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NSDHL-Related Disorders

, MSc, CCGC, CGC, , MD, PhD, , PhD, and , MD, PhD.

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Initial Posting: ; Last Update: November 25, 2015.


Clinical characteristics.

The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked dominant condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked recessive 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.


CHILD syndrome and CK syndrome are caused by pathogenic variants in NSDHL. Identification of an NSDHL pathogenic variant that results in loss of functional NSDHL protein confirms the diagnosis of CHILD syndrome. The diagnosis of CK syndrome relies on identification of a "hypomorphic" NSDHL pathogenic variant that results in partial loss of functional NSDHL protein.


Treatment of manifestations:

  • CHILD syndrome. No one therapy described to date seems 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. Antiepileptic drugs (AED) to control the seizures; behavior modification and/or drug therapy to control aggression and help with ADHD symptoms.


  • 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 inherited in an X-linked dominant manner and 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 inherited in an X-linked recessive manner. 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.

GeneReview Scope

NSDHL-Related Disorders: Included Phenotypes 1
  • CHILD syndrome
  • CK syndrome

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Suggestive Findings

An NSDHL-related disorder should be suspected in an individual with features of the 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 [Bornholdt et al 2005, Bittar et al 2006]

  • 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 testing approaches can include single-gene testing, use of a multigene panel, and genomic testing:

  • Single-gene testing. Sequence analysis of NSDHL is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes NSDHL and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes NSDHL) fails to confirm a diagnosis in an individual with features of an NSDHL-related disorder.Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Summary of Molecular Genetic Testing Used in NSDHL-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
NSDHLSequence analysis 3, 434/39 5
Gene-targeted deletion/duplication analysis 65/39 7
Unknown 8NA

See Molecular Genetics for information on allelic variants detected in this gene.


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.


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


Extrapolated from Bornholdt et al [2005]


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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.


Deletion of the gene or of multiple exons has been reported [Bornholdt et al 2005, Kim et al 2005] in CHILD syndrome only.


Although controversial [König et al 2002, Elias et al 2012], pathogenic variants in EBP have been reported in rare persons with clinical features similar to CHILD syndrome [Grange et al 2000]. To date, no other individuals with EBP pathogenic variants and clinical features similar to CHILD syndrome have been reported.

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 cases), left-sided, or bilateral [König et al 2002, Hummel et al 2003]. Based on mouse studies and family observation, CHILD-associated NSDHL pathogenic variants are usually lethal to males during gestation.

Figure 1.

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 CDPX2 (chondrodysplasia punctata type 2), 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 cases, an ichthyosiform nevus can be present without any associated symptoms of CHILD syndrome in a woman at risk of having a daughter with full-blown CHILD syndrome [Happle et al 1995]. The relative severity of disease in studied organs reflects the skewing of X-chromosome inactivation [König, unpublished results].
  • 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, which are 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

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 a patient with CHILD syndrome [Ryan et al 2013].

CK Syndrome

CK syndrome (Figure 2) is an X-linked recessive 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.

Figure 2. . A male age 11 years (A, B) and a male age 22 years (C,D) with CK 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, epicanthic folds, almond-shaped palpebral fissures, prominent nasal bridge, and small jaw. 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. As per the Autism Diagnostic Review (ADI-R) or 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, are most consistent with polymicrogyria (see Polymicrogyria Overview). Spasticity was recently reported in one individual.

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 (<3SD-<2SD), 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 methylsterol 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 correlate with the predicted severity of NSDHL pathogenic variants [Bornholdt et al 2005].

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.


Incomplete penetrance has not been reported for CHILD syndrome; therefore, the penetrance is probably very high. Of note, expressivity is highly variable and may only manifest as minor skin changes in affected females.

Penetrance is probably 100% in males with CK syndrome.


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].


The prevalence of CHILD syndrome is unknown; more then 60 individuals have been reported thus far.

The prevalence of CK syndrome is unknown; it is thought to be rare.

Differential Diagnosis

CHILD Syndrome

Chondrodysplasia punctata type 2 (CDPX2) (OMIM 302960). This X-linked dominant condition is characterized by skeletal abnormalities, skin manifestations, and ocular anomalies. The skin findings include congenital generalized ichthyosiform nevus consisting of bilateral linear or patchy whorls of follicular hyperkeratosis. Skeletal signs include asymmetric shortening of the limbs, short stature, and epiphyseal stippling. Pathogenic variants of EBP are causative [Braverman et al 1999, Derry et al 1999, Herman et al 2002].

Schimmelpenning-Feuerstein-Mims syndrome (SFMS) (OMIM 163200). SFMS is a systematized sebaceous nevus syndrome. The skin lesions, which are without erythema or scaling, typically follow the lines of Blaschko and involve the face. Associated problems include cerebral anomalies; coloboma of the iris, choroid, or eyelids; and conjunctival lipodermoid. 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 patients.

