Clinical characteristics.

NSDHL-related disorders include CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked disorder 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 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. Onychodystrophy and periungual hyperkeratosis are common. Heart, lung, and kidney malformations can also occur.

CK syndrome is characterized by mild-to-severe cognitive impairment and behavior problems (aggression, attention-deficit/hyperactivity disorder [ADHD], and irritability). All reported affected males 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 female proband with a heterozygous NSDHL pathogenic variant identified by molecular genetic testing that results in loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase, the protein encoded by NSDHL. The diagnosis of CK syndrome is established in a male proband with a hemizygous NSDHL hypomorphic pathogenic variant identified by molecular genetic testing that results in partial loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase.

Management.

Treatment of manifestations: In CHILD syndrome, no one therapy described to date appears to ameliorate the cutaneous findings for every reported individual. Oral and topical ketoconazole may reduce lesions. Topical statin treatment alone or combined with cholesterol and/or glycolic acid can be beneficial. Treatment of an inflammatory nevus by grafting skin obtained from a contralateral unaffected region has been successful. Lactic acid 12% creams or lotions can reduce itching, and urea skin creams can reduce dryness. Scoliosis and joint contractures are treated with braces and/or corrective surgery. Standard management for heart, lung, kidney, and gastrointestinal manifestations.

In CK syndrome, developmental and educational support; behavior modification and/or drug therapy to control aggression and help with manifestations of ADHD; anti-seizure medication to control seizures; standard treatments for orthopedic and ocular manifestations; support transition to adult care; and social work and family support as needed.

Surveillance: In CHILD syndrome, monitor for new cutaneous lesions, musculoskeletal deformities such as scoliosis and joint contractures, and neurologic, cardiac, and/or kidney manifestations annually or as needed.

In CK syndrome, monitor for developmental and educational progress, behavioral issues, changes in seizures, and development of scoliosis and/or kyphosis annually or as needed. Follow-up ophthalmology examination per ophthalmologist.

Genetic counseling.

NSDHL-related disorders are inherited in an X-linked manner. CHILD syndrome is usually male lethal during gestation and thus predominantly affects females. CK syndrome predominantly affects males.

CHILD syndrome: If the mother of a 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, the expected live-born distribution is: 33% heterozygous (typically) affected females; 33% unaffected females; and 33% unaffected males.

CK syndrome: If the mother of a proband is heterozygous for an NSDHL pathogenic variant, the expected 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 be heterozygous and may have a range of behavioral problems. Identification of female heterozygotes requires prior identification of the NSDHL pathogenic variant in the family.

Once the NSDHL pathogenic variant has been identified in a family member with an NSDHL-related disorder, prenatal and preimplantation genetic testing are possible.

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

• Unilateral distribution of ichthyosiform nevus
• Limb defects ipsilateral to the skin lesions
• Punctate calcifications of cartilaginous structures
• Central nervous system (CNS) anomalies
• Visceral malformations (heart, lung, and/or renal anomalies)

CK syndrome [du Souich et al 2009, McLarren et al 2010, Preiksaitiene et al 2015]

• CNS findings, including mild-to-severe intellectual disability, microcephaly, seizures, cerebral cortical malformations (polymicrogyria), and spasticity
• Characteristic craniofacial features, such as microcephaly, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high-arched palate, crowded dentition, and micrognathia
• Thin body habitus with normal height

Establishing the Diagnosis

Female proband. The diagnosis of CHILD syndrome is established in a female proband with a heterozygous NSDHL pathogenic (or likely pathogenic) variant identified by molecular genetic testing that results in loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase, the protein encoded by NSDHL (see Table 1). Note: CHILD syndrome is usually male lethal during gestation, although it has been reported in a few males and has been attributed to postzygotic mosaicism.

Male proband. The diagnosis of CK syndrome is established in a male proband with a hemizygous NSDHL hypomorphic pathogenic (or likely pathogenic) variant identified by molecular genetic testing that results in partial loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous or hemizygous NSDHL variant of uncertain significance does not establish or rule out the diagnosis.

