Background

The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is an uncommon disease. It is caused by abnormalities which are present by birth in different organ systems like internal organs, skin, musculoskeletal system, and central nervous system. The first report of this disease is from 1903 when Otto Sachs revealed the clinical symptoms in an 8-year-old girl. Zellweger and Uelinger reported a case which involved “half-sided osteochondrodermatitis and nevus ichthyosiformis” in 1948. 

Epidemiology

• Incidence: The incidence of the disease is not known. However, about 60 cases have been reported in the current literature.  
• Sex: As per the sex distribution, more female cases have been reported. This is because of the disease associated with the X-linked dominant gene and lethal in males. 2 cases are reported in males. One case has a normal 46, XY karyotype which suggest that the occurrence of an early postzygotic somatic mutation. 
• Age: CHILD syndrome is a congenital disease. It is present from birth. The dermatosis linked with the disease may occur at birth or arise within the initial weeks of life and continue during the life of patient.  

Anatomy

Pathophysiology

CHILD syndrome is a genetic condition. It is inherited in an X-linked dominant gene. It is caused by a mutation in the NSDHL (NAD[P]H steroid dehydrogenase-like protein) gene. This gene is found on Xq28. It is encoded for the 3-beta-hydroxy sterol dehydrogenase enzyme. It plays an important role in synthesis of cholesterol. Cholesterol is important for different biological processes like hormone production, cell membrane stability, digestive acid synthesis, and nerve fiber myelin formation. 

A mutation that lead to loss of function in the NSDHL gene reduces the ability of enzyme to catalyze a particular step in the biosynthesis pathway of cholesterol in CHILD syndrome. As a result, cells cannot produce cholesterol, accumulate toxic by-products from the synthesis pathway of cholesterol. 

The signs and symptoms of CHILD syndrome differs in severity. It is not affected by specific type of mutation. But the variations are because of the X chromosome inactivation patterns.  

The particular asymmetry in the syndrome is caused by impaired cholesterol production, which can disrupt the sonic hedgehog signaling. This signaling pathway is important for spinal patterning during embryonic development.  

Etiology

CHILD syndrome is caused by X-linked dominant inheritance. The NSDHL gene nutation is associated to it. This gene is found on Xq28 on the X chromosome. The NSDHL gene has few mutations like missense and nonsense which impair the function of gene.  

Genetics

Prognostic Factors

As per the studies, unilateral symptoms in CHILD syndrome may be caused by impaired sonic hedgehog signaling during embryogenesis. This can lead to impaired cholesterol production. 

The EBP gene has been identified as a cause of CHILD syndrome in some patients. Cardiovascular abnormalities are most common cause of early mortality in CHILD syndrome patients. 

Clinical History

Age group: CHILD syndrome has appeared at birth or in early infancy. The signs and symptoms may differ from person to person but continue throughout life.

Physical Examination

CHILD syndrome causes ipsilateral symptoms which affect various organs and systems. Each individual who has CHILD syndrome has ichthyosiform erythroderma from birth. 

The right side of the body has a 2-fold higher risk of getting harmed than the left side of the body. Symptoms like unilateral erythematous skin plaque and midline demarcation are present from birth. The face of the patient is untouched. Other dermatological symptoms like scaling alopecia, verruciform xanthomas, and unilateral ptychotropism have appeared. Another trait is hyperkeratosis. It occurs in 30 to 79 % of the cases. 

Age group

Associated comorbidity

Associated Comorbidity or Activity: CHILD syndrome affects the limbs and skin. There is no particular comorbidities or activities are linked with the syndrome. Individuals who have CHILD syndrome need specialized care because of the severity of limb and skin abnormalities. 

Associated activity

Acuity of presentation

The acuity and severity of the CHILD syndrome can vary into the individuals. Some individuals have mild symptoms which are manageable, and others have more severe and extensive symptoms. The limb and skin abnormalities are present at birth or in early infancy which allow to diagnose the syndrome early.   

Differential Diagnoses

Sebaceous nevus syndrome 

Epidermal nevus syndrome 

X-linked dominant chondrodysplasia puncta 

Phacomatosis pigmentokeratotica 

Inflammatory linear verrucous epidermal nevus  

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Topical emollient ointments, topical retinoids, or systemic retinoids are used to treat the skin condition in CHILD syndrome. Keratolytics also used to give some relief from the symptoms like scaly and dry skin. Lactic acid 12 % lotions or creams are effective for itching. The urea creams can help to reduce the dryness.  

Administration of Pharmaceutical Agents with Drugs

• Keratolytics: Keratolytics agents are used to provide relief for flaky and dry skin. This can be beneficial in the process of skin exfoliation. 
• Ammonium lactate (Lac-Hydrin, AmLactin): Ammonium lactate is used to reduce the itchiness and provide healing process to skin in individuals who are experiencing mild dermatoses and eczemas and mild wounds and skin irritation. Lactic acid is an alpha-hydroxy acid. It is an active component which is responsible for these therapeutic effects. 
• Urea (Ureacin, Ureaphil, Carmol) creams or lotions: Urea us used as a topical remedy to address dry skin. It is used to moisturize the skin and eliminate the surplus keratin in hyperkeratosis conditions. When it is used in 10 to 40% concentrations, it exhibits a keratolytic effects. 
• Topical and systemic retinoids: The systemic and topical retinoids are used to normalize epidermal keratinization.  
• Tretinoin topical (Retin-A, Avita, Renova): Tretinoin topical is used to normalize the keratinization. 

Orthopedic surgery can be performed to treat the limb length difference, other skeletal abnormalities, and joint deformities. Plastic surgery procedure can be used to improve both the function and aesthetic aspects of the affected extremities.  

• Diagnosis and evaluation: The initial phase includes a clinical diagnosis of CHILD syndrome depending on the symptoms like ichthyosiform skin changes and unilateral limb defects. Genetic testing can be used to verify the diagnosis and verify the underlying genetic mutation. 
• Symptomatic treatment: The treatment focuses on the individual symptoms and complications linked with CHILD syndrome. Topical emollients and moisturizers can be used to reduce the scaly and dry skin (ichthyosis). Wound care and infection prevention treatment are necessary to manage skin ulcers and lesions. Physical and occupational therapy can be suggested to address the limb abnormalities and improve mobility. 
• Genetic counseling: Genetic counseling is a necessary part of the management process. It helps families and individuals to understand the genetic base of CHILD syndrome, the risk of recurrence of future pregnancies, and inheritance patterns. Genetic concealer can give information about the reproduction options that are available and support families to make informed decisions. 

Medication

Future Trends

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References

https://pubmed.ncbi.nlm.nih.gov/29939590/