Case of the Week # 505

Case of the Week # 505

Javier Cortejoso
 on 04/08/2023
 on Saturday, April 8th, 2023
The images demonstrate the following findings:
• Image 1: mother's leg demonstrates hypovascular, hairless, atrophic patches along Blaschko lines.
• Video 1: the axial section of the fetal head shows an occipital encephalocele.

Cephalocele is a congenital defect in the cranium and dura with possible extracranial herniation of intracranial structures. Cranial meningoencephaloceles are cephaloceles in which the structures protruding consist of leptomeninges, cerebrospinal fluid, and brain. Cephaloceles are classified by the site of the cranial defect through which herniation occurs. When the defect is located between the foramen magnum and the lambda, we describe ‘occipital cephalocele’. Most cephaloceles are isolated anomalies. Rarely, there may be a concurrent intracranial or extracranial lesion. A small number of cephaloceles are linked to syndromes:
• Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. The classic triad of Meckel syndrome comprises cystic renal disease, a central nervous system malformation (most commonly occipital encephalocele), and polydactyly (most often postaxial).
• Joubert syndrome may occasionally present with a posterior cephalocele, and is characterized by a distinctive cerebellar and brain stem malformation called the molar tooth sign. With the exception of rare cases following X-linked recessive inheritance (JS-10), it is transmitted in autosomal recessive fashion.

Genodermatoses are a broad spectrum of heritable disorders that affect the skin, and are associated with anomalies of other organ systems. The group of X-linked hereditary dermatoses comprises incontinentia pigmenti, focal dermal hypoplasia, congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), and chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome).

Incontinentia pigmenti (IP, OMIM # 308300), also known as Bloch-Sulzberger syndrome, is a rare, X-linked dominant condition characterized by disorder of skin pigmentation. It is caused by mutations in the IKBKG gene (Inhibitor of Kappa B Kinase Gamma, previously known as NEMO), located in the Xq28 locus, resulting in defective melanocyte and melanoblast proliferation and migration. In 65% of cases the mutation is de novo. The first case was described by Garrod in 1906 and has an approximate incidence of 1: 50,000 newborns. Incontinentia pigmenti is lethal for most affected males in utero, so the vast majority of cases are female (37:1). Males who inherit the abnormal gene (and by definition do not have a balancing normal copy) typically demise in the first trimester due to liver failure. There are cases of surviving male patients in the literature in rare cases of mosaicism, Klinefelter syndrome (47XXY) or hypomorphic mutations in the IKBKG gene. These boys will have a condition similar to incontinentia pigmenti called ectodermal dysplasia and anhidrosis with immune deficiency.

Incontinentia pigmenti is a rare genodermatosis with multisystem involvement that presents at or soon after birth with distinctive cutaneous signs. It has a penetrance of 100%, but a variable clinical expression. This phenotypic variability observed in affected women may be due to the random inactivation of the X chromosome (also called lyonization). Symptoms vary considerably. The main features occur in the skin, but defects of teeth, hair, nails, and ophthalmic, central nervous system, and musculoskeletal abnormalities are described. Incontinentia pigmenti is typically diagnosed by its characteristic cutaneous manifestations, which progress through four well-defined stages and follow the lines of Blaschko (which represent the route of embryonic stem cell migration). All stages do not necessarily occur and the stages may overlap. It is important to note that an infant may be born at any stage, in which case, it is presumed that the previous stage(s) occurred in utero. The progressive stages are:
• vesicular, vesicobullous and/or inflammatory
• verrucous
• hyperpigmentation
• hypopigmentation and/or atrophic (usually develops in adolescence and persists into adulthood in over 75% of cases).

Central nervous system deficits represent the most important threat to normal life span in patients with incontinentia pigmenti, and together with ophthalmologic manifestations, may significantly impact quality of life. Overall prevalence of neurologic impairments occurs in just over 30%. The most common abnormalities that may be detected in utero include cortical malformations (polymicrogyria among others), hypoplasia/agenesis of the corpus callosum, dilatation of the ventricles, periventricular leukomalacia and cysts, porencephalic cysts, and cerebellar atrophy. Among the manifestations of the central nervous system, Demirel et al have reported the association of incontinentia pigmenti with an occipital encephalocele in a neonate.

Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant chondrodysplasia punctata, also known as Conradi-Hunermann syndrome, is the most well-characterized form. It arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortening, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia.

Angioma serpiginosum is an uncommon benign skin disorder characterized by asymptomatic clusters of non-purpuric punctate erythematous lesions. Females are most commonly affected, and the disorder is usually sporadic, although rarely this has been reported in families suggestive of autosomal dominant or X-linked dominant inheritance.

Bazex syndrome is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma (skin atrophy affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees), and the development of basal cell neoplasms from the second decade onward.

The predictable progression of cutaneous stages allows precise diagnosis in incontinentia pigmenti. However, other differential diagnosis include pigment mosaicism, which comprises a heterogeneous group of disorders of cutaneous pigmentation, typically presenting with linear and whorled hypopigmentation following the lines of Blaschko. Occasionally, pigment mosaicism may be associated with dental, hair, nail, neurologic, ocular, and musculoskeletal abnormalities. In the past, this has been called hypomelanosis of Ito or incontinentia pigmenti achromians, but both names have now been abandoned, because they do not constitute a single diagnostic entity and are unrelated to incontinentia pigmenti. Focal dermal hypoplasia, or Goltz’s syndrome, is an X-linked dominant disorder that is generally lethal in males. Hypopigmentation or hyperpigmentation may be observed within the atrophic areas. The X-linked dominant form of chondrodysplasia punctata, Conradi-Hünermann type, shows characteristic skeletal findings as previously discussed.

Suggested reading:
• Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002 Aug;47(2):169-87; quiz 188-90. doi: 10.1067/mjd.2002.125949. PMID: 12140463.
• Demirel N, Aydin M, Zenciroglu A, Okumus N, Tekgunduz KS, Ipek MS, Boduroglu E. Incontinentia pigmenti with encephalocele in a neonate: a rare association. J Child Neurol. 2009 Apr;24(4):495-9. doi: 10.1177/0883073808324774. PMID: 19339289.
• Garrod AE. Peculiar pigmentation of the skin of an infant. Trans Clin Soc Lond 1906; 39: 216
• Naidich TP, Altman NR, Braffman BH, McLone DG, Zimmerman RA. Cephaloceles and related malformations. AJNR Am J Neuroradiol. 1992 Mar-Apr;13(2):655-90. PMID: 1566723; PMCID: PMC8333224.

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