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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

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

CHILD Syndrome

CHILD syndrome is characterized by unilateral ichthyosiform skin lesions typically with sharp midline demarcation with ipsilateral limb defects, onychodystrophy, and periungual hyperkeratosis (see Figure 1). Some individuals have scoliosis, joint contractures, central nervous system (CNS) anomalies, and congenital heart defects. CHILD syndrome predominantly affects females and is usually male lethal during gestation. To date, more than 60 individuals have been reported with CHILD syndrome.

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.

Dermatologic findings

• Ichthyosiform nevus (or erythroderma). Cutaneous lesions are characterized by ichthyosiform inflammatory erythematous skin plaques with yellowish and waxy adherent scales and a sharp demarcation at the midline of the body. Lesions can be patchy or continuous. In some individuals, islands of normal skin are apparent within the lesion. Lesions can follow the lines of Blaschko. The skin lesions are right-sided in about two thirds of individuals but can be left-sided or bilateral [König et al 2002, Hummel et al 2003, Mi et al 2015]. The ichthyosiform skin lesions are evident at birth or in the first weeks to few months of life; new lesions may develop in later life. The face is usually spared but can be involved in some individuals. Ipsilateral scalp alopecia has been reported [Hummel et al 2003, Avgerinou et al 2010, Heda et al 2014]. Most of the skin lesions improve spontaneously, but some can cause lifelong morbidity. Lesions in the intertriginous areas tend to be more persistent; this is termed ptychotropism [Happle 1990]. Ichthyosiform 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 (foamy histiocytes) within the dermal papillae [Hebert et al 1987, Hashimoto et al 1995]. The latter phenomenon has been termed verruciform xanthomas (VX); this is a nonspecific histopathologic finding that can be seen in other entities but may help distinguish CHILD nevi from other psoriasiform lesions on histopathology. More recently, tympanoxyloid (drumstick-like) VX involving the distal digits have been reported as a likely more "pathognomonic" finding of CHILD syndrome [Juratli et al 2020]. Verrucous lesions can also involve the mucosal surfaces [Bornholdt et al 2005]. The skin lesions in persons with NSDHL pathogenic variants can be distinguished histologically and biochemically from those in individuals with chondrodysplasia punctata 2, X-linked.
  Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [Happle et al 1995].
• Nails. Onychodystrophy, onychorrhexis, and periungual hyperkeratosis are common. Claw-like nails can be seen.

Skeletal features

• Limbs. Ipsilateral hypoplasia of the limbs varies from shortening of metacarpals and phalanges and sometimes other long bones (hypomelia) to absence of the entire limb (amelia). Joint contractures are reported. Oligodactyly can be seen; polydactyly and syndactyly have been rarely reported. The skeletal involvement is right-sided in around two thirds of individuals, but can be left-sided or, rarely, bilateral [König et al 2002, Hummel et al 2003, Mi et al 2015, Rossi et al 2015].
• Other musculoskeletal defects (generally evident in infancy) include skeletal asymmetry and scoliosis. Incomplete development (hypoplasia) or absence of vertebrae, pelvis, ribs, mandible, and skull has also been reported [Bornholdt et al 2005].
• Punctate calcifications of cartilaginous structures. Unilateral punctate epiphyseal calcifications (chondrodysplasia punctata) in the pelvis, ribs, vertebrae, and extremities have been reported and are usually seen in the affected limb or body part. These can be visible on radiographs in infancy. In one child, the punctate calcifications were reported to have disappeared completely by age two years [Happle et al 1980]; it is not known whether stippling always disappears. 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 [Schmidt-Sidor et al 2008]. One individual had multiple left-sided brain anomalies as a consequence of disturbances in proliferation and migration [Schmidt-Sidor et al 2008]. The Virchow-Robin spaces of the left parietal lobe were locally enlarged in one affected female [Yu et al 2018].
  Intellect is usually normal.
• Heart defects include septal defects [König et al 2002].
• Lung hypoplasia has been observed in several individuals [Bornholdt et al 2005] and can cause respiratory compromise and death [Hummel et al 2003].
• Renal manifestations 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, Bornholdt et al 2005]. 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]. Ipsilateral vocal cord paralysis and liver lobe and spleen hypertrophy have been reported [Bornholdt et al 2005]. Small intestinal mucosal xanthoma have also been reported [Ryan et al 2013, Tan et al 2022]. Teeth are typically normal.