Incontinentia pigmenti (IP). IP is an X-linked condition, embryonic lethal in many males, affecting primarily the skin, hair (alopecia), teeth (hypodontia), nails (onychogryposis), eyes (peripheral neovascularization), and CNS (seizures, intellectual disability). The skin lesions present as erythema and then blisters at birth, progress to a wart-like rash (stage II), swirling macular hyperpigmentation following the lines of Blaschko (stage III), and finally linear hypopigmentation by adulthood (stage IV). A deletion removing exons 4-10 in IKBKG is present in approximately 65% of affected individuals.

CK Syndrome

The X-linked recessive inheritance, intellectual disability, and asthenic habitus of this disorder overlap with several disorders. Recognizing that the physical features of CK syndrome could overlap with non-X-linked disorders, evidence of X-linked inheritance is a critical diagnostic criterion. For completeness, however, other non-X-linked disorders that share similar phenotypes are included here in the differential diagnosis.

Lujan-Fryns syndrome (LFS). Individuals with LFS were originally characterized as having intellectual disability (ID) and a marfanoid habitus [Lujan et al 1984]. With time the phenotype has been extended to comprise macrocephaly, a long narrow face, maxillary hypoplasia, a long nose with a high narrow bridge, a short and deep philtrum, a thin upper lip, a high arched palate, micrognathia and retrognathia, low-set posteriorly rotated ears, nasal speech, generalized hypotonia, and abnormalities of the corpus callosum. Additionally, many have a slender habitus with long, thin fingers and toes as well as joint hypermobility and pectus excavatum [Van Buggenhout & Fryns 2006]. LFS has been associated with mutation of MED12, UPF3B, and ZDHHC9 [Raymond et al 2007, Schwartz et al 2007, Tarpey et al 2007] and with a terminal deletion of chromosome 5q [Stathopulu et al 2003]. In a recent publication by Hackmann et al [2016], the authors did not identify a pathogenic variant in any of the associated genes in 28 individuals with ID and a marfanoid habitus, cautioning clinicians that the diagnosis of LFS should be restricted to the more stringent criteria mentioned above.

Snyder-Robinson syndrome (SRS) is characterized by a slender body, a long thin face, prominent lower lip, high arched palate, and long fingers and toes [Snyder & Robinson 1969]. Other features include diminished muscle bulk, osteoporosis, kyphoscoliosis, intellectual disability, hypotonia, unsteady gait, and nonspecific neurologic problems [Arena et al 1996, Cason et al 2003]. This X-linked recessive disorder is associated with mutation of SMS, encoding spermine synthase, located on Xp22.11 [Cason et al 2003, Becerra-Solano et al 2009].

Zinc finger DHHC domain-containing 9-associated intellectual disability (OMIM 300799) is an X-linked recessive disorder of thin habitus, long face and digits, joint hypermobility, and moderate intellectual disability. It is associated with mutation of ZDHHC9, the gene encoding palmitoyltransferase ZDHHC9.

Smith-Fineman-Myers syndrome (SFM1) (OMIM 309580). Males with SFM1 have intellectual disability with severe speech delay, microcephaly, short stature, narrow face, slanted palpebral fissures, ptosis, infantile hypotonia, and development of hypertonia in adolescence to early adulthood [Smith et al 1980]. This X-linked recessive disorder is associated with mutation of ATRX.

Renpenning syndrome (OMIM 309500). Mutation of PQBP1, the gene encoding polyglutamine-binding protein 1, causes X-linked recessive intellectual disability, microcephaly, short stature, heart defects, cleft palate, and microphthalmia [Martínez-Garay et al 2007].

X-linked mental retardation with epilepsy (XMRE) (OMIM 300423) is characterized by X-linked recessive moderate to severe intellectual disability, generalized tonic-clonic seizures, scoliosis, progressive gait disturbance, and pes planus [Hedera et al 2002]. It is caused by mutation of ATP6AP2, the gene encoding the renin receptor.

Christianson syndrome. Mutation of SLC9A6, which encodes a monovalent sodium-selective sodium/hydrogen exchanger, causes profound intellectual disability, microcephaly, epilepsy, and ataxia [Gilfillan et al 2008, Tarpey et al 2009]. Christianson syndrome is inherited in an X-linked manner.

Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis, distinctive dysmorphic features, skeletal abnormalities, mild to moderate intellectual disability, and brain anomalies [Shprintzen & Goldberg 1982]. SGS can also present with cardiovascular and abdominal wall defects, myopia, decreased subcutaneous fat, and cryptorchidism in males. SGS resulting from mutation of SKI (the only gene know to be associated with SGS) is inherited in an autosomal dominant manner..

