From the Departments of Ophthalmology (RMK, KBG, NK) and Pediatrics (SYT), University of Florida College of Medicine, Gainesville, Florida.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Robert M. Knape, MD, Department of Ophthalmology, University of Florida College of Medicine, P.O. Box 100284, Gainesville, FL 32610. E-mail: firstname.lastname@example.org
Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare malformation disorder characterized by unilateral defects of several organ systems, including the skin, viscera, and musculoskeletal system.1 The syndrome, first noted by Otto Sachs in an 8-year-old girl in 1903, has subsequently been described under various terms, including unilateral ichthyosiform erythroderma, inflammatory variable epidermal nevus, unilateral erythrokeratodermia, unilateral epidermal nevus, and unilateral ectromelia.2,3 In 1980, Happle et al. proposed the acronym CHILD for congenital hemidysplasia, ichthyosiform erythroderma, and limb defects.4
CHILD syndrome is inherited in an X-linked dominant fashion and involves a mutation in the NSDHL (NAD[P]H steroid dehydrogenase-like protein) gene that encodes a key protein in the cholesterol biosynthetic pathway.5 Phenotypic variations in the extent of malformation are believed to be due to differences in the pattern of X inactivation, rather than in the specific type of mutation.6 The precise mechanism responsible for the laterality seen in CHILD syndrome has yet to be elucidated.3
Clinical manifestations of the skin findings often consist of erythematous plaques that show a unique lateralization with strict midline demarcation. In addition to the dermatosis, an ipsilateral skeletal hypoplasia of variable degree is seen. Ipsilateral involvement of internal organs, such as the brain, lung, heart, or kidney, has also been noted.7
Fewer than 60 cases of CHILD syndrome have been reported in the medical literature.8 To date, there have been no reports of specific ocular involvement in patients with CHILD syndrome. We describe a patient with CHILD syndrome and progressive bilateral optic nerve atrophy.
A girl with CHILD syndrome presented for a routine eye examination at 16 months of age, followed by a second examination at 5 years of age. Her CHILD syndrome manifestations included a sharply demarcated palpable cutaneous hyperpigmentation with salmon-colored discoloration of the left side of her body, including extremities (Fig. 1) but without facial involvement. Her erythroderma did not demonstrate classic ichthyosiform scaling, but she exhibited findings of smaller hands and feet, as well as hypotonia, that were more pronounced on her left side. Skeletal abnormalities were limited to a dysplastic clavicle.
Figure 1. Trunk Photograph Demonstrating Unilateral Erythroderma Sharply Delimited at the Midline.
Her ophthalmic examination at 16 months of age was entirely unremarkable with an age-appropriate ability to fixate and follow and mild hyperopia on retinoscopy. She had no motility defects and a normal pupillary examination without afferent pupillary abnormality. The anterior and posterior segments were normal and the optic nerves showed a pink, healthy rim with a cup-to-disc ratio of 0.1 in the right eye and 0.2 in the left eye.
Her subsequent examination at 5 years of age revealed a best-corrected visual acuity of 20/100 in the right eye and 20/80 in the left eye with Allen pictures. Clinical examination again revealed only mild hyperopia with no motility or pupillary defects. Although she was only mildly developmentally delayed, an examination under anesthesia was performed to facilitate a complete examination. Intraocular pressures were 19 mm Hg in both eyes. Gonioscopic evaluation showed open angles without abnormality and central corneal thickness was 639 and 644 μm in her right and left corneas, respectively. The posterior segment examination showed normal retinas but abnormal optic nerves, with an increase in the pallor and cup-to-disc ratio of both eyes relative to her examination during infancy. The cup-to-disc ratio was 0.7 in both eyes and pallor of the nerve was noted bilaterally (Fig. 2). Optic nerve head vasculature and scleral canal size were unremarkable. No other abnormalities were noted on examination.
Figure 2. Both Optic Nerves Showed Significant Cupping and Pallor.
To further evaluate the etiology of her optic nerve pallor and cupping, a multiplanar, multi-sequence magnetic resonance imaging of the brain and orbits was performed with a protocol directed toward the visual pathway. The images were obtained with and without contrast and revealed mild atrophy of the optic nerves and chiasm (Fig. 3).
Figure 3. Magnetic Resonance Imaging of the Brain, Including Axial and Coronal Images, Showing Mild Atrophy of the Optic Nerves and Chiasm.