Prognosis. It is unknown whether life span in females with CHILD syndrome is abnormal. Based on current data, life span is not limited by this condition, as several adults have been reported. CHILD syndrome was reported with phenotypes ranging from mild to severe in three different generations, with the oldest reported individual clinically and molecularly diagnosed at age 82 years [Bittar et al 2006]. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Hemizygous males. CHILD syndrome-associated NSDHL pathogenic variants are usually lethal to males during gestation. A few males with CHILD syndrome have been reported, and survival in these instances has been attributed to postzygotic somatic mutation in NSDHL. One reported male with the typical skin findings seen in females and normal development was mosaic for NSDHL pathogenic variant c.262C>T (p.Arg88Ter) [Bornholdt et al 2005].

CK Syndrome

CK syndrome is characterized by intellectual disability, behavior issues, seizures, characteristic facial features, thin habitus, and ocular manifestations in males. To date, 25 affected males from three unrelated families have been reported [Garg et al 2021].

Development. Affected males have mild-to-severe intellectual disability. Most cannot speak.

Neurobehavioral/psychiatric manifestations. Most males with CK syndrome 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 that, by MRI examination, are most consistent with polymicrogyria. Spasticity, tetraparesis, development of contractures, and sensory neuropathy have also been reported [Garg et al 2021].

Characteristic craniofacial features (see Figure 2). All affected males have microcephaly (greater than 2-3 standard deviations below the mean). Other features include plagiocephaly, a long, thin face, almond-shaped and upslanted palpebral fissures, epicanthal folds, posteriorly rotated ears, prominent nasal bridge, high palate, dental crowding, micrognathia, and malar hypoplasia.

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.

Skeletal manifestations and growth. All males with CK syndrome have a thin habitus, and relatively long, thin limbs, fingers, and toes. Some individuals have scoliosis and kyphosis. Hyperextensibility can be seen as well. Linear growth is normal, and height of affected individuals is average for parental heights.

Ocular findings. Strabismus is common. Optic atrophy is also seen.

Other. Left ventricular concentric hypertrophy has been reported [Garg et al 2021].

Prognosis. It is unknown whether life span in males with CK syndrome is abnormal. One reported individual is alive at age 62 years [du Souich et al 2009], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Heterozygous females. Females heterozygous for a CK syndrome-related NSDHL pathogenic variant have normal physical features, intellect, and brain imaging but may display behavioral problems including irritability and aggression [Herman & Kratz 2012].

Genotype-Phenotype Correlations

CK syndrome. The NSDHL pathogenic variants c.455G>A, c.696_698delGAA, and c.1098dupT 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 [Bornholdt et al 2005, Mi et al 2015].

Penetrance

Penetrance appears to be complete in NSDHL-related disorders.

Nomenclature

CHILD syndrome is also known as unilateral congenital ichthyosiform erythroderma (CIE) and is a syndromic form of ichthyosis.

Prevalence

The prevalence of CHILD syndrome is unknown; more than 60 individuals have been reported to date.

The prevalence of CK syndrome is unknown; it is thought to be rare. To date, 25 affected males from three unrelated families have been reported [Garg et al 2021].

Evaluations Following Initial Diagnosis

CHILD syndrome. To establish the extent of disease and needs in an individual diagnosed with CHILD syndrome, the evaluations summarized in Table 4a (if not performed as part of the evaluation that led to the diagnosis) are recommended.

CK syndrome. To establish the extent of disease and needs in an individual diagnosed with CK syndrome, the evaluations summarized in Table 4b (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5a and 5b).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Tables 6a and 6b are recommended.

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 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.

Mode of Inheritance

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

• CHILD syndrome (associated with NSDHL pathogenic variants that result in loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase, the protein encoded by NSDHL) is usually male lethal during gestation and thus predominantly affects females.
• CK syndrome (associated with hypomorphic NSDHL pathogenic variants that result in partial loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase) predominantly affects males.

