Since Conradi first described a case of chondrodystrophia calcificane congenita in 1914,1 more than 100 cases have been reported. The term chondrodysplasia punctata is now preferred in describing this heterogeneous group of disorders primarily involving the skeletal system, but also the skin and eyes. Characteristic findings of this multisystem disorder include dysplasia of the metaphyseal and epiphyseal centers of the axial skeleton and long bones that disrupts endochondral bone formation and clinically results in proximal limb shortening and dwarfism. Axial skeleton involvement is seen in more severely affected patients, resulting in a barrel-chest deformity and limited chest excursion. The characteristic stippling of epiphyseal centers seen radiographically is the hallmark of this disorder. Other findings include ichthyotic skin changes and typical facies characterized by nasal hypoplasia, hypertelorism, short neck, and frontal bossing present in most patients. Renal anomalies and congenital heart disease are uncommon. Ocular findings are commonly found. Cataracts are the most commonly reported ocular abnormality, occurring in approximately one third of cases. Less frequently seen ocular findings include heterochromia irides, optic atrophy, epicanthus, unilateral microphthalmus with microcornea, and drainage angle anomalies.2
Chondrodysplasia punctata occurs in three distinct genetic forms.3 The rhizomelic type is inherited in an autosomal-recessive manner, demonstrating more severe clinical manifestations. The epiphyseal and a metaphyseal dysplasia is severe, resulting in marked proximal shortening of extremities and secondary flexion contractures of the arms and legs. There is a high incidence of ichthyotic skin change and cataracts. Prognosis is poor with infants usually dying in infancy of respiratory failure.4-5
The underlying biochemical abnormality in rhizomelic chondrodysplasia punctata is believed to be an inborn error in the peroxisomal activity.6 Analogous to the peroxisomal dysfunction seen in Zellweger syndrome7 (cerebrohepatorenal syndrome), deficient activity of the peroxisomal enzyme, acyl-CoArdihydroxyacetone-phosphate acyltraneferase (DHAP-AT) was found in thrombocytes and skin fibroblasts of patients with rhizomelic chondrodysplasia punctata.6
FIGURE 1: Note dysmorphic cranial features including a prominent squared forehead, hypertelorism, and saddle-nose deformation.
The Conradi-Hunerman syndrome is the most common form of chondrodysplasia punctata, occurring sporadically or inherited in an autosomal dominant manner.8 Clinical expression of the disease is highly variable. In more severely affected patients, the disease is quite similar to that seen in the rhizomelic variety, with death occurring in the first few months of life. Usually, however, patients are only mildly affected, demonstrating asymmetric shortening of extremities, short stature, and typical facies with frontal bossing and a saddle-nose deformity. Radiographically, the stippling of the epiphyseal centers may be generalized and marked or minimal and localized to long bones.
Recently, x-linked forms of chondrodysplasia punctata have been described. An x-linked dominant variety,9 occurring exclusively in female patients, with lethality in affected male fetuses, has been described. Clinical characteristics include marked asymmetry of skeletal involvement, and the presence of cataracts and linear skin lesions. Curry et al10 described a pedigree of two families with an x-linked recessive form of chondrodysplasia punctata secondary to the terminal deletion of the x chromosome in affected males and carrier mothers. The phenotypic and radiologic features in the four male children studied were quite similar to those seen in other forms of chondrodysplasia punctata; the presence of mental retardation in these patients was a noteworthy clinical difference.
FIGURE 2: Note proximal limb shortening, bell-shaped chest, and joint contractions.
Although more than 100 cases of chondrodysplasia punctata have been described in the literature, no other lens anomaly other than the presence of a cataract has been reported. We herein report a case of microspherophakia in association with the rhizomelic form of chondrodysplasia punctata.
A full-term, 3080-gram, Caucasian male infant was born to a 25-year-old secundigravida by a spontaneous vaginal delivery after an uncomplicated pregnancy. There was no history of consanguinity, abnormal births, or the use of warfarin during pregnancy. There was no family history of congenital cataracts, microspherophakia, or other congenital ocular deformities.
On physical examination, the infant had dysmorphic cranial features (Fig 1). There was a prominent squared forehead, hypertelorism, and nasal hypoplasia/saddle-nose deformity. Other abnormalities included shortening of the humerus and femur, a barrel-shaped chest, and contracture of the knees, ankles, wrist, and phalanges (Fig 2). The hair was sparse; however, the skin was otherwise normal.
FIGURE 3: Slit lamp photo OD. Note lens equator (arrow) easily visible through a dilated pupil. Lens diameter was estimated to be 8 mm. The lens of OS was identical.
FIGURE 4: Radiograph of pelvis and hips demonstrating marked stippling of femoral epiphyses (closed arrows) and the ischio (open arrows).
Ocular examination revealed the presence of bilateral cataracts and microspherophakia (Fig 3). The lens diameter was estimated to be 8 mm and the zonular structures were easily visible through a dilated pupil without evidence of dislocation. Close evaluation revealed complete opacification of the lens in both eyes. Results of the remainder of the ocular examination were normal, including intraocular pressure and retinal examination.