Methylmalonic aciduria and homocystinuria, cblC type is a common autosomal recessive inborn error of vitamin B12 metabolism caused by loss-of-function variants in MMACHC on chromosome 1q34.1. The early-onset form presents with hypotonia, seizures, developmental delay, microcephaly, congenital heart malformation, pigmentary retinopathy, and anemia [Rosenblatt et al 1997, Andersson et al 1999]. Dysmorphic features include long face, high forehead, flat philtrum, and large, floppy, and low-set ears [Cerone et al 1999]. See Disorders of Intracellular Cobalamin Metabolism.

Chromosome 17p13.3 microduplication syndrome (OMIM 613215) presents with a broad phenotypic spectrum that can include microcephaly, dysgenesis of the corpus callosum, and other subtle brain defects; intellectual disability; marfanoid habitus; hypotonia; and dysmorphic features includng frontal bossing, low-set ears, broad nasal bridge, downslanting palpebral fissures, and triangularly shaped chin [Bi et al 2009, Roos et al 2009, Bruno et al 2010].

17p13.3 microduplications are grouped into two classes determined by the presence or absence of three genes: YWHAE, PAFAH1B1, and CRK [Bruno et al 2010].

  • Class I microduplications (presence of YWHAE but not PAFAH1B1) are associated with autistic features, speech and motor delays, and subtle dysmorphic features.
  • Class II microduplications (presence of PAFAH1B1 and sometimes CRK and YWHAE) are associated with intellectual disability and hypotonia and similar dysmorphic features to the class I microduplication.

Microcephaly is characteristic of individuals with duplication of PAFAH1B1 but not of YWHAE or CRK.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CHILD syndrome, the following are recommended:

  • Dermatologic evaluation
  • Radiologic examination of trunk and extremities for skeletal malformations
  • Abdominal and pelvic ultrasounds examination to identify visceral malformations
  • Chest imaging to evaluate for lung hypoplasia
  • Echocardiogram to identify cardiac involvement
  • Magnetic resonance imaging to determine brain involvement
  • Consultation with a clinical geneticist and/or genetic counselor

To establish the extent of disease and needs in an individual diagnosed with CK syndrome, the following are recommended:

  • Measurement of height, weight, and head circumference
  • Evaluation of neurologic history and EEG for evidence of seizures
  • Psychoeducational evaluations to define delays and facilitate appropriate interventions
  • Psychiatric evaluation if behavioral problems are present
  • Ophthalmologic consultation for evaluation of ocular findings including strabismus and optic atrophy
  • Orthopedic evaluation to determine the presence of scoliosis/kyphosis
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

CHILD syndrome

  • Oral aromatic retinoids (etretinate) to ameliorate cutaneous symptoms; however, this drug is often poorly tolerated [Happle et al 1980] and does not prove effective in every case [Liu et al 2015].
  • Topical treatments including lactic acid 12% creams or lotions for itching and urea creams for dry skin. Oral and topical ketoconazole were found to result in a 90% reduction of cutaneous lesions after ten days of therapy [Liu et al 2015].
  • Topical statins. The use of lovastatin topically led to complete healing of the inflammatory CHILD nevus in a few single cases, whereas cholesterol application alone had no satisfactory effect [Merino De Paz et al 2011, Paller et al 2011]. Alexopoulos & Kakourou [2015] recently reported the combined topical use of simvastatin and cholesterol and showed a correction in the cutaneous phenotype of one patient.
  • Dermatologic surgery. An inflammatory nevus was removed from an affected boy by dermabrasion; however, it recurred within eight months [Happle et al 1996]. König et al [2010] reported successful treatment of an inflammatory nevus by grafting skin obtained from a contralateral unaffected region.
  • Note: No one therapy described to date appears to ameliorate the cutaneous findings for every reported individual with CHILD syndrome. Trying different methods until the clinician finds a successful therapy seems to be typical for most affected individuals.
  • Orthopedic abnormalities. Treatment of orthopedic abnormalities such as scoliosis and joint contractures with braces and/or corrective surgery
  • Other medical care as appropriate based on clinical findings

CK syndrome

  • Antiepileptic drugs to control seizures
  • Behavior modification and/or drug therapy to control aggression and help with ADHD symptoms
  • Ophthalmologic management of ocular abnormalities


CHILD syndrome

  • Regular surveillance for cutaneous manifestations as new lesions may occur in puberty or early adulthood
  • Orthopedic surveillance for musculoskeletal deformities such as scoliosis and joint contractures
  • Neurologic, cardiologic, or renal surveillance depending on clinical involvement

CK syndrome

  • Neurologic surveillance of seizures for readjustment of medications if necessary
  • Orthopedic surveillance for scoliosis/kyphosis

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The NSDHL-related disorders are inherited in an X-linked manner.

