Nsdhl-Related Disorders
Summary
Clinical characteristics.
The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males.
- CHILD syndrome is characterized by unilateral distribution of ichthyosiform (yellow scaly) skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Nail changes are also common. The heart, lung, and kidneys can also be involved.
- CK syndrome (named for the initials of the original proband) is characterized by mild to severe cognitive impairment and behavior problems (aggression, attention deficit hyperactivity disorder, and irritability). All affected males reported have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported.
Diagnosis/testing.
The diagnosis of CHILD syndrome is established in a proband by identification of an NSDHL pathogenic variant that results in loss of functional NSDHL protein. The diagnosis of CK syndrome is established in a proband by identification of a "hypomorphic" NSDHL pathogenic variant that results in partial loss of functional NSDHL protein.
Management.
Treatment of manifestations:
- CHILD syndrome. No one therapy described to date appears to ameliorate the cutaneous findings for every reported individual with CHILD syndrome. Lactic acid 12% skin creams or lotions can reduce itching, and urea skin creams can reduce dryness. Treatment of an inflammatory nevus by grafting skin obtained from a contralateral unaffected region has been successful. Oral aromatic retinoids (etretinate) used to ameliorate cutaneous symptoms have been found to be of limited use and not well tolerated. Topical statins may be beneficial for the treatment of inflammatory nevus. Scoliosis and joint contractures are treated with braces and/or corrective surgery.
- CK syndrome. Behavior modification and/or drug therapy to control aggression and help with ADHD symptoms; antiepileptic drugs to control seizures.
Surveillance:
- CHILD syndrome. Monitoring for new cutaneous lesions and musculoskeletal deformities such as scoliosis and joint contractures.
- CK syndrome. Monitoring for the effectiveness of AEDs in controlling seizures and for the development of scoliosis/kyphosis.
Genetic counseling.
The NSDHL-related disorders are inherited in an X-linked manner. No affected male has reproduced.
- CHILD syndrome is usually male lethal during gestation. Affected females have a 50% chance of transmitting the NSDHL pathogenic variant in each pregnancy; however, the expected live born distribution of persons at risk for CHILD syndrome is 33% unaffected females, 33% affected females, and 33% unaffected males.
- CK syndrome is diagnosed in males. Heterozygous females have a 50% chance of transmitting the NSDHL pathogenic variant in each pregnancy; males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will have normal physical features, intellect, and brain imaging but may display behavioral problems such as irritability and aggression.
Testing of at-risk female relatives and prenatal testing for pregnancies at increased risk for an NSDHL-related disorder are possible if the pathogenic variant has been identified in the family.
Diagnosis
Suggestive Findings
An NSDHL-related disorder should be suspected in an individual with features of CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome (typically in females) and CK syndrome (intellectual disability and associated features in males; CK = initials of the original proband) as follows.
CHILD syndrome
- Unilateral distribution of ichthyosiform nevus
- Limb defects ipsilateral to the skin lesions
- Punctate calcifications of cartilaginous structures
- Visceral malformations
- Central nervous system anomalies
CK syndrome [du Souich et al 2009, McLarren et al 2010, Preiksaitiene et al 2015]
- Central nervous system (CNS) findings: mild to severe intellectual disability, microcephaly, cerebral cortical malformations, spasticity, and seizures
- Characteristic craniofacial features: almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high arched palate, crowded dentition, micrognathia, and plagiocephaly
- Asthenic habitus
Establishing the Diagnosis
Male proband. The diagnosis of an NSDHL-related disorder is established in a male proband with the identification of a hemizygous pathogenic variant in NSDHL by molecular genetic testing (see Table 1).
Female proband. The diagnosis of an NSDHL-related disorder is usually established in a female proband with the identification of a heterozygous pathogenic variant in NSDHL by molecular genetic testing (see Table 1).
Note: Animal models show that male conceptuses with a severe NSDHL loss-of-function allele die early in gestation, explaining the fact that with few exceptions individuals with CHILD syndrome are female [Bornholdt et al 2005, Bittar et al 2006].
