Continuing Education Activity

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome, also known as CHILD syndrome, is a rare condition that affects different parts of the body. It has been described as an X-linked dominant condition with a male-lethal trait with most surviving patients being females. It is related to mutations in the NSDHL gene. This activity review the epidemiology, evaluation and management of patients with CHILD syndrome and highlights the role of the interprofessional team in caring for affected patients and families.

Objectives:

• Identify the etiology of CHILD disease.
• Explain when to consider CHILD disease on a differential diagnosis.
• Explain the management of CHILD disease.
• Describe the importance of well-coordinated care between the interprofessional teams involved in caring for and counseling individuals and families affected by CHILD syndrome.

Introduction

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome, also known as CHILD syndrome, is a rare condition that affects different parts of the body. In 1903, Dr. Otto Sachs first described this disease in when he summarized his examination of an 8-year-old girl. Since then, many case reports have been published. In 1980, Happle et al. proposed the acronym of the CHILD syndrome for congenital hemidysplasia, ichthyosiform erythroderma, and limb defects.[1][2] It has been described as an X-linked, dominant condition with a male-lethal trait with most surviving patients being females. It is related to mutations in the NSDHL gene. This condition should be suspected at birth if a child presents with a unilateral epidermal nevus. Other commonly seen features include unilateral limb and skin, unilateral ichthyosiform erythroderma, inflammatory variable epidermal nevus, and congenital heart disease.[3][4]

Etiology

CHILD syndrome is a disorder with an X-linked dominant mode of inheritance. It involves a mutation in the NAD[P]H steroid, dehydrogenase-like protein gene which is also known as the NSDHL gene. The NSDHL gene is located on the long arm of the X chromosome at position 28, Xq28. It encodes for the enzyme 3beta-hydroxy sterol dehydrogenase that is involved in cholesterol pathways. Several types of mutations have been reported in the NSDHL gene such as nonsense mutations and missense mutations, and the net effect is a loss of function of the gene.[5][6] Some studies have suggested that the unilateral findings of the symptoms of CHILD syndrome can be related to an abnormal sonic hedgehog signaling during embryogenesis that results from impaired cholesterol processing.[7] The EBP gene has also been reported as a cause of CHILD syndrome in some patients.[8]

Epidemiology

There are about 60 reported cases in literature making CHILD syndrome a very rare condition. This disorder is lethal to males, who die in utero; however, almost all patients presenting with this conditions are females. Nevertheless, there have been 2 reported cases involving living, male patients. One of them had a normal 46 XY karyotype, and Happle et al. explained this finding as a possible early somatic mutation.[2] Features of the condition are visible at birth and persist throughout the lifetime.  Stephanie Jallen, who is a Paralympic skier and medalist, is one of the people afflicted by this condition.

Pathophysiology

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome is a congenital condition that is inherited in an X-linked dominant fashion. NAD[P]H steroid dehydrogenase-like protein gene which is responsible for the enzyme 3beta-hydroxy sterol dehydrogenase is mutated. This enzyme is vital for the synthesis of cholesterol. A deficiency of this enzyme leads to the accumulation of metabolic products from cholesterol biosynthetic pathway. Cholesterol is also essential for the proper formation of membranes and myelin that protects nerve fibers.[5] Most of the clinical and histologic abnormalities seen in CHILD syndrome result from defects in the cholesterol pathway. The most common types of mutations that have been reported in the literature include missense, nonsense, and stop mutations. They lead to a loss of function in the NSDHL gene that eventually affects the cholesterol pathway.[6][9][10]

Histopathology

Skin lesions of patients with CHILD syndrome usually reveal a psoriasiform epidermis with hyperkeratosis and parakeratosis. The papillary dermis usually also has foam cells that express surface markers such as CD68 and CD163 which are specific for macrophages. They do not express pan-cytokeratin markers AE1/AE3 and S100 proteins. Under electron microscopy, numerous lipid droplets and vacuoles are usually seen in the foam cells found in the upper dermis. These cells are made by ingestion of lipids by macrophages. When affected cells and unaffected cells from a CHILD syndrome patient is compared, there are significant differences in the markers of the keratinocytes. This strongly suggests that the difference in the affected skin originates in the keratinocytes and not from external factors or mutant cells. Mi et al. also confirmed these previous findings in their work published in 2015 where their patient with CHILD syndrome had macrophage-derived foam cells.[5]

History and Physical

This condition will present with ipsilateral symptoms affecting multiple systems and organs. All patients with CHILD syndrome will have a congenital ichthyosiform erythroderma. The right side of the body is twice as likely to be affected than the left side. It presents as a unilateral erythematous skin plaque with a midline demarcation usually present at birth. The patient’s face is often spared. Multiple other dermatologic findings are also common such as unilateral ptychotropism, verruciform xanthomas, and scaling alopecia.[11] Hyperkeratosis is also a very common finding seen in 30% to 79% of patients.

