Mario Bittar

Mutational spectrum of NSDHL in CHILD syndrome

CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects, MIM 308050) is an X linked dominant, male lethal, multisystem birth defect characterised by an inflammatory epidermal nevus showing a unique lateralisation pattern and strict midline demarcation. Hypoplasia or aplasia of skeletal or visceral structures may be found ipsilateral to the major cutaneous involvement.1 Owing to the highly characteristic clinical and histopathological features of the CHILD naevus,2 a diagnosis can be established not only in classical cases (fig 1) but also in cases with minimal or atypical involvement.3 In 2000, mutations in NSDHL (NAD(P)H steroid dehydrogenase-like protein) at Xq28 were identified by some of us to be the cause of this syndrome.4 Four additional NSDHL mutations have subsequently been reported in individuals with CHILD syndrome.5–8 Studies carried out on the murine Nsdhl mutants bare patches (Bpa) and striated (Str) have shown that this gene encodes a 3β-hydroxysteroid dehydrogenase (3β-HSD) that catalyses a step in the post-squalene cholesterol biosynthetic pathway and is localised within membranes of the endoplasmic reticulum and on the surface of intracellular lipid storage droplets.9–11 Non-functional NSDHL might cause the CHILD phenotype through a lack of cholesterol or other sterols downstream of the block in biosynthesis, or by the accumulation of intermediates upstream of the product generated by NSDHL. Figure 1  Thirteen year old patient with CHILD syndrome (case 9, table 1): ichthyosiform nevus showing lateralisation with unilateral distribution and midline demarcation; ipsilateral hypoplasia of arm and hand. Reproduced with permission. A related trait, X linked dominant chondrodysplasia punctata (CDPX2, MIM 302960),22 is caused by mutations in EBP (emopamil binding protein) at Xp11.22–p11.23 that functions similarly in the late cholesterol biosynthesis, downstream of NSDHL .23,24 In the past, a case of X linked dominant chondrodysplasia punctata showing unilateral involvement …

Linear atrophoderma of Moulin: postulation of mosaicism for a predisposing gene

Hyperpigmented atrophoderma arranged in a pattern following the lines of Blaschko and appearing during childhood or adolescence on the trunk or the limbs is a characteristic feature of linear atrophoderma of Moulin. We review 15 published reports and describe 4 additional cases. Histopathologically, there is no clear sign of atrophy found in specimens examined by light microscopy. It might well be argued that a focal reduction of subcutaneous fatty tissue contributes to the obvious clinical atrophy. The cause and pathogenesis of the disorder remains unknown. It may reflect mosaicism caused by a postzygotic mutation that occurred at an early developmental stage, in analogy to many other diseases distributed along Blaschkos lines. Linear atrophoderma of Moulin may reflect the action of an autosomal lethal gene surviving by mosaicism. There are so far no reports of a familial occurrence that could favor a paradominant transmission of linear atrophoderma of Moulin. However, theoretically, the postzygotic mutation giving rise to an aberrant cell clone could still be nonlethal. In a heterozygous individual, a postzygotic mutational event might lead to loss of the corresponding wild-type allele at the atrophoderma locus. This would give rise to a homozygous cell clone, which becomes manifest along the lines of Blaschko later in life.

Inverse Klippel-Trenaunay Syndrome: Review of Cases Showing Deficient Growth

Background: Klippel-Trenaunay syndrome is defined by a coexistence of nevus flammeus and overgrowth of one or more limbs. Remarkably, however, deficient growth of an affected limb may likewise be noted. Observations: We collected from the literature a number of cases of Klippel-Trenaunay syndrome associated with deficient growth such as shortening or hypoplastic muscle mass of the affected extremity. Discussion: The cause of the unusual deficient growth is unknown. Some patients may be compound heterozygotes carrying a ‘plus’ and a ‘minus’ allele at the responsible gene locus, and postzygotic recombination would give rise to two different cell clones homozygous for either allele. Conclusion: In order to give a name to such paradoxical cases, we propose the term ‘inverse Klippel-Trenaunay syndrome’.

Late-onset familial onychodystrophy heralding incontinentia pigmenti

Sir, Incontinentia pigmenti (IP) is an X-linked dominant trait that is intrauterine lethal for males. The disorder is caused by NEMO mutations involving the NFkB activation pathway (1). It is characterized by linear skin lesions and various defects of the central nervous system, the teeth and the eyes. The cutaneous lesions are arranged along the lines of Blaschko, reflecting functional X-chromosome mosaicism (2). Because the diagnosis can now be confirmed or excluded by molecular analysis (1), it is possible to ascertain cases showing a rather mild or atypical involvement. In the present family, nail changes acquired during adulthood were a clue to recognizing two cases of IP.