**3.2 Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome**

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare X-linked dominant disorder of cholesterol biosynthesis, with fewer than 100 cases discussed in the literature [58]. The earliest identification of the condition is thought to be in 1903 [59], through the proposal of the syndromic acronym in 1980 [60]. CHILD syndrome is nearly always male-lethal although perhaps two males with this syndrome have been identified, one with a 46, XY karyotype, postulated to have survived due to a postzygotic mutation [61]. The distinguishing hallmark of the condition is that of unilateral skin lesions with ipsilateral limb defects [60, 62, 63]. The characteristic yellow, scaly plaques are usually present at birth or emerge in the first few months of life and while there may be some resolution over time, they often remain for life [60]. These markings may follow the lines of Blaschko, but more commonly, there is a striking delineation at the midline with the lesions showing a unique lateralisation pattern [62]. This has been proposed to be due to interactions between X-inactivation and the organisation of left-right axis symmetry in the developing embryo [60]. The lateralisation of these lesions and their persistence is a distinguishing feature of CHILD syndrome compared to differentials such as CDPX2, a similar but distinct inborn error of cholesterol biosynthesis [64].

CHILD syndrome demonstrates complete limb aplasia, severe phocomelia or severe hypoplasia on the same side of the body as ichthyosiform lesions [60]. Infant radiography may show epiphyseal stippling such as that seen in CDPX2, as well as milder skeletal malformations such as scoliosis, hypo or hemi-plastic vertebrae, distal digit shortening, syndactyly or polydactyly [65]. Non-skeletal manifestations include alopecia, verruciform xanthoma, dystrophic nails and congenital malformations on the affected side that can involve the heart, kidneys and CNS [60, 65]. Intelligence may be normal or slightly reduced. Despite the severity of these symptoms, mild cases of CHILD syndrome with no skeletal and/or cutaneous involvement have been identified through molecular analysis [66].

Molecular investigation has identified various mutations in the *NSDHL* (NADH steroid dehydrogenase-like) gene as causative for CHILD syndrome [67]. *NSHDL* is located at Xq28 and encodes 3β-hydroxysteroid dehydrogenase, part of a three-part enzyme complex. This C4 demethylation complex acts on the sterol ring in the postsqualene pathway, converting 4,4-dimethylcholesta-8(9),24-dien-3β-ol to zymosterol and 4,4-diemthylcholesta-8(9)-en-3β-ol to cholesta-8(9)-en-3β-ol. Mutations are most often loss-of-function [68]. Cholesterol and sterol levels are normal and so a diagnosis requires clinical and molecular assessment. Various *NSDHL* mutations have been studied in the allelic 'bare patches' (*Bpa*) and 'striated' (S*tr*) murine models [69]. These have given insights into facets of CHILD syndrome and cholesterol synthesis disorders in general, for example, the roles of the maternal placenta [70] and Hedgehog signalling pathways [71] in disease presentation.

Treatment options for CHILD syndrome have generally focused on topical management of skin lesions with symptomatic remedies such as emollients or with pathogenesis-based therapies generally involving combinations of cholesterol and a cholesterol synthesis-inhibitor [72, 73], the latter with some efficacy.

#### **3.3 X-linked dominant chondrodysplasia punctata 2**

X-linked dominant chondrodysplasia punctata 2 (CDPX2), or Conradi-Hünermann-Happle syndrome, is estimated to have an incidence of 1/400,000 and, similarly to CHILD syndrome, is almost entirely male-lethal. The CDPX2 phenotype, like the other cholesterol biosynthesis disorders, is heavily based on the

**139**

*Human Cholesterol Biosynthesis Defects DOI: http://dx.doi.org/10.5772/intechopen.87150*

Cognition is usually normal [87].

located at Xp11.23 and encoding a Δ<sup>8</sup>

similarities with human CDPX2 [89].

**3.4 Lathosterolosis**

skeletal and cutaneous domains, and there can be significant variability even within family lines [74–76] with generational anticipation [74]. Severe manifestations can result in neonatal or infant death with considerable skeletal and internal abnormalities, while mild cases may be nearly asymptomatic. This range of phenotypic variability is likely due to the combination of somatic and/or gonadal mosaicism and X-inactivation patterns [76]. Occasional male patients are identified with CDPX2, usually due to somatic mosaicism [77, 78] with one case of 46,XXY [79]. Gonadal

