Alternative titles; symbols
SNOMEDCT: 17608003; ORPHA: 139; DO: 0111822;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | CHILD syndrome | 308050 | X-linked dominant | 3 | NSDHL | 300275 |
A number sign (#) is used with this entry because of evidence that CHILD syndrome is caused by mutation in the NSDHL (300275) on chromosome Xq28.
CHILD syndrome is an acronym for an X-linked dominant disorder characterized by congenital hemidysplasia with ichthyosiform erythroderma and limb defects. The mutations are lethal in hemizygous males (Happle et al., 1980).
CK syndrome (300831), an X-linked recessive mental retardation syndrome, is an allelic disorder with a less severe phenotype.
Falek et al. (1968) described sibs with this combination, and other familial cases are known. Tang and McCreadie (1974) described in brief the autopsy findings in a case. Many organs were asymmetric with hypoplasia on the side of ichthyosis and limb malformation. These included lung, thyroid, psoas muscle, cranial nerves V, VII, VIII, IX and X, pons, medulla, cerebellum and spinal cord. Striking cross-sectional views of the pons and medulla were presented. Happle et al. (1980) used the acronymic designation 'CHILD syndrome': congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Opitz (1982) urged use of the term 'deficiency' rather than 'absence deformity.' Happle et al. (1980) reviewed 18 cases that were earlier reported under various designations and added 2 more. They suggested that the syndrome may be inherited as an X-linked dominant trait with lethality in hemizygous males (Wettke-Schafer and Kantner, 1983). The basis for the suggestion was: sex ratio of 19 females to 1 male, an 11:3 ratio of unaffected sisters to unaffected brothers, and the observation of 5 miscarriages and 1 male stillbirth in the affected sibships. Although the linear distribution of skin lesions is consistent with lyonization, the unilateral involvement necessitates an auxiliary hypothesis. Hebert et al. (1987) reported a case, bringing the total number of cases to 29 (28 female; 1 male). Their patient had associated Shone syndrome ('parachute mitral valve,' supravalvular ring of the left atrium, subaortic stenosis, coarctation of the aorta) and meningomyelocele. Because of phenotypic overlap with chondrodysplasia punctata (215100), in which a peroxisomal defect has been identified, Emami et al. (1992) did studies of peroxisome morphology and function in fibroblasts from involved versus uninvolved skin in a patient with CHILD syndrome. They found that fibroblasts from involved skin accumulated cytoplasmic lipid, visualized with the fluorescent probe nile-red. Ultrastructurally, fibroblasts of involved skin accumulated lamellated membrane and vacuolar structures. By diaminobenzidine ultracytochemistry, fewer peroxisomes were present. Moreover, the activities of 2 peroxisomal enzymes, catalase and dihydroxyacetone phosphate acyltransferase were both about 30% of normal. However, peroxisomal oxidation of very long chain and branched-chain fatty acids was preserved. Moreover, the plasma content of very long chain fatty acids and phytanic acid, as well as red cell content of plasmalogen, was normal.
As an exception to the rule that the CHILD syndrome is observed only in females, Happle et al. (1996) described the case of a 2-year-old boy of Egyptian origin born of healthy unrelated parents. At birth, a severely deformed right leg and an inflammatory ichthyosiform skin lesion involving the right side of the body were noted. Cytogenetic analysis of peripheral blood lymphocytes showed a normal male karyotype 46,XY. Despite dermabrasion of parts of the lesion involving the trunk under general anesthesia, the CHILD nevus had completely recurred in the treated area 8 months later. Some functional improvement was achieved by orthopedic surgical correction of the dislocated right knee joint and right foot. Exceptionally, males are known to be affected by other X-linked dominant, male-lethal traits such as incontinentia pigmenti (308300), focal dermal hypoplasia (305600), and oral-facial-digital syndrome I (311200). Some of these cases have the Klinefelter syndrome with a 47,XXY karyotype, but the remaining patients have a normal karyotype 46,XY. Happle et al. (1996) stated that such cases can be best explained either by a postzygotic mutation or by a gametic half-chromatid mutation (Lenz, 1975). In view of the pattern of lateralization of the lesions, Happle et al. (1996) concluded that a postzygotic mutation appears more likely than a gametic half-chromatid mutation, which would be expected to give rise to a more finely distributed, bilateral pattern. The authors noted that, according to this concept, XY men with CHILD syndrome can transmit the trait to their daughters, provided the underlying postzygotic mutation has occurred rather early and involves the gonads.