The musculoskeletal system can also be affected. Patients present with unilateral limb defects that can range from hypoplasia to agenesis.[2] Such musculocutaneous defects can cause scoliosis in the patients. Epiphyseal stippling on radiographs has been reported in 80% to 99% of cases of CHILD syndrome.

Multiple organ abnormalities such as cardiovascular malformations have also been accounted for and are usually the most common cause of death.

Evaluation

Sterol analysis usually shows elevated levels of C4-methylated and C4-carboxy sterol intermediates due to the defect in the NAD[P]H steroid dehydrogenase-like protein gene. It is vital to detect any skeletal and visceral abnormalities early to provide appropriate care. Radiologic examination such as x-ray, CT, MRI should be performed. Confirmatory diagnosis is possible with DNA sequence analysis to detect any mutation in the NSDHL gene. Skin biopsies can also be performed for the dermatologic lesions.

Treatment / Management

The treatment plans vary according to the severity of the condition. Skin lesions can be treated with topic retinoids and keratolytics. Proper follow-ups should be done with dermatologists, orthopedic specialists, and cardiologists.

Differential Diagnosis

Multiple conditions can occur with similar findings ultimately requiring proper history and tests to be carried out to rule out epidermal nevus syndrome, sebaceous nevus syndrome, inflammatory linear verrucous epidermal nevus, phacomatosis pigmentokeratotica, and X-linked dominant chondrodysplasia puncta.[4]

Prognosis

Patients with a left-sided presentation of symptoms tend to have a less positive prognosis. The most common cause of death in CHILD syndrome is cardiovascular complications.

Complications

Since this condition is X-linked dominant, proper genetic counseling should be encouraged.

Postoperative and Rehabilitation Care

Multiple musculoskeletal deformities can be associated with CHILD syndrome. An early assessment by a pediatric orthopedic surgeon is important. Parents and the patients should be encouraged to follow proper rehabilitation plans.

Consultations

The consultations vary depending on the systems and organs affected. There should be proper follow-ups with a dermatologist for the skin lesions and a pediatric orthopedic surgeon to provide adequate help and treatment for any musculoskeletal abnormalities. Any organ abnormalities such as the heart or the central nervous system should have regular and appropriate follow-ups with a cardiologist and neurologist.

Deterrence and Patient Education

Early genetic counseling and education about the condition before pregnancy can be helpful for the parents.

Pearls and Other Issues

• CHILD syndrome stands for Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome.
• It is an X-linked, dominant condition with a male-lethal trait with most surviving patients being females.
• It is related to mutations in the NSDHL gene.
• Cardiovascular malformations are usually the most common cause of death.
• This condition will present with ipsilateral symptoms affecting multiple systems and organs. All patients have a congenital ichthyosiform erythroderma.
• Multiple other dermatologic findings are also common such as unilateral ptychotropism, verruciform xanthomas, and scaling alopecia.
• The musculoskeletal system can also be affected. Patients present with unilateral limb defects that can range from hypoplasia to agenesis. Such musculocutaneous defects can cause scoliosis in the patients.
• Epiphyseal stippling on radiographs has been reported in 80% to 99% of cases of CHILD syndrome.

Enhancing Healthcare Team Outcomes

Child syndrome is best treated with an interprofessional team of a dermatology specialist nurse and a dermatology clinician. The orthopedic surgeon and orthopedic nurse should assist with treatment for any musculoskeletal abnormalities. Organ abnormalities of the heart or the central nervous system require a cardiologist and neurologist. Genetic counseling and education about the condition before pregnancy from a nurse or clinician geneticist can be helpful for the parents. an interprofessional team approach to the care of this complex disease will provide the best results. [Level 5]