CHILD syndrome is predominantly associated with skin and skeletal limb abnormalities, both of which are well-described in the literature. Although the syndrome can encompass many organ systems, involvement of the central nervous system is infrequent. A literature review by Happle et al. noted ipsilateral central nervous system involvement in six cases, including unilateral hypoplasia of the brain and dilated lateral ventricles.4 Neurosensory hearing loss in 2 of 23 CHILD syndrome cases was also described by Bornholdt et al.5 Hebert et al.9 reported a case of CHILD syndrome with lumbar meningocele and hydrocephalus, whereas Schmidt-Sidor et al. noted a case of brain and cerebellar dysplasia ipsilateral to skin and visceral findings.10 The only report of cranial nerve involvement involved a single patient with marked hypoplasia of cranial nerves V, VII, VIII, IX, and X found on autopsy of a child who died of septicemia 1 month after birth.11 No specific optic nerve or other ocular findings in CHILD syndrome have been reported to date.
Our patient is notable because she not only demonstrated ocular abnormalities in CHILD syndrome, but she also exhibited a clinically observed progression in her ocular findings. Her optic nerve appearance at 5 years of age was found to be significantly more pale, and with a marked increase in her cup-to-disc ratio relative to her initial examination as a 16-month-old child. She was also noted to have decreased visual acuity at 5 years of age, presumably from her optic nerve atrophy, although comparison to her prior visual acuity is limited by her age at her first examination.
The differential diagnosis of optic nerve pallor and cupping is broad and includes congenital glaucoma and optic neuropathies of compressive, ischemic, infectious, and toxic etiologies. These causes are largely excluded by her otherwise normal ocular examination, history, and absence of mass lesions on neuroimaging. Optic nerve dysplasia and atrophy related to her primary diagnosis of CHILD syndrome must be considered.
The multiple comorbidities associated with CHILD syndrome and the resultant shortened lifespan can make clinical documentation of progression difficult in most affected organ systems. Findings in CHILD syndrome are usually noted at birth or in the neonatal period.8 However, our case suggests that the dysplastic changes of CHILD syndrome may develop at later stages of life.
Our case of progressive bilateral optic nerve atrophy in CHILD syndrome describes a previously unreported association with the syndrome. The noted optic nerve findings may provide additional useful diagnostic, prognostic, and counseling information for patients and families with CHILD syndrome.
- Hummel M, Cunningham D, Mullett CJ, Kelley RI, Herman GE. Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. Am J Med Genet A. 2003;122A:246–251. doi:10.1002/ajmg.a.20248 [CrossRef]
- Bittar M, Happle R. CHILD syndrome avant la lettre. J Am Acad Dermatol. 2004;50(2 Suppl):S34–S37. doi:10.1016/S0190-9622(03)01827-9 [CrossRef]
- Fenske NA. CHILD syndrome. eMedicine Web site. http://emedicine.medscape.com/article/1110427-overview. Accessed March 6, 2010.
- Happle R, Koch H, Lenz W. The CHILD syndrome: congenital hemidysplasia with ichthyosiform erythoderma and limb defects. Eur J Pediatr. 1980;134:27–33. doi:10.1007/BF00442399 [CrossRef]
- Bornholdt D, Konig A, Happle R, et al. Mutational spectrum of NSDHL in CHILD syndrome. J Med Genet. 2005;42:e17. doi:10.1136/jmg.2004.024448 [CrossRef]
- Kim CA, Konig A, Bertola DR, et al. CHILD syndrome caused by a deletion of exons 6–8 of the NSDHL gene. Dermatology. 2005;211:155–158. doi:10.1159/000086448 [CrossRef]
- Ishibashi M, Matsuda F, Oka H, Ishiko A. Abnormal lamellar granules in a case of CHILD syndrome. J Cutan Pathol. 2006;33:447–453. doi:10.1111/j.0303-6987.2006.00470.x [CrossRef]
- Avgerinou GP, Asvesti AP, Katsambas AD, et al. CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder. J Eur Acad Dermatol Venereol. 2010;24:733–736. doi:10.1111/j.1468-3083.2009.03483.x [CrossRef]
- Hebert AA, Esterly NB, Holbrook KA, Hall JC. The CHILD syndrome: histologic and ultrastructural studies. Arch Dermatol. 1987;123:503–509. doi:10.1001/archderm.123.4.503 [CrossRef]
- Schmidt-Sidor B, Obersztyn E, Szymanska K, et al. Brain and cerebellar hemidysplasia in a case with ipsilateral body dysplasia and suspicion of CHILD syndrome. Folia Neuropathol. 2008;46:232–237.
- Tang TT, McCreadie SR. Congenital hemidysplasia with ichthyosis. Birth Defects Orig Artic Ser. 1974;10:257–261.