Identification of a "hypomorphic" NSDHL pathogenic variant that results in partial loss of functional NSDHL protein confirms the diagnosis of CK syndrome [McLarren et al 2010].
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing, exome array) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of NSDHL-related disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NSDHL-related disorders has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of NSDHL-related disorders molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of NSDHL detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- A multigene panel that includes NSDHL and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of NSDHL-related disorders is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in NSDHL-Related Disorders
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| NSDHL | Sequence analysis 3, 4 | 45/51 5 |
| Gene-targeted deletion/duplication analysis 6 | 6/51 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Extrapolated from Bornholdt et al [2005], Mi et al [2015], Preiksaitiene et al [2015], Yu et al [2018]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Deletion of the gene or of multiple exons has been reported [Bornholdt et al 2005, Kim et al 2005, Yu et al 2018] only in individuals with CHILD syndrome.
Clinical Characteristics
Clinical Description
CHILD Syndrome
CHILD syndrome (Figure 1) is characterized by unilateral distribution of ichthyosiform skin lesions and ipsilateral limb defects (see Bornholdt et al [2005] for a summary of features). The skin and skeletal involvement can be right-sided (seen in ~2/3 of individuals), left-sided, or bilateral [König et al 2002, Hummel et al 2003, Mi et al 2015]. Based on mouse studies and family observation, CHILD-associated NSDHL pathogenic variants are usually lethal to males during gestation.
Figure 1.
Photographs of a female with CHILD syndrome A. Upper left limb. Note the forearm hypoplasia, ectrodactyly, onychodystrophy, and characteristic ichthyosiform skin lesions with yellow scales.
Early death of affected females is usually the result of cardiovascular malformations.
A few males with CHILD syndrome have been reported [Zellweger & Uehlinger 1948, Happle et al 1996]. The male reported by Happle et al [1996] had the typical skin findings seen in females with CHILD syndrome and was developmentally normal. He was mosaic for the c.262C>T (p.Arg88Ter) pathogenic variant in NSDHL [Bornholdt et al 2005].
Dermatologic findings
- Ichthyosiform nevus. The hallmark of CHILD syndrome is the presence of ichthyosiform skin lesions with yellow scales and a sharp demarcation in the midline of the body. The initial ichthyosiform skin lesions are evident at birth or in the first weeks of life; new lesions may develop in later life [Happle et al 1980]. The face is usually spared; scalp alopecia has been reported [Hummel et al 2003]. Most skin lesions improve spontaneously, but some can cause lifelong morbidity. Other skin lesions can develop after infancy at sites of injury such as a surgical wound.Histologically the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates within the dermal papillae [Hebert et al 1987, Hashimoto et al 1995]. The skin lesions from persons with NSDHL pathogenic variants can be distinguished histologically and biochemically from those with chondrodysplasia punctata 2, X-linked, in which unilateral skin and skeletal lesions can occur.Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. Regardless, the specific finding of an ichthyosiform nevus should always raise the possibility of heterozygosity for an NSDHL pathogenic variant. In some females, an ichthyosiform nevus can be present without any associated symptoms of CHILD syndrome in a woman at risk of having a daughter with typical CHILD syndrome [Happle et al 1995]. The relative severity of disease in studied organs reflects the skewing of X-chromosome inactivation [König, unpublished results].
- Verruciform xanthoma-like lesions. Although rare, these types of lesions were reported in a girl age nine years with CHILD syndrome harboring a large deletion of NSDHL exons 3 and 4 [Yu et al 2018].
- Nails. Onychodystrophy and periungual hyperkeratosis are common.
Skeletal features
- Limbs. Ipsilateral hypoplasia of the limbs varies from shortening of metacarpals and phalanges to absence of the entire limb [Happle et al 1980]. Incomplete development or absence of vertebrae, ribs, and long bones has also been reported [Bornholdt et al 2005].