CHILD Syndrome – Risk to Family Members

Parents of a female proband

• A female proband may have inherited the NSDHL pathogenic variant from her mother or the pathogenic variant may be de novo. Theoretically, an affected female may have inherited the pathogenic variant from a father with gonadal mosaicism.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Although CHILD syndrome-associated NSDHL pathogenic variants appear to be highly penetrant, mothers heterozygous for an NSDHL pathogenic variant who have only mild skin lesions, Blaschko-linear inflammatory scaly lesions, patchy alopecia, and nail changes have been reported [Bittar et al 2006]. Favorably skewed X-chromosome inactivation has been proposed to explain this milder phenotype, and theoretically could on occasion result in a phenotypically normal heterozygous female. Therefore, de novo occurrence of an NSDHL pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that the mother is not heterozygous for the NSDHL pathogenic variant.

Parents of a male proband

• If a male proband has CHILD syndrome as the result of mosaicism for a postzygotic NSDHL pathogenic variant [Bornholdt et al 2005], neither the mother nor the father is heterozygous or hemizygous, respectively, for the pathogenic variant.
• An affected male fetus may have inherited the NSDHL pathogenic variant from his mother or the pathogenic variant may be de novo. Transmission of an NSDHL pathogenic variant from an unaffected mother to affected male fetuses has been reported [Zhuang et al 2023].
• Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment.

Sibs of a female proband. 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% heterozygous (typically) affected females;
  • 33% unaffected females who have not inherited the NSDHL pathogenic variant;
  • 33% unaffected males who have not inherited the NSDHL pathogenic variant.
• If the proband represents a simplex case (i.e., a single affected family member) and if pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal gonadal mosaicism.
• Theoretically, if the father of a female proband has gonadal mosaicism for an NSDHL pathogenic variant, all female sibs are at risk of inheriting the pathogenic variant and being affected; male sibs are not at risk of inheriting the pathogenic variant.

Offspring of a female proband

• The risk to the offspring of a female 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 live-born distribution is 33% (typically) affected females, 33% unaffected females, and 33% unaffected males.
• Of note, a female proband with comparatively minor skin lesions (e.g., an ichthyosiform nevus without any additional manifestations of CHILD syndrome) is at risk of having a daughter with typical CHILD syndrome [Happle et al 1995].

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 male proband

• The father of a male with CK syndrome 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 individual, the mother of an affected male is an obligate heterozygote. Note: If a female 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 most likely has gonadal mosaicism.
• If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a de novo NSDHL pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/gonadal mosaicism. The frequency of de novo pathogenic variants is unknown.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment.

Sibs of a male proband. 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 expected 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 be heterozygous and may have a range of behavioral problems (see Clinical Description, CK Syndrome, Heterozygous females).
• If the proband represents a simplex case and if the NSDHL pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism.

Offspring of a male proband. To date, no male with CK syndrome has reproduced.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having an NSDHL pathogenic variant.

Heterozygote detection. Identification of female heterozygotes requires prior identification of the NSDHL pathogenic variant in the family.

Note: Heterozygous females may have a range of behavioral problems (see Clinical Description, CK Syndrome, Heterozygous females).

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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, heterozygous, or at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the NSDHL pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for an NSDHL-related disorder are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

NSDHL encodes decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase. This enzyme localizes to the surface of the endoplasmic reticulum and to lipid droplets. It 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].

Mechanism of disease causation. Well-studied CHILD syndrome-associated NSDHL variants result in loss of function of the protein, and many are null alleles. CK syndrome-associated variants cause partial loss of enzyme function.

Author History

Cornelius F Boerkoel, MD, PhD; University of British Columbia (2010-2024)
Christèle du Souich, MSc, CCGC, CGC; University of British Columbia (2010-2024)
Jinia El Feghaly, MD (2024-present)
Karl-Heinz Grzeschik, PhD; Philipps-Universität, Marburg (2010-2024)
Lamiaa Hamie, MD, MSc (2024-present)
Arne König, MD; Philipps-Universität, Marburg (2010-2015)
Mazen Kurban, MD (2024-present)
F Lucy Raymond, MD, PhD; University of Cambridge (2010-2024)

Revision History

• 5 September 2024 (sw) Comprehensive update posted live
• 25 October 2018 (sw) Comprehensive update posted live
• 25 November 2015 (me) Comprehensive update posted live
• 27 June 2013 (me) Comprehensive update posted live
• 1 February 2011 (me) Review posted live
• 9 January 2010 (cb) Original submission