Widespread epiphyseal stippling is seen on infant radiographs, often including not just the long bones but the trachea and vertebrae as well [81–83]. Additional skeletal stigmata include short stature and scoliosis (which can be congenital), clubfoot, joint contractures, and postaxial polydactyly [74, 77, 83]. Cutaneous manifestations include skin with patches of scaly hypo or hyper-pigmentation, which usually follows the lines of Blaschko. The initial skin scaling and erythroderma present at birth usually fades over the first few months of life, leaving follicular atrophoderma, pigmentation and alopecia, although ichthyosis can persist [84, 85]. The pattern and then resolution of skin scaling as well as its histological profile is a differentiating diagnostic feature for CDPX2 compared to CHILD syndrome. Diagnosis of CDPX2 in adulthood can be difficult due to the childhood resolution of the characteristic skin lesions and epiphyseal stippling [86]; however, a combination of cutaneous manifestations, asymmetric limb reduction and cataracts (found in 65% of patients) is a good suggestion of this condition for further investigation [86]. CDPX2 presents with characteristic facial features including frontal bossing, midface hypoplasia and flat nasal bridge [74, 81]. The condition is also associated with microphthalmia or microcornea, congenital heart disease, renal abnormalities including hypoplasia and hydronephrosis and sensorineural hearing loss [87].

CDPX2 is caused by mutations in the *EBP* (emopamil binding protein) gene [88, 89]



and are found throughout the entire length of the gene [74].

downstream of the C4-demethylation complex affected in CHILD syndrome and converts zymosterol and cholesta-8(9)-en-3β-ol to cholesta-7,24-dien-3β-ol and lathosterol, respectively. There is a phenotypic correlation with enzyme function with lethality of homozygous females and clinically affected heterozygous females; however, there is no clear genotype-phenotype correlation, presumably due to X-inactivation patterns [74, 76]. Surviving males with CDPX2 are almost always due to mosaic postzygotic mutations as a hemizygous male genotype is lethal *in utero*. CDPX2 mutations (including deletions, insertions, nonsense, missense and splice-site) of *EBP* have been identified as both *de novo* and inherited mutations

While there is no clear CDPX2 genotype-phenotype correlation, there is a distinct association between genotype and CDPX2 sterol profile [74], and plasma sterol assay is a highly specific indicator for an *EBP* mutation [83]. Plasma shows increased 8-dehydrocholesterol and 8(9)cholesterol levels, with the ratios compared to cholesterol increased 0.71–0.80% [74]. Plasma cholesterol is usually normal. Treatment and surveillance are symptomatic, and studies in these areas have been advanced by the 'tattered' (*Td*) mouse which shares both phenotypic and molecular

Lathosterolosis (OMIM 607330) results from impaired 3-hydroxysteroid-5-desaturase (SC5D) activity [90]. In the Kandutsch-Russel synthetic pathway, SC5D catalyses the conversion of lathosterol to 7-dehydrocholesterol (7DHC)

mosaicism is possible which is relevant for recurrence risk [80].

#### *Human Cholesterol Biosynthesis Defects DOI: http://dx.doi.org/10.5772/intechopen.87150*

*Apolipoproteins, Triglycerides and Cholesterol*

**defects syndrome**

**3.2 Congenital hemidysplasia with ichthyosiform erythroderma and limb** 

involvement have been identified through molecular analysis [66].

and Hedgehog signalling pathways [71] in disease presentation.

**3.3 X-linked dominant chondrodysplasia punctata 2**

cholesterol synthesis-inhibitor [72, 73], the latter with some efficacy.

Molecular investigation has identified various mutations in the *NSDHL* (NADH steroid dehydrogenase-like) gene as causative for CHILD syndrome [67]. *NSHDL* is located at Xq28 and encodes 3β-hydroxysteroid dehydrogenase, part of a three-part enzyme complex. This C4 demethylation complex acts on the sterol ring in the postsqualene pathway, converting 4,4-dimethylcholesta-8(9),24-dien-3β-ol to zymosterol and 4,4-diemthylcholesta-8(9)-en-3β-ol to cholesta-8(9)-en-3β-ol. Mutations are most often loss-of-function [68]. Cholesterol and sterol levels are normal and so a diagnosis requires clinical and molecular assessment. Various *NSDHL* mutations have been studied in the allelic 'bare patches' (*Bpa*) and 'striated' (S*tr*) murine models [69]. These have given insights into facets of CHILD syndrome and cholesterol synthesis disorders in general, for example, the roles of the maternal placenta [70]

Treatment options for CHILD syndrome have generally focused on topical management of skin lesions with symptomatic remedies such as emollients or with pathogenesis-based therapies generally involving combinations of cholesterol and a

X-linked dominant chondrodysplasia punctata 2 (CDPX2), or Conradi-Hünermann-Happle syndrome, is estimated to have an incidence of 1/400,000 and, similarly to CHILD syndrome, is almost entirely male-lethal. The CDPX2 phenotype, like the other cholesterol biosynthesis disorders, is heavily based on the