- Other skeletal defects (generally evident in infancy) include scoliosis and joint contractures.
- Punctate calcifications of cartilaginous structures. Unilateral punctate epiphyseal calcifications in the pelvis, ribs, vertebrae, and extremities have been reported [Happle et al 1980] and are usually seen in the affected limb or body part [Hashimoto et al 1995, Hummel et al 2003]. These can be visible on x-ray examination in infancy. In one child, the punctate calcifications were reported to have disappeared completely by age two years [Happle et al 1980]; however, it is not known whether this is the case for every affected child. Ipsilateral stippling has also been observed in the sella turcica and the laryngeal, nasal, and thyroid cartilage [Happle et al 1980, Grange et al 2000].
Other structural anomalies
- CNS anomalies include unilateral hypoplasia or underdevelopment of the brain, lissencephaly type II, and cerebellar malformation [Tang & McCreadie 1974, Schmidt-Sidor et al 2008]. Hypoplasia of cranial nerves V, VII, VIII, IX, and X and the spinal cord was identified on autopsy in the same individual reported by Tang & McCreadie [1974]. The individual reported by Schmidt-Sidor et al [2008] showed multiple left-sided brain anomalies as a consequence of disturbances in proliferation and migration. The Virchow-Robin spaces of the left parietal lobe were locally enlarged in an affected female reported by Yu et al [2018].Intellect is usually normal; some reported individuals have intellectual disability [Baden & Rex 1970].
- Heart defects include septal defects [König et al 2002], unilateral ventricle [Falek et al 1968], and a single coronary ostium [Tang & McCreadie 1974].
- Lung hypoplasia, observed in several individuals [Tang & McCreadie 1974, Bornholdt et al 2005], can cause respiratory compromise and death [Hummel et al 2003].
- Renal findings range from unilateral hydronephrosis to renal agenesis. The frequency of these is unknown.
Other findings. Reported additional findings include hearing loss, absence of facial muscles, and unilateral hypoplasia of the thyroid gland, adrenal glands, ovaries, and fallopian tubes [Happle et al 1980, König et al 2002]. Bilateral optic atrophy has been reported in one individual [Knape et al 2010], as have thrombocytosis and congenital bilateral dislocation of the hip [Chander et al 2010]. Small intestinal mucosal xanthoma was reported in an individual with CHILD syndrome [Ryan et al 2013].
CK Syndrome
CK syndrome (Figure 2) is an X-linked intellectual disability syndrome that affects males. Although 24 affected males from three unrelated families have been identified and fully evaluated, characterization of the syndrome remains limited.
syndrome.">Figure 2.
A male age 11 years (A, B) and a male age 22 years (C,D) with CK syndrome. Note the long thin face, epicanthal folds, almond-shaped palpebral fissures, prominent nasal bridge, and micrognathia. The long thin face becomes more apparent with age.
Development. Affected males have mild to severe intellectual disability. Most cannot speak.
Behavior. Most manifest aggression, attention deficit hyperactivity disorder (ADHD), and irritability. These behaviors appear in infancy and early childhood. According to the Autism Diagnostic Review (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), affected males do not fulfill the criteria for an autism spectrum disorder.
Neurologic findings. All affected males have developed seizures in infancy. These range from multiple daily episodes of brief unresponsiveness associated with staring and facial and/or limb twitching to prolonged generalized tonic-clonic seizures. These likely arise from cerebral cortical malformations which, by MRI examination, are most consistent with polymicrogyria (see Polymicrogyria Overview). Spasticity, tetraparesis, and development of contractures have also been reported.
Craniofacial. Affected males have a long thin face, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high palate, dental crowding, and micrognathia. The ears are normally shaped but rotated posteriorly.
Growth and skeletal. All affected males have microcephaly (<3 SD to <2 SD), a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. The height of affected individuals is average for parental heights.
Ocular findings. Strabismus is common. Optic atrophy is also seen.