Literature Cited

• Alexopoulos A, Kakourou T. CHILD syndrome: successful treatment of skin lesions with topical simvastatin/cholesterol ointment--a case report. Pediatr Dermatol. 2015;32:e145–7. [PubMed: 25845514]
• Avgerinou GP, Asvesti AP, Katsambas AD, Nikolaou VA, Christofidou EC, Grzeschik KH, Happle R. CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder. J Eur Acad Dermatol Venereol. 2010;24:733–6. [PubMed: 19906044]
• Bajawi SM, Jafarri SA, Buraik MA, Al Attas KM, Hannani HY. Pathogenesis-based therapy: cutaneous abnormalities of CHILD syndrome successfully treated with topical simvastatin monotherapy. JAAD Case Rep. 2018;4:232–4. [PMC free article: PMC5909487] [PubMed: 29687057]
• Bergqvist C, Abdallah B, Hasbani DJ, Abbas O, Kibbi AG, Kurban M, Rubeiz N. CHILD syndrome: a modified pathogenesis-targeted therapeutic approach. Am J Med Genet A. 2018;176:733–8. [PubMed: 29392821]
• Bittar M, Happle R, Grzeschik KH, Leveleki L, Hertl M, Bornholdt D, König A. CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol. 2006;142:348–51. [PubMed: 16549711]
• Bornholdt D, König A, Happle R, Leveleki L, Bittar M, Danarti R, Vahlquist A, Tilgen W, Reinhold U, Poiares Baptista A, Grosshans E, Vabres P, Niiyama S, Sasaoka K, Tanaka T, Meiss AL, Treadwell PA, Lambert D, Camacho F, Grzeschik KH. Mutational spectrum of NSDHL in CHILD syndrome. J Med Genet. 2005;42:e17. [PMC free article: PMC1735983] [PubMed: 15689440]
• Caldas H, Herman GE. NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. Hum Mol Genet. 2003;12:2981–91. [PubMed: 14506130]
• Caughey AB, Krist AH, Wolff TA, Barry MJ, Henderson JT, Owens DK, Davidson KW, Simon MA, Mangione CM. USPSTF approach to addressing sex and gender when making recommendations for clinical preventive services. JAMA. 2021;326:1953-61. [PubMed: 34694343]
• Chander R, Varghese B, Jabeen M, Garg T, Jain M. CHILD syndrome with thrombocytosis and congenital dislocation of the hip: a case report from India. Dermatol Online J. 2010;16:6. [PubMed: 20804683]
• Cunningham D, Swartzlander D, Liyanarachchi S, Davuluri RV, Herman GE. Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts. J Lipid Res. 2005;46:1150–62. [PubMed: 15805545]
• du Souich C, Chou A, Yin J, Oh T, Nelson TN, Hurlburt J, Arbour L, Friedlander R, McGillivray BC, Tyshchenko N, Rump A, Poskitt KJ, Demos MK, Van Allen MI, Boerkoel CF. Characterization of a new X-linked mental retardation syndrome with microcephaly, cortical malformation, and thin habitus. Am J Med Genet A. 2009;149A:2469–78. [PubMed: 19842190]
• Gachotte D, Barbuch R, Gaylor J, Nickel E, Bard M. Characterization of the Saccharomyces cerevisiae ERG26 gene encoding the C-3 sterol dehydrogenase (C-4 decarboxylase) involved in sterol biosynthesis. Proc Natl Acad Sci U S A. 1998;95:13794–9. [PMC free article: PMC24900] [PubMed: 9811880]
• Garg M, Kulkarni SD, Sayed R, Hegde AU. CK syndrome: a rare cause of developmental delay in a young boy. Clin Dysmorphol. 2021;30:201-3. [PubMed: 34091503]
• Grange DK, Kratz LE, Braverman NE, Kelley RI. CHILD syndrome caused by deficiency of 3beta-hydroxysteroid-delta8, delta7-isomerase. Am J Med Genet. 2000;90:328–35. [PubMed: 10710233]
• Happle R. Ptychotropism as a cutaneous feature of the CHILD syndrome. J Am Acad Dermatol. 1990;23:763-6. [PubMed: 2229513]
• Happle R, Effendy I, Megahed M, Orlow SJ, Küster W. CHILD syndrome in a boy. Am J Med Genet. 1996;62:192–4. [PubMed: 8882402]