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare X-linked dominant disorder of cholesterol biosynthesis, with fewer than 100 cases discussed in the literature [58]. The earliest identification of the condition is thought to be in 1903 [59], through the proposal of the syndromic acronym in 1980 [60]. CHILD syndrome is nearly always male-lethal although perhaps two males with this syndrome have been identified, one with a 46, XY karyotype, postulated to have survived due to a postzygotic mutation [61]. The distinguishing hallmark of the condition is that of unilateral skin lesions with ipsilateral limb defects [60, 62, 63]. The characteristic yellow, scaly plaques are usually present at birth or emerge in the first few months of life and while there may be some resolution over time, they often remain for life [60]. These markings may follow the lines of Blaschko, but more commonly, there is a striking delineation at the midline with the lesions showing a unique lateralisation pattern [62]. This has been proposed to be due to interactions between X-inactivation and the organisation of left-right axis symmetry in the developing embryo [60]. The lateralisation of these lesions and their persistence is a distinguishing feature of CHILD syndrome compared to differentials such as CDPX2, a similar but distinct inborn error of cholesterol biosynthesis [64]. CHILD syndrome demonstrates complete limb aplasia, severe phocomelia or severe hypoplasia on the same side of the body as ichthyosiform lesions [60]. Infant radiography may show epiphyseal stippling such as that seen in CDPX2, as well as milder skeletal malformations such as scoliosis, hypo or hemi-plastic vertebrae, distal digit shortening, syndactyly or polydactyly [65]. Non-skeletal manifestations include alopecia, verruciform xanthoma, dystrophic nails and congenital malformations on the affected side that can involve the heart, kidneys and CNS [60, 65]. Intelligence may be normal or slightly reduced. Despite the severity of these symptoms, mild cases of CHILD syndrome with no skeletal and/or cutaneous

**138**

skeletal and cutaneous domains, and there can be significant variability even within family lines [74–76] with generational anticipation [74]. Severe manifestations can result in neonatal or infant death with considerable skeletal and internal abnormalities, while mild cases may be nearly asymptomatic. This range of phenotypic variability is likely due to the combination of somatic and/or gonadal mosaicism and X-inactivation patterns [76]. Occasional male patients are identified with CDPX2, usually due to somatic mosaicism [77, 78] with one case of 46,XXY [79]. Gonadal mosaicism is possible which is relevant for recurrence risk [80].

Widespread epiphyseal stippling is seen on infant radiographs, often including not just the long bones but the trachea and vertebrae as well [81–83]. Additional skeletal stigmata include short stature and scoliosis (which can be congenital), clubfoot, joint contractures, and postaxial polydactyly [74, 77, 83]. Cutaneous manifestations include skin with patches of scaly hypo or hyper-pigmentation, which usually follows the lines of Blaschko. The initial skin scaling and erythroderma present at birth usually fades over the first few months of life, leaving follicular atrophoderma, pigmentation and alopecia, although ichthyosis can persist [84, 85]. The pattern and then resolution of skin scaling as well as its histological profile is a differentiating diagnostic feature for CDPX2 compared to CHILD syndrome. Diagnosis of CDPX2 in adulthood can be difficult due to the childhood resolution of the characteristic skin lesions and epiphyseal stippling [86]; however, a combination of cutaneous manifestations, asymmetric limb reduction and cataracts (found in 65% of patients) is a good suggestion of this condition for further investigation [86]. CDPX2 presents with characteristic facial features including frontal bossing, midface hypoplasia and flat nasal bridge [74, 81]. The condition is also associated with microphthalmia or microcornea, congenital heart disease, renal abnormalities including hypoplasia and hydronephrosis and sensorineural hearing loss [87]. Cognition is usually normal [87].

CDPX2 is caused by mutations in the *EBP* (emopamil binding protein) gene [88, 89] located at Xp11.23 and encoding a Δ<sup>8</sup> -Δ<sup>7</sup> -sterol isomerase. This enzyme functions downstream of the C4-demethylation complex affected in CHILD syndrome and converts zymosterol and cholesta-8(9)-en-3β-ol to cholesta-7,24-dien-3β-ol and lathosterol, respectively. There is a phenotypic correlation with enzyme function with lethality of homozygous females and clinically affected heterozygous females; however, there is no clear genotype-phenotype correlation, presumably due to X-inactivation patterns [74, 76]. Surviving males with CDPX2 are almost always due to mosaic postzygotic mutations as a hemizygous male genotype is lethal *in utero*. CDPX2 mutations (including deletions, insertions, nonsense, missense and splice-site) of *EBP* have been identified as both *de novo* and inherited mutations and are found throughout the entire length of the gene [74].

While there is no clear CDPX2 genotype-phenotype correlation, there is a distinct association between genotype and CDPX2 sterol profile [74], and plasma sterol assay is a highly specific indicator for an *EBP* mutation [83]. Plasma shows increased 8-dehydrocholesterol and 8(9)cholesterol levels, with the ratios compared to cholesterol increased 0.71–0.80% [74]. Plasma cholesterol is usually normal. Treatment and surveillance are symptomatic, and studies in these areas have been advanced by the 'tattered' (*Td*) mouse which shares both phenotypic and molecular similarities with human CDPX2 [89].