Analyte testing associated with CHILD syndrome and CK syndrome
- When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxy-sterols and slightly decreased levels of cholesterol [Grange et al 2000, Hummel et al 2003, McLarren et al 2010].
- In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxy-sterols [RI Kelley, personal communication].
- Serum concentrations of methyl-sterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome.
Heterozygous females. Females heterozygous for an NSDHL pathogenic variant have normal physical features, intellect, and brain imaging but display behavioral problems including irritability and aggression [Herman & Kratz 2012]. Since heterozygous females have normal plasma cholesterol and plasma 24S-hydroxycholesterol levels, du Souich et al [2012] hypothesized that methyl-sterol accumulation accounts for the behavioral and cognitive problems.
Genotype-Phenotype Correlations
CHILD syndrome. Phenotypic variability within the spectrum of CHILD syndrome does not strictly correlate with the predicted severity of NSDHL pathogenic variants [Bornholdt et al 2005, Mi et al 2015].
CK syndrome. The three reported pathogenic variants (c.696_698del, c.1098dup, and c.455G>A) are associated with the same phenotype in affected males.
Penetrance
Incomplete penetrance has not been reported for CHILD syndrome; therefore, the penetrance is probably very high. Of note, expressivity is highly variable; in affected females, CHILD syndrome may manifest as minor skin changes only.
Penetrance is probably 100% in males with CK syndrome.
Nomenclature
CHILD is an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects. CHILD syndrome was first reported in 1903 by Dr Otto Sachs [Bittar & Happle 2004].
CK syndrome represents the initials of the original proband. CK syndrome was first described by du Souich et al [2009].
Prevalence
The prevalence of CHILD syndrome is unknown; more than 60 individuals have been reported thus far.
The prevalence of CK syndrome is unknown; it is thought to be rare.
Differential Diagnosis
See Table 2 (CHILD syndrome) and Table 3 (CK syndrome).
Table 2.
Disorders to Consider in the Differential Diagnosis of CHILD Syndrome
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping | Distinguishing | |||
| Chondrodysplasia punctata 2 | EBP | XL |
|
|
| Schimmelpenning-Feuerstein-Mims syndrome (SFMS) (OMIM 163200) | HRAS KRAS NRAS | See footnote 1 | Skin lesions, which are w/o erythema or scaling, typically follow the lines of Blaschko & involve the face. |
|
| Incontinentia pigmenti | IKBKG | XL |
|
|
MOI = mode of inheritance; XL = X-linked
- 1.
SFMS is sporadic and variable in severity [Wiedemeyer & Hartschuh 2009]. Somatic mosaic pathogenic variants in HRAS, KRAS, or NRAS have been reported in lesional tissue of some individuals.
Table 3.
Disorders to Consider in the Differential Diagnosis of CK Syndrome
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping | Distinguishing | |||
| Lujan syndrome | MED12 | XL |
|
|
| Snyder-Robinson syndrome | SMS | XL |
|
|
| Zinc finger DHHC domain-containing 9-associated ID (OMIM 300799) | ZDHHC9 | XL |
| Joint hypermobility |
| Smith-Fineman-Myers syndrome (OMIM 309580) | ATRX | XL |
|
|
| Renpenning syndrome (OMIM 309500) | PQBP1 | XL |
|
|
| X-linked ID with epilepsy (OMIM 300423) | ATP6AP2 | XL |
|
|
| Christianson syndrome | SLC9A6 | XL |
| Ataxia |
| Shprintzen-Goldberg syndrome | SKI | AD |
|
|
| Methylmalonic aciduria and homocystinuria, cblC type (early-onset form) (see Disorders of Intracellular Cobalamin Metabolism) | MMACHC | AR |
|
|
| Chromosome 17p13.3 microduplication syndrome (OMIM 613215) | See footnote 1 | AD |
|
|
| Chromosome 3q27.3 microdeletion syndrome | See footnote 3 | AD |
|
|