A thorough radiologic and metabolic evaluation was performed. Radiographs (Fig 4) revealed bilaterally symmetrical punctate stippling and enlargement of multiple epiphyseal centers and dysplasia of the thoracic spine. The activity of DHAP-AT (performed by Dr Amiya Hajra, University of Michigan), determined from fibroblast tissue culture, was low and compatible with the rhizomelic form of chondrodysplasia punctata. The remainder of the systemic evaluation was within normal limits (Table 1).
A diagnosis of rhizomelic chondrodysplasia punctata was made. The poor prognosis for long-term survival was explained to the parents, but they desired and consented to cataract surgery. When the infant was 4 weeks of age, lensectomy and anterior vitrectomy were performed on the right eye via a pars plana approach. The postoperative course was complicated by Staphylococcus epidermidis endophthalmitis, which was successfully treated with an intravitreal injection of gentamicin and cefazolin, daily subconjunctival injection of gentamicin and dexamethasone, and a 14-day course of intravenous vancomycin. The infection cleared without sequelae in 14 days. A lensectomy and anterior vitrectomy were then performed on the left eye without complication. The postoperative course was unremarkable, and on postoperative day 3 aphakic extended-wear contact lenses were placed in both eyes.
The patient tolerated the contact lenses well; however, 4 weeks later he developed a respiratory infection and subsequently died of a respiratory arrest.
To the best of our knowledge, this is the first reported case of microspherophakia associated with the rhizomelic form of chondrodysplasia punctata. More than 100 cases of chondrodysplasia punctata have been reported, yet no mention of microspherophakia is made in any case even though ocular examinations were performed. Several possible explanations for this inconsistency exist.
The accuracy of our diagnosis must first be questioned. Microspherophakia has been found to occur in association with several other clinical syndromes (Table 2).11-18 Most of these possibilities have characteristics that are sufficiently dissimilar from our case and can confidently be excluded from diagnostic consideration. However, WeiUMarchesani and Lowe's syndromes must be strongly considered in the differential diagnosis. As in our case, microspherophakia, lens opacities, and skeletal abnormalities are important diagnostic findings in these syndromes. In Weill-Marchesani syndrome,13,14 affected individuals are short in stature with proximal limb shortening, marked joint immobility, and flattened nasal bridges. In contradistinction to our case, epiphyseal stippling is not seen. Also, no metabolic abnormality is associated with this disorder, and life expectancy is normal. We therefore discarded Weill-Marchesani syndrome as a diagnostic possibility.
Lowe's syndrome is an x-linked disorder with multisystem involvement. Characteristic ocular findings include congenital cataract, also associated with glaucoma and pupillary miosis.18 On close examination, the cataractous lens is generally found to be small in size and discoid in shape.19 As in chondrodysplasia punctata, radiographs occasionally reveal epiphyseal stippling.3 In contradistinction, however, there is no proximal lens shortening, aminoaciduria is always present secondary to a proximal renal tubular abnormality, and 30% of Lowe's syndrome patients have congenital glaucoma.18 These dissimilarities allowed us to eliminate Lowe's syndrome from consideration.
Results of Systemic Evaluation
Causes of Microspherophakia
It is unlikely that this case represents the coincidental occurrence of two unusual syndromes. The incidence of chondrodysplasia punctata is reported to be 1 in 500,000 births.20,21 The incidence of isolated microspherophakia in patients without a systemic syndrome has not been determined; however, we estimate it to be less than 1 in 500,000 births. The probability that these two rare diseases occurred coincidentally in our patient is 1 in 2.5 × 1012; therefore, this possibility seems unlikely as well.
We propose that microspherophakia is a commonly occurring yet previously unrecognized ocular manifestation of the rhizomelic or autosomal-recessive form of chondrodysplasia punctata. In the present case, the presence of microspherophakia was not definitively determined until the anterior segment details were examined using the operative microscope. Initially, it was thought that the cataract was lamellar in type and that the clear zone peripheral to the lens opacity represented uninvolved peripheral lens cortex. However, at surgery the cataract was found to be total, and the clear peripheral zone was the zonular region and not normal peripheral lens cortex. Detailed descriptions of cataract location are generally lacking in previous case reports; however, in two instances cataracts were described as "cortical" in one patient3 and as "small central" in two other patients.10 It is possible that these authors were fooled, as we were initially, and that these patients also had microspherophakia with complete lens opacifications surrounded by the clear zonular apparatus. We suspect that microspherophakia is commonly present in the severely affected autosomalrecessive rhizomelic type of chondrodysplasia punctata. Because slit lamp examination is difficult and surgery is deferred because of the poor prognosis, the presence of microspherophakia has been unrecognized until now.
In summary, we report the first case of microspherophakia in association with chondrodysplasia punctata. We encourage careful examination of future cases of the rhizomelic or autosomal-recessive form of chondrodysplasia punctata to determine whether this is a chance association or a common ocular manifestation.
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Results of Systemic Evaluation
Causes of Microspherophakia