• Happle R, Koch H, Lenz W. The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr. 1980;134:27–33. [PubMed: 7408908]
• Happle R, Mittag H, Kuster W. The CHILD nevus: a distinct skin disorder. Dermatology. 1995;191:210–16. [PubMed: 8534939]
• Hashimoto K, Topper S, Sharata H, Edwards M. CHILD syndrome: analysis of abnormal keratinization and ultrastructure. Pediatr Dermatol. 1995;12:116–29. [PubMed: 7544893]
• Head PE, Meier JL, Venditti CP. New insights into the pathophysiology of methylmalonic acidemia. J Inherit Metab Dis. 2023;46:436-49. [PMC free article: PMC10715492] [PubMed: 37078237]
• Hebert AA, Esterly NB, Holbrook KA, Hall JC. The CHILD syndrome. Histologic and ultrastructural studies. Arch Dermatol. 1987;123:503–9. [PubMed: 3827283]
• Heda GD, Valivade V, Sanghavi P, Kukreja RM, Phulari YJ. CHILD syndrome. Indian J Dermatol Venereol Leprol. 2014;80:483. [PubMed: 25201868]
• Herman GE, Kratz L. Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet. 2012;160C:301–21. [PubMed: 23042573]
• Hu CC, Sun YJ, Liu CX, Zhou BR, Li CY, Xu Q, Xu X. NSDHL-containing duplication at Xq28 in a male patient with autism spectrum disorder: a case report. BMC Med Genet. 2018;19:192. [PMC free article: PMC6208182] [PubMed: 30376821]
• Hummel M, Cunningham D, Mullett CJ, Kelley RI, Herman GE. Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. Am J Med Genet A. 2003;122A:246–51. [PubMed: 12966526]
• Joosten MDW, Clabbers JMK, Jonca N, Mazereeuw-Hautier J, Gostyński AH. New developments in the molecular treatment of ichthyosis: review of the literature. Orphanet J Rare Dis. 2022;15;17:269. [PMC free article: PMC9287901] [PubMed: 35840979]
• Juratli HA, König A, Happle R. Tympanoxyloid verruciform xanthoma is a distinct feature of CHILD nevus. J Eur Acad Dermatol Venereol. 2020;34:e70-e72. [PubMed: 31502355]
• Kallis P, Bisbee E, Garganta C, Schoch JJ. Rapid improvement of skin lesions in CHILD syndrome with topical 5% simvastatin ointment. Pediatr Dermatol. 2022;39:151-2. [PubMed: 34787337]
• Knape RM, Gandhi KB, Tuli SY, Khuddus N. Optic nerve findings in CHILD syndrome. J Pediatr Ophthalmol Strabismus. 2010;47 Online:e1-3. [PubMed: 20886807]
• König A, Happle R, Fink-Puches R, Soyer HP, Bornholdt D, Engel H, Grzeschik KH. A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J Am Acad Dermatol. 2002;46:594–6. [PubMed: 11907515]
• König A, Skrzypek J, Loffler H, Oeffner F, Grzeschik KH, Happle R. Donor dominance cures CHILD nevus. Dermatology. 2010;220:340–5. [PubMed: 20389027]
• Liu T, Qian G, Wang XX, Zhang YG. CHILD syndrome: effective treatment of ichthyosiform naevus with oral and topical ketoconazole. Acta Derm Venereol. 2015;95:91–2. [PubMed: 24696032]
• Maceda EBG, Kratz LE, Ramos VME, Abacan MAR. Novel NSDHL gene variant for congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome. BMJ Case Rep. 2020;13:e236859. [PMC free article: PMC7607564] [PubMed: 33139364]
• McLarren KW, Severson TM, du Souich C, Stockton DW, Kratz LE, Cunningham D, Hendson G, Morin RD, Wu D, Paul JE, An J, Nelson TN, Chou A, DeBarber AE, Merkens LS, Michaud JL, Waters PJ, Yin J, McGillivray B, Demos M, Rouleau GA, Grzeschik KH, Smith R, Tarpey PS, Shears D, Schwartz CE, Gecz J, Stratton MR, Arbour L, Hurlburt J, Van Allen MI, Herman GE, Zhao Y, Moore R, Kelley RI, Jones SJ, Steiner RD, Raymond FL, Marra MA, Boerkoel CF. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. Am J Hum Genet. 2010;87:905–14. [PMC free article: PMC2997364] [PubMed: 21129721]
