboo stick hair (Figs. 1 and 2).

Case Report
A baby boy delivered after 34 weeks of gestation via Cesarian section to first degree consanguineous parents had an unusually thick layer of vernix caseosa. After cleaning of the vernix, the underlying skin was found to be erythematous with generalized peeling and scales in all areas. The baby was admitted to the neonatal intensive care unit (NICU) because of initial respiratory distress and was treated with antibiotics because of suspicion of sepsis, given that his mother had a history of urinary tract infection in her last trimester. Later, antibiotics were stopped after a negative blood culture and negative markers of sepsis were determined. Initially, the baby remained on continuous positive airway pressure support (CPAP) but was gradually weaned to room air, and feeding was started. For his skin conditions, a dermatology opinion was obtained, which advised skin culture and continuing broad spectrum antibiotics until the culture results were available. Meanwhile, a detailed history collected from the mother revealed that two of her brothers had died in early infancy because of skin disorders, and one of her sisters (13 years) had a skin disease for which no diagnostic workup had been conducted. The dermatologist advised skin biopsy and testing of immunoglobulin levels. The IgE level was found to be high, thus prompting suspicion for NS. Later, a hair sample was sent for microscopic examination.
On day 6 of admission, the baby developed hypernatremia with sudden disruption in kidney function, an increase in serum sodium to 185 mmol/l, a creatinine level of 112 µmol/l and a urea level of 14.4 mmol/l. Hypernatremia was managed with half saline infusion and strict intake  output monitoring. The serum sodium gradually decreased, and renal parameters returned to normal ranges.
The skin biopsy results indicated parakeratosis, acanthosis, focal spongiosis and inflammation in the dermis. Hair sample microscopy showed a bamboo stick appearance. Hence, a diagnosis of NS was confirmed on basis of the skin findings, high IgE levels and bamboo stick hair.
After initial respiratory support, intravenous antibiotics and establishment of feeding, the boy was discharged home in stable condition on day 22 of life. Follow up with dermatology, genetic and immunology clinics was advised.

Discussion
NS, a rare autosomal recessive disorder affecting the skin, immune system and hair, is caused by defect in the SPINK5 gene. The incidence of NS has been estimated to be 1 in 200,000, and NS may account for as much as 18% of congenital erythrodermas [4]. The patient reported herein presented with the typical features of erythroderma, bamboo stick hair, respiratory symptoms and later, on day 6, hypernatremia. A similar case has been reported by Okulu et al., in which a 39-week-old newborn was admitted to the NICU with severe respiratory distress requiring mechanical ventilation and ECMO. The child presented with a triad of generalized erythroderma, severe hypothermia and respiratory distress, and a diagnosis was made after a scalp hair sample showed the characteristic trichorrhexis invaginata consistent with a clinical diagnosis of NS [5]. In our case, the newborn was initially treated with intravenous antibiotics because of suspicion of sepsis, given that his mother had a history of urinary tract infection in the last trimester. Antibiotics were stopped after negative blood cultures were obtained. In our case, diagnosis was confirmed after a hair sample showed a typical bamboo stick appearance. Hypernatremia on day 6 was treated with fluid therapy.
The gene responsible for NS has been identified to be SPINK5 on chromosome 5q32 [5]. Only one NS associated mutation has been identified in Arab populations, although more than 80 NS-associated pathogenic mutations in the SPINK5 gene have been reported worldwide [6]. A case report from Hamza et al. has described a boy at the age of 34 days treated in a pediatric immunology clinic, who had a generalized erythematous desquamative skin rash from birth with initially normal IgE levels that later increased. The child had repeated infections, skin and food allergy, and multiple hospitalizations during his infancy. The index patient was suspected to have primary immunodeficiency. Later, at the age of 5 months, hair biopsy and histopathology evaluations using hematoxylin showed psoriasiform acanthosis spongiosis and mild lymphocytic exocytosis with occasional dyskeratotic cells, thus indicating a clinical diagnosis of NS [7]. Similarly, in our case the IgE levels were high, and skin biopsy showed parakeratosis and acanthosis, which prompted suspicion for NS.
Currently, no definitive treatment for NS is available, and diagnosis can be difficult. Supportive management includes treatment of skin lesions with emollients, antihistamines, topical corticosteroids and antibiotics to avoid sepsis. In adults, a role of monoclonal antibodies in management has been reported. However, in the pediatric population, a role of monoclonal antibodies (particularly dupilumab) has been described [8]. In our case, we managed the newborn with initial respiratory support (CPAP), early antibiotic prophylaxis for sepsis, and supportive skin management including emollients and topical corticosteroids.

Conclusion
NS is a rare genetic disorder that can be life threatening in newborns without proper management. Early diagnosis is key for decreasing mortality. Diagnosis is difficult, but early diagnosis can help prevent later poor outcomes. Genetic diagnosis can aid in correct and effective management. Genetic testing for such a rare disorder necessitates the provision of genetic counseling and future reproductive options, particularly for families with high consanguinity who are opposed to abortion. otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.