Risk to Family Members ‒ CHILD syndrome

Parents of a proband with CHILD syndrome

Sibs of a proband with CHILD syndrome

  • The risk to sibs depends on the genetic status of the mother.
  • If the mother of the proband has an NSDHL pathogenic variant, the chance of transmitting it in each pregnancy is 50%. However, since studies suggest that male conceptuses with an NSDHL pathogenic variant generally abort or resorb spontaneously [Cunningham et al 2005], the expected live born distribution is 33% unaffected females, 33% affected females, and 33% unaffected males.
  • If the pathogenic variant identified in the proband cannot be detected in leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism in the mother.

Offspring of a female with CHILD syndrome

  • The risk to the offspring of females with CHILD syndrome must take into consideration the presumed lethality to affected males during gestation.
  • At conception, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, since male conceptuses with an NSDHL pathogenic variant generally abort or resorb spontaneously, the expected liveborn distribution is 33% unaffected females, 33% affected females, and 33% unaffected males.

Offspring of a male with CHILD syndrome. Most males with CHILD syndrome are not born alive. No reproductive data are available on males with CHILD syndrome.

Other family members. The risk to other family members depends on the status of the proband's mother: if the proband's mother has the NSDHL pathogenic variant, her family members may be at risk.

Risk to Family Members ‒ CK syndrome

Parents of a proband with CK syndrome

  • The father of an affected male will not have the disorder nor will he be hemizygous for the NSDHL pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected male, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the NSDHL pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. The frequency of germline mosaicism is unknown.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo NSDHL pathogenic variant, in which case the mother is not a heterozygote. The frequency of de novo pathogenic variants is unknown.

Sibs of a proband with CK syndrome. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband is heterozygous for an NSDHL pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will usually not be affected.
  • If the pathogenic variant cannot be detected in the DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a male with CK syndrome. No affected male has reproduced.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes for the pathogenic variant and the aunts’ offspring, depending on their gender, may be at risk of being heterozygotes for the pathogenic variant or of being affected.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: Females who are heterozygous for this X-linked disorder may have a range of clinical manifestations (see Clinical Description).

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the NSDHL pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for an NSDHL-related disorder are possible.

Biochemical testing is theoretically possible, although it has not been reported for NSDHL-related disorders. Additionally, limb deficiency or another skeletal anomaly detected by fetal ultrasound suggests the possibility of recurrence; however, mild manifestations may not have detectable limb findings.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

NSDHL-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
NSDHLXq28Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylatingNSDHL @ LOVDNSDHLNSDHL

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for NSDHL-Related Disorders (View All in OMIM)


Gene structure. NSDHL comprises eight exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants

Table 3.

Selected NSDHL Pathogenic Variants

PhenotypeDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
CHILD syndromec.262C>T 1p.Arg88TerNM_001129765​.1
CK syndromec.455G>Ap.Gly152Asp

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Identified as mosaic mutant allele in male with CHILD syndrome (see Clinical Description)

Normal gene product. The NSDHL enzyme, which localizes to the surface of the endoplasmic reticulum and to lipid droplets, is a member of a multiprotein complex and functions as a C4 demethylase in post-squalene cholesterol biosynthesis [Gachotte et al 1998, Mo et al 2002, Caldas & Herman 2003]. The protein contains 362 amino acids.

Abnormal gene product

  • In CHILD syndrome, NSDHL pathogenic variants result in substantial or complete loss of functional NSDHL protein. Some pathogenic variants result in deletion of all or portions of NSDHL protein, whereas pathogenic nonsense and frameshift variants likely result in loss of protein expression by nonsense-mediated RNA decay [Rebbapragada & Lykke-Andersen 2009, McLarren et al 2010]. CHILD syndrome-associated missense variants studied by Lucas et al [2003] fail to complement in the yeast complementation system.
  • In CK syndrome, NSDHL pathogenic variants result in severely reduced steady-state levels of NSDHL protein and thus lead to a partial loss of NSDHL protein function. In yeast complementation studies, these pathogenic variants complement as well as the wild type human NSDHL protein because the mutant proteins are stable at 30º C [McLarren et al 2010].


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Chapter Notes

Author History

Cornelius F Boerkoel, MD, PhD (2010-present)
Christèle du Souich, MSc, CCGC, CGC (2010-present)
Karl-Heinz Grzeschik, PhD (2010-present)
Arne König, MD; Philipps-Universität, Marburg (2010-2015)
F Lucy Raymond, MD, PhD (2010-present)

Revision History

  • 25 November 2015 (me) Comprehensive update posted live
  • 27 June 2013 (me) Comprehensive update posted live
  • 16 February 2012 (cd) Revision: deletion/duplication analysis for NSDHL available clinically
  • 1 February 2011 (me) Review posted live
  • 9 January 2010 (cb) Original submission
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