Martinez et al. (2022) reported a 37-year-old female patient with CHILD syndrome. She presented at birth with ichthyosiform erythroderma lesions in the abdomen and the proximal third of the right leg following the midline. She also had longitudinal discrepancy of the right leg. When first evaluated at 33 years of age, she had 3.8 cm shortening of her right arm and 4.3 cm shortening of her right fifth finger. Right leg hypoplasia was noted, with a 23 cm shortening. She had a right ichthyosiform nevus in the hypoplastic leg, low hemiabdomen, and lumbar region. Flexion at the right hip and knee were limited to 95 degrees, but joint extension was complete. Her trochanteric prominence angle was 15 degrees, and she had anterior cruciate insufficiency, right genu valgum, and a right flexible flat valgus foot. She also had dorsolumbar scoliosis with left convexity and a vertebral hemangioma in L2.
Because of the clinical similarities between X-linked dominant Conradi-Hunermann syndrome (CDPX2; 302960) and CHILD syndrome, Grange et al. (2000) analyzed plasma sterols in a patient with typical CHILD syndrome. The levels of 8-dehydrocholesterol and 8(9)-cholestenol were increased in this patient to the same degree as in CDPX2 patients. The authors subsequently identified a nonsense mutation in exon 3 of the patient's 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase gene (300205.0006). The authors suggested that at least some cases of CHILD syndrome are caused by 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase deficiency and are allelic to CDPX2, although the almost exclusively unilateral distribution of abnormalities in CHILD syndrome versus the bilateral disease of CDPX2 remains to be explained.
Herman (2003) reviewed the cholesterol biosynthetic pathway and the 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), CDPX2, CHILD syndrome, lathosterolosis (607330), and hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM; 215140).
Konig et al. (2000) analyzed 6 patients with CHILD syndrome for mutations in the NSDHL gene at Xq28 and in the EBP gene, which functions downstream of NSDHL in a later step of cholesterol biosynthesis. Four of the cases were sporadic, including one in a previously reported 46,XY male (Happle et al., 1996), and 2 cases were familial, in a mother and her daughter. No mutations were identified in the EBP gene; however, mutations were identified in the NSDHL gene in all of the patients. The NSDHL mutations included 2 missense mutations (300275.0001-300275.0002) and 2 nonsense mutations (300275.0003-300275.0004). One of these mutations was found in both the mother and daughter and in another patient, although based on their family history and ethnic background, they were highly unlikely to be related. The authors concluded that CHILD syndrome can be added to the list of developmental defects associated with mutations affecting cholesterol synthesis.
Konig et al. (2002) identified a novel missense mutation in NSDHL (300275.0005), that potentially may impair protein function, in a patient with an almost symmetric CHILD nevus. They concluded that a diagnosis of CHILD syndrome can be based on clinical features such as the highly characteristic morphology of the CHILD nevus. A symmetric distribution of this nevus can exceptionally be seen in patients with CHILD syndrome, and this bilateral involvement should not mislead the clinician to any other diagnosis. They proposed that the effect of random X inactivation is responsible for different patterns of cutaneous involvement in female carriers of NSDHL mutations. Konig et al. (2002) asserted that CHILD syndrome is not caused by mutations in EBP, the gene involved in X-linked dominant chondrodysplasia punctata (CDPX2). They pointed out that an X-linked dominant disorder usually showing an asymmetric involvement, such as CDPX2, may give rise by way of exception to extreme lateralization, whereas the CHILD syndrome usually shows extreme lateralization but may exceptionally manifest itself in almost symmetrically arranged skin lesions.
Hummel et al. (2003) reported a novel mutation in the NSDHL gene (E151X; 300275.0006) in a female infant with left-sided CHILD syndrome, demonstrating that both right- and left-sided CHILD syndrome can be caused by mutations in the same gene.
In a 37-year-old female with CHILD syndrome including torsional and angular deformities of the limbs, Martinez et al. (2022) reported a novel 3-basepair deletion in the NSDHL gene (c.896_898del), resulting in deletion of the amino acid valine at position 299 (val299del).
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Konig, A., Happle, R., Fink-Puches, R., Soyer, H. P., Bornholdt, D., Engel, H., Grzeschik, K.-H. A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J. Am. Acad. Derm. 46: 594-596, 2002. [PubMed: 11907515] [Full Text: https://doi.org/10.1067/mjd.2002.113680]
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Martinez, R., Pena, C., Quiroga-Carrillo, M., Ordonez-Reyes, C., Rincon, J., Suarez-Obando, F., Nossa, S., Garcia, M. F. Musculoskeletal abnormalities and a novel genomic variant in an adult patient with CHILD syndrome: a case report. Clin. Dysmorph. 31: 162-166, 2022. [PubMed: 35394469] [Full Text: https://doi.org/10.1097/MCD.0000000000000422]
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