• Merino De Paz N, Rodriguez-Martin M, Contreras-Ferrer P, Garcia Bustinduy M, Gonzalez Perera I, Virgos Aller T, Martin Herrera A, Noda Cabrera A. Topical treatment of CHILD nevus and Sjögren-Larsson syndrome with combined lovastatin and cholesterol. Eur J Dermatol. 2011;21:1026–7. [PubMed: 21983059]
• Mi XB, Luo MX, Guo LL, Zhang TD, Qiu XW. CHILD syndrome: case report of a Chinese patient and literature review of the NAD[P]H steroid dehydrogense-like protein gene mutation. Pediatr Dermatol. 2015;32:e277–82. [PubMed: 26459993]
• Mo C, Valachovic M, Randall SK, Nickels JT, Bard M. Protein-protein interactions among C-4 demethylation enzymes involved in yeast sterol biosynthesis. Proc Natl Acad Sci U S A. 2002;99:9739–44. [PMC free article: PMC124998] [PubMed: 12119386]
• Paller AS, van Steensel MA, Rodriguez-Martín M, Sorrell J, Heath C, Crumrine D, van Geel M, Cabrera AN, Elias PM. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol. 2011;131:2242–8. [PMC free article: PMC3193573] [PubMed: 21753784]
• Preiksaitiene E, Caro A, Benušienė E, Oltra S, Orellana C, Morkūnienė A, Roselló MP, Kasnauskiene J, Monfort S, Kučinskas V, Mayo S, Martinez F. A novel missense mutation in the NSDHL gene identified in a Lithuanian family by targeted next-generation sequencing causes CK syndrome. Am J Med Genet A. 2015;167:1342–8. [PubMed: 25900314]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Ryan C, Quinn S, McDermott M. Small intestine mucosal xanthoma in a patient with CHILD syndrome. J Clin Pathol. 2013;66:1094–5. [PubMed: 23969275]
• Rossi M, Hall CM, Bouvier R, Collardeau-Frachon S, Le Breton F, Bucourt M, Cordier MP, Vianey-Saban C, Parenti G, Andria G, Le Merrer M, Edery P, Offiah AC. Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis. Pediatr Radiol. 2015;45:965-76. [PubMed: 25646736]
• Schmidt-Sidor B, Obersztyn E, Szymańska K, Wychowski J, Mierzewska H, Wierzba-Bobrowicz T, Stepień T. Brain and cerebellar hemidysplasia in a case with ipsilateral body dysplasia and suspicion of CHILD syndrome. Folia Neuropathol. 2008;46:232–7. [PubMed: 18825599]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207.. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tan EC, Chia SY, Rafi'ee K, Lee SX, Kwek ABE, Tan SH, Ng VWL, Wei H, Koo S, Koh AL, Koh MJ. A novel NSDHL variant in CHILD syndrome with gastrointestinal manifestations and localized skin involvement. Mol Genet Genomic Med. 2022;10:e1848. [PMC free article: PMC8801147] [PubMed: 34957706]
• Yu X, Chen L, Yang Z, Gu Y, Zheng W, Wu Z, Li M, Yao Z. An excellent response to topical therapy of four congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome patients with an increased concentration of simvastatin ointment. J Eur Acad Dermatol Venereol. 2020;34:e8-e11. [PubMed: 31374135]
• Yu X, Zhang J, Gu Y, Wu Z, Bao L, Li M, Yao Z. CHILD syndrome mimicking verrucous nevus in a Chinese patient responded well to topical therapy of compound of simvastatin and cholesterol. JEADV. 2018;32:1209–13. [PubMed: 29341259]
• Zhuang J, Luo Q, Xie M, Chen Y, Jiang Y, Zeng S, Wang Y, Xie Y, Chen C. Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole-exome sequencing: A rare case report and literature review. Mol Genet Genomic Med. 2023;11:e2121. [PMC free article: PMC10009909] [PubMed: 36504312]