Clinical Guidance

CK syndrome. The NSDHL pathogenic variants , , and have been consistently associated with CK syndrome. CHILD syndrome. Phenotypic variability within the spectrum of CHILD syndrome does not strictly correlate with the predicted severity of NSDHL pathogenic variants .

Source: GeneReviews — "NSDHL-Related Disorders"

Penetrance

Penetrance appears to be complete in NSDHL-related disorders.

Source: GeneReviews — "NSDHL-Related Disorders"

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . No consensus clinical diagnostic criteria for NSDHL-related disorders have been published.

Suggestive Findings

An NSDHL-related disorder should be suspected in an individual with features of CHILD (congenital hemidysplasia with ichthyosiform nevus [also known as ichthyosiform erythroderma] and limb defects) syndrome (typically in females) or CK syndrome (intellectual disability and associated features in males) as follows.

CHILD syndrome

Source: GeneReviews — "NSDHL-Related Disorders"

Differential Diagnosis

Table 2.

Genes of Interest in the Differential Diagnosis of CHILD Syndrome

Gene(s) | Disorder | MOI | Key Features of Disorder

Overlapping w/CHILD syndrome | Distinguishing from CHILD syndrome

EBP | Chondrodysplasia punctata 2, X-linked | XL | • ≥95% of affected persons are female.

• Linear or blotchy scaly ichthyosiform plaques in newborns; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) scarring

• Asymmetric limb shortening, kyphoscoliosis, chondrodysplasia punctata (epiphyseal stippling)

| • Absence of strict midline demarcation lack of unilaterality seen in CHILD syndrome

• Skin findings fade over time.

• Most persons have follicular atrophoderma by age 2 yrs.

• Ocular anomalies are prominent (develop early in life).

HRAS

KRAS

Source: GeneReviews — "NSDHL-Related Disorders"

Management Guidelines

No clinical practice guidelines for NSDHL-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with CHILD syndrome and CK syndrome.

Evaluations Following Initial Diagnosis

CHILD syndrome. To establish the extent of disease and needs in an individual diagnosed with CHILD syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4a.

CHILD Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Integument

| Dermatologic eval |

Musculoskeletal

| • Radiographs as needed of extremities spine

• Clinical assessment for joint contractures scoliosis

• Referral to orthopedist as needed

| Evaluate for skeletal malformations incl scoliosis.

Neurologic

| • Referral to neurologist

• EEG

• Brain MRI/CT

|

Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Cardiac

| Echocardiogram | Evaluate for congenital heart disease.

Pulmonary

| Chest imaging | Evaluate for lung hypoplasia.

Genitourinary

| Abdominal pelvic ultrasound | Evaluate for renal or other genitourinary anomalies.

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of CHILD syndrome to facilitate medical personal decision making

MOI = mode of inheritance

Source: GeneReviews — "NSDHL-Related Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "NSDHL-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in and are recommended. Table 6a. CHILD Syndrome: Recommended Surveillance

Source: GeneReviews — "NSDHL-Related Disorders"