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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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NSDHL-Related Disorders

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

Author Information
, MSc, CCGC, CGC
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada
, MD, PhD
Cambridge Institute for Medical Research
University of Cambridge
Cambridge, United Kingdom
, PhD
Department of Human Genetics
Philipps-Universität
Marburg, Germany
, MD
Department of Dermatology
Philipps-Universität
Marburg, Germany
, MD, PhD
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada

Initial Posting: ; Last Update: June 27, 2013.

Summary

Disease 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 [ADHD], 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.

Diagnosis/testing. CHILD syndrome and CK syndrome are caused by mutation of NSDHL. CHILD syndrome is a clinical diagnosis generally based on the findings described above and the presence of unilateral punctate epiphyseal calcifications seen on x-rays of the pelvis, ribs, vertebrae, and extremities in early childhood. Identification of a characteristic methylsterol pattern or of an NSDHL mutation 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 mutation that results in partial loss of functional NSDHL protein.

Management. Treatment of manifestations:

  • 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 try and 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; further studies are necessary. 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.

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 inherited in an X-linked dominant manner and is usually male lethal during gestation. Affected females have a 50% chance of transmitting the NSDHL mutation 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. Carrier females have a 50% chance of transmitting the NSDHL mutation in each pregnancy; males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Female carriers of the NSDHL mutation 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 mutation has been identified in the family.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

The spectrum of NSDHL-related disorders includes CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome and CK syndrome.

CHILD syndrome is diagnosed by its clinical features [Bornholdt et al 2005, Bittar et al 2006]. 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 affected individuals are female. Most are simplex cases (i.e., a single occurrence in a family) although a few families with more than one affected female have been reported [Bornholdt et al 2005, Bittar et al 2006].

Although presentations of CHILD syndrome can be milder (i.e., non-classic) [Bittar et al 2006], the classic features include:

  • Unilateral distribution of ichthyosiform nevus
  • Limb defects ipsilateral to the skin lesions
  • Punctate calcifications of cartilaginous structures
  • Visceral malformations
  • Central nervous system anomalies

Identification of an NSDHL mutation that results in loss of functional NSDHL protein or identification of 4-carboxysterol in skin flakes from the affected area confirms the diagnosis of CHILD syndrome [Bornholdt et al 2005; RI Kelley, personal communication]. (See Molecular Genetic Testing.)

CK syndrome (CK = initials of the original proband) is characterized by intellectual disability and associated features in males [du Souich et al 2009, McLarren et al 2010]:

  • Central nervous system (CNS) findings. Mild to severe intellectual disability, microcephaly, cerebral cortical malformations, and seizures
  • Characteristic craniofacial features. Almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high arched palate, crowded dentition, micrognathia
  • Asthenic habitus

Identification of a “hypomorphic” NSDHL mutation that results in partial loss of functional NSDHL protein confirms the diagnosis of CK syndrome [McLarren et al 2010].

Testing

Analyte

  • 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.

Molecular Genetic Testing

Gene. A mutation in NSDHL is identified in the vast majority of persons with CHILD syndrome and all reported individuals with CK syndrome.

Evidence for locus heterogeneity. Although controversial [König et al 2002, Elias et al 2012], mutations 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 mutations and clinical features similar to CHILD syndrome have been reported.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in NSDHL-Related Disorders

Gene 1PhenotypeTest MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FemalesMales
NSDHLCHILD syndromeSequence analysis 4Sequence variants~90% 5NA 6
Deletion/duplication analysis 7Whole- or partial-gene deletion10% 5, 8NA 6
CK syndromeSequence analysis Sequence variants 4NA 9Unknown 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Extrapolated from Bornholdt et al [2005]

6. Not applicable: CHILD syndrome is male lethal during gestation.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Deletion of the gene or of multiple exons has been reported [Bornholdt et al 2005, Kim et al 2005].

9. Not applicable: females with CK syndrome have not been reported.

10. Only two affected families have been reported to date [Tarpey et al 2009, McLarren et al 2010]. See Molecular Genetics.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • CHILD syndrome. In females with findings of classic CHILD syndrome, the diagnosis is easily confirmed by sterol analysis of affected skin flakes. When molecular genetic testing is needed, sequence analysis of all NSDHL coding regions should be performed first. If a mutation is not identified, deletion/duplication analysis could be considered.
  • CK syndrome. In males with CK syndrome, sequence analysis of NSDHL can detect sequence variants. If a mutation is not detected, further genetic testing to evaluate for other XLMR syndromes is recommended (see Differential Diagnosis, CK Syndrome). In males with suspected CK syndrome from families lacking a family history with clear X-linked inheritance of the syndrome, similar non-X-linked disorders should also be considered (see Differential Diagnosis, CK Syndrome).

