Child Syndrome

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 the 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 condition 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 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 the 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 are 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][11][5]

History and Physical

This condition will present with ipsilateral symptoms affecting multiple systems and organs. All patients with CHILD syndrome will have 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.[12] 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 [13]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 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.