History

Erythroderma

Most children with Netherton syndrome develop congenital erythroderma, which is evident at birth or during the first weeks of life, placing them at risk for thermal and electrolyte imbalances, dehydration, and sepsis, owing to the profoundly altered epidermal barrier.

Some children do not survive the neonatal period.

Pruritus is a near constant feature.

The erythrodermic phenotype may persist in some individuals for life, but it is more commonly replaced by the characteristic atopic appearance.

Failure to thrive

Failure to thrive may be marked in the first year of life and is often accompanied by symptoms of dermopathic enteropathy, which is a vague condition characterized by steatorrhea that occasionally accompanies erythroderma. Jejunal villous atrophy has been demonstrated in some patients with Netherton syndrome.

Delayed growth and bone development may continue until approximately the second year of life, when most children improve. However, the majority of patients remain below the 25th percentile for height (short stature) and weight secondary to malnutrition.

Allergic manifestations

All patients eventually develop food allergy, particularly to peanuts, eggs, and fish. Most have an atopic predisposition, with a strong family history of asthma, eczema, and hay fever.

Physical Examination

The origin of the term ichthyosis comes from the Greek ichthys, meaning scaly. In fact, Netherton syndrome has been classified as an ichthyosiform syndrome given the occurrence of ichthyosis linearis circumflexa. However, in most children, the most common eruption is an eczematous dermatitis, with characteristic periorificial accentuation. In one study, flexural lichenification was found in all 7 patients and 2 patients had verrucous hypertrophy of the axillae, the inguinal folds, and the lower legs. Ectropion and taut facial skin can develop in older patients with severe disease.

Collodial membrane

It is generally accepted that collodion membrane is distinct and unrelated to Netherton syndrome. In fact, one study reports that colloidal membrane never leads to Netherton syndrome.^[52]However, Netherton syndrome has been described as a rare outcome of collodion baby, and the accuracy of this association is debated.

Ichthyosis linearis circumflexa

Ichthyosis linearis circumflexa is characterized by polycyclic and serpiginous migratory pink-red plaques with double-edged scale at the margins. It is a hallmark of Netherton syndrome.

Ichthyosis linearis circumflexa usually occurs after age 2 years and is fairly short-lived, lasting from a few weeks (followed by clearance for months) to years.

Ichthyosis linearis circumflexa appears to last longer in adults than in children.

Ichthyosis linearis circumflexa has been reported as an isolated cutaneous finding in the absence of documented Netherton syndrome in very rare cases,^[53]largely prior to our understanding of the genetics of the condition. However, in 2015 its presence was reported in two siblings with a SPINK5 mutation, and it was the only clinical manifestation suggestive of Netherton syndrome.^[54]It is likely pathognomonic of the condition.

Atopic diathesis

Findings include atopic dermatitis, allergic rhinitis, and asthma. There is a case report of a single child with concomitant SPINK5 and FLG2 mutations, resulting in Netherton syndrome and atopic dermatitis.^[55]

Complications

The following complications are recognized:

Cutaneous and systemic infections
Failure to thrive and diarrhea
Temperature instability
Electrolyte imbalances, including hypernatremic dehydration
Severe angioedema and allergies
Atopic manifestations with abnormal accumulation of affected keratinocytes: In children this may lead to altered hearing if the keratin debris is not frequently removed from the ear canal.
Erythroderma and ichthyosis linearis circumflexa

Some patients affected by Netherton syndrome have shown cognitive impairment and developmental delay. Impaired cellular immunity may also be a feature of this condition. The development of aminoaciduria has been described.^[56]

Patients with Netherton syndrome are prone to skin and systemic infections. A study of 12 Finnish patients found that S aureus was the most common skin bacterial species present. Additionally, the patients had lower skin microbiome diversity compared to healthy individuals.^[57]

Rare complications have also been described, including intracranial hemorrhage, hypothyroidism, rickets, pulmonary hypertension, renal vein thrombosis, and acute pancreatitis.^{[48, 58, 59, 60, 61, 62]}

It remains unclear whether patients have an increased susceptibility for skin malignancies such as squamous cell carcinoma.^[63]However, the development of squamous cell carcinomas has been reported in at least 6 patients, including in the vulva and on the penis.^[64]

At least 1 case of dilated cardiomyopathy in a patient with Netherton syndrome, ultimately requiring cardiac transplantation, has been described in the literature. In the setting of resulting immune suppression, the patient went on to develop CD 30⁺ primary cutaneous T-cell lymphoproliferative disorder.^[65]

Differential Diagnoses

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Author

Laura F McGevna, MD Assistant Professor of Medicine, Dermatology Division, University of Vermont College of Medicine

Laura F McGevna, MD is a member of the following medical societies: American Academy of Dermatology, Dermatology Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Van Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

James W Patterson, MD Professor of Pathology and Dermatology, Director of Dermatopathology, University of Virginia Medical Center

James W Patterson, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Dermatopathology, Royal Society of Medicine, Society for Investigative Dermatology, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Tina S Chen Twu, MD Pediatric Dermatologist/Dermatologist, Sharp Rees-Stealy Medical Group, San Diego, CA

Tina S Chen Twu, MD is a member of the following medical societies: American Academy of Dermatology, Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

The author and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Mohsin Ali, MBBS, FRCP, MRCP, and David T Robles, MD, PhD, to the development and writing of this article.