Carrier testing for at-risk relatives of a male with CK syndrome requires prior identification of the disease-causing mutation in the family.

Note: CK syndrome is an X-linked disorder in which female carriers generally do not manifest signs or symptoms of the disorder. Identification of female carriers requires an appropriate family history and/or prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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 mutations are usually male lethal during gestation.

Figure 1

Figure

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.
B. Lower left limb and groin. The leg (more...)

Early death of affected females is usually the result of cardiovascular malformations.

CHILD syndrome is usually male lethal during gestation; however, 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) mutation in NSDHL [Bornholdt et al 2005].

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 life-long morbidity. Other skin lesions can develop after infancy at sites of injury such as a surgical wound.

Onychodystrophy and periungual hyperkeratosis are common.

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 mutations 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 mutation. 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].

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. 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 were 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.

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].

CK Syndrome

CK syndrome (Figure 2) is an X-linked recessive intellectual disability syndrome that affects males. Because only 13 affected males from two unrelated families have been identified and fully evaluated, characterization of the syndrome is limited. To date, no other affected individuals have been reported.

Figure 2

Figure

Figure 2. An 11-year-old (A, B) and a 22-year-old (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).

Craniofacial. Affected males have a long thin face, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high arched 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.

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

Female carriers of the NSDHL mutation have normal physical features, intellect, and brain imaging but display behavioral problems such as irritability and aggression [Herman & Kratz 2012]. They also show deficits in working memory and lower neuron activation as estimated by the hemodynamic response measured using functional MRI [du Souich et al 2012]. Since carrier females have normal plasma cholesterol and plasma 24S-hydroxycholesterol levels, du Souich et al [2012] hypothesized that methyl sterol accumulation causes their behavioral and cognitive problems.

Historical note. CHILD syndrome was first reported in 1903 by Dr. Otto Sachs [Bittar & Happle 2004]. CK syndrome was first described by du Souich et al [2009].

Genotype-Phenotype Correlations

CHILD syndrome. Phenotypic variability within the spectrum of CHILD syndrome does not correlate with the predicted severity of NSDHL mutant alleles [Bornholdt et al 2005].

CK syndrome. The two reported mutations (c.696_698del and c.1098dup) 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 and may only manifest as minor skin changes in affected females.

Penetrance is probably 100% in males with CK syndrome.

Anticipation

Anticipation does not occur with either CHILD syndrome or CK syndrome.

Nomenclature

CHILD is an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects.

CK syndrome represents the initials of the original proband.

Prevalence

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

The prevalence of CK syndrome is unknown.

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. Mutations in 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 Blashko 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].

Incontinentia pigmenti (IP). IP is a male lethal, X-linked dominant condition 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 the cause of disease in 80% of individuals [Fusco et al 2008].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to CHILD syndrome, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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 have mild to moderate intellectual disability, 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 mutations in MED12 and UPF3B [Schwartz et al 2007, Tarpey et al 2007] and with a terminal deletion of chromosome 5q [Stathopulu et al 2003].

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 mutations in SMS, encoding spermine synthase, located on Xp22.1 [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 mutations in ZDHHC9, the gene encoding the zinc finger DHHC domain-containing protein 9.

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 mutations in ATRX.

PQBP1 (OMIM 300463). Mutations in PQBP1, the gene encoding polyglutamine-binding protein 1, cause X-linked recessive intellectual disability, microcephaly, short stature, heart defects, cleft palate, and microphthalmia [Martinez-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 mutations in ATP6AP2, the gene encoding the renin receptor.

SLC9A6 (OMIM 300231). Mutations in this gene, which encodes a monovalent sodium-selective sodium/hydrogen exchanger, cause profound intellectual disability, microcephaly, epilepsy, and ataxia [Gilfillan et al 2008, Tarpey et al 2009].

Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis, distinctive dysmorphic features, skeletal abnormalities, mild to moderate intellectual disability, and brain anomalies [Shprintzen & Goldberg 1982]. It can also present with cardiovascular and abdominal wall defects, myopia, decreased subcutaneous fat, and cryptorchidism in males. The gene in which mutation is causative and the mode of inheritance are unknown.

Methylmalonic aciduria and homocystinuria, cblC type is a common autosomal recessive inborn error of vitamin B12 metabolism caused by loss-of-function mutations 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to CK syndrome, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

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

  • Radiologic examination of trunk and extremities for skeletal malformations
  • Abdominal ultrasound examination to identify visceral malformations
  • Echocardiogram to identify cardiac anomalies; most often present with left-sided involvement
  • Magnetic resonance imaging to determine brain involvement
  • Medical genetics consultation

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
  • Medical genetics consultation

Treatment of Manifestations

CHILD syndrome

  • Oral aromatic retinoids (etretinate) to ameliorate cutaneous symptoms; however, this drug is often poorly tolerated [Happle et al 1980]. Topical treatments include lactic acid 12% creams or lotions for itching and urea creams for dry skin. An inflammatory nevus was removed from an affected boy by dermabrasion; however, it recurred within eight months [Happle et al 1996]. Recently König et al [2010] reported successful treatment of an inflammatory nevus by grafting skin obtained from a contralateral unaffected region.
  • 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]. Further studies may be necessary to evaluate the therapeutic benefit of topical statins.
  • 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 (AED) to control seizures
  • Behavior modification and/or drug therapy to control aggression and help with ADHD symptoms
  • Ophthalmologic management of ocular abnormalities

Surveillance

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 ClinicalTrials.gov 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

  • The father of an affected male will not have the disease nor will he have an NSDHL mutation.
  • The mother of a female with CHILD syndrome may be heterozygous for an NSDHL mutation. Although CHILD syndrome-associated NSDHL mutations appear to be highly penetrant, mothers heterozygous for an NSDHL mutation who have only mild skin lesions, Blaschko-linear inflammatory scaly lesions, patchy alopecia, and nail changes have been reported [Bittar et al 2006]. Extreme lyonization has been proposed to explain this milder phenotype, and theoretically could on occasion result in a phenotypically normal heterozygous female.

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

  • If the mother of a female proband is also affected or heterozygous for the NSDHL mutation identified in her daughter, the risk at conception to sibs of inheriting the mutant NSDHL allele is 50%. However, since model animal and family studies suggest that male conceptuses with a mutant NSDHL allele generally abort or resorb spontaneously, the expected live born distribution is 33% unaffected females, 33% affected females, and 33% unaffected males.
  • If the disease-causing mutation 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 risk that the mutant NSDHL allele will be transmitted is 50%. However, since male conceptuses with a mutant NSDHL allele generally abort or resorb spontaneously, the expected live born 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. If the mother of the proband also has a disease-causing mutation, her female family members may be at risk of having CHILD syndrome.

Risk to Family Members — CK syndrome

Parents of a proband with CK syndrome

Sibs of a male with CK syndrome

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband is heterozygous for an NSDHL mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected.
  • If the disease-causing mutation 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 are at risk of being carriers and the aunts’ offspring, depending on their gender, are at risk of being affected or of being carriers.

Carrier Detection

Carrier testing of female relatives at risk of being carriers of CK syndrome is possible if the mutation has been identified in the family.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

CHILD syndrome. If the disease-causing mutation has been identified in an affected family member, prenatal testing for CHILD syndrome is possible by analysis of DNA extracted from fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks’ gestation) or amniocentesis (usually performed at ~15-18 weeks’ gestation).

Biochemical testing is theoretically possible, although it has not been reported for CHILD syndrome. 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.

CK Syndrome. If the disease-causing mutation has been identified in an affected family member, prenatal testing for CK syndrome is possible. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks’ gestation) or amniocentesis (usually performed at ~15-18 weeks’ gestation). If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

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.

  • Foundation for Ichthyosis and Related Skin Types, Inc. (FIRST)
    2616 North Broad Street
    Colmar PA 18915
    Phone: 215-997-9400
    Fax: 215-997-9403
    Email: info@firstskinfoundation.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
NSDHLXq28Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylatingNSDHL @ LOVDNSDHL

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

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

300275NAD(P)H STEROID DEHYDROGENASE-LIKE PROTEIN; NSDHL
300831CK SYNDROME
308050CONGENITAL HEMIDYSPLASIA WITH ICHTHYOSIFORM ERYTHRODERMA AND LIMB DEFECTS

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

Benign allelic variants. Bornholdt et al [2005] reported two benign variants that did not result in disease: c.132T>G and c.306C>T. McLarren et al reported one additional benign variant, c.43C>T [McLarren et al 2010].

Table 2. Selected NSDHL Benign Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.43C>Tp.Arg15TrpNM_001129765​.1
NP_001123237​.1
c.132T>Gp.= 2
(Gly44Gly)
c.306C>Tp.= 2
(Phe102Phe)

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.= designates that protein has not been analyzed, but no change is expected.

Pathogenic allelic variants

Table 3. Selected NSDHL Pathogenic Variants

PhenotypeDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
CHILD syndromec.262C>T 1p.Arg88TerNM_001129765​.1
NP_001123237​.1
c.370G>Ap.Gly124Ser
c.613G>Ap.Gly205Ser
c.1046A>Gp.Tyr349Cys
c.314C>Tp.Ala105Val
CK syndromec.696_698delp.Lys232del
c.1098dupp.Arg367SerfsTer33

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Identified as mosaic mutant allele in male with CHILD Syndrome (see Natural History)

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

References

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Chapter Notes

Revision History

  • 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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